Blood Transfus 18, Supplement No. 3, October 2020

Home , Catridecacog

ABSTRACT BOOK Blood Transfus 18, Supplement no. 3, XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite October© 2020 SIMTIPROMilano, 8 - 11 ottobre 2020 Srl -ISSN 1723-2007- Guest Editors: Antonio Coppola, Angiola Rocino, Giovanni Di Minno, Chiara Biasoli, Raimondo De Cristofaro, Adele Giampaolo, Renato Marino

OFFICIAL JOURNAL OF: Società Italiana di Medicina Trasfusionale e Immunoematologia, SIMTI Associazione Italiana dei Centri Emofilia, AICE Hrvatsko Društvo za Transfuzijsku Medicinu, HDTM Sociedad Española de Transfusión Sanguinea y Terapia Celular, SETS Società Italiana per lo Studio dell'Emostasi e della Trombosi, SISET

EDITOR-IN-CHIEF FOUNDER INTERNATIONAL EDITORIAL BOARD Luca Mascaretti Lorenzo Lapponi Walter Ageno, Italy [email protected] Giuseppe Aprili, Italy Michael Auerbach, United States of America PAST EDITORS-IN-CHIEF ASSOCIATE EDITORS Sanja Balen, Croatia Lorenzo Lapponi, 1956-1964 Ines Bojanić, Croatia Pierluigi Berti Carlo Alberto Lang, 1965-1966 Pierpaolo Berti, Italy Alessandra Berzuini Roberto Venturelli, 1967-1968 Pietro Bonomo, Italy Serelina Coluzzi Rosalino Sacchi, 1969-1978 Giancarlo Castaman, Italy Antonio Coppola Mario Colucci, Italy Giorgio Reali, 1979-2006 Vincenzo De Angelis Raimondo De Cristofaro, Italy Patrizia Di Gregorio Claudio Velati, 2007-2014 Valerio De Stefano, Italy Giovanni Di Minno Giancarlo Maria Liumbruno, 2015-2019 Willy A Flegel, United States of America Anna Falanga Gilles Folléa, France Joan R. Grífols PUBLISHER Jose Garcia Gala, Spain Pier Mannuccio Mannucci Gabriella Girelli, Italy SIMTIPRO Srl Ana Hećimović, Croatia Ana Planinc Peraica Via Desiderio, 21 Teresa Jimenez-Marco, Spain Luisa Romanò 20131 Milan, Italy Luis Larrea, Spain Armando Tripodi Marco Lorenzi, Italy Tomislav Vuk Aurelio Maggio, Italy Alberto Zanella EDITORIAL OFFICE Michael Makris, United Kingdom Luisa Stea Paola Maria Manzini, Italy AFFILIATED SOCIETY EDITORS SIMTIPRO Srl Manuel Muñoz, Spain Pierluigi Berti, SIMTI Arturo Pereira, Spain Thierry Peyrard, France Anna Falanga, SISET WEBSITE Flora Peyvandi, Italy Irena Jukić, HDTM www.bloodtransfusion.it Paolo Rebulla, Italy Eduardo Muñiz-Diaz, SETS Marina Samardžija, Croatia Angiola Rocino, AICE PRINTING Cristina Santoro, Italy © SIMTIPROGianluca Ubezio,Srl Italy Grafica Briantea Srl EXECUTIVE DIRECTOR Melina Verso, Italy Stefano Antoncecchi Via per Vimercate, 25/27 - 20040 Usmate (MI) Jonathan H Waters, United States of America

The journal is indexed in PubMed-MEDLINE, Tribunale di Milano - Authorisation n° 380, th Google Scholar, Embase and Scopus and PubMed 16 June 2003 Associated with USPI Central. This number is published in 500 copies. Blood Transfusion articles are indexed in Journal of English revision by Rachel Stenner Unione Stampa Periodica Italiana Citation Reports (JCR) for Impact Factor determination. and Anne Freckleton. Impact Factor 2019: 3.662 Printed in September 2020

PROGRAMMA s297

RELAZIONI s303

ABSTRACTS s321

1.01 - Acquired coagulation disorders s323

1.04 - Comorbidities s326

1.06 - Epidemiology, databases and registries s329

1.07 - Genetics of congenital bleeding disorders s330

1.08 - Health and social economics, organizational issues s332

1.09 - Hemophilia, clinical issues s335

2.02 - Inhibitors s338

2.03 - Laboratory issues s339

2.04 - Novel therapeutic agents s341

2.06 - Orthopedic issues s346

2.08 - Pharmacokinetics s350

2.09 - Prophylaxis s351

3.01 - Psychosocial and quality of life issues s354

3.02 - Rare bleeding disorders s361

3.03 - Von Willebrand Factor and von Willebrand Disease s364

PREMI AICE © SIMTIPRO Srls366 ELENCO AUTORI s367

Citation of the manuscripts published in this volume should be as follows: Author(s). Title. Journal year; Volume (Suppl 3): page.

E.g.: Oliovecchio E. The AICE Clinical Pharmacological Prospective Epidemiological Registry (CliPPER). Blood Transfus 2020; 18 (Suppl 3): s305.

Blood Transfus 2020; 18 (Suppl 3): III-IV DOI 10.2450/2020.S3 IV All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite Milano, 8-11 ottobre 2020

ASSOCIAZIONE ITALIANA CENTRI EMOFILIA (AICE)

FEDERAZIONE delle ASSOCIAZIONI EMOFILICI (FedEmo)

con il patrocinio di Fondazione Paracelso

XVII CONVEGNO TRIENNALE sui PROBLEMI CLINICI e SOCIALI dell’EMOFILIA e delle MALATTIE EMORRAGICHE CONGENITE

Milano 8-11 ottobre 2020

Giovedì 8 ottobre 2020

14.00 - 20.00 Riunioni Gruppi di Lavoro AICE Comitato Scientifico AICE

20.30 Welcome Dinner

Venerdì 9 ottobre 2020 08.30 - 12.30 Riunioni Gruppi di Lavoro AICE - II parte Riunione Referenti Regionali

Consiglio Direttivo 13.00 Apertura del Convegno Saluti delle Autorità

Saluti del Presidente di Fondazione Paracelso - A. Buzzi Comunicazioni del Presidente Reggente AICE - A. Rocino Comunicazioni del Presidente FEDEMO - C. Cassone Lettura Magistrale - Introduce: G. Di Minno 14.00 Much progress and a few issues for hemophilia therapy in the Third Millennium - P.M. Mannucci I sessione© - La raccolta SIMTIPRO delle informazioni e la ricerca clinica in emofilia in Italia Srl Moderatori: M. Luciani, A. Tosetto 15.00 Il Registro CliPPER - E. Oliovecchio 15.20 Il Registro Nazionale delle Coagulopatie Congenite - A. Giampaolo 15.40 La ricerca clinica AICE: dal progetto alla conduzione - A. Tagliaferri 16.00 Break

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s297 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite Milano, 8-11 ottobre 2020

II sessione - Qualità dei laboratori e raccomandazioni cliniche: due obiettivi fondamentali Moderatori: A. Tripodi, A.C. Molinari 16.30 Il ruolo del laboratorio nei Centri AICE - R.C. Santoro 16.50 I dati del Programma VEQ ECAT- AICE - P. Meijer 17.10 Le Raccomandazioni AICE per la diagnosi, trattamento delle emorragie e gestione generale del paziente con Emofilia A acquisita - E. Zanon 17.30 Emicizumab nella profilassi dell’emofilia A grave senza inibitore: survey dei clinici italiani - A. Coppola 17.50 Le Raccomandazioni AICE per la gestione dell’emergenza nei pazienti in profilassi con emicizumab in regime di emergenza/urgenza - G. Castaman 18.10 Discussione

18.30 Comunicazioni scientifiche sponsorizzate - I parte 19.00 Chiusura dei lavori

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s298 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite Milano, 8-11 ottobre 2020

Sabato 10 ottobre 2020 - Programma AICE Assemblea Soci AICE (in parallelo Assemblea Fedemo) Presiede: A. Rocino 08.30 Introduzione ai lavori e nomina Commissione Elettorale 08.45 Relazione del Presidente del Comitato Scientifico AICE - M. Morfini 09.00 Relazione dei Revisori dei Conti - A. Catalano, L. Contino Approvazione del bilancio consuntivo 2019 09.15 Aggiornamenti Gruppi di Lavoro - P. Radossi, E. Marchesini, A.C. Giuffrida, C. Biasoli 10.15 Varie ed eventuali - Discussione 10.30 Break 11.00 Comunicazioni scientifiche sponsorizzate - II parte III sessione - Comunicazioni scientifiche e Premi AICE giovani

Moderatori: M. Franchini - C. Santoro 12.00 Migliori abstract selezionati per comunicazioni orali 12.40 Progetti Vincitori Premi “Idee Giovani per la Ricerca 2020” 13.00 Proclamazione vincitori Premi in memoria del Prof. Raffaello De Biasi con il supporto di CSL Behring per i migliori abstract di giovani ricercatori e dei Premi AICE per i migliori abstract su Innovazioni Terapeutiche

13.10 Colazione di lavoro 14.30 Comunicazioni scientifiche sponsorizzate - III parte 16.00 Coffee break IV Sessione - Migliori Comunicazioni Scientifiche Moderatori: A. Borchiellini - I. Cantori 16.30 Migliori abstract selezionati per comunicazioni orali

18.00 Comunicazione risultati delle votazioni per il rinnovo del Consiglio Direttivo AICE per il triennio 2020-2023 e ratifica dell’Assemblea 18.10 Chiusura dei lavori © SIMTIPRO Srl

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s299 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite Milano, 8-11 ottobre 2020

Sabato 10 ottobre 2020 - Programma FedEmo (in parallelo) Assemblea Soci FedEmo Presiede: C. Cassone 08.30 Assemblea dei Soci Nomina nuovo Consiglio Direttivo 10.30 Break Soddisfazione della gestione clinica e problemi aperti in emofilia 11.00 La survey tra i pazienti, i loro caregiver e i clinici italiani: risultati - P. Cortesi Discussione risultati - C. Cassone e A. Rocino 11.45 Q&A Progetto EMuOviti 12.00 Intervengono: S. Cabigiosu - TeamBuilder Soci FedEmo, Comitato Giovani FedEmo 13.30 Colazione di lavoro Progetto “#FedEmoSport: le nuove frontiere dell’emofilia nello sport” Moderatore: C. Biasoli 14.30 Introduzione - C. Cassone Il progetto - S. Farace, C. Biasoli Le Raccomandazioni - C. Biasoli, G. Pasta Intervengono: P. Borrione - Federazione Medico Sportiva Italiana; A. Spataro - C.O.N.I.; A. Gianfelici - C.O.N.I. 15.10 Q&A La Terapia Genica

15.30 Introduce - A. Rocino La terapia genica in emofilia: nuova prospettiva terapeutica - M. Pinotti 16.00 Q&A

19.30 B-side: siamo tutti diversi

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s300 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite Milano, 8-11 ottobre 2020

Domenica 11 ottobre 2020 V Sessione - Coagulazione ed emofilia ai tempi del Coronavirus Moderatori: P.M. Mannucci, A. Rocino 08.30 Il punto di vista dell’epidemiologo - P.L. Lopalco 08.50 Il punto di vista dell’infettivologo - A. Gori

09.10 Coagulazione ed infezione da Coronavirus - L. Spiezia 09.30 Le implicazioni nei pazienti con emofilia e MEC - A. Coluccia 09.50 Discussione Tavola Rotonda - Dalla diagnosi molecolare alle scelte riproduttive nelle carrier di emofilia

Conduce: F. Bernardi 10.00 Introduzione - A. Rocino, C. Cassone

10.05 Aggiornamenti sulla diagnostica molecolare dell’emofilia - D. Belvini 10.20 Il supporto dei Centri Emofilia italiani alle portatrici - F. Riccardi 10.35 La consulenza genetica - G. Castaldo

10.50 Procreazione assistita, problemi e opportunità - W. Vegetti 11.05 Presentazione progetto FedEmo “PMA” - C. Cassone 11.20 Discussione

11.30 Break VI Sessione - Educazine al movimento e gestione delle problematiche articolari dell’emofilia

Moderatori: L.P. Solimeno - S. Linari 12.00 Raccomandazioni per il trattamento della sinovite - M.N.D. Di Minno 12.20 Sport ed emofilia - G. Pasta 12.40 La piramide del movimento - C. Biasoli 13.00 Saluto dei Presidenti e dei componenti del nuovo consiglio direttivo (2020-2023) di AICE e di FedEmo 13.15 Compilazione questionari ECM e conclusione dei lavori © SIMTIPRO Srl

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s301 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite Milano, 8-11 ottobre 2020

Consiglio Direttivo AICE Angiola Rocino Presidente Reggente Giovanni Di Minno Past President Antonio Coppola Segretario Chiara Biasoli Consigliere Raimondo De Cristofaro Consigliere Renato Marino Consigliere Adele Giampaolo Rappresentante Istituto Superiore di Sanità

Comitato Scientifico AICE Massimo Morfini Presidente Giancarlo Castaman Massimo Franchini Gabriella Gamba Hamisa Jane Hassan Maria Gabriella Mazzucconi Alberto Tosetto

Federazione delle Associazioni Emofilici - FedEmo Cristina Cassone Presidente Stefania Farace Vice Presidente Anna Fragomeno Segretario Generale Luigi Ambroso Consigliere Francesco Cucuzza Consigliere Daniele Preti Direttore Esecutivo Francesca Loddo Segreteria Presidenza Simone Sandri Project Manager Barbara Ponte Project Manager

Responsabili Scientifici: Dott.ssa Angiola Rocino Presidente Reggente AICE Prof. Giovanni Di Minno Past President AICE

Provider ECM e Segreteria Organizzativa: Congress Team Project Srl Via Fratelli Cuzio, 42 - 27100 Pavia Tel. 0382/22650 - Fax 0382/33822 [email protected] © SIMTIPRO Srl

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s302 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite Milano, 8-11 ottobre 2020

Relazioni

RE01 - The AICE Clinical Pharmacological diagrams, with the possibility of filtering specific data to Prospective Epidemiological Registry (CliPPER) allow more personalized analyses. Indeed, interactions Emily Oliovecchio (1) - On behalf of the ad hoc Working Group with each graph make possible to highlight specific AICE - Italian Association of Haemophilia Centres (1) features. Thanks to its structure, CliPPER is aimed to produce epidemiological data about the prevalence and The epidemiologic and scientific activities of AICE the incidence of CBD in Italy, also providing information in the past were based on data collection from AICE- about genotype, bleeding phenotype, patients’ survival affiliated haemophilia treatment centres (HTC) to and main comorbidities. Moreover, CliPPER will make make information of Italian patients with congenital available pharmacovigilance data for all therapeutic bleeding disorders (CBD) available to the community. products used in CBD patients, including treatment These data were collected on a voluntary and non- regimens, consumptions and safety information. systematic basis with an obviously dispersion and fragmentation. As a result of the current requirement of a continuous epidemiological and clinical monitoring and pharmacovigilance (in terms of safety and efficacy of therapeutic products and of patients’ adherence to treatment), AICE in 2018 started a systematic data collection, in line with other European Countries, through a new information technology platform, the CliPPER (Clinical Pharmacological Prospective Epidemiological Registry). CliPPER collects clinical and treatment data of patients with CBD followed at Italian HTCs. This Registry can also coordinate the flow of specific information between the HTC and Regional and National health institutions. CliPPER is provided with a specific database, made up by a predefined set of anonymized data from a dedicated medical record called SIGMEC (Management System for Congenital Bleeding Disorder), created by AICE and distributed to all HTCs. CliPPER shows an aggregated view of data both from all HTCs (for all qualified users) and from each participating Centre (for the qualified users of the specific Centre), organizing data according to the main sections of SIGMEC medical record. In particular, sociodemographic, clinical, laboratory and treatment data are divided into 4 sections in CliPPER: 1) Home: provides total patients’ data, according to their alive/dead/lost© at follow-up SIMTIPRO status, the trend of Srl recorded patients during the last 6 months period and the variations compared to the previous six months. 2) Alive patients: contains statistics according to patients’ gender, age, age at diagnosis and type of disease. 3) Dead patients: provides the trend of the deaths during the 6 months period, statistics about age at death, sex of dead patients and causes of death. 4) Treatment data: collects treatment regimens of patients according to the of CBD. All types of data are shown through tables and

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s305 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE02 - Italian National Registry of Congenital and Afstyla® for HA and Idelvion® and Alprolix® for HB) it Coagulopathies has been possible to increase the half-life of circulating Adele Giampaolo (1) - Francesca Abbonizio (1) - Romano Arcieri (2) e AICE FVIII of about 1.5-2 times and that of circulating FIX of Dipartimento di Oncologia e Medicina Molecolare, Istituto Superiore about 4-6 time. (1) di Sanità, Roma - Servizio tecnico scientifico Grant Office e Prophylaxis was the regimen of choice in the treatment of Trasferimento Tecnologico, Istituto Superiore di Sanità, Roma (2) patients with severe HA (91.1%) and severe HB (90.2%). The National Institute of Health (ISS) has been dealing The total amount of FVIII prescribed for HA home with inherited bleeding disorders for more than 15 therapy was 380,000,000 International Units (IU): 82.6% years, collaborating with the Italian Association of recombinant FVIII and 14.1% EHL-FVIII. The total amount Haemophilia Centres (AICE) for the realization of the of FIX prescribed for HB home therapy was 39,400,000 National Registry of Congenital Coagulopathies (NRCC). IU: 97.3% recombinant FIX and 38.6% EHL-FIX. The NRCC collects epidemiological and therapeutic The availability of a national registry on blood clotting data from patients affected by Haemophilia A (HA), disorders improves knowledge of the epidemiology, Haemophilia B (HB), von Willebrand Disease (vWD) related diseases and health needs of these disorders. and other rare inherited bleeding disorders (deficiencies However, the NRCC has an important limit due to the of factor I, II, V, VII, X, XI, XIII). The NRCC has been voluntary contribution of each HTC. The establishment officially established at the ISS by the Decree of March of the NRCC, by the Italian Decree of 3 March 2017, based 3, 2017. on a mandatory data flow from all the Italian Regions, Demographic and clinical data are collected and sent, on will provide a more complete information. This flow will voluntary basis, from the local Haemophilia Treatment start when the law will be implemented at regional level. Centres (HTCs) to the national AICE database, shared with ISS. When missing in the database, therapeutic plans are requested directly from ISS to HTCs. Personal data are collected in accordance with current privacy laws and standards; quality of the information collected is verified through logical and formal controls. In the 2018 survey, the total number of patients included in the NRCC was 10,554: 4,109 with HA, 882 with HB, 3,245 with vWD and 2,318 with defects of other coagulation factors. The overall prevalence resulted 6.8/100,000 inhabitants (13.8/100,000 males) for HA, 1.5/100,000 inhabitants (2.9/100,000 males) for HB and 5.4/100,000 inhabitants for vWD. The collected therapeutic plans were relative to 54.2% of patients with severe HA and 53.2% of patients with severe HB vs more than 70% of the 2017 survey. This decrease depended on the missing, or extremely partial, submission of therapeutic© plansSIMTIPRO by four Italian Regions. Srl Based on therapeutic plans collected, patients using an extended half-life (EHL)-FVIII were 195 (mean age: 26 years old), corresponding to 13.5% of HA patients with therapeutic plans; patients using an EHL-FIX product were 101 (mean age: 30 years old), corresponding to 37.0% of HB patients with therapeutic plans. As expected, the prescription of EHL products had a strong increasing trend during 2018, since with these products (Elocta®

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s306 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE03 - The Italian Association of Haemophilia strengthen the research proposals from methodological, Centres and Clinical Research: from projects to ethical and organizational points of view. Moreover, study conduct Annarita Tagliaferri (1) - Antonio Coppola (1) On behalf of after the study starting, monitoring of enrolment, study the AICE Working Group “Clinical Studies” phases, data collection and analysis is carried out by the Regional Reference Centre for Inherited Bleeding Disorders, Parma Working Group every 6 months, in order to identify and University Hospital, Parma (1) overcome barriers or challenges as early as possible. The experience gained so far led to highlight the need Providing contributions to the scientific progress in the for support by data managers/study coordinators in field of haemophilia and congenital bleeding disorders is many AICE centres, in particular to proceed with the stated as an institutional aim of the Italian Association of submission of study protocols and document to the IRB Haemophilia Centres (AICE). This objective has become and in some cases with data collection. In this respect, even more important after the recognition of AICE as a the Working Group proposed and obtained by the AICE scientific society according to the rules established by Council the establishment of a centralized research the Italian Ministry of Health. organization, in order to provide the required support Over the last decades AICE carried out relevant by research professionals where and when needed, and multicentre clinical studies, thanks the enthusiastic to improve the conduct of multicentre clinical studies. contributions of its members, particularly in the field With this background, the AICE centres will be hopefully of management of inhibitors, genotyping, prophylaxis, better translate into research projects and scientific intracranial haemorrhage, infectious complications and achievements their high-quality clinical activities and comorbidities in haemophilic patients. However, more experience. recently, increasing difficulties have been encountered in implementing and conducting clinical studies in the AICE network. Main reasons reside in the increasingly demanding procedures of study approvals by the different Institutional Review Boards (IRB), together with the complexity of addressing rules concerning data privacy and protection. Moreover, many AICE centres suffer because of the reduction of human and economic resources to be devoted to research. Therefore, some studies resulted in poor enrolment or data collection, being participating centres unable to provide the expected contributions. For these reasons, in 2015 AICE established a working group aimed to improve the management of multicentre studies to be carried out in the frame of the AICE network, starting from their proposal and protocol development, up to the implementation and conduct at the different centres. Therefore, the “Clinical Studies” Working Group currently© review SIMTIPRO the study proposals Srl submitted to the AICE Council, particularly addressing their methodology, feasibility and potential issues hampering IRB approval. After revision according to the comments and suggestions by the Working Group, the study proposals undergo assessment and approval by the AICE Council and then confirmation by the AICE members during assembly or through online consultation. This multi-step process now allows to

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s307 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE04 - The role of laboratories in AICE Centers We observed an increase of participation in the EQAP (1) (2) Rita Carlotta Santoro - Angelo Claudio Molinari On over the years 2018 and 2019: the median of responders behalf of the AICE Laboratories Quality Working Group Reg. Ref. Centre Bleeding and Thrombotic Dis., AOPC, was 24 and 25 for FVIII and FIX respectively in 2018 Catanzaro (1) - Reg. Ref. Centre Bleeding Dis., Gaslini Inst., and 36 for both factors in 2019. In 2019 the median Genova (2) of responders for VWF:Ag and RCo was 33.5 and 27.5 respectively. The Table describes some parameters of The laboratory problems related to the introduction of participation. new therapeutic molecules, the growing importance In conclusion EQAP was well accepted by the CL personnel. of pharmacokinetics and the criticalities highlighted However, several critical issues remain: on several in many Centers after the absorption of specialist occasions some laboratories did not receive the kits sent laboratories into the central ones led to the establishment by ordinary mail; participation in the VEQ remains rather in 2014 of the Laboratories Quality Working Group uneven with some Laboratories that never reported the (LQWG) inside the Italian Association of Hemophilia results of FVIII and FIX in the first two years; the same Centers (AICE). laboratories did not send any response regarding the LQWG promoted several training initiatives in the field diagnosis of Von Willebrand disease. of Congenital and Acquired Bleeding Diseases (CABD)

dedicated to the personnel working in the coagulation Table: Parameters of CL participation in AICE EQAP Assay Maximum participation (%) laboratories (CL) that support the AICE registered 2018 2019 FIX one stage 59% 86% centers (AC). FVIII and FIX 4/4 times: 32% 43% Thanks to AICE financial support seven one-year FVIII CHA: 45% 7% FVIII and FIX inhibitors: 26% 2% residential scholarships for biologists/biotechnologists FVIII and FIX 0/4 times: 13% 2% FVIII CHA 0/4: 45% 47% have been attributed; each of the recipients spent six FVIII and FIX inhibitors 0/2: 13% 4%

months in a training laboratory and subsequent six months in the home laboratory. Moreover, LQWG promoted 4 training courses in the field of CABD diagnostics addressed to CL workers. The main LQWG initiative was the External Quality Assessment Program (EQAP) for all the laboratories supporting the AC; the interest of AC Directors was confirmed by a survey (2016). The EQAP, financially supported by AICE and supplied by ECAT Foundation was gradually developed and tailored on the needs of the CL. Initially the annual EQAP included four exercises with assays of factors XII, XI, IX and VIII, the last two both with one stage assay (OSA) and chromogenic assy (CHA), and two exercises for research and titration of FVIII and FIX inhibitors. Von Willebrand disease diagnosis was added to EQAP© in 2019 SIMTIPRO and from 2020 a specific Srl hemophilia module with very low levels of F VIII and FIX was included. Currently, the program provides the following exercises sent by ordinary mail to the CL: FVIII and FIX (activity <5%) OSA and CHA, VWF:RCo, VWF:Ag, VWF:CBA, VWF ristocetin activity, VWF/ FVIII binding (every 3 months); FVIII and FIX inhibitors (every 6 months).

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s308 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE05 - Results of the AICE participants in the context of the total group of participants in the ECAT ECAT external quality assessment programme EQA programme. On the other hand, it may help to Piet Meijer (1) ECAT Foundation, Voorschoten, The Netherlands (1) reveal potential problems in the laboratory diagnostics of parameters relevant in the diagnosis and treatment For the proper diagnosis and treatment management of bleeding disorders. This supports laboratories in their it is of major importance that clinical laboratories are quality improvement management. able to deliver reliable and accurate test results to the physician. One of the pillars in the quality management of laboratories is participation in an External Quality Assessment (EQA) programme. EQA plays an important role in assuring the accuracy of measurement. From EQA results important insight could be obtained into the quality of coagulation testing. From results of this ECAT EQA programme is has been demonstrated that 10-25% of the participants was not able to correctly measure Factor VIII in the range of severe haemophilia (van Moort I, Meijer P, Priem-Visser D, et al., Analytical variation in factor VIII one-stage and chromogenic assays: experiences from the ECAT external quality assessment programme. Haemophilia, 2019; 25: 162-169). The ECAT Foundation is one of the largest global EQA providers is specialized coagulation testing. This includes, for instance, programmes for Factor VIII, Factor IX and von Willebrand Factor testing. Since 2018 laboratories belonging to the Italian Association of Haemophilia Centres (AICE) participate in this EQA programme. In the presentation the results of the period 2018-July 2020 will be discussed. The results of the “AICE-group” will be compared with those of all participants in the ECAT EQA programme. The ECAT has also developed a long-term evaluation model which provides insight into the precision and accuracy of measurement over time (Meijer P, de Maat MP, Kluft C, Haverkate F, van Houwelingen HC. Long- term analytical performance of hemostasis field methods as assessed by evaluation© of theSIMTIPRO results of an external Srl quality assessment program for antithrombin. Clin Chem, 2002; 48: 1011-5). This may help the laboratory in better understanding in the potential causes of deviating results. This long-term evaluation tool will be presented and the results for the “AIBCE-group” will be discussed. The presentation of these EQA data has a twofold purpose. On one hand to demonstrate how well laboratories belonging to the “AICE-group” are performing in the

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s309 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE06 - AICE recommendations for diagnosis, guidance focused on identification, diagnosis, treatment treatment of bleeding and general of bleeds and general management of AHA patients. management of patients with acquired haemophilia A The document, drafted by the AICE Guideline Working Antonio Coppola (1) - Ezio Zanon (1) On behalf of the AICE Group and approved through online consultation Guideline Working Group by AICE members, will be shared with the scientific Regional Reference Centre for Inherited Bleeding Disorders, Parma societies of haemostasis, laboratory, emergency and University Hospital, Parma (1) - Haemophilia Centre, Padua University Hospital, Padua (2) of specialties which can first observe AHA patients (oncology, geriatrics, internal medicine, rheumatology, Acquired haemophilia A (AHA) is an autoimmune obstetrics). disorder caused by autoantibodies neutralizing Factor The document provides information about clinical VIII (FVIII), revealed by prolonged activated partial presentation and bleeding symptoms, together with thromboplastin time (APTT) and resulting in often a detailed section addressing diagnostic issues. severe bleeding tendency. Identification and diagnosis Management is focused on treatment of bleeds, of AHA is challenging, as sudden-onset bleeds occur highlighting the need for direct involvement or in persons without personal or family bleeding history, formalized supervision by specialist HTC physicians. often with comorbidities and comedication potentially Indeed, the choice between the two main approaches responsible for haemorrhagic complications. As AHA (i.e. bypassing agents and replacement treatment, is highly prevalent in the elderly and is secondary (i.e. including the recently introduced recombinant porcine associated with other diseases/conditions-cancer, FVIII) mainly relies on the availability and charge by autoimmune disorders, infections, pregnancy, drugs) clinical and laboratory experts. This guidance provides in about 50% of cases, patients are often first observed a reference pathway to be implemented in the different by physicians without specific coagulation expertise contexts, also addressing the challenging emergency and in the lack of adequate laboratory facilities. Indeed, and management in the lack of specialist consultancy. suspicion of AHA simply arises from the detection of prolonged APTT, not normalized by mixing test at baseline and after incubation (37 °C, 2 hrs), however the diagnosis needs to be confirmed by specific coagulation tests (FVIII activity and inhibitor search and titration), often not available, particularly in the emergency setting. Even more challenging is treatment of bleeds, requiring haemostatic agents (bypassing agents or replacement treatment), which should be managed by expert haemophilia treatment centre (HTC) physicians, taking into account the severity of bleeding, patients’ characteristics (including comorbidities, in particular the concomitant thromboembolic/cardiovascular risk) and the availability of laboratory monitoring. AHA management© always includesSIMTIPRO early eradication Srl immunosuppressive treatment and the search for possible (still undiagnosed) associated conditions. Indeed, treating/removing the latter deserve relevant prognostic implications. In order to promote awareness about AHA and overcome the numerous challenges and, in parallel, to update the recommendations published in 2015, the Italian Association of Haemophilia Centres (AICE) issued a

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s310 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE07 - Emicizumab for prophylaxis of severe patients for 25 (43%), only 1 declaring that treatment haemophilia A patients without inhibitors. costs can affect the choice. Most (62%) also included The opinion of clinicians of Italian Haemophilia Centres children immediately after diagnosed as severe PWHA. Antonio Coppola (1) On behalf of the AICE Guideline Difficulties in management of prophylaxis due to Working Group venous access and unacceptable bleeding rates on Regional Reference Centre for Inherited Bleeding Disorders, Parma prophylaxis with FVIII concentrates were chosen as the University Hospital, Parma (1) most important reasons for prescribing emicizumab The HAVEN clinical trials showed the efficacy of irrespective of patients’ age, followed by the need for emicizumab in preventing bleeding episodes in patients starting prophylaxis in patients with high inhibitor with haemophilia A (PWHA) with and without inhibitors. risk in children and problems in implementing home After the introduction in PWHA with factor VIII (FVIII) treatment with factor concentrates in adults. Italian <2% and high-responding inhibitors, emicizumab treaters highlighted the need for defining agreed has been recently licensed for prophylaxis in severe recommendations for the management of bleeding haemophilia A (FVIII <1%) without inhibitors in several and invasive procedures/surgery to be implemented countries, including Italy. In parallel with the obvious in all Centres (57%), but 38% recognized that this advantages of s.c. administration, clinicians must face depends on the availability of monitoring with FVIII some challenges concerning laboratory testing and chromogenic assays with bovine reagents. Long-term emergency management. Moreover, real-world evidence outcomes, particularly in terms of efficacy in preventing is still scarce and data about long-term outcomes are arthropathy, but also of safety, and management of lacking. In this evolving scenario, the Italian Association invasive procedures/surgery were indicated as the of Haemophilia Centres (AICE) aimed to collect the most relevant open issues in PWHA on emicizumab opinion of specialist physicians, who were asked to prophylaxis. participate in a survey available at the institutional website, consisting of 15 items. Fifty-eight clinicians, working at 40 AICE centres (80%), taking care for >95% of Italian PWHA, responded to the questionnaire. Paediatric or prevalent adult care were reported by 7 (5 Centres) and 12 (10 Centres) respondents, respectively. The remaining centres assisted both children and adult patients. Only 7 respondents worked in the field for <10 yrs. Most clinicians (86%) reported that available data adequately support efficacy and safety of emicizumab but real-world evidence is needed to assess long-term outcomes; however according to 7 respondents (9%), data are limited for assessing efficacy and/or safety, but only 2 (3.4%) declared to wait for further literature data or clinical experience before prescribing emicizumab. Most treaters (66%)© responded toSIMTIPRO consider emicizumab Srl in patients of all ages, while use mainly in children/ adolescents or in patients without cardiovascular risk factors was indicated by 20% and 14% respectively. However, 60% of respondents reported that emicizumab should be considered only in conditions of very high bleeding risk in patients with cardiovascular risk. Candidates to emicizumab prophylaxis should be most severe PWHA for 32 respondents (55%) and selected

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s311 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE08 - AICE recommendations on emergency These documents, drafted by an AICE expert panel and management in patients with haemophilia A approved through online consultations, were further with and without inhibitors on prophylaxis with emicizumab revised by a multidisciplinary working group, including Giancarlo Castaman (1) On behalf of the ad hoc Working members of the other scientific societies. The final Group versions were approved by the Councils of each society. Centre for Bleeding Disorders and Coagulation, Department of These guidance documents provide a reference Oncology, Careggi University Hospital, Florence (1) pathway to be implemented in the different healthcare Emicizumab prophylaxis reduces the bleeding risk and organizations, especially for the challenging emergency improves quality of life in patients with haemophilia A management in this setting. (PWHA) with and without FVIII inhibitors. Although protection appeared improved, however, there is still a need to provide guidance for managing breakthrough bleeds or surgery/invasive procedures which may occur while on emicizumab. Since venous thrombosis or thrombotic microangiopathy complications have been reported in inhibitor patients on emicizumab with the associated use of activated prothrombin complex concentrates at high doses, recombinant Factor VIIa is usually considered for these situations, which proved substantially safe and effective. In patients without inhibitors, no serious adverse events have been reported when combining with Factor VIII concentrates. Few data are available, however as a general rule, on whether FVIII dosing (both standard or extended half-life products) should be the same as usually recommended in patients with severe haemophilia A, according to the type and severity of bleeding (or the bleeding risk of surgery/invasive procedure), especially at the first administration. Management of emergency situations in these patients requires multidisciplinary competences and expertise by clinicians of Haemophilia Centres. Specific pathways should be developed focusing on laboratory testing and treatment of breakthrough bleeds and invasive procedures/surgeries, especially when patients are managed by non-specialist professionals. Therefore, the direct involvement or officially recognized supervision by specialist physicians© should SIMTIPRO be warranted. Srl To promote awareness and overcome these challenges, the Italian Association of Haemophilia Centres (AICE) issued specific guidance on management of PWHA with and without inhibitors on emicizumab prophylaxis, focused on emergency and shared with other National Scientific Societies of haemostasis, laboratory and emergency medicine.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s312 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE09 - FedEmoSport project: activities” (because they are very risky). The drafting of recommendations recommendations was completed with an evaluation Chiara Biasoli (1) - Gianluigi Pasta (2) U.O. Medicina Trasfusionale Cesena, Centro MEC AUSL Romagna (1) - form for a thorough multidisciplinary assessment. U.O.C. Ortopedia e Traumatologia, Fondazione IRCCS Policlinico The FedEmoSport project foresees the publication of (2) San Matteo, Pavia recommendations in a peer-review journal thereby allowing a wider dissemination of the awareness of the With the advent of factor replacement and prophylaxis, existence of this issue in the community of PWHs and people with hemophilia (PWH) can participate in sport of their caregivers and specialists of sport medicine and and exercise. In addition to its beneficial effects on sciences and sports clubs and associations. Moreover, the body in general and protection of health, regular additional targets of the FedEmoSport project are the physical activity helps to prevent bleeds and joint identification, for each Region, of a reference centre for damage therefore it is recommended for PWH. It was Sport Medicine in order to share and draft certifications with this spirit that to celebrate “XI World Hemophilia for competitive sports activity and promotion of Day” in 2015, FedEmo (Italian Federation of Patients’ scientific research on this topic. Associations) organized a press conference and a round table in Rome, at the CONI (Italian National Olympic Committee) headquarters, on the theme “The new frontiers of sport in hemophilia”. After the meeting, the FedEmoSport project started with the aim of making possible to access competitive and not competitive sports for patients with congenital hemorrhagic coagulopathies across Italy, and a multisciplinary board was formed. Members of FedEmo (representing patients), AICE (Italian Association of Haenophilia Centres, represented by health professionals operating in the specialist treatment Centers as hematologists, orthopedists, physiotherapists), and sport medicine specialists of FMSI (Italian Sport Medicine Federation) and CONI started to work together and the first meeting held in February 2016. The need to draft a document containing recommendations on the practice of sports activities in patients with congenital hemorrhagic coagulopathies was immediately shared. This phase required time and energy from all the members of the board because it was necessary to share different knowledge and skills as the efficacy of the replacement treatment currently available for PWH, the traumatic risk of the different sports disciplines, the need of a thorough clinical and instrumental assessment© of PWHSIMTIPRO and, not least, the Srl socio-cultural implications at any stage of life, taking into account how physical activity impact on the quality of life. The recommendations foster the need of a multidisciplinary team including specialists of sports medicine and haemophilia specialists and not refer to the division into sports in different classes of risk but maintain the criterion of “recommended activities” (because they are safe) and “contraindicated

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s313 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE10 - Gene therapy for hemophilia: current RE11 - COVID-19-associated coagulopathy status and perspectives for a definitive cure Luca Spiezia (1) - Francesco Poletto (1) - Elena Campello (1) - Mirko Pinotti (1) Paolo Simioni (1) Department of Life Sciences and Biotechnology, University of Ferrara (1) Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova (1) The advances of recombinant DNA technologies have offered the intriguing opportunity to deliver or edit Coronaviruses (CoVs) are enveloped RNA viruses known “genes” into the affected patients’ cells with the aim to cause infections in birds, mammals and humans. In of providing with a definitive cure for patients with particular, human coronaviruses (hCoVs) are mainly genetic disorders. Monogenic disorders such has associated with respiratory, enteric and neurologic hemophilia A and B, caused by defects in the genes symptoms but hCoVs may also occasionally induce lower encoding coagulation factor VIII (FVIII) and IX (FIX), respiratory tract diseases such as bronchitis, bronchiolitis in which even a partial rescue of plasma levels has a and pneumonia. Many studies on the global COVID-19 remarkable impact on patients’ clinical phenotype, have pandemic caused by a novel coronavirus coined SARS- represented preferred models for the development of CoV-2, have reported a hypercoagulable state in patients these therapeutic approaches. affected by the disease. In fact, Tang N et al. (JTH The intensive work in the field in the last decades led 2020) conducted a study on 183 COVID-19 patients scientists to manipulate adeno-associated virus to (85 females and 98 males) with an overall mortality of deliver a normal copy of the FVIII or FIX expression 11.5%, and demonstrated that non-survivors showed cassettes into the patients’ hepatocytes (“Replacement significantly higher D-dimer and fibrin degradation Gene Therapy”). Several studies demonstrated that one products (FDP) levels, longer prothrombin time (PT) injection only of the appropriately equipped recombinant and activated partial thromboplastin time (aPTT) vs virus can guarantee the synthesis and secretion of the survivors; furthermore, 71.4% of non-survivors met the functional proteins in plasma, ultimately leading to a criteria of disseminated intravascular coagulation (DIC) correction of the coagulation and bleeding phenotype vs. only 0.6% of survivors. These findings appear to be over years. For Hemophilia B gene therapy, researchers corroborated by Han H et al. (CCLM 2020) in a case- also took advantage from the discovery of the FIXPadua control study that compared coagulation parameters of variant having a specific activity eight-fold higher 94 COVID-19 patients and 40 healthy controls and found than that of wild-type FIX, thus promoting a robust significantly lower levels of antithrombin (AT) activity restoration of coagulation in patients. and higher levels of D-dimer, FDP and fibrinogen in On the other hand, through the exploitation of the former; they also divided patients into three groups “molecular scissors” able to specifically insert double according to severity of illness, highlighting that most strand breaks into the affected F8 or F9 gene and critical patients had significantly higher D-dimer indeed trigger homologous recombination, scientists and FDP levels than patients with milder forms of the can directly modify and correct the affected gene in disease, thus suggesting a prognostic role for these hepatocytes (“Genome Editing”). laboratory coagulation parameters. Our group (Spiezia In this lecture we will discuss the main achievements L et al., Thromb Haemost 2020) was able to demonstrate obtained with these approaches, and the most recent the presence of a hypercoagulable state via traditional results from clinical© trials, andSIMTIPRO the open issues still to be coagulation tests but also thromboelastometrySrl in 22 addressed. consecutive patients admitted to Intensive Care Unit of Padova University Hospital. This coagulative pattern may be linked both to markedly increased levels of fibrinogen and an excessive fibrin polymerization, and may have contributed to the development of thromboembolic events observed in a remarkable percentage of cases. The existence of a complex coagulopathy in COVID-19 patients is also highlighted by the tendency to develop

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s314 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI thrombocytopaenia during disease course, likely via RE12 - COVID-19: the implications consumption rather than a mechanism attributable to for patients with haemophilia and congenital haemorrhagic diseases SARS-CoV-2 itself. Lippi G et al. (Clin Chim Acta 2019) Antonella Coluccia (1) recently published a literature review of nine studies Centro Emofilia e Coagulopatie Rare, P.O. di Scorrano-ASL Lecce (1) comprising 1779 COVID-19 patients that revealed a significantly lower platelet count in more severe cases, Since January 2020 the infection by SARS-CoV-2, which correlated with an increased mortality rate. causing the Coronavirus Disease 2019 (COVID-19), In conclusion, COVID-19 patients show an alteration of the spread worldwide as a pandemic starting from the city haemostatic equilibrium towards hypercoagulation as of Wuhan, China. Unlike Coronaviruses responsible for confirmed by many laboratory and clinical findings. This previous pandemics (SARS-Cov and MERS-CoV), SARS- condition may lead to multi-district fibrin deposition, CoV-2 spreads quickly and does not seem to reduce namely, in pulmonary alveoli and interstitium, thus its virulence. Over 6 mo. over 15,000,000 people were worsening respiratory and thromboembolic events infected and 600,000 deaths were recorded, mainly that could precipitate the clinical status of the patient. because of severe respiratory failure due to interstitial Anticoagulant therapy is now recommended by many pneumonia. In Italy more than 240,000 symptomatic authors even though strong data and evidence on and asymptomatic infected subjects and about 35,000 dosages and risk-benefit ratio are still lacking. Clinical deaths are reported. After a significant reduction of the trials are urgently needed in order to identify classes of individual contagious rate index, together with the drop patients who may benefit from anticoagulant therapy in hospital admissions and deaths thanks to lockdown, and which drug to use. an increase is expected in the coming months because of lowering of security measures and return of cold seasons. Pathophysiological knowledge is still limited. In particular, mechanisms triggering the most serious forms which can lead to the poor outcome are unclear. Numerous studies have shown changes in coagulation tests in patients with COVID-19, which reflect a hypercoagulable state and thromboembolic risk, strongly related to clinical severity and mortality. Pulmonary and systemic thrombotic manifestations, such as disseminated intravascular coagulation (DIC), have been observed and appear to significantly affect prognosis. In this hypercoagulable state, proven clinically and by laboratory tests, anticoagulants, such as low molecular weight heparin, appears effective. However, the dose is not clearly defined and is being evaluated in specifically designed clinical trials. Patients © SIMTIPROwith haemophilia and congenital haemorrhagicSrl diseases (CHD) exhibit a hypocoagulable state, which is corrected by replacement therapies, on demand or on prophylaxis regimens. These patients are carefully and regularly followed by specialist Centers, for bleeding and related or unrelated comorbidities. At present it is unknown at which extent the population of CHD patients has been involved in COVID-19 pandemic. The high incidence of thromboembolic complications in infected patients and treatment with anticoagulants at therapeutic or

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s315 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

prophylactic dose represent challenges for patients with RE13 - Molecular diagnosis in haemophilia (1) (1) (2) CHD. On the other hand, the inherited hypocoagulability Donata Belvini - Roberta Salviato - Paolo Radossi UOSD Medicina Trasfusionale, AULSS2 Azienda 2 Marca could somehow limit thrombotic complications. Trevigiana, Castelfranco Veneto (TV) (1) - Oncoematologia, Istituto Among discomforts of pandemic, possible shortage of Oncologico Veneto, Ospedale Castelfranco Veneto (TV) (2) plasma-derived and recombinant factor concentrates due to difficulties in international transport is feared. Molecular diagnosis of haemophilia is a complex process Particularly for plasma-derived products, there is a that begins with genetic counseling and aims to identify the variant in F8 and F9 genes. It is recommended in all fear of a drastic reduction in blood donations. Reduced affected males since the type of identified variant provides consumption of these concentrates is hypothesized informations in relation to the risk of developing an anti- due to the unjustified fear of virus transmission, as Factor inhibitor and allows carrier and prenatal diagnosis. happened in the years of HIV and HCV infections. DNA is extracted from peripheral blood leukocytes or Clinical trials could provide useful information from chorionic villi. The diagnostic path depends on the type and an epidemiological and clinical point of view. In this severity of the patient’s disease and involves (only in the cases respect, an observational multicentric cohort study of severe haemophilia A) the search for Intron1 and Intron22 evaluating the impact of COVID-19 in the Italian Inversions (by PCR or Long PCR), followed by large deletions population of patients with CHD was designed on and duplications (by MLPA), finally, it points variants behalf of the Association of Italian Haemophilia Centres such small deletions or duplications and single nucleotide (AICE). This retrospective-prospective study will substitutions (by screening or sequencing methods). provide data on prevalence and incidence of COVID-19 In order to understand if the identified variant is the in patients followed by the Italian AICE Centres, since real cause of the disease, its pathogenic role has to be the beginning of pandemic (february 2020) up to one- determined considering the type of damage it might year prospective follow-up. produce on the protein, the presence of the variant in the disease databases, the classification of the pathogenicity and the genotype-phenotype correlation. The carrier status in the maternal patient-related women and their consequent risk of transmitting the disease can be verified, looking for the pathogenic variant by the specific technique by which it was previously identified in the patient. So, PCR will then be used on woman’s DNA for Inversions detection, while MLPA for large deletions or duplications detection and direct sequencing of the fragment in which the variant is present for point variant detection. Molecular diagnosis is the only way able to classify a patient as a real sporadic case: when the causal variant is not present in his mother’s leukocytes DNA, the patient could be the result of a de novo variant that appeared in the oocyte at his conception or the mother is a germinal mosaic in which some germ cell bring the variant. The © SIMTIPROdiscrimination between this Srl situation is not easy to perform so the mother has to be considered as a possible carrier who can transmit the disease to other children. Prenatal diagnosis in haemophilia carriers is primarily performed to know the sex of the unborn child: in the case of male, the haemophilia causative variant identified in the family will be searched to determine whether or not the foetus is affected. In the case of female sex, no further investigation is carried out.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s316 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE14 - Haemophilia Centres and Respondents reported that preconceptional information the multidisciplinary support of carriers is usually given at the HCs, whereas for pregnant carriers planning and during pregnancy: results of the 2020 AICE survey specific genetic counselling is performed at 14 medical Federica Riccardi (1) - Maura Acquila (2) - Antonio Coppola (1) - genetic services (8/2/4, North, Central and South Italy). Giancarlo Castaman (3) - Francesco Bernardi (4) - Angiola Prenatal molecular diagnostics are carried out at 7 (5) Rocino specialized laboratories (4/1/2, North, Central, South Haemophilia Centre, University Hospital, Parma (1) - Genetic Lab, Gaslini Hospital, Genoa (2)- Haemophilia Centre, Careggi Hospital, Italy). Obstetric management is usually carried out at Florence (3) - DLSB, University, Ferrara (4) - Haemphilia Centre, OdM, the HC hospital site. While the majority of HC specialists (5) Naples (73%) consider to be able to provide carriers adequate information about prenatal invasive techniques (villo/ Genetic counselling and management of carriers plays amniocentesis), this rate is lower when knowledge about an important role in haemophilia comprehensive care. non-invasive prenatal tests (57%) and, even more, pre- Physicians of Haemophilia Centres (HCs) are crucial implantation procedures (46%) are requested. to support women in the steps leading to pregnancy In conclusion, management and need for support of and in the prenatal process. Different invasive and haemophilia carriers planning and during pregnancy non-invasive tests as well as pre-implantation genetic is a well-recognized issue by HC specialists. However, diagnosis currently offer women the opportunity to institutional multidisciplinary pathways are not approach pregnancy and the disease according to homogeneously available throughout Italy. The personal, psychological and familial attitudes. continuous progress in diagnostic approaches and The Italian Association of Hemophilia Centre (AICE) techniques requires reference to specialized centres, promoted a survey to define the state-of -the-art about the definition of regional/multi-regional operative hemophilia carrier management in Italian HCs. A protocols, shared by the HCs and all collaborating questionnaire with multiple open-ended questions professionals, possibly istitutionally established. was proposed to all AICE HCs. The survey focused on awareness with regard to genetic counselling, molecular prenatal diagnosis and obstetrician care. Thirty-seven HC physicians, responsible for 72% of Italian HCs, following >90% of haemophilic patients and covering all regions but one, responded to the questionnaire.

QUESTION: How often in a year do you meet a woman who is planning a pregnancy or in pregnancy? MANAGEMENT In the same HC Hospital Outside Hospital but Inside HC region Outside Hospital and outside HC region UNDEFINED tot SEVERAL TIMES 7 5 / / 12 AT LEAST ONCE 3 6 2 5 16 LESS THAN ONCE / 3 3 3 9 © SIMTIPRO Srl

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s317 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE15 - Assisted reproduction and reimbursement for ICSI without any adjunctive preimplantation genetic diagnosis: economic burden for couples. More the 100 patients problems and opportunity Walter Vegetti (1) have been treated so far and more than 50 healthy Infertility Unit - Fondazione Ca’ Granda Ospedale Maggiore babies were born. Policlinico, Milan (1)

Assisted Reproduction Techniques (ART) are actually used to treat fertility problems in millions of couples worldwide. Preimplantation genetic diagnosis (PGT-M) is increasingly applied in couples carrying genetic diseases in order to avoid the psychological burden and clinical risk of elective termination of pregnancy after classic prenatal diagnosis (villocentesis or amniocentesis). In 1990 the first healthy child after PGT-M was born in England and since then thousands of babies were born all over the world. The technique has various steps: ovarian hormonal stimulation to achieve multiple follicular growth, oocytes retrieval, intracytoplasmic sperm injection (ICSI) of oocytes with embryo culture until blastocyst stage, blastocysts biopsy and genetic analysis of embryonic cells: this make possible intrauterine transfer of selected not affected embryos in more than 400 different genetic diseases. This technology has less than 3% risk of misdiagnosis, compared to 25% to 50% risk of abnormal offspring after spontaneous pregnancy in couples carrying monogenic recessive or dominant conditions, respectively. Clinical and biological skills and expertise in ICSI technique, culture to blastocyst stage, embryo biopsy, genetic test availability and an efficient embryo cryopreservation program are all mandatory to establish an effective ICSI with PGT-M program. In Italy ICSI’s cost is covered by national health service but availability of PGT-M for genetic diseases is still scarce due to political problems: PGT-M has been forbidden ©by the Italian SIMTIPRO law until few years ago Srl and actually the costs are not covered by the national health system or by personal health insurances. At present few centers in Italy offer PGT-M and almost all for a fee around 2.000 Euros. In the Infertility Unit of our public Hospital in Milan we started and ICSI program with PGT-M in 2015 and, first in our country, we were able to offer the treatment using the generous national health service

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s318 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE16 - Diagnosis and treatment of chronic Forty-four experts (34 haematologists, 2 radiologists, 3 synovitis in patients with hemophilia: orthopaedic surgeons, 5 physiatrists/physiotherapists) consensus statements from the Italian Association of Haemophilia Centers evaluated statements and reached consensus on 15 (Table 1). Matteo Nicola Dario Di Minno (1) - Gianluigi Pasta (2) Most of experts agreed that synovitis represents a On behalf of the AICE MSK Working Group disease activity marker in PwH and that it must be (1) Federico II University of Naples, Naples - IRCCS Policlinico S. searched in patients with pain. Moreover, they agreed Matteo, Pavia (2) to screen for the presence of synovitis not only target Joint bleeding is the main manifestation in persons with joints, but all joints. hemophilia (PwH) and prophylaxis has been introduced Ultrasound was judged as the most feasible and reliable to reduce bleeding rate and to preserve joint function. imaging tool to screen joints in PwH to identify synovitis, However, some PwH develop arthropathy despite over HJHS, X-ray and MRI. adequate prophylaxis. Thus, growing interest has been The presence of synovitis was judged as a criterion to given to screening of early signs of arthropathy. On this tailor ongoing prophylaxis or to start prophylaxis in hand, chronic synovitis is known as an expression of on-demand treated PwH. After any treatment schedule joint disease activity in PwH. change, experts agreed on the need to monitor clinical We performed a Delphi consensus on diagnosis and and ultrasound evolution within 3 months. treatment of chronic synovitis in PwH involving PwH subjects with synovitis should always be assessed by experts in haemophilia care who expressed agreement/ a physiotherapist and the rehabilitation program should disagreement on 37 statements using a 5‐point Likert‐ be performed under adequate factor replacement. type scale (1: strongly disagree, 2: disagree, 3: somewhat Although our results represent the rationale for including agree, 4: agree and 5: strongly agree). The percentage of synovitis assessment in the frame of a comprehensive participants who scored each item as 1-2 (disagreement) care approach in PwH, future studies are needed to or 4-5 (agreement) was calculated. evaluate the impact on clinical outcomes.

Agreement Disagreement Statement (%) (%)

Chronic synovitis represents a disease activity marker in PwH 93 2

The presence of chronic synovitis must be searched in PwH with joint pain 89 2 The presence of chronic synovitis must be searched at each clinical follow-up 16 70 visit only for target joints The presence of chronic synovitis must be searched at each clinical follow-up 70 2 visit regardless the presence of joint symptoms

After finding of chronic synovitis, its evolution must be evaluated periodically 98 0

The presence of chronic synovitis must be searched using ultrasound 98 0 examination The presence of chronic synovitis must be searched using magnetic resonance 5 82 imaging examination The presence of chronic synovitis must be searched using computed tomography 0 98 imaging examination The presence of chronic synovitis must be searched using standard radiographic 2 91 imaging© examination SIMTIPRO Srl The finding of chronic synovitis support the switch to prophylaxis schedule in 95 0 on-demand treated patients The finding of chronic synovitis support changes in treatment schedule 93 0 (dose/frequency) in patients under prophylaxis. In case of treatment schedule change a clinical follow-up is indicated after 75 0 3 months

A patient with chronic synovitis should always be assessed by a physiotherapist 80 5

All physiotherapeutic treatments should be performed after clotting concentrate 75 9 replacement therapy In patients with chronic synovitis, posture control exercises are indicated to avoid 86 5 pathologic postures due to antalgic positions

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s319 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite RELAZIONI

RE17 - Sport and haemophilia RE18 - The pyramid of the movement Gianluigi Pasta (1) Chiara Biasoli (1) UOC Ortopedia e Traumatologia Fondazione IRCCS Policlinico San Centro MEC AUSL della Romagna, Medicina Trasfusionale, Matteo, Pavia (1) Ospedale Bufalini Cesena (1)

In the past, people with haemophilia (PWH) had to be Promoting hemophilic patients’ health also means very cautious and talking about sports was out of the establishing prevention programs relating to both the question. Today, with the advent of factor replacement disease, behaviours and situations. and prophylaxis, PWH can participate in sport and People with hemophilia have a higher risk of chronic exercise. In addition to its beneficial effects on the body in arthropathy and obesity due to inactivity because of general, regular physical activity helps to prevent bleeds joint bleeding and excessive protection. Strength, and joint damage therefore it is recommended for PWH. flexibility and coordination are important for improving Sport and exercises are able to improve strength, balance joint stability and function, increasing bone density and and coordination protecting joints from pressure and reducing the risk of bleeding. trauma, and reducing joint bleeding. Regular physical Regular exercise can help improve joint stability and activity keeps joints mobile through movements with a function, reduce the risk of acute bleeding episodes and large range of motion, which may promote lubrication the consequent complications, improve physical fitness of the cartilage and fights stiffness. Moreover, exercise along with emotional and social integration and improve reduces the risk of being overweight. Choosing the right overall the quality of life of the patient with hemophilia exercise is important and will be different for every Hemophilia requires multidisciplinary management child, and should be based on discussions between the due to the presence of both hematological and skeletal patient, the family and the medical doctor who looks muscle issues. after their haemophilia. Many factors will influence The most appropriate advice must come from the choice of exercise, including overall enjoyment experts working in sport medicine and hemostasis and risk to their joint health. This has raised plenty of field and alongside with skeletal muscle experts; the questions about suitable exercise and sport for PWH. haematologist must optimize the factor replacement Classifying sports and exercises into low- and high-risk (medicine) therapy, the sport medicine specialist must categories for PWH can often be too simplistic, leading check the patient’s condition and these experts together to excessive restriction. For most activities, there is must identify the right type of sport. the need to distinguish between a leisure activity, club In this perspective, a board of hematologist and skeletal activity and competitive activity: the stresses on muscles muscle expert (with expertise in congenital bleeding and joints will be very different. Sports activities are not disorders) write the document of Recommendations without risk, nevertheless PWH can participate in many about recommended physical activities and frequencies. sports and the benefits of the sport clearly outweigh the risks. The need of a thorough assessment and follow- up performed by a multisciplinary team has to be recommended in© order to minimiseSIMTIPRO the risks. Srl

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s320 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite Milano, 8-11 ottobre 2020

Abstract

onwards could be due to an increased mortality rate 1.01 - ACQUIRED COAGULATION DISORDERS in older people (because of COVID-19 infection or to a referral bias (patients not seeking medical attention, for fear of the COVID-19 infection). ABS01 - Trend of diagnoses of acquired hemophilia A in 25 year-period Eugenia Biguzzi (1) - Simona Maria Siboni (1) - Roberta Gualtierotti (1) - Raffaella Rossio (1) - Simon Braham (1) - Cristina Novembrino (1) - Nicolò Rampi (1) - Ida Martinelli (1) - Flora Peyvandi (1) Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Milano (1)

Background. Acquired hemophilia A (AHA) is a rare disease, characterized by circulating neutralizing antibodies directed against FVIII. Its estimated incidence, in the absence of cohort studies, is 1.5 cases per million persons/years. The main challenge of AHA is its clinical suspicion, followed by an accurate laboratory ABS02 - The role of the von Willebrand factor evaluation. Aim of this study was to evaluate AHA propeptide (VWFpp) in the evaluation of diagnosis at our Center over time, from January 1995 to desmopressin (DDAVP®) response in a patient June 2020. with acquired von Willebrand syndrome (AVWS) Methods. The clinical charts of patients followed at A. Paola Colpani (1) - Luciano Baronciani (1) - Giovanna Cozzi (1) - Bianchi Bonomi Hemophilia and Thrombosis Center for Simona Maria Siboni (1) - Eugenia Biguzzi (1) - Cristina AHA were reviewed and data on the date of diagnosis, Novembrino (1) - Federica Rossi (1) - Flora Peyvandi (1) age, sex and underlying comorbidities were collected. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Results are presented as frequencies (and percentages) Italy (1) for cathegorical variables, median and interquartile range (IQR) for continous variables. Background. AVWS is a rare disease characterized by Results. One-hundred and 13 patients were followed clinical and laboratory findings similar to VWD, but at our Center in the study period, 62 (55%) men and 51 occurring later in life. The main pathogenic mechanism (45%) women. The median age at diagnosis was 35 years is due to an accelerated VWF clearance from plasma. (32-37) for patients with postpartum AHA (n=10). In the Case Report. A 40 years old male was referred to our remaining (n=103), median age at diagnosis was 74 years Center for repeated epistaxis associated to anemia. Mild (IQR 68-81) and an underlying disease was present in 45 nose bleeding was present since childhood, but without (49%), absent in 47 (51%) patients (missing data in 7). The need of medical attention. Surgery had been performed underlying disease was autoimmune in 20, cancer in 18, in the past without bleeding complications. Patient infection/vaccination/drug in 7 patients and >1 cause in plasma was evaluated as recommended by ISTH-SSC 4. The absolute number of diagnoses per year increased guidelines: FVIII:C, 5%; VWF:Ag, 5%; VWF:RCo, <6%; progressively, with ©at least 4 cases/yearSIMTIPRO after 2007 and 7 VWF:CB, <1%, with an elevated VWFpp/VWF:AgSrl ratio cases/year after 2012. In the year 2020, 3 patients cases of 19(nr 0.6-1.6). In consideration of the severe VWF were referred to our Center before March 2020 (see deficiency in the absence of a major personal and familial graph). history of bleeding, an AVWS was hypothesized and Conclusions. In the past 25 years, an increasing number confirmed by the presence of a monoclonal gammopathy of suspected cases of AHA were referred to our Center for (IgG kappa, 0.1g/dL). ELISA assay of anti-VWF IgG was diagnosis and treatment. This could be due to increasing positive and Bethesda assay with VWF:RCo yield 1BU of aging of the population or to a better awareness of the inhibitor. Patient DDAVP test was performed twice with disease. The absence of referrals from March 2020 different detection times (Fig. A/B). The 2nd DDAVP test

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s323 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

showed increased levels of FVIII and VWF after 20 min surgery. No family history of hemophilia A was reported. and their almost complete clearance after 1 h, associated The patient reported previous surgeries (tonsillectomy with increasing VWFpp/VWF:Ag ratios. before diagnosis, not complicated by bleeding, and Conclusions. Low level of FVIII and VWF at 1 h after cervical spinal surgery in prophylaxis with a not DDAVP, as requested by guidelines, means no response specified treatment not complicated by bleeding). The to DDAVP, which usually imply the diagnosis of VWD. patient was tested with the following results: FVIII:C 20 Yet, such conclusion did not match with our patient IU/dL, VWF:Ag 16 IU/dL, VWF:GpIbR 10 IU/dL, VWF:CB bleeding history and laboratories finding. In this context, 13 IU/dL. The full multimeric pattern and the VWF evaluation of VWFpp might help to understand why the propeptide/antigen ratio (4.6) suggest a type 1 Vicenza, patient had a poor response to DDAVP. The elevated but the genetic test was negative for the p.Arg1205His VWFpp values obtained after the 1st DDAVP test indicate mutation. An AVWS was therefore suspected (probable its normal synthesis and this is likely to apply also to in the absence of bleeding after tonsillectomy with such VWF. Indeed, as confirmed by the nd2 DDAVP test, after low VWF levels), and intraplatelet VWF was test and 20 min FVIII and VWF are released into bloodstream to found normal. Non neutralizing anti-VWF antibodies be cleared out almost fully in 1 h, due to the presence of (IgG and IgM) were negative. A screening for diseases an inhibitor. associated to AVWS revealed a monoclonal component (IgG kappa). A DDAVP test was performed with a normalization of FVIII and VWF levels after 15 minutes, followed by a decrease of the values after 4 hours. Conclusions. An unsuspected diagnosis of AVWS was made in a middle aged male, previously diagnosed with mild hemophilia A. AVWS diagnosis, at difference with other acquired bleeding disorders, is not based on a specific test, but on: 1) specific characteristic of the biochemical profile, 2) exclusion of congenital VWD, 3) diagnosis of known associated diseases. ABS03 - Unsuspected case of acquired von Willebrand Syndrome (AVWS) in a middle aged man ABS04 - Management of an Acquired Paola Colpani (1) - Eugenia Biguzzi (1) - Simona Maria Hemophilia A case with COVID19 Siboni (1) - Roberta Gualtierotti (1) - Simon Braham (1) - Cristina Dainese (1) - Jacopo Agnelli Giacchello (1) - Luciano Baronciani (1) - Giovanna Cozzi (1) - Ida Martinelli (1) - Enirco Dosio (2) - Alessandra Valpreda (2) - Alessandra Flora Peyvandi (1) Borchiellini (1) Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University Hospital City of Health and Science of Turin, Regional Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Center Hemorrhagic and Thrombotic Diseases, Hematology Unit, Italy (1) Turin (1) - University Hospital City of Health and Science of Turin, Hematology Lab, Turin (2) Background. Measurement of von Willebrand factor (VWF) is necessary to differentiate between mild Background. Acquired Hemophilia A (AHA) is a rare hemophilia A and von Willebrand disease (VWD), bleeding disorder caused by auto-antibodies directed © SIMTIPROagainst clotting factor VIII (FVIII),Srl often resulting in but in most cases the clinical history of the patient is characterized by specific symptoms (joint or muscle severe bleeding manifestations. Its treatment is based on bleeding vs mucosal bleeding). The sudden development haemostatic control and immunosuppressive treatment of bleeding symptoms (spontaneous or after a challenge) (IST) to eradicate circulating inhibitors. Since COVID19 later in life, is a clinical feature of acquired bleeding pandemic breakout, the management of autoimmune disorders. disorders represented a challenge for clinician. Case report. A middle-aged man of 43 years, diagnosed as Case Report. A 63-years old woman was admitted at mild hemophiliac at the age of 31 years (FVIII:C 14 IU/dL), the emergency department (ED) at the end of May 2020 was referred to our Center from another hospital before for development of hematomas at the upper right arm

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s324 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT and left leg. The same patient accessed to ED 3 months ABS05 - Change of the bleeding phenotype in a before for severe anemia (Hemoglobin, Hb, 4.3 g/dl) and patient affected by mild hemophilia A Nicolò Rampi (1) - Eugenia Biguzzi (1) - Simona Maria renal failure (Creatinine, Crs, 3.45 mg/dl). A nephrologic Siboni (1) - Simon Braham (1) - Paola Colpani (1) - Roberta consultancy lean for a multifactorial renal failure (acute Gualtierotti (1) - Luciano Baronciani (1) - Ida Martinelli (1) - anemia and anti-inflammatory drugs abuse). In the Flora Peyvandi (1) recent ED access, anemia and impaired renal function Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, A. (1) were again detected (Hb 4.9 g/dl, Crs 4,4 mg/dl) with Bianchi Bonomi Hemophilia and Thrombosis Center, Milano prolongation of the partial thromboplastin time (aPTT Background. Hemophilia A is characterized by a ratio, 2.91). An aPTT-mix test was performed and resulted distinctive bleeding phenotype (joints and muscle indicative of inhibitor presence. Factor VIII (FVIII) was bleeding or bleeding after surgery). quantified (FVIII 0.5 UI/dl) and FVII-Inhibitor titred Case report. Male patient, affected by mild hemophilia A, (29 UB). A diagnosis of AHA was made. As indicated diagnosed at the age of 76 years, because of post-surgical by Hospital guidelines, a RT-PCR nasal swab (NS) for bleeding since childhood. At diagnosis, laboratory tests Coronavirus Disease 2019 (COVID19) was performed showed discrepant levels of FVIII:C (26 IU/dL with a and resulted positive. Thus, the patient was admitted in one-stage assay, 10 IU/dL with a chromogenic assay) and a dedicated Unit. Here, a screening for other infections, normal levels of VWF (VWF:Ag 190 IU/dL, VWF: GpIbR autoimmune disorders and occult neoplasms was carried 144 IU/dL, normal binding of VWF to FVIII). The family out, resulting negative. From the immunosuppressive history was negative for hemophilia A. Comorbidities point of view, the case was discussed with an infective were high blood pressure and dyslipidemia, for which disease consultant and pneumologists. Given the absence he was on treatment with an antihypertensive drug of any symptoms or sign related to the viral infection and a statin. The patient was regularly followed-up and and the necessity to initiate a specific IST, an initial received recombinant FVIII concentrate for 4 surgeries management with prednisolone (1 mg/Kg) was started. Given the lack of appreciable response, a second line IST after diagnosis, without bleeding events: left and right was needed. In order to avoid a viral infection awakening, hernioplasty, endovascular prothesis for abdominal aortic silent so far, it was waited until two consecutive negative aneurism and carotid thromboarterectomy. After the RT-PCR NS for COVID19 were obtained. After that, as a latter, he started acetylsalicylic acid 75 mg/day. At the age precautionary measure we waited for other two weeks of 81 years, the patient had an episode of epistaxis which and finally performed a third RT-PCR NS. As it resulted required nasal tamponade. He was invited to monitor negative, a second line IST with Rituximab (RTX) blood pressure regularly. After a second episode he came 375 mg/m2 weekly was started. In the meanwhile, an back to the Center and was tested for a full blood count, optimized hemostatic control was assured, first with that was normal except for thrombocytosis (platelets recombinant activated FVII and then with recombinant 1.217.000/mmc). Primary thrombocytemia was confirmed porcine FVIII. The patient remains asymptomatic from at a bone marrow biopsy, performed with a prophylactic the infective point of view. A hematologic response treatment with recombinant FVIII concentrate and started to emerge after the third RTX infusion. tranexamic acid.Coagulation tests revealed an acquired Conclusions. This AHA case management resulted Von Willebrand syndrome: FVIII:C 15 IU/dL (one-stage challenging since its association with silent COVID19 assay), 10 IU/dL (chromogenic assay), VWF:Ag 142 IU/DL, infection. It was © probably notSIMTIPRO associated from an VWF:GpIbR 20 IU/dL, decreased highSrl molecular weight etiological point of view with COVID19 infection VWF multimers, altered nucleotides in platelet granules. as it did not resolve with the negativization of the A cytoreductive therapy (hydroxyurea) was started, with COVID19 NS. Our strategy, consisting in a gradual normalization of platelet count and of VWF levels. implementation of the IST while moving forward from Conclusions. Unusual changes in the bleeding the NS negativization, together with the optimization of phenotype must be carefully evaluated, even in the the hemostatic control, resulted safe, as the patient did presence of clearly diagnosed congenital disease like not experienced an awakening of the silent COVID-19 mild hemophilia, because they can be associated with infection, and efficacy at the same time. acquired bleeding disorders.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s325 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

yrs showed higher figures (≥1 85%, ≥3 64%). Consistent 1.04 - COMORBIDITIES with comorbidities, the most used comedications were anti-hypertensive drugs (37%), statins and proton- pump inhibitors (both 13%). Benzodiazepine use was ABS06 - Impact of comorbidities and comedication reported by 9%, while 4 PWH were on antithrombotic in adult/elderly hemophilic patients treatment (3 aspirin and 1 warfarin). Healthcare burden (1) (1) Gabriele Quintavalle - Antonio Coppola - Gianna resulted in (mean ±1SD) 11.2±11.7 accesses to HC/hospital Franca Rivolta (1) - Federica Riccardi (1) - Annalisa services, with higher impact in severe vs non-severe Matichecchia (1) - Annarita Tagliaferri (1) University Hospital, Reg. Ref. Centre for Inherited Bleeding PWH (20.8±16.7 vs 8.6±8.0, p<0.001), in older patients Disorders, Parma (1) (>70 yrs; 14.1±17.9, p<0.01) and in severe HA vs. HB, only concerning HC visits (10.7±5.1 vs 6.3±2.1, p<0.01). Background. During recent years, life expectancy of Comorbidities were responsible for 9% of HC visits, persons with hemophilia (PWH) significantly improved, increasing to 22% in PWH >70 yrs. About 42% of specialist until approaching that of the general population. This consultancies and 41% of diagnostic investigations were achievement was increasingly associated with the due to NOID-related issues, with increasing impact in emergency of comorbidities typical of adult/elderly age older patients (54/52% in those 60-69 yrs and 57/67% in and with the challenges of their management and of >70 yrs). concomitant drug intake in PWH, affecting bleeding Conclusions. Comprehensive care in adult/elderly risk. Few data are currently available about the prevalence PWH is increasingly addressing the comorbidity and and impact of comorbidities and comedication in the comedication issues, in parallel with ageing. Among healthcare of ageing PWH. We addressed these issues in PWH aged >40 yrs more than 70% suffer from at least a cohort of adult/elderly PWH. 1 comorbidity and more than 50% report comedication Methods. Two-year (2018-2019) clinical records of intake, rates increasing with ageing. The healthcare PWH (A and B, any severity) aged >40 yrs followed at burden is relevant, being responsible for up to 50% of a comprehensive care hemophilia center (HC, Parma, service accesses in adult PWH and even >70% in elderly Italy) were retrospectively reviewed. Data about patients. comorbidities and regular intake of medications (type and number) were collected, together with number of outpatient visits at the HC, specialist consultancies ABS07 - Hemophilia and Polyglobulia: three case report and diagnostic/instrumental investigations, taking Mariapia Falbo (1) - Simona Prejano (1) - Lucia Concetta into account those performed due to comorbidities, Elia (1) - Francesca Leo (1) - Piergiorgio Iannaccaro (1) - Rita and particularly those related to non-orthopaedic and Carlotta Santoro (1) infectious disease (NOID) issues. UO Emostasi e Trombosi, Azienda Ospedaliera Pugliese-Ciaccio, Emato-Oncologico, Catanzaro (1) Results. PWH aged >40 yrs accounted for 49% of PWH followed at the HC. Eighty-four patients (hemophilia Background. Polyglobulia is defined by the increase A/B 74/10; severe 19) were enrolled. Age range was 40-96 of hematocrit and haemoglobin respectively. Possible yrs (40-49 yrs: 29; 50-59 yrs: 28; 60-69 yrs: 12; >70 yrs: 15). causes might be neoplastic diseases like polycythemia Overall, 60 (71%)© PWH reported SIMTIPRO at least 1 comorbidity vera with proliferation of a cell clone.Srl More often one will and 23 (27%) ≥3, with higher prevalence in PWH aged find reactive forms resulting from chronic hypoxemia. >60 yrs (≥1 93%, ≥3 64%). No significaant difference was Some complications of polycythemia include thrombosis found according to type and severity of hemophilia. and bleeding. Hemophilia is an X-linked congenital Hypertension was the most frequent condition (41%), bleeding disorder caused by a deficiency of coagulation followed by gastrointestinal diseases (26%), dyslipidemia factor VIII or FIX. We diagnosed this two rare entity in (19%), cardiovascular diseases (16%), diabetes mellitus three patient. (12%), urologic diseases (10%). Concomitant medications Case Report. Case n.1: 69 years old male, affected by (range 1-11) were used by 45 PWH (54%), 23 (27%) moderate hemophilia B (FIX basal concentration 3.5%). reporting intake of ≥3 drugs. Again, PWH aged >60 At the age of 56, due to the onset of acute coronary

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s326 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT syndrome, he underwent a surgery for a drug-eluting ABS08 - Low bone mass and hypovitaminosis stent (DES). In the last year (February 2019) the lab D in haemophilia: a single center study in patients with severe and moderate values underlighted polyglobulia (Ht 50.5%; Hb 16.8 haemophilia A and B g/dL; GR 6.60 x 106). At the physical exam a cardiac Silvia Linari (1) - Lisa Pieri (1) - Daniela Melchiorre (2) - arrhythmia was confirmed by ECG which highlighted Lorenzo Tofani (2) - Rajmonda Fjerza (1) - Giancarlo (1) atrial fibrillation (AF) treated with anticoagulant and Castaman SODc Malattie Emorragiche e della Coagulazione, AOU Careggi, then by the closure of the auricle and simultaneous Firenze (1) - SODc Reumatologia, AOU Careggi, Firenze (2) cardioversion. The hematocrit value was maintained at 46% through periodic bloodletting. Background. Haemophilia (H) is frequently associated Case n.2: Patient with diagnosis of Hemophilia A severe. with a multi-factorial reduction of bone mineral density At the age of 18, finding of polyglobulia (RBC 5.85 x (BDM), but little is known about possible differences 106, Hb 17,3g / dl, Ht 50.5%). Values of white blood cells between HA and HB and according to their severity. and platelets were normal as well as the research of The aim of our study was to evaluate the association JAk2 mutation, the respiratory functionality tests and between low BMD, 25-hydroxyvitamin D [25(OH)D] abdominal ultrasound for liver and spleen evaluation. concentrations and bone turnover markers in patients Currently the patient is 30 years old. He has practiced (pts) with HA and HB younger or older than 50 years periodic bloodletting; it was not considered to start an Methods. In 78 pts<50 years and 33 pts>50 years with antithrombotic prophylaxis with aspirin, for the young severe or moderate HA and HB BMD was measured age of the subject and not to increase the bleeding risk. by dual energy X-ray absorptiometry at femoral neck Case n.3: Patient with diagnosis of Hemophilia A severe. (FN) and lumbar spine then correlated to annual At the age of 30, finding of polyglobulia (RBC 5.65 x 106, bleeding rate (ABR), World Federation of Haemophilia Hb 17 g / dl, Ht 50%). Also in this case the data were all orthopaedic joint scale (WFH score), 25(OH)D negative, with the exception of a moderate splenomegaly concentrations, parathyroid hormone (PTH), amino- likely related to HCV liver disease. The treatment terminal telopeptide of type 1 collagen (NTx), urinary consisted of sporadic bloodletting. No antiplatelet pyridinolines, osteocalcin and bone-specific alkaline therapy has been used. phosphatase. Conclusions. Hemophilia and polyglobulia are not Results. Overall a high prevalence of hypovitaminosis often found together in the literature. With the D was diagnosed. In pts<50 years low FN-BMD increased life span in hemophilia patient, arterial was significantly more frequent in HA than in HB, and venous thromboembolism are detected, but while PTH, pyridinolines, ABR and WFH score were there is no evidence based treatment guidelines for associated to H type and severity. In pts>50years these patients. Antiplatelet/anticoagulant therapy in similarly low FN-BMD was observed in HA and HB, hemophilia patients can be performed by appropriate while ABR and WFH score were associated to H type factor replacement if necessary. When considering and severity, being milder in HB. anticoagulant or antiplatelet therapy in patients with Conclusions. Low bone mass is a frequent comorbidity inherited bleeding disorders, age, bleeding phenotype, in haemophilic pts of all ages, apart from those with thrombotic risk factors of the patient, characteristics, moderate HB. Clinical and laboratory assessments intensity and duration© of the SIMTIPRO anticoagulant must be confirm a higher bone impairment Srl and faster bone evaluated. resorption in HA compared to HB. Looking at H type and severity, moderate HB seems to have a normal bone metabolism and a less severe disease.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s327 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

ABS09 - COVID-19 in patients with respectively. Twenty-three patients reported to have coagulopathies: an Italian survey had symptoms of influenza in the period from March Roberta Palla (1) - Marco Boscarino (2) - Roberta Gualtierotti (1) - Ida Martinelli (2) - Angiola Rocino (3) - to June 2020 and only two patients answered to have Flora Peyvandi (2) been positive for SARS-Cov-2 tests, one detected by Università degli Studi di Milano, Department of Pathophysiology nasal swab and one by serological test (IgG positive, but (1) and Transplantation, Milano - Fondazione IRCCS Ca’ Granda negative nasal swab). The former reported fever, cough, Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano (2) - Ospedale del Mare, ASL NA1 breathing fatigue, nausea, diarrhoea, anosmia and Centro, UOC di Ematologia-Centro Emofilia e Trombosi, Napoli (3) ageusia; the latter was accidentally found to be positive for IgG against SARS-Cov-2 following a serological Background. The severe acute respiratory syndrome test done for occupational health surveillance despite coronavirus 2 (SARS-CoV-2) is the cause of the ongoing asymptomatic. pandemic of coronavirus disease 2019 (COVID-19). Very Conclusions. In patients with coagulopathies, we few data are available on the epidemiology of COVID-19 observed a low rate of COVID-19 (1.7%), mainly in patients with coagulopathies. However, based on presenting as asymptomatic or mild course cases, the published case reports, patients with bleeding although one limitation of this survey is the lack of an disorders and COVID-19 seem to have mild symptoms, adequate laboratory screening in this population. One not different from those in most individuals without possible explanation of our findings may rely on the bleeding disorders. strict quarantine observed by these patients who were Our aim was to investigate whether COVID-19 affects probably more careful than the general population in patients with coagulopathies with the same extent as the avoiding contacts and traumas, due to their underlying general population and, in case of disease, whether the disease. related symptoms are similar. Methods. We designed a cross-sectional, national survey based upon an online questionnaire in Italian available on the cloud-based software SurveyMonkey. The link to the questionnaire was distributed between May 13th and June 16th, 2020 to 217 patients followed up at Angelo Bianchi Bonomi Hemophilia and Thrombosis Center of Milan and advertised on different websites (www.cetbianchibonomi.it, www.aiceonline.org, www. siset.org). Results. One hundred and sixteen patients (86 from the mailing list and 30 who accessed the questionnaire from the websites) filled the questionnaire. We collected data from patients with haemophilia A (n = 66), haemophilia B (n = 12), von Willebrand Disease (n = 6), rare coagulation disorders (n = 8), thrombotic thrombocytopenic© SIMTIPRO purpura (n = 21) and Srl other coagulopathies (protein S deficiency = 1, immune thrombocytopenia = 1 and Glanzmann thrombasthenia = 1). Roughly 60% of patients are treated prophylactically for their underlying disease; around 22% of patients are active smokers and 17% are former smokers. Obesity (calculated as BMI ≥ 30) was reported by 11% of patients. Cardiovascular diseases, venous thrombosis, diabetes, pulmonary diseases and oncological diseases were reported by 15%, 5%, 6%, 4% and 7% of patients,

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s328 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

asymptomatic siblings with PLGD that allows to 1.06 - EPIDEMIOLOGY, DATABASES AND REGISTRIES investigate triggers of initial symptom development. Conclusions. HISTORY is the first comprehensive retrospective/prospective international registry to ABS10 - Hypoplasminogenemia: an investigate the current knowledge gaps in PLGD. All International retroSpecTive and prOspective interested parties are strongly encouraged to participate cohoRt studY (HISTORY) (information at www.plgdeficiency.com). Marzia Menegatti (1) - Amy D. Shapiro (2) - Roberta Palla (1) - Marcela Torres (3) - Muhammed Batur (4) - Rungrote Natesirinilkul (5) - Simona Maria Siboni (1) - Christopher Roberson (2) - Joel Bowen (2) - Neelam Thukral (2) - Charles Nakar (2) - Flora Peyvandi (1) IRCCS Ca’ Granda Maggiore Hospital, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy (1) - Indiana, Hemophilia & Thrombosis Center, Indianapolis, IN, USA (2) - Cook Children’s, Hematology/Oncology, Fort Worth, TX, USA (3) - Van Yuzuncu Yil University, Ophthalmology Department, Van, Turkey (4) - Chiang Mai University, Department of Pediatrics, Chiang Mai, Thailand (5) ABS11 - Real-world analysis of prevalence, drug-utilization and healthcare direct costs of Background. Plasminogen deficiency (PLGD) is a rare, patients affected by hemofilia A life-long, multi-system disorder affecting ~1.6 per Margherita Andretta (1) - Alberto Tosetto (2) - Valentina million population and is characterized by uncontrolled Perrone (3) - Chiara Poggiani (1) - Elisa Giacomini (3) - Diego growth of fibrin-rich pseudomembranes on mucous Sangiorgi (3) - Luca Degli Esposti (3) (1) membranes. The most common manifestation is ligneous Azienda Zero, HTA Unit, Padova - Ospedale S. Bortolo, AULSS 8 Berica, UOS Centro Malattie Emorragiche e Trombotiche, Vicenza (2) - conjunctivitis which can result in vision impairment/ CliCon S.r.l. Health, Economics & Outcomes Research, Ravenna (3) loss; other affected systems may include oral cavity, respiratory tract, ears, female genitourinary tract, Background. Data collected from administrative kidneys and CNS. Patients have delayed/misdiagnosis databases may represent a useful tool to evidence-based and can suffer significant morbidity, reduction in quality clinical practice and health policy decisions. In this of life, and mortality. Current non-specific treatments context, the aim of the study was to evaluate hemofilia are inadequate. A (HA) prevalence and to analyse among HA patients Aims. HISTORY collects data on patients with PLGD the drug-utilization and direct healthcare costs by using and their first-degree family members; its goal is to administrative databases. comprehensively investigate PLGD natural history and Methods An observational retrospective study was develop severity categories and treatment guidelines. conducted by using administrative databases of one Methods. HISTORY expands upon the Prospective Rare Italian region, accounting approximately 4.9million Bleeding Disorders Database (PRO-RBDD). Probands health-assisted individuals. During a period from and family members will be enrolled in the 4-year 01/2010 to 06/2019, patients were included as observational study. Clinical, genetic, and laboratory “confirmed-HA” if they presented a HA diagnosis (ICD- data are collected at baseline (with a year lookback) with 9-CM: 286.0) or prescriptions for coagulation factor (F) additional data obtained© on at leastSIMTIPRO 6 scheduled follow- VIII (ATC B02BD02); as “potential-HA” Srl if they received up visits. Specimens are collected to support planned von Willebrand factor and FVIII in combination (ATC and future research. Markers that assist in disease code B02BD06 or concomitant presence of ATC codes course prediction, triggers of disease manifestations B02BD02 and B02BD10). Index date corresponded and utility of diagnostic assays will be evaluated. to the date patients met one of the inclusion criteria. Therapeutic interventions will be recorded along with Drug-utilization and costs analysis were performed on efficacy and safety observations. confirmed HA patients receiving FVIII during the last Results. To date, 26 centers in 12 countries have enrolled 2 years of study period (up-to-date cohort). Prophylaxis 51 subjects (Table). Initial results have identified and on-demand regimens were identified with FVIII

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s329 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

International Unit (IU) respectively higher and lower 1.07 - GENETICS OF CONGENITAL BLEEDING than defined thresholds set for specific age-groups. DISORDERS Results. Prevalence of HA was 71/1,000,000 health-assisted individuals: confirmed-HA prevalence 60.83/1,000,000, potential-HA prevalence 10.17/1,000,000. Overall, 387 ABS12 - Non-canonical F8 variants causing patients (mean age: 45.6±24.3) were included, 334 of which mild hemophilia A (1) (1) with confirmed-HA (mean age: 44.7±24.7). Considering Annalisa Matichecchia - Federica Riccardi - Antonio Coppola (1) - Gianna Franca Rivolta (1) - Gabriele the up-to-date cohort of confirmed-HA patients Quintavalle (1) - Lelia Valdrè (2) - Chiara Biasoli (3) - (N=168), 46.8% of them (mean age: 26.1±17.3) received Annarita Tagliaferri (1) prophylaxis, 53.2% (mean age: 40.7±22.3) on-demand. Haemophilia Centre, AOU, Parma (1) - Haemophilia Centre, AOU, (2) (3) In the last 6 months of study period, 86.3% of patients Bologna - Haemophilia Centre, AUSL, Cesena still received FVIII. Mean annual FVIII IU dispensed Background. Haemophilia A (HA) is caused by was 289,081.1 (prophylaxis) and 46,620.8 (on-demand). quantitative or qualitative deficiency of the coagulation Overall (prophylaxis and on-demand) IU consumption factor VIII (FVIII) due to variants in the F8 gene. lowered with increasing age, in line with a downward Different molecular techniques (e.g. Long distance PCR, trend of prophylaxis in older age-groups: proportion of Multiplex Ligation Probe Amplification, High Resolution patients in prophylaxis was up to 80% in young patients Melting) are useful to detect causative mutations in (<18 years) and less than 50% in those ≥18 years. No HA patients. In recent years, rapid progress in the consistent differences were observed comparing the IU massively parallel sequencing technology known as consumption range by age with the expected one. Mean next-generation sequencing (NGS) revolutionized the total annual healthcare cost was €99,477 (€185,047 for identification of variants (including those without clear patients in prophylaxis, €32,113 for those on-demand). pathologic meaning) in almost all studied subjects. Alongside with IU consumption results, costs were Inversions, missense, nonsense, frameshift and splice higher in patients ≤12 years (€50,2010) than ≥65 years site variants as well as large deletions can be considered (€16,476). Moreover, a greater consumption of most- the canonical causing mutations, detected in about 98% expensive therapy was observed in younger patients. of patients. However, there is increasing awareness that Conclusions. This study provided the most up-to-date other types of genetic variations (non-canonical) can be insights on HA in Italian real-world settings. Prevalence involved in the disease. was consistent with the expected one reported by AICE In this study, we focused on synonymous mutations (6.9/100,000), showing the usefulness of administrative occurring in the gene-coding regions, not affecting databases for HA identification. Moreover, using the protein sequence, deep intronic variations and such databases could allow to increase knowledge on nucleotidic changes in 3’-5’ Untranslated regions (UTRs) the pharmaco-utilization of HA patients and their detected in a cohort of mild HA patients from Emilia- healthcare direct costs, that could be helpful to inform Romagna hemophilia centers. health decision making. Methods. F8 gene was genotyped by NGS and confirmed with direct sequencing. Results. Among 198 screened HA patients, mutational © SIMTIPROanalysis revealed 34 patients (24Srl index cases) carrying 11 non-canonical variants: 3 different deep intronic variants, 2 variants in the promoter region, 1 variant in 5’UTR, 4 synonymous nucleotide changes, 1 3’UTR change. Table summarizes all variants and their effect. Conclusions. Our study supports the increasing literature evidence of the pathogenetic role of “non canonical” variants in F8 gene. All identified intronic

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s330 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT variants, a 3’UTR nucleotidic change and a synonymous assays on media and cell lysates, in which luciferase change in exon 11 are causative of alterations in the activity is related to the presence of full-length FVIII-GL splicing mechanism. Two variants in 5’ upstream arising from readthrough. region decrease promoter activity affecting the Results. F8 nonsense mutations were rationally selected binding efficiency of the transcription machinery on the basis of high (12 mutations; patient number n>10) factors. Finally, 3 synonymous SNPs in exon 2 seem or low (32 mutations; patient number n=1-5) frequency, to be benign; this type of variants could affect mRNA with the latter group including mutations predicted to stability as well as the efficiency of translation, correct have favorable features in terms of readthrough output folding and physiological activity of the FVIII protein. In (i.e. predicted re-insertion of the original residue). vitro studies could be useful to clarify the role of these Noticeably, the selected mutations (44 out of 216) were variants. reported in 384/611 (63%) HA patients. Foglio1 Expression of all chimeras bearing F8 nonsense variants

Gene Position nucleotide n.tot. index dbSNP ClinVar Reported in predicted effect In details bibliography patients cases EAHAD F8 db 5'upstream region c.-257T>G 16 8 not reported yes affects promoter decreases promoter activity to 40% Riccardi et al. (2009), Zimmermann (2012) revealed the synthesis of full-length FVIII-GL in cell 5'upstream region c.-219C>T 3 3 not reported yes affects promoter decreases promoter activity to 0,5% Bogdanova et al. 2007 ∼ 5'UTR c.-1C>T 1 1 rs1557287621 not reported no not known ∼ Exon 2 c.222G>A 2 2 / not reported no not known no effect on splicing. Other effects? Zimmenrmann (2013) Exon 2 c.222G>T 1 1 / not reported yes not known Exon 2 c.240C>T 2 2 no not known lysates, indicating the occurrence of intracellular Exon 11 c.1569G>T 3 2 Pathogenetic yes affects splicing potential new acceptor splice site 3'UTR c.*56G>C 2 1 / not reported no affects splicing create a new donor splice site Pezeshkopoor et al.2016* premature stop codon, 24 nucleotides after the end of IVS16 c.5587-93C>T 1 1 rs1264918703 not reported yes affects splicing exon 16 Castaman et al. 2011 nucleotide change appears to lead to inclusion of a readthrough. Strikingly, a clearly detectable luciferase IVS18 c.5999-277G>A 1 1 / not reported yes affects splicing cryptic exon Castaman et al. 2011 IVS10 c.1538-18G>A 2 2 rs1482306571 Likely pathogenetic yes affects splicing Deletion of 36bp at the beginning of exon 11 Santacroce et al. 2008 db: database; SNP: Single Nucleotide Polymorphism; bp: base pair activity in media (0.3-7% of wild-type FVIII-GL) * in the article is described a different nucleotidic change in the same 3'UTR position. provided the experimental evidence for the presence of ABS13 - An in vitro sensitive system unravels secreted full-length FVIII. The ratio between secreted traces of full-length factor VIII from the and intracellular luciferase activity, corresponding to majority of F8 nonsense mutations the efficiency of the readthrough process, showed a (1) (1) Maria Francesca Testa - Silvia Lombardi - Mattia significant correlation with luciferase activity in media, Ferrarese (1) - Paolo Radossi (2) - Donata Belvini (3) - thus highlighting the impact of the inserted amino acid Giancarlo Castaman (4) - Francesco Bernardi (1) - Mirko Pagina 1 Pinotti (1) - Alessio Branchini (1) on FVIII biosynthesis and secretion. Università degli Studi di Ferrara, Dipartimento di Scienze della Conclusions. Data from our in vitro expression platform Vita e Biotecnologie, Ferrara (1) - Castelfranco Veneto Hospital, indicate that the majority of F8 nonsense mutations, Oncohematology - Oncologic Institute of Veneto, Castelfranco Veneto (2) - Castelfranco Veneto Hospital, Transfusion Service, Haemophilia relatively frequent in HA, undergo readthrough and can Centre and Haematology, Castelfranco Veneto (3) - Careggi University be associated with residual FVIII protein levels that, Hospital, Center for Bleeding Disorders, Florence (4) although partially functional or dysfunctional, might have relevant pathophysiological implications. Background. Nonsense mutations caused by premature termination codons (PTCs) are frequently associated with the so-called “null” genetic conditions. As a result, this mutation type is predicted to produce truncated molecules with loss-of-function features. However, at a very low rate, a process named “ribosome readthrough”, which is driven by mis-recognition of PTCs and incorporation of an amino acid, may restore the synthesis of full-length proteins. The main aim of this© study is toSIMTIPRO evaluate, through a very Srl sensitive tool optimized in our expression platform, the synthesis of full-length factor VIII (FVIII) arising from readthrough over a wide panel of F8 nonsense mutations. Methods. Creation of a high-sensitivity fusion protein, consisting of FVIII and a naturally secreted luciferase (Gaussia, GL), bearing a wide panel of F8 nonsense mutations. Expression of wild-type (FVIII-GL) and PTC- containing chimeras in HEK293 cells and luciferase

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s331 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

1.08 - HEALTH AND SOCIAL ECONOMICS, However, we had all the baseline data obtained at the ORGANIZATIONAL ISSUES time of the check up and we evaluated again the patients after the quarantine, by means of HJHS, HEAD US, EQ- 5D-5L and baropodometric and static analysis. Comparing ABS14 - Telerehabilitation and “Zoomtherapy” the data before and at the end of the project, we found during SARS-CoV-2 no worsening despite the prolonged time spent at home (1) (1) Valentina Begnozzi - Elena Anna Boccalandro - Ida without access to rehabilitation and physical activity. Martinelli (1) - Flora Peyvandi (1) Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Conclusions. Due to the viral pandemic, we developed Bianchi Bonomi Hemophilia and Thrombosis Center, Milano (1) a tool that proved to be useful to deal with patients remotely and that may be re-proposed to train them Background. Hemophilia patients suffer from chronic in everyday normal life. It gave us the opportunity to arthropathy due to recurrent hemarthrosis. The remain in contact and to foster in them an adequate Hemophilia and Thrombosis Centre A. B. Bonomi offers health state. The tool led patients to focus more on to hemophilia patients a physiotherapy and osteopathy postural exercises. Furthermore, working in group service twice weekly, during the annual check-ups, motivated them to participate and to be more compliant. within a multidisciplinary team involving different Moreover, the availability of our direct feedback on the professionals (e.g. orthopedists, hematologists, performance of the exercises stimulated patients to rheumatologists, internists). A musculoskeletal improve and to perform safely and effectively during the evaluation is carried out using assessment scales such as sessions. In conclusion, this effort of telerehabilitation the Hemophilia Joint Health Score (HJHS), the EuroQol proved to be a useful tool for patients. 5D - 5Levels questionnaire (EQ-5D-5L / EQ-5D-Y for children (ref)), a stabilometric and baropodometric ABS15 - Management satisfaction and unmet examination, postural analysis and ultrasound (HEAD- need in haemophilia: an Italian survey US). The current health emergency due to the spread in Paolo Angelo Cortesi (1) - Angiola Rocino (2) - Antonio Italy and globally of the SARS-CoV-2 virus and related Coppola (3) - Daniele Preti (4) - Anna Fragomeno (4) - COVID-19 enforced the temporary stop of outpatient Francesco Cucuzza (4) - Nicola Ceresi (4) - Arianna Fornari (1) - Rita (1) (5) (6) activities at the Milan Hemophilia and Thrombosis Facchetti - Chiara Biasoli - Paolo Cozzolino - Cristina Cassone (4) - Lorenzo Giovanni Mantovani (1) Centre, with the only exception for urgent or priority University Milano-Bicocca, CESP, Monza (1) - Ospedale del Mare-ASL cases. Due to this situation, we transferred the service to NA1, EC, Napoli (2) - University Hospital of Parma, EC, Parma (3) - FedEmo, an online mode that allowed us to continue to get in touch Roma (4) - Hospital of Cesena, EC, Cesena (5) - IRCCS Multimedica, Sesto San Giovanni (6) with patients through live lessons based upon guided and controlled exercise sessions, with the ultimate goal Background. In past decades, haemophilia of an adequate health state and quality of life. management and patients’ quality of life in Italy Methods. We organized one session per week, lasting improved mainly due to extensive use of prophylaxis 45 minutes, every week for 3 months on the “Zoom” app. and development of specialized haemophilia centers. In each class, there were 4 different therapists: one led However, data on current limitations of prophylaxis and the exercises, the others controlled patients in order to haemophilia management are needed to assess impact stimulate them ©to improve. SIMTIPROEvery session started with of new treatment approaches. Srl This study assessed the a slow warm up, whereas the central part changed management satisfaction and unmet needs from the every week, in order to meet different needs. We always perspective of patients with severe haemophilia without ended the lessons with proprioception and a whole body inhibitors and specialist physicians. stretching to cool down. We selected 20 patients who Methods. Online surveys (for patients≥18 years and for were already doing idrokinetherapy, age 18+, who had caregivers of children <18 years) were developed by a no neurological complication. multidisciplinary working group and conducted from Results. Due to physical distance and quarantine, we November 2019 with the support of Italian Federation were not able to evaluate our patients in presence. of Haemophilia Associations. The surveys collected data

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s332 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT about demographic, clinical characteristics, disease’ that should define this professional figure by analyzing management, treatment satisfaction, quality of life, the opinion of physicians, nurses, patients, caregivers. working and daily life, barriers to treatment and sources Methods. We created a questionnaire to analyse the of information. importance of the skills defined by EAHAD (Harrington et Results. As of May 2020, 208 subjects (119 adults/89 al., Haemophilia 2016), and we administered it to several caregivers) and 35 physicians completed the survey. figures of our MEC center: physicians (4), CM (1), nurses Severe haemophilia A (SHA) was reported in 57.2% and B (2), patients (10), caregivers (4), specialist consultants of (SHB) in 12% of cases. In the six months preceding survey the center (5: pediatrician, gynecologist, orthopedist, enrolment, diseases control for the majority of time was physiatrist, physiotherapist), pharmacists (4). It was reported by more than 90% of patients and 75.8% of composed by 20 questions, 17 of which asked to assign a score physicians. (Table 1) However, 49.0% (58.5% adult/37.2% (1-5) about the importance of each skill. To better analyse the children) with SHA and 28.0% (33.3% adult/23.1% results, we divide EAHAD skills into 3 categories: clinical children) with SHB reported bleeding events. Treatment (knowledge of diagnoses and treatments, patient and family adherence ≥90% of prescribed infusions were reported education, support on home prophylaxis, management of by 88.8% (87.5% adults/90,2% children) of SHA, 90.9% electronic medical record, multidisciplinar collaboration, (88.9% adults/92.3% children) of SHB and 32.4% of management of clinical trials), organizative (coordination physicians. Treatment burden (number of infusions) was of assistance from the first access to the center, regulation considered acceptable for only 37.4% (45.0% adults/28.6% of activity flow, organization of the follow-up agenda, children) of SHA, 70.8% (72.8% adults/69.3% children) of management of the relationships with general practitioners, SHB and 39.4% of physicians. cooperation with the associations) and managerial (control of drug supplies, communication with local pharmacies, Table 1. Survey results of severe haemophilia A and B patients without inhibitors and specialist physicians

Haemophilia A Haemophilia B monitoring of the pharmaceutical expenditure). Specialist Parameters Children Children physicians Adults Total Adults Total (caregivers) (caregivers) Results. We found that our physicians gave the highest

Age mean (sd) 45.2 (14.5) 27.4 (23.4) 30.2 (20.3) 9.1 (6.6) 11.7 (6.2) 47.2 (17.9) N.A.

Diseases control – N (%) Most of the time/Always 50 (96.1) 23 (92.0) 90 (94.7) 12 (92.4) 40 (93.0) 11 (91.6) 25 (75.8) score (5) to some of the clinical skills (the education, Patients with at least one bleed in the last 6 months – N (%) 31 (58.5) 16 (37.2) 47 (49.0) 4 (33.3) 3 (23.1) 7 (28.0) N.A. the support on prophylaxis); they assigned a score of N° of bleeding in the last 6 Total - mean (SD) 3.4 (5.8) 1 (2.2) 2.6 (4.9) 0.8 (1.6) 1.5 (3.2) 1.2 (2.9) N.A. months Treated - mean (SD) 2.1 (4.2) 0.8 (2.2) 1.7 (3.5) 0.5 (1.5) 1.1 (2.3) 1.1 (2.9) N.A. Efficacy to prevent or treat Satisfy/Very satisfy 45 (86.5) 22 (91.7) 84 (89.4) 11 (84.6) 39 (92.9) 11 (100.0) 31 (91.2) 3-4 to organizative and managerial skills (particularly bleeding – N (%) Number of infusions – N (%) Satisfy/Very satisfy 22 (45.0) 17 (70.8) 34 (37.4) 9 (69.3) 12 (28.6) 8 (72.8) 13 (39.4) Treatment adherence More than 90% 42 (87.5) 37 (90.2) 79 (88.8) 8 (88.9) 12 (92.3) 20 (90.9) 11 (32.4) to the organization of the follow-up, to the control of

EQ-5D VAS Mean (SD) 74.2 (17.3) 79.2 (15.4) 78.9 (16.1) 83.2 (14.5) 84.9 (11.9) 75.2 (15.8) N.A. Days of work/school loss in None 11 (24.4) 13 (61.9) 25 (32.5) 5 (50.0) 14 (43.8) 8 (72.7) 7 (21.2) drug supplies and to the communication with local the last 6 months – N (%)

pharmacies). Our patients and caregivers stressed the needs of adequate information about the disease, of This large nationalstudy provides an updated Conclusions. the support on prophylaxis and to have a link with the overview of haemophilia condition, highlighting unmet associations (score 5) but also gave importance to the needs from different point of views. This information can management of the agenda and to the communication guide future interventions to manage haemophilia and with the pharmacies (score 4). Nurses underlined the the impact assessment of new treatment options. importance of the regulation of activity flow, of the management of follow-up, of drug stocks monitoring ABS16 - Case manager: a link figure in (score 5). Our consultants gave the highest score to Haemophilia Center the ability of multidisciplinar collaboration, even in Anna Chiara Ferrini ©(1) - Paola Pedrazzi SIMTIPRO (1) - Marilena Lessi (1) - Srl terms of communication between the several figures. Tiziano Martini (1) - Chiara Biasoli (1) “Bufalini” Hospital, Haemophilia and Transfusion Centre, Cesena (1) Pharmacysts stressed the need of communication with local pharmacies to improve the access to drugs (score 5). Background. The professional figure of the Case Manager Conclusions. Our work shows that CM plays a central role Nurse (CM) in haemophilia care is still difficult to define in haemophilia center; we demonstrated that the several in a exhaustive way, given its recent introduction and figures involved in haemophilia care have confirmed the the presence of few experimental studies in the areas in importance of the skills described by EAHAD. We used which it is operating. Our study aims to describe the skills these skills as the backbone of the joblist of our CM.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s333 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

ABS17 - Emergency care pathway in diagnosis helps the physicians: it’s a bright colour card haemophilia: the model of Cesena Congenital immediately visible among the personal effects of the Bleeding Disorders Center Tiziano Martini (1) - Paola Pedrazzi (1) - Anna Chiara patient; CBD physician, alerted immediately after the Ferrini (1) - Chiara Biasoli (1) identification, establishes the most appropriate hospital “Bufalini” Hospital, Haemophilia and Transfusion Centre, Cesena (1) for the characteristics of the event and the need of RT, and dosage, time and modality of infusion of the Haemophilia and other congenital Background. clotting factor (that can be found with the same modality bleeding disorders (CBD) are characterized by described for scenario 1). hemorrhagic episodes (spontaneous or trauma-related) Conclusions. The model of emergency pathway we that sometimes can occur frequently, and that must be apply in our center allows us to correctly manage a early recognized and treated. Cesena CBD center (1 of the hemorrhagic event ensuring a rapid identification of a 3 spoke centers of Emilia-Romagna) has a care pathway CBD patient (even in the situations of unconsciousness) about emergency in haemophilia that allows us to ensure followed by an immediate alert of a CBD physician, to to the patient, within 30 mins from its activation, the adequately address the patient to the most appropriate administration of replacement therapy (RT). clinical structure and, mostly, to obtain the clotting Our CBD center physicians involved the Methods. factor within 30 mins from the alert. Our experience colleagues belonging to the Emergency Department suggests that this care pathway, realized thanks to (ED), First Aid Department (FAD) and Pharmacy in the the cooperation with the colleagues of Emergency creation of a multidisciplinar working group to define an Department, First Aid Department and Pharmacy, can integrated care pathway about emergency for CBD. be an excellence model that could be exported into other We identified 2 main scenarios to describe the Results. CBD realities. real life conditions of emergency: in the first one, the patient goes independently to emergency room (ER); in the second one, the patient is rescued by ambulance. In the scenario 1 the identification of the patient can easily made (also with the help of caregivers and the web identity for patients from Emilia-Romagna or EmoWeb for other regions’ patients); the triagist must give a moderate/high priority; the CBD physician, who’s always available at a specific phone number (24 hours/day every day), should be alerted immediately to establish dosage, time and modality of infusion of the clotting factor that can already be available (if brought by the patient) or can be found in each of the transfusion centers of Romagna or (out of their working time) in the corresponding hospital pharmacy (available 24 hours/ day every day): it’s available, for each of these points, an equipment of 1 recombinant© SIMTIPROVIII factor, 1 recombinant Srl IX factor and 1 bypassing agent; if there’s a need of therapy ≥ 8 hours, we ensure the access to the central storage of AUSL Romagna (24 hours/day every day). The colleagues of the ER, following the prescription of CBD physician, activate the request of the drug following a well described procedure that allows to begin the infusion within 30 mins from the alert. In the second scenario, if the patient is unconscious (and a caregiver is not present), an alert ticket given by the center at

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s334 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

used to engage patients but seem not used to relate to 1.09 - HEMOPHILIA, CLINICAL ISSUES nurses to better understand patients’ perspective (item mean score = 2,72 on a scale from 1 to 5). Regarding the ad hoc items, rated on a Likert scale from 1 to 7, some ABS18 - Words in hemophilia: a project for a misalignments have been highlighted. Particularly, better patient engagement patients considered hemophilia partially limiting Serena Barello (1) - Caterina Bosio (1) - Chiara Biasoli (2) - Andrea Buzzi (3) - Cristina Cassone (4) - Elena Guida (1) - their daily lives (mean=4,55), while hematologists Guendalina Graffigna (1) underestimate the patients’ perceived impact of the EngageMinds HUB -Università Cattolica del Sacro Cuore, Milano (1) AICE, disease (mean=3,56). Drugs are considered as life- (2) (3) (4) Cesena - Fondazione Paracelso, -, Milano - FedEmo, Taranto saving from patients (mean= 6,79), but this perspective is underestimated from hematologists (mean=5,94). Background. Greater patient adherence and health Patients barely think to abandon their therapies (mean= engagement are crucial in prophylactic therapies 1,45), while hematologists overestimate this intention in hemophilia. An improved patient-hematologist (mean= 2,61). relationship leverages this objective. The aims of this Conclusions. These preliminary findings of an ongoing project are to: A) investigate the level of engagement project support the importance of improving medical of patient and hematologist; B) investigate differences communication to increase engagement for an effective between the patient’s and hematologist’s experience of management of prophylactic therapy in hemophilia. care and therapeutic relationship. Data also support the opportunity of educational Methods. The research adopts a mixed method design. intervention to align communication approach of the A cross-sectional online survey is conducted in parallel hematologist with patient’s expectations. on a sample of patients and hematologist in order to compare perspectives. Data collection on patients and hematologist is based on a self-report questionnaire ABS19 - Efficacy of replacement (patient questionnaire: PHE-S®, HCCQ; hematologist and antiplatelet therapies in a patient with severe haemophilia A undergoing questionnaire: UWES, SMS). In both questionnaires ad coronary stenting hoc items about care and therapeutic relation experience Dorina Cultrera (1) - Sergio Cabibbo (2) - Anna Bulla (3) - are included and make the two questionnaires Antonino Cipolla (1) comparable. Participants are recruited by their reference UOC Ematologia - Centro Regionale di Riferimento per Emofilia, Az. Osp. - Univ. Policlinico, Catania (1) - UOSD Ematologia, ASP, Association. Quantitative data of both questionnaires Ragusa (2) - UOC Ematologia, Az. Osp. - Univ. Policlinico, Catania (3) are analyzed with SPSS software. The study is supported by Kedrion with an unrestricted research grant. Background. Severe Haemophilia A (HA) 58 years Results. Up to date, 33 questionnaires from patients and old patient, without inhibitors, with HCV and HIV 22 from hematologist have been fully completed. 82% of seroconversion, undergoing plasma derived replacement the patients’ sample are male, 38% have children, 92% therapy and then rFVIII (octocog-alfa). The patient are affected by Hemophilia A. Therapies are prophylaxis moved to our Centre in Catania in 2016. for the 77% and only 67% refers a general good health Case Report. The infectious pathology was treated condition. Preliminary results show that 21% of with Dolutegravir and Darunavir, with negativization the patients’ sample© refers lowSIMTIPRO level of engagement of viral load and good compensation Srl of liver function (Blackout or Alert of the PHE-S®). Concerning the indices. Despite replacement therapy given every patient-hematologist relationship, trust and perceived other day with 3,000 IU of rFVIII, the patient kept acceptance are reported as positive elements (items mean showing recurrent hemarthroses, mainly in knees, scores > 6, on a scale from 1 to 7), but the shared decision elbows and ankles and a poor control of bleeding events making about therapies is more critical (item mean scores (approximately ABR=15). In April 2017 an inferior acute <5). Hematologists’ work engagement is high (means myocardial infarction (AMI) occurred and a coronary score= 5 on a 1 to 6 scale). Regarding hematologists’ angiography was performed with implant of a metallic behavior to improve patients’ engagement, they are stent, followed by a double antiplatelet therapy with

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s335 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

acetylsalycilic acid and Clopidogrel. However, despite ABS20 - The impact of dental care in mild of the replacement treatment with rFVIII, an increase in haemophilia: should we do more? Simona Raso (1) - Mariasanta Napolitano (2) - Maria hemorrhagic manifestations occurred and, on the other Francesca Mansueto (2) - Davide Sirocchi (2) - Giuseppe hand, suspension of the cardiologic therapy would have Agliastro (2) - Sergio Siragusa (2) - Cedric Hermans (4) led to e new ischemic episode. So we decided to switch University of Palermo, Dep. of Surg. Oncol. Stomatol. Disciplines, (1) the patient’s therapy to Simoctocog alfa (Nuwiq®), a Palermo, Italy - University of Palermo, Unit of Haematology PROMISE Department, Palermo, Italy (2) - Saint-Luc University fourth generation Factor VIII, thinking that this drug Hospital, Haemostasis and Thrombosis Unit, Division of could be more effective in preventing bleeds and, as Haematology, Brussels, Belgium (3) manufactured in human embryonic kidney cell lines, also less immunogenic.1 From September 2017 the Background. The bleeding phenotype of mild patient started with Nuwiq®, 3,000 I.U. every other haemophilia (MH) A (HA) or B (HB) is mainly day. Despite hemarthroses, related to the concomitant characterized by haemorrhages secondary to surgery/ antiplatelet treatment, the dosage was reduced to 3,000 invasive procedure or trauma. Minor oral surgery or I.U. three times a week, in order to avoid the occlusion dental extractions can represent a frequent haemostatic of the stent and a pharmacokinetic test was performed, challenge in MH requiring tranexamic acid (TA), which showed 3% of activity level at 96 hours from the desmopressin (DDAVP) or replacement therapy. Some last infusion. The patient remained in good clinical of these measures are costly and can result in inhibitor condition until April 2020, when he was hospitalized formation in predisposed patients (PTs). Purpose of the for an episode of rabdomyolysis, probably related to the study is to evaluate the impact of dental care (DC) on the antiretroviral drugs. During hospitalization the patient burden of treatment in MHP. continued the therapy, no bleeding episodes were Methods. We retrospectively evaluated adult PTs with reported, cardiac function remained stable, although mild HA or HB regularly examined at the Haemophilia ventricular ejection fraction was approximately 30%. Treatment Centre (HTC) of the Saint-Luc University Concomitant replacement and cardiological therapies Hospital, Brussels (Belgium) and of Paolo Giaccone allowed to obtain a good hemodynamic balance and Hospital, Palermo (Italy). Data of PTs were retrieved a clear reduction of bleeding episodes (about 1 every 3 from clinical records backwards to 24 months before the months). last follow-up. The following information was collected: Conclusions. Replacement therapy and an apparently age, basal level of deficient clotting factor, numbers contraindicated treatment can be effectively admistered of dental procedures during the study period and in a patient with severe HA that underwent coronary treatment received. angioplasty with implant of metallic stent. Nuwiq® Results. The population consisted of MHP with a mean was well tolerated, effective in preventing bleeds and age of 39 years (range 18-81). Of the 106 MHP evaluated, characterized by a satisfactory pharmacokinetic profile. 95 had HA and 11 HB. The mean level of coagulation factor There was a reduction of about 20% in drug consumption was 0.18 IU/mL (range 0.05-0.28 IU/mL) for HA and 0.19 compared to previous therapy and, at the same time, a IU/mL (0.07-0.29 IU/mL) for HB. All PTs were treated on- reduction also of the ABR (5 vs 15). demand except 1 who was episodically on prophylaxis References during sport activities and 1 who has been never treated. 1. Lissitchkov et al.© Haemophilia 2017;SIMTIPRO 23: 697-704. The majority of patients (81/106, Srl 76%) needed at least one treatment within the study period and 46% (38/81) of them received haemostatic therapy for DC. Total dental procedures were 42: 22 single and 3 multiple dental extraction respectively, 7 teeth cleaning, 7 dental caries, 1 dental implant placement and 2 abscess incisions. The great majority of oral interventions (67%), including non- surgical procedures, was managed with clotting factor concentrates. Five PTs at HCT of the Saint-Luc hospital

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s336 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT were treated with DDAVP while only one in Palermo Results. Overall 44 ICH were found in 3077 received DDAVP as single agent. Systemic therapy with haemophiliacs treated at the different participating only oral TA was used in 5 PTs whereas 4 PTs did not Centres. ICH occurred in 10/15 children ≤ 2 yrs, none of receive any haemostatic therapy. All treatments were them were on prophylaxis at the time of bleeding; one given preventively before dental procedures; only 2 PTs ICH occurred in a child during ITI. The annualized rate received TA and r-FVIII respectively for a postoperative of ICHs for the whole cohort over the entire follow-up bleeding. period was 0.36 events per 1000 patients (95% CI: 0.27 – Conclusions. In our study, DC is a frequent reason for 0.48), significantly lower than that obtained from in the haemostatic treatment in MH, mainly with clotting factor previous study (Zanon et al, Haemophilia 2012) where the concentrates, even in non-surgical procedures. DDAVP annualized rate of ICHs on the entire cohort analyzed in was used sporadically even if it is considered a valid the period 1987-2008 was 2.50 events per 1000 patients option for management of minor surgery (such as dental (95% CI 1.90–3.31). Similar rates have been obtained in extractions) in mild HA. Moreover, few data are available case of patients with severe haemophilia, in which in the in literature for management of non-surgical dental most recent cohort the incidence of ICH was 0.56 events procedures in mild haemophilia hence treatment results per 1000 patients against 3.40 reported in the previous heterogeneous and potentially conditioned by experiences cohort. ICH occurred in 29 adults, 44.8% with mild of treating physician from the HTC. Prospective studies haemophilia. Overall patients with severe haemophilia are needed to investigate the appropriate haemostatic were 61.4%; 100.0% (15/15) of children. Only 7/44 patients therapy for DC and to avoid unnecessary treatments. received a prophylactic regimen before ICH. Inhibitors were present in 13.6% of patients. In adult PWHs 15/29 ABS21 - Incidence, management and outcomes suffered from hypertension, 84.6% were mild subjects of intracranial haemorrhage in haemophilia and 25.0% were moderate to severe (p< 0.05). ICH patients: a 10-year Italian study - The final was spontaneous in the 69.8%. Surgery was required results of the EMO.REC Registry in 19/44 patients for cerebral hematoma evacuation. Ezio Zanon (1) - Samantha Pasca (1) - Francesco Demartis (2) - Annarita Tagliaferri (3) - Cristina Santoro (4) - Isabella Patients treated with FVIII/FIX concentrates or rFVIIa Cantori (5) - Angelo Claudio Molinari (6) - Chiara Biasoli (7) - for at least three weeks were 76.7%. Subjects who died Antonio Coppola (3) - Matteo Luciani (8) - Rita Carlotta before starting or during treatment were 31.8%. Of the Santoro (9) - Berardino Pollio (10) - Alessandra Borchiellini (11) - survivors 43.3% became permanently disabled. Only (12) Elena Santagostino one-third of patients continued the prophylaxis after the University Hospital, Hemophilia Center, Padova (1) - University Hospital, Hematology, Firenze (2) - University Hospital, Hemophilia acute treatment. Center, Parma (3) - Umberto I Hospital, Hematology, Roma (4) - Conclusions. The final results obtained by our Registry (5) Hospital, Transfusion Medicine, Macerata - Gaslini Hospital, show that the incidence of ICH in PWH in the last 10 Hemophilia Center, Genova (6) - Hospital, Transfusion Medicine, Cesena (7) - Bambin Gesù Hospital, Pediatrics, Roma (8) - Hospital, years has decreased compared to the previous 20 years Hemophilia Center, Reggio Calabria (9) - Regina Margherita probably due to the positive role of prophylaxis. Most (10) Hospital, Hematology, Torino - Molinette Hospital, Hematology, ICH occurred in patients treated on demand aged <2 Torino (11) - University Hospital, Hemophilia Center, Milano (12) years and> 50. A high number of cases has also been Background. Intracranial hemorrhage (ICH) is the reported in mild adult patients with comorbidities. most serious event© in patients withSIMTIPRO hemophilia (PWH) Srl which leads to disability and in some cases to death. Aim of our Registry was to evaluate incidence, mortality, management, the risk factors and the outcomes for ICH in a population of PWH. Methods. All ICH in PWH were retrospectively and prospectively collected at 13 Italian Haemophilia Centres. Clinical features of PWH, data of ICH management and outcomes were evaluated from 2009 to 2018.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s337 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

2.02 - INHIBITORS

ABS22 - Prediction markers for development of persistent inhibitors in previously untreated patients with severe hemophilia A Syna Miri (1) - Paolo Bucciarelli (2) - Carla Valsecchi (2) - Lucia Schiavone (2) - Marco Boscarino (2) - Roberta Palla (3) - Pier Mannuccio Mannucci (3) - Frits Rosendaal (4) - Flora Peyvandi (3) Università degli Studi di Milano, Department of Biomedical Sciences for Health, Milan (1) - Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan (2) - Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan (3) - Leiden University Medical Center, Department of Clinical Epidemiology, Leiden (4)

Background. Neutralizing antibodies (inhibitors) Conclusions. Within 60 days from inhibitor formation, are the main complication of replacement therapy in the presence of more than one anti-FVIII IgG subclass hemophilia A. Some of these inhibitors disappear shortly was associated with an increased risk of inhibitor after development (transient), while others remain persistence. Over 6 months, IgG2 was the only IgG (persistent), through a mechanism still unknown. This subclass that could be considered as an early hallmark of study aimed to investigate the predictive value of anti- inhibitor persistence. FVIII IgG subclasses (IgG1, IgG2, IgG3, IgG4) within 6 months from inhibitor development on inhibitor persistence in previously untreated patients (PUPs) with severe hemophilia A. Methods. Initially, we analyzed 43 PUPs from the SIPPET study who developed inhibitors (31 persistent, 12 transient), using samples taken within the first 60 days from inhibitor development. Subsequently, from the 43 PUPs we studied 14 (9 persistent, 5 transient) at 5 time points over a period of 6 months post inhibitor development: T0: at inhibitor detection, T1: 1-30 days after, T2: 31-60 days, T3: 61-120 days, T4: 121-180 days. Anti-FVIII IgG subclasses were measured by ELISA as reported previously (Cannavò et al. Blood, 2017) with minor modifications. Logistic regression was applied to assess the association of number of IgG subclasses with inhibitor persistence.© SIMTIPRO Srl Results. Relative Risks (RR 95% CI) within 60 days are shown in Table 1A. The analysis of IgG subclass profiles over 6 months showed a predominant presence of IgG1 and IgG4 in all inhibitor patients, regardless of transience/persistence. IgG3 antibodies were present in the early response and progressively reduced in both groups. IgG2 was the only subclass that showed a clear difference; disappeared in the transient group and increased in the persistent (Table 1B).

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s338 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

levels. To perform specific rpFVIII reference curves, 2.03 - LABORATORY ISSUES the value 100% is attributed to the calibrator whatever reagent is used. For aPTT-SS reagent 100% porcine calibrator potency is uncorrect (about 3 times higher). ABS23 - Obizur and FVIII activity levels The overestimation of rpFVIII levels generates issues in monitoring: which reagent in one stage assay? the establishment of further rpFVIII dose and in rpFVIII (1) (1) Enrico Dosio - Alessandra Valpreda - Cristina inhibitor titration with the Nijmegen modified Bethesda Dainese (1) - Federica Valeri (1) - Jacopo Agnelli Giacchello (1) - assay (where Obizur should be used as a source of normal Alessandra Borchiellini (1) University Hospital City of Health and Science, Regional center FVIII, data not shown). Hemorrhagic and Thrombotic Diseases, Hematology Unit, Turin (1)

Background. Obizur®, recombinant B domain deleted FVIII porcine sequence (rpFVIII), is a new hemostatic therapy for acquired hemophilia. Subsequent doses are established based on clinical response and in vivo FVIII levels. One stage assay (OSA) is recommended as chromogenic assay (CSA) strongly underestimates rpFVIII. A field study showed minimal difference between aPTT reagents (ellagic acid and silica) in OSA. However, studies are mostly conducted on samples spiked with rpFVIII and do not distinguish among OSA reagents. Here we investigated the differences in ABS24 - Recombinant FVIII in pharmacokinetic rpFVIII concentration, in vivo activity levels and in anti studies: a comparison among assays rpFVIII inhibitor titration. Enrico Dosio (1) - Alessandra Valpreda (1) - Federica Methods. Coagulometer: ACLTOP 500 (IL Werfen Valeri (1) - Jacopo Agnelli Giacchello (1) - Cristina Dainese (1) - (1) Company) – aPTT reagents (IL Werfen Company): silica Alessandra Borchiellini University Hospital City of Health and Science, Regional center reagent HemosIL SynthASil (aPTT-SS), ellagic acid Hemorrhagic and Thrombotic Diseases, Hematology Unit, Turin (1) reagent HemosIL SynthAFax (aPTT-SFX) and HemosIL aPTT-SP. On a human FVIII reference curve we dosed Background. Personalized Factor VIII (FVIII) rpFVIII level of Obizur diluted in FVIII deficient plasma prophylaxis is the best treatment for Hemophilia A. at a 1U/ml concentration and of patient plasma collected Recombinant FVIII (rFVIII) therapy with modified post Obizur infusion. rpFVIII was also tested on porcine molecules is a challenge for laboratories. Literature FVIII reference curve. reports discrepancies between rFVIII levels detected Results. Obizur 1U/ml (corresponding to 100% FVIII), with one stage clotting assay (OSA) with different dosed in different analytical sessions on reference reagents and chromogenic substate assay (CSA), with a curves with human FVIII calibrator, was higher than the high risk of over/underestimating FVIII levels. Here we assigned potency (>300% instead of 100%) with aPTT- report pharmacokinetic (PK) data from personalized SS reagent, close to© 100% with SIMTIPRO the other 2 (Tab 1). On prophylaxis with different rFVIII. Srl reference curves with rpFVIII calibrator no differences Methods. From 2017 to 2019 we performed 41 PK studies appeared between the 3 reagents. Similarly, the rpFVIII with 10 different rFVIII, chosen on product and patient activity levels in vivo, on the first treatment day, was characteristics. For each PK point, factor levels were higher when dosed with aPTT-SS compared to aPTT- measured on two replicates with coagulometer ACL TOP SFX reagent; the differences gradually decreased from 500 (IL Werfn Company) using: (A) OSA with HemosIL the last Obizur dose. SynthASil, (B) OSA with HemoSIL SynthAFax, (C) CSA Conclusions. aPTT-SS is used in many laboratories with COMATIC Factor VIII (all IL Werfen Company that perform OSA, however our results indicate that reagents). The average of the replicates was used to it strongly overestimates Obizur potency and rpFVIII compare data.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s339 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

Results. Coefficient Variability (CV%) between replicates ABS25 - Role of D-Dimer and physiological was good (<5% for FVIII levels above 10%). For 7 rFVIII coagulation inhibitors testing as markers of coagulation after administration of PK number of treated patients was insufficient to allow concentrate factor any comparison. Thus we analyzed data of 21 PK studies: Giovanna Maria Nicolò (1) - Gianluca Sottilotta (2) - 10 Fc Fusion protein rFVIII (Elocta®), 6 full length Francesca Luise (2) - Diego Chilà (1) - Bruno Modafferi (3) - (2) (2) rFVIII (Kovaltry®) and 5 single chain rFVIII (Afstyla®). Vincenzo Oriana - Angela Piromalli Università Catania, Patologia Clinica e Biochimica Clinica, Catania The variability in FVIII levels detected with A, B and C (1) - Centro Emofilia-Servizio di Emostasi e Trombosi, GOM, Reggio assays was acceptable for Elocta and Kovaltry while for Calabria (2) - Laboratorio Analisi, GOM, Reggio Calabria (3) Afstyla the differences between OSA and CSA results were evident (Figure 1). Afystla OSA PK curves showed Background. The evaluation of blood coagulation an underestimation in comparison with CSA especially parameters after factor concentrate infusion is an aspect at the peak. The difference remains relevant after 9 of medical management in patients with Haemophilia hours and almost undetectable after 24 hours. Results (PWHs).The aim of this study was to assess the effect of obtained with A and B assays are comparable. The curve administration of recombinant factor VIII(FVIII) and obtained by doubling the average values of both OSA factor XIII(FXIII) concentrates, especially if they might results, as recommended by the Company, showed an induce a prothrombotic state by increasing the level of overestimation for each point. D-Dimer and other coagulation factors or by decreasing the level of physiological coagulation inhibitors. Methods. In our department, we evaluated 5 male patients (from 25 to 75 years old, mean age 39.4): 4 patients with severe Haemophilia A and 1 patient with moderate FXIII deficiency. All of them received a prophylactic treatment with concentrates of coagulation factor according to their initial diagnosis. All the patients, except one, were young and without other significant comorbidities. Three patients with severe Hemophilia A presented knee arthropathy, one of them with associated ankle arthropathy. One patient with severe Hemophilia A was treated with a knee prosthesis. The patient with XIII deficiency, with a history of recurrent brain hemorrhage, presented atrial fibrillation Conclusions. No significant differences in Elocta and under preventive treatment with enoxaparin 4000 UI Kovaltry levels measured with OSA and CSA were found, per day. All the patients were evaluated after a switch as previously reported. For Afstyla the choice method to another treatment. All testing was carried out after is CSA, since OSA underestimates single chain rFVIII a 4-day wash-out in patients with severe Haemophilia A activity. In our experience, the suggested correction and after a 4-week wash-out in the patient with FXIII factor is not suitable for in vivo recovery, especially close deficiency. They underwent D-Dimer, protein C, protein to the trough level, with risk of prophylaxis failure. A S, antithrombin, and the V, VII, VIII, von Willebrand, IX, modified correction© factor isSIMTIPRO under investigation. Srl X, XI, XII, XIII coagulation factors testing. Lonoctocog alfa concentrate was used in two cases, as well, Octocog alfa was administrated two patients. In the FXIII deficiency case Catridecacog was used. Result. We do not report any alterations of coagulation after administration of different replacement clotting factors or any changes in the hemostatic balance; specifically, we do not report an increased level of

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s340 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

D-Dimer or a decreased level of physiological coagulation inhibitors, moreover no abnormal increase of 2.04 - NOVEL THERAPEUTIC AGENTS coagulation factors was evidenced. The levels of the FVIII and FXIII, in terms of trough-level, also showed results corresponding to those expected. Patients underwent ABS26 - A next-generation rFVIIa fusion protein prophylactic therapy for a period ranging from 11 to with enhanced half-life as a novel by-passing tool in hemophilia 35 months, demonstrating good compliance with the Alessio Branchini (1) - Mattia Ferrarese (1) - Jeannette prescribed therapy. No spontaneous hemorrhagic Nilsen (2) - Malin Bern (2) - Robert Davidson (3) - Rodney events occurred, except in one case of severe hemophilia Camire (3) - Derry Roopenian (4) - Inger Sandlie (2) - Silvia A where we report an elbow hemarthrosis after intense Lombardi (1) - Jan Terje Andersen (2) - Mirko Pinotti (1) sports activity, in a patient who had not complied with University of Ferrara, Department of Life Sciences and Biotechnology, Ferrara (1) - University of Oslo, Centre for Immune Regulation (CIR) the normal prophylaxis protocol. and Department of Immunology, Oslo (2) - Children’s Hospital of Conclusion. Our study showed that the administration Philadelphia, Research Institute, Philadelphia (3) - The Jackson (4) of FVIII and rFXIII concentrate, in addition to being Laboratory, The Jackson Laboratory, Bar Harbor effective in preventing bleeding, does not modify Background. Recombinant activated factor VII (rFVIIa) clotting parameters in a prothrombotic state. Broader has represented an enormous therapeutic advancement, studies, which include PWHs with comorbidities, may particularly for hemophilia A (HA) and B (HB) patients confirm the usefulness of D-Dimers and physiological with inhibitors. However, rFVIIa short half-life still coagulation inhibitors as markers for the evaluation represents a major limitation posing the need for of coagulation concentrate factors in patients with strategies improving its pharmacokinetics. congenital bleeding diseases. To this purpose several approaches have been developed, including human albumin (HSA) fusion, which relies on the acquired capacity of the fused molecule to undergo the recycling pathway mediated by the neonatal Fc receptor (FcRn). However, infused albumin-based therapeutics may suffer from the high abundance of endogenous albumin that may affect FcRn binding. Engineered variants with improved properties provide ideal tools to develop unique molecules for therapeutic purposes. In particular, tailored mutagenesis of albumin residues would translate into enhanced FcRn binding, and thus improved half-life. The aim of this study was to develop a next-generation rFVIIa with superior half-life through fusion with a novel engineered HSA variant (HSAQMP) with improved FcRn binding. Methods. Wild-type (rFVIIa-HSAwt) and engineered © SIMTIPRO(rFVIIa-HSAQMP) fusion proteins Srl were expressed in HEK293 cells, purified and characterized in vitro through activity (PT-based, thrombin generation) and binding (SPR, ELISA) assays, as well as in vivo in state- of-the art mouse models. Results. The engineered rFVIIa-HSAQMP showed the same ability of commercial rFVIIa (Novoseven®) to restore coagulation in FVII-depleted plasma and, most importantly, to act as by-passing agent in HA patient

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s341 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

plasma with high-titer inhibitors. In vitro, binding FIX variant would result in strongly improved biological affinity of rFVIIa-HSAQMP to human (h)FcRn was features, which would translate into a widen therapeutic significantly higher than that of rFVIIa-HSAWT. window. After injection in HB mice (expressing mouse FcRn), The aim of this study was to develop a novel fusion rFVIIa-HSAQMP by-passing activity was detectable up protein by combining the gain-of-function FIX Padua to 72 hours, while activity of Novoseven® was negligible (FIXPadua) with an engineered HSA variant (HSAQMP) after 6 hours. Strikingly, rFVIIa-HSAQMP showed a half- with enhanced FcRn binding, resulting in improved life of 2.9 days, compared to only 0.8 days of rFVIIa- coagulant features and extended half-life. HSAWT, in transgenic mice expressing hFcRn. Methods. The FIXPadua variant was fused to the Overall, these data demonstrate the therapeutic engineered HSAQMP through an optimized cleavable potential of the rFVIIa-HSAQMP fusion protein as well as linker. Wild-type (FIXwt-HSAwt) and improved (FIXPadua- the strong half-life improvement conferred by the QMP HSAQMP) fusion proteins were expressed in HEK293 cells, albumin variant. purified and characterized for activity (chromogenic Conclusions. Fusion of the engineered QMP variant and aPTT-based assays), FcRn binding properties (SPR preserved rFVIIa by-passing activity both in vitro and in and ELISA-based assays), and half-life (state-of-the-art vivo, and strongly extended its half-life profile by 4-fold mouse models with different FcRn settings). compared with the wild-type fusion. This supports Results. Preliminary evaluation of the activity profile the novel rFVIIa-HSAQMP protein as a promising next- showed that the hyperactive features of the FIXPadua were generation tool for hemophilia patients with inhibitors preserved after fusion with HSA in chromogenic and as well as the engineered albumin variant as an attractive coagulant activity assays, as further confirmed after carrier for half-life extension of other coagulation purification of fusion proteins. Binding assays to FcRn proteins. clearly indicated the extremely improved FcRn binding Padua QMP capacity of the FIX -HSA variant (KD=0.4 nM) in comparison with that of FIXwt-HSAwt (K =200 nM). ABS27 - Design of a novel factor IX variant with D enhanced procoagulant activity and half-life Fusion proteins were pre-clinically characterized by in Alessio Branchini (1) - Silvia Lombardi (1) - Jeannette vivo studies in different mouse models, namely knock- (2) (2) (1) Nilsen - Kristin Hovden Aaen - Mattia Ferrarese - out for FcRn (FcRn KO mice) or expressing human (2) (3) (2) Malin Bern - Derry Roopenian - Inger Sandlie - Jan FcRn (Tg32 mice). In FcRn KO mice, the contribution of Terje Andersen (2) - Mirko Pinotti (1) University of Ferrara, Department of Life Sciences and Biotechnology, HSA to half-life was negligible, confirming the central Ferrara (1) - University of Oslo, Centre for Immune Regulation (CIR) role of FcRn binding for half-life prolongation in vivo. (2) and Department of Immunology, Oslo - The Jackson Laboratory, Noticeably, in Tg32 mice the half-life of the improved The Jackson Laboratory, Bar Harbor (3) FIXPadua-HSAQMP fusion protein (2.5 days) was more than wt wt Background. Several approaches have been developed 2-fold extended than that of FIX -HSA (1.1 days), as to prolong half-life of coagulation factors, including well as of the commercial product Idelvion® (1.0 days) factor IX (FIX), such as fusion with human albumin used as control. (HSA). This strategy relies on the acquired capacity of Conclusions. The combined improvements conferred by Padua QMP the fusion partner to undergo the recycling pathway FIX and HSA variants resulted in a novel fusion mediated by the© neonatal Fc SIMTIPROreceptor (FcRn). However, protein endowed of hyperactive Srl features, enhanced the improvement of biological properties of coagulation FcRn binding and extended half-life in pre-clinical factors may be achieved either in terms of half-life or relevant mouse models. This would translate into a activity, or by a synergistic combination of these two significantly widened therapeutic window, and thus features. In this view, rationally-engineered variants a lower frequency of administration, which represent provide ideal tools to develop unique molecules to be major goals to improve treatment, patient care and exploited for therapy. patients’ quality of life. To this purpose, rational engineering aimed at improving FcRn binding combined with a natural gain-of-function

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s342 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

ABS28 - Development of AMT-061 treatment, and no clinically significant elevations in liver (etranacogene dezaparvovec) for persons with enzymes. One participant self-administered a single severe or moderately severe hemophilia B Giancarlo Castaman (1) - Wolfgang Miesbach (2) - Steve infusion of FIX. One participant experienced 2 mild AEs W. Pipe (3) - Annette Von Drygalski (4) - Adam possibly related to treatment shortly after dosing (self- Giermasz (5) - Kathleen Meijer (6) - Michiel Coppens (7) - Peter limiting headache and slightly elevated CRP). Kampmann (8) - Robert Klamroth (9) - Roger Conclusions. A single AMT-060 treatment was (10) (11) (12) Schutgens - Nigel S. Key - Susan Lattimore - associated with long-term stable endogenous FIX Michael Recht (12) - Esteban Gomez (13) - Eileen K. Sawyer (14) - activity and no-late emergent safety concerns, despite a Robert Gut (14) - Frank W.G. Leebeek (15) Azienda Ospedaliera Universitaria Careggi, Firenze, IT (1) - University retrospective finding of NAbs in 3 participants. This led Hospital Frankfurt, DE (2) - University of Michigan, US (3) - University to the inclusion of patients with NAbs in the AMT-061 (4) (5) of California, San Diego, US - University of California Davis, US - trial. Sustained elevation of FIX activity into the mild- University Medical Center Groningen, NL (6) - Academic Medical Center, Amsterdam, NL (7) - Rigshospitalet, Copenhagen, DK (8) - Vivantes to-normative range was observed in all participants Klinikum, Berlin, DE (9) - University Medical Center, Utrecht, NL (10) - 36-weeks after AMT-061 treatment. AMT-061 was well- University of North Carolina, US (11) - Oregon Health and Science tolerated with no clinically significant elevations of liver University, US (12) - Phoenix Children’s Hospital, US (13) - uniQure Biopharma BV, US (14) - Easmus University MedicalCenter, NL (15) enzymes and/or requirement for immunosuppression. Data support the ongoing Phase 3 study, which includes Background. Gene therapy for hemophilia can 52 participants with hemophilia B. potentially ameliorate disease severity to a milder or functionally curative state through a single treatment. ABS29 - Monitoring of prophylaxis with AMT-061 is an investigational gene therapy for Emicizumab in patient with inhibitors - Case hemophilia B comprising an adeno-associated virus Report serotype-5 (AAV5) vector containing a codon-optimized Patrizia Di Gregorio (1) - Alberto Catalano (1) - Franco (1) (1) (1) Padua variant human factor IX (FIX) gene with a liver- Salvatore - Maria Luisa Di Cocco - Raniero Malizia - Fabrizio Paolini (1) - Sandra Verna (1) specific promoter. AMT-061 is an enhanced version of the Servizio Immunotrasfusionale Ospedaliero Aziendale, Policlinico “SS wildtype FIX construct, AMT-060.We present results Annunziata” AS2 Abruzzo, Chieti (1) from the Phase 2b study (AMT-061) and long-term Phase 1/2 data (AMT-060). Background. The onset of high titre inhibitors in patients Methods. AMT-060 was studied at 2 doses (5x1012 and with Haemophilia A is an extremely dramatic occurrence 2x1013gc/kg; n=5 per dose) in an open-label, multicenter because it reduces the effectiveness of both plasma- Phase 1/2 study. AMT-061 (2x1013gc/kg; n=3) was studied derived or recombinant factor concentrates. In the past, in an open-label, multi-center Phase 2b trial. All the approach to this event was based on bypassing agents participants were adult males with FIX≤2% and severe (rFVIIa or APCC) and on the possibility of eradicating bleeding phenotype. inhibitors by means of ITI (Immunotolerance). The ITI is Results. 10 participants in the Phase 1/2 study continue particularly problematic for pediatric patients due to the to express stable FIX after 3.5-4 yrs (mean FIX activity difficulty of venous access, often leading to the insertion 5.1% (95% CI 1.6–8.6) over 4yrs in the low-dose cohort; of central catheters. 7.5% (95% CI 4.2–10.7) over 3.5 yrs in the higher-dose Case Report. Patient 16 months old, with diagnosis cohort). 8 of 9 participants© on FIXSIMTIPRO prophylaxis at study of moderate sporadic Haemophilia Srl A (FVIII:C 2% entry discontinued use post-treatment and remain performed in other Hemophilia Center), treated prophylaxis-free at last follow-up. 3 participants with FVIIIr for a gluteal hematoma. For recurrence experienced transient asymptomatic elevations in liver of haemorrhagic manifestations it is treated with enzymes 4-16wks after dosing that had no impact on recombinant FVIII (rFVIII) at a dosage of 450 IU. FIX expression and were treated with corticosteroids. On first admission at our Centre FVIII:C level was No late-emergent AEs have occurred. After AMT-061 0.28%. The search for inhibitors resulted positive with treatment, mean FIX activity increased to 31% at 6wks a titre of 7 B.U. A following test gave a peak of 11 B.U. and to 41% at 52wks. All participants had low titers We recommended the switch from rFVIII to of AAV5 NAb at baseline. There were no bleeds post- Emicizumab to the family. It was therefore practiced

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s343 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

Emicizumab at the usual dosage of 3 mg/Kg. After rFVIIa or FVIII when possible because of the thrombotic the first administration of Emicizumab, the baby had risk associated with the use of aPCC and emicizumab. an important right hip hemarthrosis that impeded The aim of the study is to report our experience in walking. In this event, as per shared protocols, the management of surgical procedures in PWHA and patient was treated with rFVIIa at dosage of 90 μg/kg in inhibitors on emicizumab. three doses administered at distance of three hours. The Methods. Between 2018 and 2019, three PWHA and next day the baby started to walk normally. After the high titre inhibitors underwent 4 major orthopaedic first month, the dosage of the emicizumab is 1,5 mg/kg surgeries: one amputation above the knee and a total as the usual therapeutic scheme. knee arthroplasty; a total hip arthroplasty; a partial Regular monitoring of inhibitors and factor VIII:C levels revision knee arthroplasty. All subjects were previously with bovine reagent and chromogenic method was managed for surgery by rFVIIa. VAS, Haemophilic praticed. Joint Health Score (HJHS), and radiologic study were Currently the inhibitor titre is 0,4 B.U. and the FVIII:C performed. Emicizumab was continued once weekly and activity is 0,9%. the patients were treated just before and after surgery by Conclusions. Emicizumab is particularly effective bolus infusions of rFVIIa (90 µg/kg) every 4 hours during in prophylaxis of hemophilic pediatric patients with the first two days, every 6 hours for other two days, inhibitors, although in case of haemorrhagic event the every 8 hours for additional two days, then with longer use of bypassing factors remains essential. A particularly intervals, up to two weeks. Four PWHA and high titre important feature is the significant reduction of inhibitors underwent 10 minor surgeries: two ligations inhibitors even if the activity of factor VIII:C remains of hemorrhoidal varices; one tooth extraction; six less than 1.0% while at first diagnosis it was 2.0%, intra-articular injections of hyaluronan acid; a cataract classifiable as moderate hemophilia. surgery. Minor surgeries were managed without rFVIIa It is foreseeable the activation of an ITI program with prophylaxis, except for tooth extraction. A bolus of rFVIIa a concentrate of EHL rFVIII when, at an older age, (90 µg/kg) was infused before procedure, followed by oral the patient will have easier venous accesses for drug tranexamic acid (1g every 8 hours for 5 days). administration. Results. With regard to major orthopedic surgeries, all patients were successfully managed by a single surgeon, ABS30 - Surgical procedures in subjects with without any complications. The mean follow-up was 20.3 Haemophilia A and inhibitors treated with months (range:10-27). An effective bleeding control was emicizumab: a single centre experience Silvia Linari (1) - Lisa Pieri (1) - Christian Carulli (2) - confirmed during surgery. Drains were used only for the Francesco Demartis (1) - Rajmonda Fjerza (1) - Massimo transfemoral amputation and maintained for 36 hours Innocenti (2) - Giancarlo Castaman (1) after surgery. All patients were regularly discharged after SODc Malattie Emorragiche e della Coagulazione, AOU Careggi, early rehabilitation with a mean hospital stay of 12.1 days Firenze (1) - Clinica Ortopedica, AOU Careggi, Firenze (2) (range:12-13), then admitted to the rehabilitative ward. All Background. Persons with Haemophilia (PWH) A patients reported pain reduction and improved joint and and inhibitors needing surgery have been treated for global function at VAS and HJHS scores. No post-operative a long time by using activated prothrombin complex bleeds resulted in minor surgeries. No adverse events, in © SIMTIPROparticular no significant changes Srl of thrombophilia or concentrates (aPCC) or recombinant activated FVII (rFVIIa). The bi-specific monoclonal antibody microangiopathy markers were observed. emicizumab has been used in PWHA and inhibitors, Conclusions. Major orthopaedic surgery with a regimen with marked improvement of protection of bleeding of emicizumab and rFVIIa in PWHA and inhibitors has episodes compared to the prophylaxis with aPCC/ been safely and efficaciously performed. This represents rFVIIa. There have been very few anecdotal experiences the first series of major orthopaedic surgery ever reported reported with emicizumab and by-passing agents during using an internal developed protocol. In PWHA and major surgery, and in particular orthopaedic surgery. inhibitors treated with emicizumab, minor surgeries can In these setting, emicizumab was used together with be safely performed without prophylaxis with rFVIIa.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s344 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

ABS31 - Plasminogen eye drops for the Law receiving 2 drops/eye every 6 hours. As of June 30th, treatment of ligneous conjunctivitis (LC) and no recurrence has been observed. The second patient, the prevention of recurrences in patients with type 1 plasminogen deficiency under female 32 years, presented with a soft lesion in her right compassionate use (CU) and 648/96 Law eye. Following diagnosis (1999) the patient underwent (1) (2) Maria Teresa Sartori - Andrea Leonardi about 50 surgeries and was treated with topical Clinical Medicine 1, University of Padova, Department of Medicine, PD, Italy (1) - University of Padova, Department of Neuroscience, cyclosporine, corticosteroids, heparin and tobramycine Padova (2) with no/temporary effect; she started hpdPlg eye drops treatment on July 2nd under the 648/96 Law at a dosage Background. LC is a rare form of chronic conjunctivitis of 2 drops/eye every 6 hours. The first patient developed characterized by the development of fibrin-rich, transient anti-aprotinin antibodies during the trial, not woody pseudomembraneous lesions, mainly on the impacting clinical management and outcome; no other palpebral conjunctiva. LC is the most common clinical product-related adverse events were recorded. manifestation of type-1 plasminogen (plg) deficiency; in Conclusions. hpd PLg eye drops proved to be effective the most severe cases, it can lead to visual impairment in preventing LC recurrence after surgical excision in or blindness. Some non-specific treatment modalities, our first patient throughout a 6 years treatment. The like FFP, have been reported to result in partial lesion second patient has recently started the treatment and is improvement/resolution, but only topical/systemic plg currently under evaluation. In both cases, the product is showed to be consistently effective. Surgical intervention well tolerated. without effective replacement therapy results in pseudomembranes recurrence. Availability of a locally administered plasminogen concentrate (human plasma- derived (hpd) Plg eye drops manufactured by Kedrion SpA at S. Antimo plant - NA) represents an important advance in the therapeutic options for LC. Between 2006 and 2019 the product has been provided in the frame of a clinical study and CU program and, since Feb 2020, is available under 648/96 Law conditions. Methods. Patients treated under 648/96 Law, exiting from the clinical study or CU program, continued to be treated with hpdPlg eye drops under the same therapeutic regimen as before. The therapeutic regimen for newly treated patients was assigned by the treating physician according to subject’s clinical conditions. Results. As of June 30th 2020, 2/6 patients on treatment with hpdPlg eye drops under the 648/96 Law referred to the Padova center. The first one, female 13 years, diagnosed at the age of 1, was included in the phase II/ III study in April 2013.© By the SIMTIPRO time of enrolment, she Srl had lesions in the right eye, a history of partial response to corticosteroid eye drops and 4 previous surgeries for the removal of pseudomembranes, with quick recurrences after 6-9 days. 4 weeks after starting the hpdPlg eye drops treatment, she underwent surgery for the excision of hard pseudomembranes; no recurrence was reported thereafter. At the end of the study, she entered the maintenance phase of the trial, and, since April 2020, continued to be treated under the 648/96

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s345 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

Results. All patients were successfully treated and 2.06 - ORTHOPEDIC ISSUES followed-up for at least two years (mean follow-up: 8.1 years). No patient showed early postoperative complications or issues related to the use of cast; no ABS32 - The management of fractures in bleedings and DVTs were recorded. A satisfactory persons with haemophilia: experience at a fracture healing and functional recovery was referred single Haemophilia Centre by all patients except two subjects: they complained Christian Carulli (1) - Silvia Linari (2) - Giancarlo Castaman (2) - Massimo Innocenti (1) symptoms or functional impairments at mid-term and Dip. Scienze della Salute, Clinica Ortopedica, Firenze (1) - AOU needed further surgery. (2) Careggi, SOD Malattie Emorragiche e della Coagulazione, Firenze Conclusions. Fractures in PWH are not common but need a close cooperation between Haemophilia Background. Persons with Haemophilia (PWH) may specialists. Thanks to this multidisciplinary treatment it be interested by trauma and fractures as the general is possible to manage such challenging conditions in a population. Due to their bleeding disorder, PWH safe manner and with a low complications rate. Further usually need a specific multidisciplinary management studies should be performed to assess why the low levels starting from the emergency room and either for of vitamin D and osteoporosis in PWH do not correlate conservative treatments or surgical solutions, in to a increased numbers of fractures. order to limit severe complications. Recent papers report about a status of low bone quantity/quality ABS33 - Viscosupplementation with high due to early onset of osteopenia or osteoporosis at molecular weight hyaloronic acid for the DEXA evaluation, associated to low levels of Vitamin treatment of chronic synovitis and early stages D: however, these findings seem not to correlate to a of arthropathy Christian Carulli (1) - Lisa Pieri (2) - Giancarlo Castaman (2) - higher risk of fracture. Massimo Innocenti (1) Few specialized centres dedicated to the orthopaedics Dip. Scienze della Salute, Clinica Ortopedica, Firenze (1) - AOU management of Haemophilia are available worldwide, Careggi, SOD Malattie Emorragiche e della Coagulazione, Firenze (2) thus there is a lack of standard treatment regimens Background. Arthropathy is the most common regarding the management of fractures in these complication of Haemophilia, due to recurrent patients. The purpose of this paper is to report the haemarthrosis and synovitis. The modern bleeding experience of the authors on the management of prevention strategy has limited the incidence of such fractures in haemophilic subjects by a multidisciplinary clinical issue in the recent generations of subjects, and team at a single institution. the number of cases of severe arthropathy decreased. Methods. In the period 2000-2018, 19 PWH were However, there are still many cases of mild to moderate admitted and treated in our centre. 15 patients with arthropathy. Surgery is considered the gold standard Haemophilia type A, 4 with type B. Patients were treatment for the severe arthropathies; conservative classified according to the fracture site (15 lower limbs, strategies have been proposed over the decades to 4 upper extremities) and to the type of haematological patients with mild to moderate arthropathy with treatment (secondary prophylaxis - 15 patients or “on variable results. demand” regimen© - 4 patients). SIMTIPRO All patients were treated Srl Viscosupplementation is one of the conservative by the same orthopaedic surgeon in collaboration options, consisting in the intra-articular injection of with the institutional Haemophilia multidisciplinary hyaluronic acid (HA) that finds indication for chronic team who provided a specific haematologic protocol synovitis without highly recurrent bleedings, mild according to the characteristics of each patient during to moderate arthropathy. As for all other treatments, the peri-operative period. All patients were also literature reports several experiences with poor to low evaluated by specific clinical scores as Numeric Rating level of evidence, even if it is recommended for the Scale (NRS) and Short Form-36 (SF-36) preoperatively management of early- and mid-stages of primary and and at specific times postoperatively. secondary arthritis.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s346 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

Several types of HA have been proposed in the market ABS34 - Ultrasound and clinical assessment of joint status in patients with haemophilia A in the last decades. Low molecular weight HA (LMWHA) switched to recombinant FVIII-Fc has been tested with safety and good results years Gianna Franca Rivolta (1) - Gabriele Quintavalle (1) - ago with long follow-ups; high molecular weight HA Antonio Coppola (1) - Annalisa Matichecchia (1) - Federica (HMWHA) has not been diffusely adopted and with Riccardi (1) - Giacomo Scita (2) - Raul Marco Polo (2) - (1) limited experience, in terms of number of patients and Annarita Tagliaferri University Hospital, Reg. Ref. Centre for Inherited Bleeding follow-up. Disorders, Parma (1) - University Hospital, Dep. of Orthopaedics, The aim of the study is to report the recent analysis of Parma (2) outcomes of the viscosupplementation with HMWHA at a single centre. Background. Regular prophylaxis with factor Methods. Between October 2017 and November 2018, an concentrates is the only strategy able to prevent the authorised and independent study was conducted on 14 onset/progression of haemophilic arthropathy. The patients with a total of 21 joints. The mean age was 45.8 introduction of extended half-life (EHL) concentrates years (range: 18-64). Thirteen subjects were affected by improved personalization and convenience of prophylaxis severe Haemophilia A, one with moderate Haemophilia by reducing the infusion frequency. Moreover, higher A. No surgery or other injections were performed in protection from bleeding and adherence to treatment the treated joints. All subjects were studied by x-rays, may result in improved joint protection. Few real- Petterson score and US to assess the status of synovium life data are available on EHL product prophylaxis, and the presence of blood. The Haemophilia Joint Health particularly about joint assessment. This study aimed score (HJHS) was administered before and after the to collect data about joint status in patients with injections, as range of movement (ROM) and Numeric haemophila A switched to EHL recombinant Factor VIII Rating scale (NRS) for pain evaluation. The protocol (rFVIII) concentrate, rFVIII-Fc, by routine follow-up, consisted in three monthly injections in knees and including ultrasound (US) assessment, useful to early two monthly injections in ankles using a HMWHA. detect and monitor arthropathy. Questions were asked regarding their satisfaction, the Methods. At annual check-up 6 major joints (both annual bleeding rate and the return to a better lifestyle. elbows, knees and ankles) were evaluated by physical All subjects were followed-up for at least 1 year. examination (PE; children: Haemophilia Joint Health Score; adults: Gilbert score) and US scan (Haemophilia Results. No patient was lost at follow-up: the mean Early Arthropathy Detection with UltraSound, HEAD- follow-up was 20 months (17-23). No side effects were US score). Last available scores before switch and on recorded after injections. The median Petterson score rFVIII-Fc were compared, together with patients’ was 8.75 (7.5-9.5). Median HJHS, NRS, and ABR improved annualized bleeding rates (ABR), trough levels, with a statistical significance; ROM showed slight not concentrate weekly dose over comparable period on statistically significant improvements. standard rFVIII (SrFVIII) and rFVIII-Fc. Conclusions. Viscosupplementation with HMWHA Results. Ninety-four joints in 16 patients (14 severe, may be considered an economic, reproducible, and 2 moderate with FVIII:C <2%; age, mean±1 standard safe strategy as those with LMWHA, even if has to be deviation 35±14 yrs) switched to rFVIII-Fc (mean follow-up associated to other forms of conservative treatment 23±8 mo) were evaluated. Two knees were excluded (total in the management© of chronic SIMTIPRO synovitis and early- to Srl replacement. Compared with pre-switch assessments, mid-stages of arthropathy. Costs of HMWHA, even in parallel with significant reductions in FVIII weekly slightly higher than LMWHA, may be managed by local dose (85±18 vs 96±19, -12%, p=0.04) and annual infusion pharmaeconomic policy of the Haemophilia center. number, (93±14 vs 161±10, -40%, p<0.001) and comparable ABR (0.5±1.0 vs. 0.9±0.9, p=0.1) and FVIII through levels (3.2±1.6 vs 3.1±1.8, p=0.6), mean HEAD-US (2.36±2.65 vs 2.39±2.57, p=0.68) and PE (0.91±1.97 vs 0.92±1.93) scores did not significantly change on rFVIII-Fc, overall and considering each joint type. PE and HEAD-US scores

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s347 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

were significantly correlated (r≥0.51, p<0.001) on both these. Alternatively, telematic support was offered to all SrFVIII and rFVIII-Fc prophylaxis. Sixty-three (67%) patients to ensure continuity with respect to what was joints were healthy at both PE assessments; however, learned during the meetings. absence of abnormalities was confirmed at US in 38/94 Results. 11 patients, reffered to Hemophilia Center of (40%), thus 24 joints (38% of joints with PE score=0) the “Regina Margherita Children’s Hospital” in Turin, showed HEAD-US scores ≥1, improving after switch in have been subjected to evaluation but only 9 of them 8. On rFVIII-Fc HEAD-US scores improved in 12 joints participated in the group sessions following the first (13%) and increased in 9 (10%), with unchanged PE score evaluation. Considering the different age groups, two in 10 and 5 joints, respectively. In 18 joints changes were working groups have been created. From a first analysis detected only by one assessment type (HEAD-US n=11) of the collected data it emerges: no patient is overweight and were discordant in 4 joints. while 5 patients belong to underweight category; the Conclusions. Switch to prophylaxis with rFVIII-Fc anthropometric values show some alteration in terms was associated with reduced infusion frequency and of heterometry of the lower limbs, rather than a slight FVIII consumption, maintaining unchanged ABR and difference in the circumference of the thigh, leg and preserved joint-status. The availability of US assessment arm, sign of hypothetical muscle hypotrophy; the joint at routine follow-up provided information about joint test shows a decrease in the joint range in two clinical early abnormalities (25%) or changes on prophylaxis cases involving the ankle and one elbow; the muscle (16%), not shown at PE. strength test is positive in all patients with the exception of a single case that has shown a decrease in muscle ABS35 - Fisiocare 2.0: the experience of strength in the knee/ankle/elbow; HJHS was 0 in 8/11 pediatric Hemophilia Center of Turin patients, while 3 patients showed some type of clinical Eleonora Forneris (1) - Irene Ricca (1) - Berardino Pollio (1) - sign of the disease; regarding sports activities, 7/11 (1) Mauro Pagliarino patients carry out regular sports while the others are not Città della Salute e della Scienza di Torino, S.S.D. Medicina Trasfusionale Materno Infantile Traumatologica, Torino (1) yet mainly due to organizational difficulties on the part of the family. Background. The project was born from the need to During the meetings, no patient experienced any educate patients and their care givers, as well as to bleeding episode. However, it should be noted that raise awareness of the health system, to the importance only one patient reported a traumatic haemarthrosis of physical and sports activity in a preventive way. that occurred outside of the context and following this Therefore, it is considered useful to implement a path episode, was no longer able to participate in subsequent capable of delivering accessible motor activity services meetings due to aching of the joint. with adequate times, in a setting more available for Conclusions. The fisiocare project was a valuable pediatric patients, to integrate and in continuity with experience capable of implementing the care of the the already existing pathways. hemophilia center. Sports activity should be considered Methods. A clinical-functional evaluation was initially a useful strategy for the prevention of musculoskeletal performed (joint test, muscle test, HJHS, 6 minutes complications related to hemophilia. At the same time, walking test, motor test), followed by 12 weekly group physical activity should be integrated into common treatment sessions,© based mainlySIMTIPRO on the preparatory process of managing rare diseases, Srl in order to encourage for some sports including: football, minibasket, ping de-hospitalization of patients with these diseases. pong, athletics, rowing, fencing. For each sport, the fundamental elements have been addressed and proposed in a preparatory form, in order to sensitize the children involved in different types of sport. Unfortunately, due to the health emergency caused by Covid, it was not possible to complete the last 2 scheduled meetings and the evaluations at the end of

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s348 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

ABS36 - The HEMS (Hemophilic-Empowerment- ܁܁ Evaluation with validated scales (VAS, ROM, HJHS, MuscoloSkeletal) Project EQ5D-3L), at the entrance and at the discharge. Marco Martinelli (1) - Valter Emilio Passeri (1) - Sonia Chairi (1) - Vincenzo Gatteri (1) - Stefania Pivetti (1) - Results. Expected results would be: Rossella Tosini (1) - Luisa Cigolini (1) - Ilaria Poli (1) - Stefano ܁܁ improvement of motor performances, with Bernardi (1) - Luciano Bissolotti (1) particular regard to the period related to post- Fondazione Teresa Camplani Casa di Cura Domus Salutis, surgical hospitalization; Riabilitazione, Brescia (1) ܁܁ a better condition of tone-trophism is expected upon Background. Rehabilitation treatment represents arrival at rehabilitation center after surgery; the logical consequence of the surgical treatment of ܁܁ a consequent reduction in the time of hospitalization hemophilic arthropathy: it is not possible to think to of the second hospitalization (on average 5 days); do a total joint replacement without to think to do an ܁܁ a reduction in the consumption of replacement factor adequate rehabilitation period. or, at a minimum, the same quantity administered. In order to continue to obtain a better post-surgical Conclusions. The current “PROJECT” (Hemo- result, it was considered appropriate also to plan a Empowerment-Muscle-Skeletal project: HEMS) should specific rehabilitation treatment prior to the operating have started finally in January 2020, but the current time. The purpose is to increase muscle tone-trophism, pandemic has postponed any planned activities to to stimulate physical activity and to predispose the 2021. The project HEMS requires the involvement of condition musculoskeletal before surgery, assuming hematologists, orthopedic rehabilitators, and, in the a better response to rehabilitation. Another desired foreground, of the associations of hemophilics. outcome is the reduction of hospitalization time with probably savings in the use of replacement therapy. Methods. Hemophilic patients in the previous two months (or better 1 month if feasible for the patient!) surgical hospitalization. Main indication (essential condition): the active collaboration of the patient to follow a specific and “tailored” rehabilitation course. (Another important aspect of this “pre-surgical period” is the presence of specialized physiotherapists for the treatment of hemophilic arthropathy. ܁܁ Patients with hemophilia A or B (and patients with Von Willebrand disease); in the initial phase without inhibitor. ܁܁ A length of stay of 12-day of rehabilitation in hospital, from Monday to Friday of the following week, for a total of 11 rehabilitation treatments, of which: 11 “dry” (in the gym) every day and 5 accesses to hydro- kinesitherapy (every other day). ܁܁ Also, if necessary, it will be to provide access to analgesic physical© therapy andSIMTIPRO / or electrotherapy. Srl ܁܁ During the hospital stay, an educational course will be carried out for the patient, with dedicated materials such as brochures and / or with tailored indications for the continuation of physical activity also at home. ܁܁ The replacement treatment will follow the standard pattern of “prophylaxis”, with factor VIII or IX, 2-3 times a week, with the appropriate indications provided by the reference Hematology Center.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s349 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

to those affecting the FIX activation sites (R191 and 2.08 - PHARMACOKINETICS R226), and the effects on FIX secretion and activity of natural and artificial substitutions in these sites were compared in relation to PK parameters in patients ABS37 - Genotype and PK Hemophilia B affected by mutations at the 191 and 226 sites. International Study (GePKHIS) - A progress Conclusions. We have explored the hypothesis that Report mutations in the FIX activation sites could be related to (1) (2) Alessio Branchini - Massimo Morfini - Paolo better PK parameters with SHL rFIX. The preliminary Gresele (3) - Paolo Radossi (4) - Donata Belvini (5) - Roberta Salviato (5) - Angelo Claudio Molinari (6) - Maria Luisa data obtained support the GePKHIS main aim, to Serino (7) - Donato Gemmati (8) - Chiara Biasoli (9) - Dorina provide evidence for the influence of specific F9 Cultrera (10) - Cristina Santoro (11) - Rita Carlotta Santoro (12) - mutations on PK of rFIX infused to treat HB patients, Mariasanta Napolitano (13) - Mirko Pinotti (1) - Giancarlo exerted by the residual amounts and quality of the (14) (1) Castaman - Francesco Bernardi mutated endogenous FIX. University of Ferrara, Department of Life Sciences and Biotechnology, Ferrara (1) - Careggi University Hospital, Italian Association or Hemophilia Centers (AICE), Firenze (2) - University of Perugia, Department of Medicine, Perugia (3) - Castelfranco Veneto Hospital, ABS38 - The asialoglycoprotein receptor ASGR2 Oncohematology-Oncologic Institute of Veneto, Castelfranco 5’ UTR polymorphisms influence several Veneto (4) - Castelfranco Veneto Hospital, Haemophilia Centre and parameters of full-length FVIII concentrate Haematology, Castelfranco Veneto (5) - Gaslini Hospital, Thrombosis pharmacokinetics and Haemostasis Unit, Genova (6) - University Hospital of Ferrara, Barbara Lunghi (1) - Massimo Morfini (2) - Nicola Haemostasis and Thrombosis Centre, Ferrara (7) - University of Martinelli (3) - Sabrina Frusconi (4) - Dario Balestra (1) - Alessio Ferrara, Department of Biomedical and Specialty Surgical Sciences, Branchini (1) - Silvia Linari (5) - Giovanna Marchetti (6) - (8) Ferrara - Hospital of Cesena, Hemophilia Center and Transfusion Giancarlo Castaman (7) - Francesco Bernardi (1) (9) Department, Cesena - “Vittorio Emanuele” University Hospital, University of Ferrara, Dept of Life Sciences and Biotechnology, (10) Haemophilia Regional Reference Center, Catania - “Policlinico Ferrara (1) - Italian Association Hemophilia Centers (AICE), Milan Umberto I” University Hospital, Department of Haematology, (2) - University of Verona, Dept of Medicine, Verona (3) - Careggi (11) Roma - “Pugliese Ciaccio” Hospital, Centre for Haemorrhagic University Hospital, Genetic Diagnostics Unit, Laboratory (12) and Thrombotic Disorders, Catanzaro - University Hospital “P. Department, Florence (4) - Careggi University Hospital, Center for Giaccone”, Department of Health Promotion, Mother and Child Bleeding Disorders, Department of Oncology, Florence (5) - University Care, Internal Medicine and Medical Specialties and Haematology of Ferrara, Dept of Biomedical and Specialty Surgical Sciences, (13) Unit, Palermo - Careggi University Hospital, Center for Bleeding Ferrara (6) - Careggi University Hospital, Center for Bleeding (14) Disorders, Firenze Disorders, Dept of Oncology, Florence (7) Background. Acquired and congenital components Background. The asialoglycoprotein receptor (ASGPR) of the ample inter-patient variabilily in factor IX (FIX) binds with high affinity the factor VIII (FVIII) B domain, pharmacokinetic (PK) parameters have been poorly particularly through its N-linked oligosaccharide defined. The main study hypothesis is that F9 mutations structures. Evidences in mouse models support a could influence PK parameters through the endogenous role for this receptor in the VWF and FVIII clearance. biosynthesis of mutated FIX variants. The human oligomeric receptor is composed of major Methods. Hemophilia B (HB) patients enrolled in (ASGPR1) and minor (ASGPR2) subunits. Alternative the AICE centers were characterized in relation to splicing of the ASGR2 mRNA originates multiple RNA recombaint (r)FIX (Nonacog Alpha) PK analysis and F9 transcripts, potentially encoding transmembrane and mutations. Patients’© F9 mutations SIMTIPRO were recombinantly soluble isoforms and differing Srlamong individuals. expressed, and secreted rFIX variants investigated for We investigated the relation between the potentially FIX:Ag and FIX:C levels. regulatory ASGR2 5’ UTR polymorphisms and patient Results. We have expressed 18 different F9 mutations variability in FVIII pharmacokinetic (PK) outcomes. detected in patients, and in addition 15 rationally Methods. Twenty-eight hemophilia A (HA) patients designed and topologically equivalent F9 mutations. with FVIII:C ≤ 2 IU/dL underwent 55 FVIII single dose Mutations, and the associated FIX antigen expression (22.7-51.8 IU/Kg) PKs using pd-FVIII and/or FL r-FVIII values, have been grouped in relation to their type. concentrates. FVIII:C was measured up to 72 hours and Among missense mutations, special attention was paid analyzed by two-compartment PK model. PK parameters

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s350 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT were evaluated in relation to F8 mutations, ABO blood- group and eight polymorphisms in the ASGR2 5’ UTR, 2.09 - PROPHYLAXIS investigated by sequencing. Results. Patients grouping by the ASGR2 g.5173T/C (c.- 95T/C) and ABO genotypes displayed several significant ABS39 - The evolving treatment of haemophilia differences in PK parameters. The c.-95 TT homozygotes B: real-life experience with rIX-FP (1) (1) (n=9) differed from homozygotes and carriers of the Antonio Coppola - Gabriele Quintavalle - Gianna Franca Rivolta (1) - Annalisa Matichecchia (1) - Federica C allele (n=19) for the K 1-2 (P=0.048), K 2-1 (P=0.021), Riccardi (1) - Ruben Dario Ruenes (2) - Francesca Lyda Alpha (P=0.022), Alpha HL (P=0.01) and CLD2 (P=0.046) Dallari (2) - Rossana Rossi (2) - Paola Ranalli (3) - Valeria parameters. Homozygotes (n=5) for the common TT Coluccio (4) - Marco Marietta (4) - Annarita Tagliaferri (1) haplotype (H1), including the most frequent 5’ UTR University Hospital, Reg. Ref. Centre for Inherited Bleeding Disorders, Parma (1) - University Hospital, Lab. of Coagulation, alleles conserved in primates, showed significantly Parma (2) - S. Spirito Hospital, Oncohematology Dep., Pescara (3) - lower K 1-2, Alpha and CLD2 values, and higher Alpha University Hospital, Hematology Unit, Modena (4) HL values than the CC homozygous genotypes. In linear regression models including the ASGR2 c.-95T/C Background. Extended half-life (EHL) recombinant and ABO genotypes, with PK parameters as dependent Factor IX (rFIX) products enabled prophylaxis in variables, the K 2-1, Alpha and Alpha HL parameters were haemophilia B (HB) patients with infusions every 7-14 significantly predicted by the ASGR2 c.-95T/C (P=0.032, days, reducing treatment burden and concentrate β coefficient 0.373; P=0.033, β coefficient 0.401 and consumption compared to standard half-life (SHL) FIX. P=0.016, β coefficient -0.426, respectively). In the non-O Few studies currently document the real-life adoption patients (n=19) the ASGR2 c.-95T/C genotypes were and efficacy of EHL rFIX prophylactic regimens. We here associated with a significant gradient of K 1-2 (P=0.032), report data from patients switched to albutrepenonacog K 2-1 (P=0.042), Alpha (P=0.020), Alpha HL (P=0.011) and alfa, a EHL rFIX-albumin fusion protein (rIX-FP). Clearance (P=0.045) values. Methods. Data collection included pharmacokinetic Conclusions. Several parameters of full-length FVIII (PK) studies (50 IU/Kg rFIX-FP, ≥96 h wash-out, FIX:C PK in HA patients were significantly associated with at baseline up to 240h after infusion) and clinical and frequent ASGR2 c.-95T/C genotypes also after correction laboratory assessments in patients switching to rIX- for ABO genotypes. The homozygous ASGR2 c.-95TT FP (bleeding and infusion report, FIX:C through and genotype noticeably improved PK parameters in non-O inhibitor; monthly for 3 mo, every 3 mo for further 9 mo, blood group patients. The relation between the ASGR2 then every 6 mo) from market availability to Feb 2020. H1 haplotype and specific RNA transcripts with FVIII For patients previously on SHL-FIX prophylaxis, rIX-FP PK parameters remains to be established. data were compared with those from 2 yrs before switch. Results. Twelve patients (10 severe, 2 moderate; age, mean±1SD, 36±15 yrs) switched to rIX-FP, i.e. all HB patients previously on prophylaxis and 92% of those with indication to prophylaxis (67% on SHL rFIX). Indeed, 3 patients (2 severe) started prophylaxis with rIX-FP, © SIMTIPROpreviously unfeasible due to venousSrl access or home treatment problems. At PK analysis (n=10), mean half-life was 85.5±8.3 h. Mean prophylactic dose was 46±7 IU/Kg, every 7 (n=5), 10 (n=6) or 14 d (n=1). All patients but one remained on rIX-FP, for mean 22±11 mo. Over follow-up, 7 patients prolonged infusion intervals and all but one (a 12-yr boy) achieved every ≥10 d-dosing regimens, being mean trough FIX:C 8.5±1.7%. Annualized bleeding rates (ABR) was 0.9±1.1, higher than on SHL FIX (0.3±0.4, p=0.02), but unchanged for joint and spontaneous

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s351 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

bleeds. Four patients reported relevant increase in Methods. Following approval by Ethics Review Boards, physical activity, 87% of bleeds occurred after trauma a retrospective observational study was conducted in 5 and 80% in the last dosing interval tertile. Increased Italian Haemophilia Centers. Patients with haemophilia adherence and satisfaction to treatment (HemoSat) A under prophylactic treatment with Kovaltry® for at were shown on rIX-FP, in parallel with significant least one year, and previously on prophylaxis with a reductions in mean annual infusion number (33±8 vs. second or third generation standard half-life product 108±8, -68±10%; p<0.001) and FIX IU consumption for a year prior to switching to Kovaltry® were included (107444±14898 vs. 313250±121349; -67±7%; p<0.001), in the study. Annual bleeding rate (ABR) and overall resulting in 10% saving of prophylaxis costs. No (prophylaxis and breakthrough bleeds) annual FVIII serious adverse events or inhibitor development consumption relating to both treatment periods were occurred. However, a 14-yr boy resumed SHL rFIX extracted from patients’ medical records and compared. due to post-traumatic hematomas and lower than Results. A total of 44 patients (mean age [SD], 37.2 expected FIX:C, in the absence of inhibitors. A total [17.4] years) were included in the study. The main hip replacement was safely carried out in a 62-yr reasons for switching to Kovaltry® were to increase patient, using 40,500 IU rIX-FP (540 IU/Kg) over 27 protection against bleeds (16/44, 36.4%) and to improve d-hospitalization. compliance to prophylaxis by reducing the frequency Conclusions. This real-life experience document of administration (16/44, 36.4%). As reported in Table advantages of prophylaxis with rIX-FP, able to reduce 1, after switching to Kovaltry®, ABR was significantly treatment burden and improve prophylaxis feasibility reduced (1.76 vs 0.23; −1.53), the percentage of patients and treatment adherence, satisfaction and cost- with zero bleeds increased from 54.6% to 84.1% and benefit ratios. Careful patients’ follow-up, considering the overall FVIII consumption reported a reduction individual PK and lifestyle, is crucial to optimize of 25,542 (-7.2%) IU per patient year. In parallel, the prophylaxis regimens and outcomes. percentage of patients treated every 3 days or 2 times per week increased from 0% to 27.3%. ABS40 - Real-word clinical outcomes and Conclusions. Our results suggest that prophylaxis with replacement factor VIII consumption in Kovaltry® can improve clinical outcomes and reduce patients with haemophilia A in Italy: a FVIII consumption compared to prophylaxis with comparison between prophylaxis pre and post standard half-life products. Kovaltry® Paolo Angelo Cortesi (1) - Giovanni Di Minno (2) - Table 1. Clinical outcomes and FVIII consumption reported in the study periods pre- and post-switch (3) (4) Ezio Zanon - Gaetano Giuffrida - Rita Carlotta to Kovaltry®. (5) (6) (1) One year One year Santoro - Renato Marino - Danilo Di Laura - Variable Delta (2) (3) (4) Pre-Kovaltry® Post-Kovaltry® Ernesto Cimino - Samantha Pasca - Daniela Nicolosi - Clinical outcomes (1) 13 Lorenzo Giovanni Mantovani Patients with zero bleeds, N° (%) 24 (54.6%) 37 (84.1%) (1) (54.2%) University Milano-Bicocca, CESP, Monza - Federico II University -1.53 ABR, Mean (SD) 1.76 (±4.15) 0.23 (±0.60) Hospital, HC, Napoli (2) - University Hospital of Padua, HC Padova (3) - (-87%) (4) Frequency of administration A.O.U. Policlinico Vittorio Emanuele, HC, Catania - “Pugliese Every 3 days/2 times per week, 0 (0%) 12 (27.3%) 12 (+27.3%) Ciaccio” Hospital, HC, Catanzaro (5) - Giovanni XXIII Hospital of N° (%) Bari, HC, Bari (6) FVIII consumption per patient* -13,613 Prophylaxis, IU 341,319 327,707 (-4.0%) -11,929 Bleeds, IU 13,746 1,818 Backgrounds. Kovaltry® (octocog alfa, Bayer Pharma (-86.8%) © SIMTIPRO Srl -25,542 Total, IU 355,066 329,524 AG) is an unmodified full-length recombinant factor (-7.2%) * Estimated on an average weight of 70.4 Kg. VIII (FVIII). Extensive clinical trials have demonstrating the consistent efficacy of Kovaltry®, and the possibility to reduce the prophylactic dosing frequency without increasing FVIII consumption. The aim of this study was to describe prophylaxis with Kovaltry® in the real-world setting and to assess the impact of the use of Kovaltry® on FVIII consumption.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s352 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

ABS41 - Adherence to prophylaxis in Italian Respondents had a mean age of 21,8 years (range: 5-75), patients with haemophilia: results from a most of them (82,4%) were receiving SHL concentrates, multicentre study Mariasanta Napolitano (1) - Erminia Baldacci (2) - Renato either recombinant (94%) or plasma- derived (6%), 17,6% Marino (3) - Samantha Pasca (4) - Irene Ricca (5) - Agostino were under EH. Enrolled patients with HA were 115 Antolino (6) - Angiola Rocino (7) (severe, N=98, moderate, N=17), patients with HB were (1) Università di Palermo, PROMISE, Palermo - Umberto I, Centro 75 (severe, N=50, moderate, N=25). VERITAS-Pro total Emofilia, Roma (2) - Policlinico, Centro Emofilia, Bari (3) - AO, Centro Emofilia, Padova (4) - Città della Salute, Immunoematologia, mean score was 36,8 (r: 24-76), for each sub-scale, the Torino (5) - ASP7, Ematologia, Ragusa (6) - Loreto Mare, UOC following mean scores were recorded: Time:7 (r:4-20); (7) Ematologia, Napoli Dose:4.8 (r:4-13); Plan: 6.3 (r=4-17); Remember:5.8 (r =4- 16);Skip: 6.2 (r=4-16);Communicate: 7 (r=4-18). As for Background. Adherence to the prescribed prophylactic supplementary questions, 159 patients replied, with a regimen is crucial for treatment efficacy in haemophilia, mean score of 13.3 (range:4-16). poor-adherence has been associated with increased Conclusions. Promotion of adherence to treatment breakthrough and target joint bleeds, increased bodily protocols remains one of the main goals of haemophilia pain and reduced quality of life. So far, studies on management. Data here reported show an overall good adherence to treatment are scant, quite discordant and adherence to prophylaxis, however areas involving not homogenously collected. The primary aim of the treatment dose skip and communication to the Center current study was to evaluate adherence to treatment in can be clearly improved. Compliance to prophylaxis Italian patients with haemophilia A (HA) and B (HB) on schedules should be addressed in every single patient to prophylaxis. avoid ineffective treatment and waste resources. Methods. A multicentre study was conducted from January 2018 to December 2019, during regular follow- up visits, patients were asked to complete the VERITAS- Pro questionnaire. This 24-item questionnaire divided into 6 (4-item) subscales (Time, Dose, Plan, Remember, Skip and Communicate) was validated to assess adherence to prophylaxis in haemophilia patients. Total scores range from 24 (most adherent) to 120 (least adherent); questionnaire completion takes 10 minutes. Eligible patients were affected by HA and HB under regular prophylaxis, either with standard half-life (SHL) or extended half-life (EHL) molecules, from at least 6 months before enrolment. Regular prophylaxis was defined as: coagulation factors administration for more than once weekly in HA, treatment administered from twice weekly up to every 14 days for HB. The VERITAS- Pro adopted was the official, authorised, Italian version, for paediatric patients it was completed by parents. Furthermore, a supplementary© questionnaireSIMTIPRO including 4 Srl questions specifically focused on product characteristics and storage conditions was administered. Demographic characteristics were summarized as count and percentage within group for categorical data, whereas mean ± standard deviation, and median with range(r) were calculated for continuous variables. Results. Overall, 190 Italian patients with haemophilia from 8 Haemophilia Centers completed the questionnaire.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s353 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

anxious mood of different severity. Of note, this 3.01 - PSYCHOSOCIAL AND QUALITY OF LIFE systematic psychological evaluation let us to come ISSUES across to the diagnosis of neuropsychiatric disorders in 8 children (3 with autistic spectrum disorders; 3 with ABS42 - Quality of life in pediatric haemophilia learning disorder; 1 with severe cognitive impairment patients: a psychological approach to detect and 1 with developmental language disorder non linked unmet needs to autism). Carola Cisiano (1) - Irene Ricca (2) - Berardino Pollio (2) - Marina Bertolotti (1) - Mauro Pagliarino (2) Conclusions. A multidisciplinar approach to Psiconcologia pediatrica Città della Salute e della Scienza di Torino, management of haemophilia patients should involve (1) Oncologia pediatrica, Torino - Centro di Riferimento Regionale psycological dimension in order to detect any early Malattie Emorragiche e Trombotiche in età pediatrica Città della Salute e della Scienza di Torino, SSD Medicina Trasfusionale neuropsychiatric disorders mainly in a paediatric Materno Infantile Traumatologica, Torino (2) setting. Our experience showed a very high prevalence of cognitive disorders. Even if this finding should be Background. The diagnosis of haemophilia is confirmed in a wider population, it suggests a specific frequently a traumatic event and living with a chronic focus of investigation in paediatric haemophilia disease may cause psychological stress. For children, patients. learning difficulties may occur because of both frequent missing school and attention problems due ABS43 - Addressing the overall health to anxiety. During adolescence, chronic sickness may dimensions: the psycho-pedagogical interfere with relationships and the physiological intervention at the Haemophilia Centre of process of gaining independence. Finally, adherence to Parma (1) (2) recommended cure is often reduced in case of disease Alessandra Malori - Maria Losio - Antonio Coppola (3) - Gianna Franca Rivolta (3) - Gabriele management burnout. Quintavalle (3) - Annarita Tagliaferri (3) Aim of our study was to evaluate quality of life (QoL), IAAP, Psychologist, Jungian Analytical Psychotherapist, Parma (1) - treatment adherence and psychological status of our Counselor, Pedagogist, Parma (2) - University Hospital of Parma, (3) pediatric patients. Regional Reference Centre for Inherited Bleeding Disorders, Parma Methods. 51 patients (26 Severe Haemophilia A –HA, 7 Background. Haemophilia and inherited bleeding Moderate HA, 7 Mild HA, 5 Severe Hemophilia B –HB, disorders (IBD) are associated with relevant emotional 1 Moderate HB, 5 Mild HB; median age 10, range 2-22 strains and worries for patients and their families, since yrs) were evaluated during their annual follow-up. diagnosis throughout the different stages of life. This QoL was assessed by means of the PedsQL 4.0 Generic psychological burden jeopardises the individual’s health, Core Scales. For children younger than 5 years old (4 as defined by the World Health Organisation (WHO), pts) the questionnaire was filled by caregivers. The Validated Hemophilia Regimen Treatment Adherence i.e. the ability to adapt to social, physical and emotional Scale-Prophylaxis’ (VERITAS-Pro) was administered challenges. Based on this concept of health, in the frame to patients with active prophylaxis older than 9 years of the comprehensive care, the Haemophilia Center (26 pts). The Hospital Anxiety and Depression Scale (HC) of Parma aimed at making available a program (HADS) was used to assess the presence of anxiety and of psycho-pedagogical intervention for patients with © SIMTIPROhaemophilia and IBD and caregivers, Srl in order to favour depression in patients older than 9 years (26 pts). The study was supported by Bayer Italia. their overall bio-psycho-social well-being and to make Results. Mean overall PedsQL was 73.93. In details, them active subjects of their own health, in line with 78,15 for Physical Functioning, 68.6 for Emotional WHO indications. Functioning, 84 for Social Functioning and 65 for School Methods. In continuity with previous experience of Functioning. As far as adherence, mean VERITAS-Pro psychological support at the HC, a program of psycho- score was 41, corresponding to a rate of 66%. One 19 yrs pedagogical intervention was developed, including old patient showed overt anxiety and depression, 1 22 multi-step/multi-dimensional activities: 1) the "listening yrs old patient suffered of anxiety and 6 pts experienced point’" available at regular patients’ check-ups; 2)

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s354 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT individual psychological/psychotherapeutic support psychosomatic approach of the Diagnostic Criteria for or counseling interventions on critical issues or needs, Psychosomatic Research-Revised version (DCPR-R) on identified through the listening point; 3) group meeting haemophilia patients. of families, aimed at sharing experience and emotional Methods. The study is currently ongoing. The Piedmont issues related to haemophilia; 4) meetings at schools Regional Reference Center for Haemorrhagic and with teachers and classmates of haemophilic children; 5) Thrombotic disorder of the Adults is currently following psychomotricity paths for haemophilic children. 263 hemophilic patients of which 74 severe cases (59 HA, Results. The intervention program, provided by 2 15 HB). To date, 59 severe haemophilia adult patients (44 professionals, started in its current form in 2016 and is HA, 15 HB) were interviewed through the Diagnostic still on-going at the HC, with the contribution of local Criteria for Psychosomatic Research-Revised version. patients’ association, aiming at ensuring continuity. Over Results. The presence of at least one psychosomatic 3 years, mean 80 counselling sessions/year at the listening syndrome was observed in 50,8% (n=30) of the point were offered by a counsellor/pedagogist, to parents/ haemophilia patients, whereas two or more diagnoses caregivers (31%, in most cases combined sessions with were made for 13.6% (n=8) of them. The top three children) or patients (69%; children 5%, adolescents 26%, more frequent syndromes diagnosed were Type A adults 37%), 68% regarding haemophilia (severe/moderate behaviour (16.9%), Irritable mood (20.3%) and Persistent 38%, mild 30%) and 32% other IBD. Counselling activity Somatisation (10.2%). Interestingly, the severity reported led to deliver 15 specific psychotherapeutic interventions by the patients not always matched the objective severity by a psychologist/analytical psychotherapist. Twenty of the disease, suggesting that the impact of the disease families participated in the group meetings. Four school on patient quality of life in not directly proportioned to situations were followed-up. Fifteen children attended disease severity. psychomotricity paths. Conclusions. The aforementioned preliminary results Conclusions. The psycho-pedagogical intervention suggest the presence of psychosomatic syndromes, program, harmonized within the regular clinical follow- encouraging to continue this assessment among up, meets the actual needs of patients and families to haemophilia patients in order to expand the already high actively cope with their existential condition and to standard of care request for such patients. Given the address the overall dimensions of health. This approach small amount of moderate-mild haemophilia cases so far was particularly useful for parents/caregivers and interviewed, no comparison between severity group have adolescent patients and appreciated also in milder IBD. been proposed but with the continuation of the study we hope to collect enough data to be able to carry out this analysis, since from our preliminary data suggest that ABS44 - Psychosomatic syndromes among hemophilia patients: experimental the severity of the disease does not seem to correlate contribution directly with the severity felt and reported by the patient. Mariagiulia Bailon (1) - Cristina Dainese (2) - Marco Miniotti (1) - Jacopo Agnelli Giacchello (2) - Alessandra Borchiellini (2) - Paolo Leombruni (1) ABS45 - Emo Personal Story: the issues related to therapeutic adherence University Hospital City of Health and Science of Turin, Rita Levi (1) (2) (3) Montalcini” Department of Neuroscience, Turin (1) - University Giulio Feola - Veronica Grippa - Vincenzo Sabatino Hospital City of Health and Science of Turin, Regional Center Ospedale San Luca/ Vallo Della Lucania, Centro Trasfusionale e (1) © SIMTIPRO(2) Centro di Riferimento per le Coagulopatie, Srl Salerno - Santobono- Hemorrhagic and Thrombotic Diseases, Hematology Unit, Turin Pausilipon, Rianimazione, Napoli (2) - Ospedale San Giovanni Di Dio e Ruggi D’Aragona, Radioloogia, Salerno (3) Background. Given the impact of the diseases and their treatments, a general impairment in the quality of life Background. The issues related to therapeutic of Hemophilia A and B (HA and HB) patients is well adherence and the impact of the disease on patients documented. Despite expected, to date no information have led us to elaborate a Project (Emo Personal Story) is available in literature about the possible presence of able to analyse the difficulties and highlight criticalities psychosomatic syndromes in these patients. The current to be overcome and solved by the personalisation of a study tries to bridge this gap, aiming to apply the shared care path in which doctor-patient relationship

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s355 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

is based on a therapeutic alliance. Patient-Centered trust in the doctor-patient relationship, increasing Medicine recognises the importance of sick people’s patients’ awareness and responsibility, and analysing the subjective experience and patient’s pathology holistic best solution among the different possible combinations. approach. Diaries’ mission is to enable patients to However, patient (and clinician) satisfaction can only freely express their difficulties and doubts concerning be reached with continuous communication because, pharmacological treatments and disease complications in this context, the patient is willing to actively and that will have to be resolved by the personalisation of conscientiously collaborate at his care path. an agreed-upon care path involving Shared Making Decision processes. ABS46 - Health and mental status perceptions Methods. The questions that have been formulated of patients with mild haemophilia A adopt an approach connected to Narrative Medicine Mariasanta Napolitano (1) - Maria Francesca Mansueto (1) - (2) (1) and they have been contextualised and included in the Simona Raso - Sergio Siragusa Università di Palermo, PROMISE, Palermo (1) - Università di Palermo, “Emo Personal Story” diaries. Narrative Medicine is a DICHIRONS, Palermo (2) clinical-care intervention method, based on a specific communicative competence. The narrative is the crucial Backgorund. Mild haemophilia bleeding phenotype element to acquire, comprehend, and integrate the is mainly secondary to surgical procedures or trauma, different points of view of the people involved in the thus diagnosis frequently is made later in life than for disease and the care process. Narrative-Based Medicine more severe forms of the disease. Patients with mild (NBM) is integrated with Evidence-Based Medicine haemophilia A (PWMHA) are however at risk of severe (EBM). Since a variety of perspectives is taken into haemorrhagic events, such as joint bleeds or cerebral consideration, clinical-care decisions become more bleeds, with secondary limitations in daily activities, complete, personalised, effective, and adequate. The impaired health-related quality of life (HRQoL) and health Patient narrative is an essential element in modern care resources utilization. Data on mild haemophilia are medicine, based on the active participation of the people very limited. Aim of the current observational study was involved in the decision process. A perspective change to evaluate HRQoL in PWMHA. is needed: from a Disease-Centered approach, which Methods. Each PMWHA, underwent clinical and examines all the measurable biological and somatic laboratory follow-up every 12 months after diagnosis variables of pathology, to a Patient-Centered approach, as part of standard haemophilia care. The following which finally pay attention to the patient, seen not only questionnaires were administered at each visit to as a person affected by the disease but also as a person evaluate HRQoL: SF36, EQ-5D. Data on HRQoL were marked by pain and suffering. collected in a dedicated database and evaluated in Results. Diaries enabled us to fully explore and face correlation with variables like age, age at diagnosis, difficulties and discomfort related to therapeutic school education level, bleeding phenotype, replacement adherence. The personalisation process of the care path therapy (RT). Demographic characteristics were has taken into account the Pharmacokinetic profile, the summarized as count and percentage within group for gravity of factor deficiency, the lifestyle and the trauma categorical data, whereas mean ± standard deviation, risk, the patient expectancies, preferences, and everyday and median with range (minimum and maximum) were life. Therefore, it© means that SIMTIPRO“therapy should be adjusted calculated for continuous variables. Srl according to the patient rather than to his disease”. The Results. The study started in January 2017. In June positive outcomes and results motivated us to expand our 2020, a twenty-four months follow-up was available for studies involving other patients of different haemophilia 30 PWMHA. Patients had mean FVIII activity levels of centres. 13% (range: 6-38), most PMWHA (25/30) were diagnosed Conclusions. The active involvement of patients in the following trauma or surgery–related bleeds during Making Decision process improves their compliance. adolescence or adulthood, median age at diagnosis was The problems related to therapeutic adherence should be 30 years (range:1-76). All PMWHA received on demand faced with communication, which is capable of building treatment. At 24-months follow-up, 8 subjects received

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s356 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT treatment for one trauma-related bleeding episode/year, on prophylaxis, 12.9% on-demand, and 3.2% were ITIs; 15 PWMH did not need any replacement treatment, in Naples the percentages were 91.9%, 2.7%, and 5.4% 7 patients experienced two trauma-related bleeding respectively. Median infused dose was higher in Naples, episode/year requiring RT. Median SF36 score for the 2000 IU, then in Padua, 1500 IU. At the Naples Hemophilia physical dimension (PCS) was 54.2 (range:25.5-56.9) and Center 37.8% of patients are treated every other day and 47 (range: 42-61) for the mental dimension (MCS). Scores 32.4% three times a week; while in Padua 29.0% of subject remained stable throughout the observation period. EQ- are treated two times a week, 25.8% three times a week and 5D mean utility score was 0.81 (range: 0.74-1). 19.4% every 72-96 hours. Mean ABR(Joints) and ABR (major Conclusions. SF-36 scores show that the disease impacts and minor bleeds) were 1.85 and 2.3 respectively in Naples, quality of life, however it seems to affect either mental or and 1.70 and 2.4 in Padua. Psychological aspects: infusions physical aspects on a individual basis. PWMHA are able were considered a problem by 12.9% of the Paduan patients to perform daily activities according to EQ5D scores. and 10.8% of the Neapolitan ones, while the percentage of Patient perceptions of illness in mild haemophilia may patients who consider the number of infusions a problem be related to the time of first diagnosis and bleeding rose to 22.6% and 24.3% respectively. The negative impact of phenotype. Upcoming treatment strategies should focus the needle on therapy and the pain caused by it were higher on this evidence. in Southern Italy patients, where reached respectively 13.5% and 29.7% (mean pain score 5.3), while in Northern patients ABS47 - Clinical, psychological and physical the percentages were respectively 9.7% and 22.6%, with a aspects of hemophilia: face to face between mean pain score of 4.5. In neither group did hemophilia North and South Italy elicit negative emotions or result in an obstacle to daily Samantha Pasca (1) - Maria Rosaria Villa (2) - Ezio Zanon (1) - activities. For patients in Naples the used drug is easy to Angiola Rocino (2) Azienda Ospedale Università di Padova, Centro Emofilia - Medicina store in 97.3% of cases and easy to transport in 89.2%. On Generale, Padova (1) - Ospedale del Mare, Centro Emofilia e Trombosi - the other hand, 32.3% of patients in Padua showed the poor (2) UOC Ematologia, Napoli handling of the drug and 16.1% the difficulty of preserving it. Physical aspects: physical activity compared in two Background. In recent years, the treatment of hemophilia homogeneous groups of nine pediatric patients (2-15 years) has changed considerably, new more effective and manageable drugs are available to clinicians, new showed that young people in the North practiced sports in personalized therapeutic approaches have become an almost double percentage compared to the same age routine practice, but in order to make the most of these children in the South (77.8% vs 44.4%). opportunities, it is necessary to know the clinical, physical Conclusions. Infusion timing, storage and transport of the and psychological situation of each patient, in each drug, perception of the pain caused by the needle and sports different Country. Aim of this survey was to evaluate the practice resulted different between the two groups, while similarities and the difference between two groups of no difference was found regarding the outcomes and the patients, one from the North and the other from Southern psychological aspects related to the hemophilia treatment. Italy, by comparing all these aspects. Methods. A survey in which are investigated: 1) baseline ABS48 - The invisible girl characteristics of patients; 2) treatment and outcomes; Simona Prejano (1) - Mariapia Falbo (1) - Lucia Concetta 3) impact of treatment© on daily SIMTIPRO life; 4) physical activity Elia (1) - Francesca Leo (1) - Piergiorgio Srl Iannaccaro (1) - Rita (1) (pediatrics only) has been administered to two groups of Carlotta Santoro UO Emostasi e Trombosi. Azienda Ospedaliera Pugliese-Ciaccio, patients of any age treated at the Hemophilia Centers of Emato-Oncologico, Catanzaro (1) Padua (Northern Italy) and Naples (Southern Italy). Results. Overall 68 patients have filled out the survey, 31 Background. The diagnosis of severe hemophilia, in Padua and 37 in Naples. In both Hemophilia Centers especially if complicated by the inhibitor diagnosis, about 90% had severe hemophilia A. Mean age was lower involves all family members. Among all, the most fragile in Northern patients, than Southern ones (20 vs 33 years). subjects, in addition to the patient, are certainly the Clinical aspects: in Padua 83.9% of patients were treated youngest, any brothers and / or sisters.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s357 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

Case Report. We present a case of a pediatric patient perceived by the girl who started again to feel part of the diagnosed with severe Hemophilia A, carried out at family, to socialize, and to smile carefree, like all 7 year the age of 9 months. There was no family history of old children. Hemophilia. The baby started primary prophylaxis The presence of an inhibitor in a hemophilic patient has a with octocog alfa after a first episode of left elbow big impact not only on the patient himself but on all the haemarthrosis at the age of 13 months. After only 8 members of the family. days of exposure, a high titer inhibitor (18 UB) appeared and subsequently he started immunotolerance (ITI) ABS49 - Long term neuro-psychological after CVC positioning. The course of the ITI has been sequalae in Thrombotic thrombocytopenic characterized by recurrent infectious episodes both at purpura (1) (2) (3) the catheter and general levels. After the umpteenth Silvia Riva - Ilaria Mancini - Alberto Maino - Barbara Ferrari (1) - Andrea Artoni (1) - Pasquale Agosti (2) - infectious recurrence, the catheter was removed and Flora Peyvandi (2) arteriovenous fistula were packaged, but it matured IRCCS Ca’Granda, Centro Emofilia e Trombosi “Angelo Bianchi only after a second attempt. Meanwhile, the inhibitor’s Bonomi”, Milano (1) - University of Milan, Department of title continued to rise and after the failure of an initial Pathophysiology and Transplantation and Fondazione Luigi Villa, Milano (2) - Azienda Provinciale per i Servizi Sanitari, Internal ITI cycle, a rescue attempt was tried, which also failed. Medicine Unit, Trento (3) At the time of the decision to permanently suspend the ITI, after about 33 total months of treatment, the Background. Thrombotic thrombocytopenic purpura inhibitor’s title was 8000 UB. The numerous intercurrent (TTP) represents a rare haematological condition which hemorrhagic episodes, 1-4 events per month, have been presents a frequent impairment of neuropsychological treated with rFVIIa. For this reason, hospital visits were functioning. Main neurological disturbances may very frequent. include headaches, mental changes, confusion, speech During this period the little sister, very close to her abnormalities. While these symptoms represent the mother, felt a little pushed aside. At first cheerful and hallmark of the acute phase of the disease, patients engaging, she had become very silent, almost invisible. affected by such critical illness often have a prolonged He refused to play with his little brother, and even at and disabling form of cognitive impairment that school or with her friends she often isolated herself. She remains inadequately characterized. cried often and complained of psychosomatic pain and Methods. TTP patients underwent a neuropsychological discomfort. evaluation of memory and attentional functions with We decided to suspend ITI to the hemophilic child and the standardized Neuropsychological Battery (ENB to start prophylaxis with emicizumab. This therapy was Profile) at least 6 months after the acute event. Health- well tolerated, no adverse events have occurred, the related Quality of Life (HRQL) was also assessed by the child has no longer been hospitalized and, in particular, SF-36 as well as the emotional wellbeing (depression and after 12 months of follow-up and despite four traumatic anxiety) with the Hamilton Depression Scale and the episodes, he did not present any bleeding events. Hamilton (HAM-D) and the Hamilton Anxiety rating The patient’s and the whole family’s quality of life has Scale (HAM-A). improved significantly. The boy, visibly more serene, Results. 35 patients (median age at 41 years, range 27-77) started attending© kindergarten SIMTIPRO and socializing with peers. affected by acquired TTP underwent Srl the psychological Mom has started working again. The little sister who was assessment. Half sample (17/35, 49%) referred persisting very closed in on herself, began to reopen and now plays neurological impairment in remission phase (confusion, quietly with her little brother and with her friends. loss of concentration, dizziness, lack of balance, headache, Conclusions. Twelve months after the start of and diplopia). With regard HrQoL, the mental was emicizumab prophylaxis, the young patient had a significantly most impacted than physical component (p marked improvement in clinical conditions and quality < 0.005), especially at the level of emotional role, vitally of life. The absence of bleeding and the end of continuous and mental health with a mean score ranging from 50 to checks in the hospital, allowed the whole family to 52. With regard to emotional assessment, the presence of resume a normal life. This new normality was also anxiety (with the HAM-A interview) was detected in 56%

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s358 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT of interviewed patients while the presence of depression evaluating HrQoL, emotional and functional status with (with the HAM-D interview) was present in 36%. Among a set of international standardized instruments. Italian the type of disturbances, we found that the most impaired PWHsev aged ≥60 were compared with controls men domains in in HAM-A there were “intellectual symptoms” without bleeding disorders matched for age and geography. (i.e., difficulty in concentration and poor memory) Results. 102 patients (N=90, 88% hemophilia A pts and (N=6,82%) and “tension” (N=4, 54%) while in HAM-D were N=12, 12% hemophilia B pts, Mean age=64,SD=1.8) “diminishment of work activities” (N=10, 77%), “negative from 14 Italian hemophilia treatment centers (HTCs) mood” (N=8, 60%) and “insomnia” (N=4, 27%). were matched with a group of 204 age-controlled men Finally, in relation with neuropsychological assessment without bleeding disorders (Mean age=65,SD=2.2), mean scores in memory domains revealed a an impaired chosen randomly from 6 general practices across score in TTP patients especially in the specific domain all Italy. Pertaining HrQoL, although the subjective of direct memory (p<.005), indirect memory (p<.005) perception of health (measured with the EQ5D-VAS) and deferred memory (p<.001) in comparison with the was worse in patients than controls according to published Standard Normal Distribution values of general (p <.001), other life dimensions (measured with the Italian population. WHOQOL_Old) were equally impacted among the 2 Conclusion. In this study, a large proportion of TTP groups with patients showed the highest impairments patients suffer from long-term neurological sequelae in the domain “death“(p=.004), while controls reported even years after the acute phase. TTP patients with more impairments than PWHSEV in ”sensory“ (p=.006) neurological involvement at the first acute episode seem and “intimacy” (p=.024). At the emotional level, the to be at higher risk of developing memory dysfunction. degree of depression (measured with the GDS scale) Furthermore, TTP patients have increased levels of was higher in patients than controls (Mean total score anxiety and depression, which negatively affect their 12.5+3.2 for PWHSEV vs 11.3+2.7 for controls, p=.001) with quality of life. A faster improvement of the acute state of the most impacting dimensions for worry (29%), drop of the disease by novel drugs might have a role in this process activities and interests (49%) and general dissatisfaction and further studies are required to solve this question. (40%). In regards with the functional status, there were Future prospective cohort studies are necessary to no difference between PWHSEV and controls (PWHSEV evaluate long-term consequences and longitudinal Mean score 6.4 vs 6.5) pertaining with complex activities development of such impairments. of daily living (e.g. managing money) measured with the IADL scale while patients showed slightly lower mean ABS50 - Psycho-emotional SPHERE and scores (5.5 +1.1 vs 5.9 + 0.4, p<.001) for simpler activities functional status of elderly patients with of daily living (e.g. walking) as detected by the ADL scale. haemophilia: the multicenter S+PHERA study Conclusions. Using an array of psychological tools and a Silvia Riva (1) - Emanuela Marchesini (2) - Alfonso Iorio (3) - suitable control, we were able to measure that current life Emily Oliovecchio (2) - Pier Mannuccio Mannucci (1) on behalf of the SPHERA Study Team status and functional capacities of older hemophiliacs are IRCCS Ca’Granda, Centro Emofilia e Trombosi “Angelo Bianchi similar or only marginally lower than those of their age (1) Bonomi”, Milano - University of Perugia, Italy, Hemophilia Centre- peers without hemophilia. Two points emerged as relevant: SC Vascular and Emergency Department, Perugia (2) - McMaster University, Department of Clinical Epidemiology and Biostatistics, i) to monitor the emotional disorders over the time; ii) to Department of Medicine,© Hamilton (3) SIMTIPROcheck physical abilities progressively Srl to preserve functional independency. These results emphasize the role that Background. Today, many patients with severe specialized and comprehensive HTCs, as well as specific hemophilia (PWH ) reach the elderly age thanks to the SEV programs meant to make aging successful in PWH, play to availability of new treatment and the presence of multi- reduce the gap with age-matched peers without hemophilia specialized hemophilia centers. Despite this dramatic who receive standard care by their general practitioners. improvement, there is little information on health‐ related quality of life (HRQoL) of these patients. Methods. A prospective, longitudinal, multicenter, and non-interventional study was designed with the aim of

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s359 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

ABS51 - Let’s talk of sex. A starting study on a was also asked if the haemorrhagic and joint problems neglected topic had affected sexual life: the answer was yes in 30.6%, Gianluca Sottilotta (1) - Dora Messina (2) - Andrea Buzzi (3) - Francesca Luise (1) - Giovanna Maria Nicolo’ (4) - Vincenzo no in 29.6% and sometimes in 39.8%. When asked if Oriana (1) - Angela Piromalli (1) an infusion is performed before sexual intercourse, G.O.M., Centro Emofilia - Servizio Emostasi e Trombosi, Reggio respondents replied: yes in 3.9%, no in 59.7% and (1) (2) (3) Calabria - AIMeF, Catania - Fondazione Paracelso, Milano - sometimes in the remaining 36.4%. Università di Catania, Patologia Clinica e Biochimica Clinica, Catania (4) Conclusions. Further research on this subject where there are cultural interdictions and taboos, would allow Backgrounds. The aim of this survey was to investigate to focus better on issues such as: the type of support the need for information about sexuality in patients to offer to PWHs and to whom to entrust him (doctor, with haemophilia (PWHs), from different countries, counsellor, psychologist, sexologist or other professional representing a variety of cultural and economic settings, figures); how to intercept the needs of individuals and different health care access. by overcoming embarrassment; if and what other Methods. An 18-item anonymous online survey was medications (pain relievers, anti-inflammatories, etc.) translated into English, Italian and Spanish and sent are taken. to adult PWHs belonging to the most active national haemophiliacs groups worldwide. The survey consisted of multiple-choice responses and checkboxes. Data were collected between October 2019 and March 2020, through an 18-question online individual interview composed of 5 questions about age, diagnosis, nationality, education level, employment, treatment regime, and 12 questions regarding the importance and need for information about sexuality related to haemophilia. Results. The participating patients were 206 from 26 countries. 175 with haemophilia A and 31 with haemophilia B, with a prevalence of cases of severe haemophilia; of these, 14 had inhibitors (10 against FVIII and 4 against FIX); 85 patients (41.3%) underwent prophylaxis and 121 (58.7%) were on-demand. 188 (91.3%) patients believe that sex education is useful, but only 14.5% have already talked about sexuality with a doctor of the Haemophilia Centre: this even if 76.7% thinks it is useful, and just over half (61.2%) declare they are indifferent to the fact that the doctor is a man or a woman. 56.8% of the respondents said they felt the need to be able to talk freely to someone about their sexuality beyond the doctor/patient© relationship:SIMTIPRO in particular Srl during the adolescent period this was an experience reported by 64.1% (132/206), who spoke about it in 47% of cases with peers, in 34.1% with parents and in 18.9% with other adults. When asked why there is little talk about this topic in the context of haemophilia, the cause is mainly attributed to the presence of cultural barriers (39.8%), fear of being judged (19.9%) or shame (9.7%); while the remaining 30.6% preferred not to respond. It

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s360 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

then 20 µg/kg iv every 12 hours for 4 days. The patient 3.02 - RARE BLEEDING DISORDERS was monitored with TG and ROTEM after surgery, confirming ex-vivo data. Elastic stockings were used as antithrombotic prophylaxis. The patient had no bleeding ABS52 - Management of surgery in a patient or thrombotic complications. Results of TG and ROTEM with congenital factor XI deficiency and before and after treatment confirmed the response to inhibitor the drug, as in ex-vivo tests, performed in preparation Simona Maria Siboni (1) - Eugenia Biguzzi (1) - Erica Scalambrino (1) - Marigrazia Clerici (1) - Roberta for surgery. Gualtierotti (1) - Massimo Boscolo (1) - Simon Braham (1) - Conclusions. Testing for anti-FXI inhibitors is important Lidia Padovan (1) - Ida Martinelli (1) - Armando after exposure to plasma or FXI concentrate in patients Tripodi (1) - Flora Peyvandi (1) with factor XI deficiency, particularly in the presence Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, A. of p.Glu117X mutation. In such patients, low doses of Bianchi Bonomi Hemophilia and Thrombosis Center, Milano (1) rFVIIa appear to be sufficient, as shown by laboratory Background. Development of anti-factor XI (FXI) and clinical data, to ensure adequate haemostasis antibodies is a rare complication of severe FXI deficiency during major surgery. (<1%), but it was reported in 30% of patients carrying the mutation p.Glu117X. The use of recombinant activated ABS53 - Von Willebrand disease and factor XI factor VII (rFVIIa) in patients with severe FXI deficiency deficiency: report of four cases and inhibitor was associated to thrombotic events in Mariapia Falbo (1) - Simona Prejano (1) - Lucia Concetta (1) (1) (1) some patients. Elia - Francesca Leo - Piergiorgio Iannaccaro - Rita (1) Case Report. A Caucasian woman with severe FXI Carlotta Santoro UO Emostasi e Trombosi. Azienda Ospedaliera Pugliese-Ciaccio, deficiency and homozygous p.Glu117X mutation Emato-Oncologico, Catanzaro (1) developed an anti FXI inhibitor (59 BU) at the age of 70 years after 15 infusions of fresh frozen plasma, the latter Background. Von Willebrand disease (vWD) is a common, given before the biopsy of a gastric polyp, that revealed inherited, genetically and clinically heterogeneous a gastro-intestinal stromal tumor (GIST). Laparoscopic hemorrhagic disorder caused by a deficiency or surgery (gastric wedge resection and correction of dysfunction of the protein termed von Willebrand factor concomitant epigastric hernia) was proposed to the (vWF). Factor XI (FXI) is a plasma glycoprotein that patient, in order to remove the lesion. Before surgery, participates in the contact phase of blood coagulation ex-vivo tests (thrombin generation [TG] and rotational (ie, the intrinsic pathway). Combined deficiency of VWF thromboelastometry [ROTEM]) were performed, by and FXI is an extremely rare condition. We report of five spiking increasing amounts of rFVIIa. In the TG assay cases with VWD plus FXI deficiency. low doses of rFVIIa (as low as 15 µg/kg) were sufficient Case Report. In our center, 35 patients with Factor XI to generate a burst of thrombin, comparable to that of defect of various severity are followed. Among these a normal plasma; in the ROTEM assay with the INTEM four patients also suffer from von Willebrand disease. reagent, the clotting time (CT) and clotting formation Case n.1. 17 year old young woman, who came to our time (CFT) were only slightly shortened by the rFVIIa, observation for hemorrhagic diathesis: metrorrhage while the maximal ©clot formation SIMTIPRO (MCF) was within the history, spontaneous bruising, post-extractionSrl bleeding. normal range and unmodified by rFVIIa. FXI inhibitor Not family history for bleeding. Complete blood count was spontaneously decreased to 16 BU at the time of and prothrombin time were normal, the activated partial the procedure. The patient received rFVIIa (40 µg/kg) thromboplastin time (aPTT) was increased (aPTT 40”, before surgery, and the same dose was repeated every 4 ratio 1.28) and the mix tests showed complete correction. hours during the first 24 hours, then every 12 hours on The dosages of the coagulation factors showed a post-surgery day 1. The dose of rFVIIa was reduced to reduction of the FXI (35%), an FVIII at the lower limits of 20 µg/kg every 8 hours on post-surgery day 2 and every normal range (55%), a VWF: Ag of 44% and a VWF: RCo 12 hours on post-surgery day 3. Tranexamic acid was of 39%. A diagnosis of a mild Factor XI defect and von used as adjuvant therapy (10 µg/kg iv before surgery, Willebrand disease type I was made.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s361 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

Case n.2. A woman, currently 34 years old, came to our (pts) can be asymptomatic, but can also present bleeding observation for the first time at the age of 18 for bleeding or thrombotic symptoms. Routinary coagulation tests after minor dental surgery. The exams highlighted normal are useful for diagnosis but not to predict the clinical prothrombin time and complete blood count, increased phenotype. Molecular biology assays should be performed activated partial thromboplastin time (aPTT) (aPTT 43”, in all pts because can provide important prognostic ratio 1.41) with complete correction of the mixing tests. information, but they are available in very few centers. Aim The dosages of the coagulation factors showed a reduction of this study is to analyze whether platelet function testing of the FXI (31%), of the FVIII (40%), of the VWF: Ag (40%) and global coagulation assays can serve as clinical tools in and of the VWF: RCo (34)%. A diagnosis of a mild Factor predicting clinical phenotype in Dys/Hypodys pts. XI defect and von Willebrand disease type I was made. Methods. Dys/Hypodys pts were enrolled at our center. The A few years ago the patient gave birth without the need for ISTH-Bleeding Assessment Tool (BAT) was used to classify replacement therapy. At the time of delivery, the values of bleeders (score >3 for males, >5 for females). The occurrence FVIII and VWF: RCo were normalized, with an FXI of 35%. of thrombosis was also reported. To explore platelet Case n.3 and n.4. Two siblings, a 24 year old young man function, light transmission aggregometry (LTA) was and a 25 year old woman were evaluated. The first has performed utilizing these reagents: ADP 5μM, Arachidonic a history of bleeding after major surgery and an episode Acid 1 mM, Collagen 2 mg/mL, Adrenalin 10 μM. As of hematoma, probably spontaneous. No bleeding was global coagulation assays, Thromboelastography (TEG) reported by the female patient, except for sporadic and Thrombin Generation Assay (TGA) were performed. abundant menstruation. In both laboratory data showed Thrombin generation was measured in platelet-poor FXI reduction (24% and 20% respectively). In the man plasma by calibrated automated thrombography (CAT). FVIII was 35%, VWF: RCo 34% and VWFAg 35%, while Results. 10 dysfibrinogenemic pts were enrolled: 8 FVIII 36%, VWF RCo 38%, VWFAg 40% were found in the females, 2 males; median age 45 years (24-74). Median female. fibrinogen activity was 52 mg/dL (27-136) and median Conclusions. Combined factor deficiencies are rare, fibrinogen antigen was 250 mg/dL (198-380). ISTH-BAT in particular VWD combined with FXI deficiency is was negative for all pts (median value 1, range 0-3); no extremely rare entity. FXI deficiency may be diagnosed one experienced a thrombosis. As regard LTA and CAT as a result of bleeding or be found incidentally as part parameters (endogenous thrombin potential, lag time, of presurgical work up for a prolonged aPTT. Type I von peak, time to peak) all median values were in normal Willebrand disease is the most frequent coagulopathy and range. As regard as TEG performed with citrated kaolin often occurs with mucous hemorrhages or after surgery. reagent, we observed an increased median R [7 minutes, In case of bleeding, the choice of treatment must take range 5.2-8.6, (n.v.:4.3- 6.3)] and a reduced median Lysis30 into account the presence of a combined defect. [0.1%, range 0-0.1, (n.v.:0.2- 3.8)] and Lysis60 [1.8%, range 0-2.7 (n.v.:3.1- 14.6)]. When TEG was performed with ABS54 - Investigation of possible correlation functional fibrinogen reagent an increased median R was between clinical and laboratory phenotype confirmed [3.2 minutes, range 2.2-4.8, (n.v.:<3)] and an in congenital Dysfibrinogenemia/ increased median MA was observed [21.1 mm, range 4.5- Hypodysfibrinogenemia: preliminary results 28.0 (n.v.<20.9)]; lysis was absent at 30 and 60 minutes. from a single center Antonietta Ferretti© (1) - Francesco SIMTIPRO Barone (1) - Erminia Conclusions. In this small case Srlseries of pts, TEG showed Baldacci (1) - Maria Lucia De Luca (1) - Simona Michela increased median values of R and MA and reduced Aprile (1) - Raffaele Bocchicchio (1) - Antonio Chistolini (1) - values of Lysis30 and Lysis60. Despite these laboratory Maria Gabriella Mazzucconi (1) - Cristina Santoro (1) alterations, our patients did not present a bleeding or Università Sapienza, Dipartimento di Medicina Traslazionale e di Precisione, Roma (1) thrombotic phenotype. Therefore we could hypothesize that these findings can be related just to the in vitro Background. Dysfibrinogenemia/Hypodysfibrinogenemia interactions of a different fibrinogen molecule, without a (Dys/Hypodys) is a very rare bleeding disorder in which clinical prognostic value. These preliminary data need to the clinical phenotype is heterogeneous. In fact, patients be confirmed on a larger population of Dys/Hypodys pts.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s362 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

ABS55 - Comparison between three different Results. 57 total patients were included in this study, bleeding scores and the Thrombin Generation 63.2% of them were females. 31.6% had a severe disease, Assay (TGA) to assess the haemorrhagic phenotype in patients with different degrees 14.0% moderate, and the remaining 54.4% mild. of FVII deficiency Mean age at diagnosis was 26 years. Family history (1) (1) (2) Marta Milan - Samantha Pasca - Cristina Santoro - for FVII deficiency was found in 45.6% of cases. The (3) (4) Chiara Ambaglio - Marisanta Napolitano - Letizia statistical analyses carried out in order to evaluate Natali (5) - Silvia Nannizzi (5) - Filippo Mori (5) - Ezio the correlation between the four TGA parameters, the Zanon(1) Padua University Hospital, Hemophilia Center, Padova (1) - Umberto FVII (%) according to ISTH-SSC definition, and the I University Hospital, Hematology, Roma (2) - S. Matteo Hospital, three bleeding scores used for the classification of FVII Internal Medicine, Pavia (3) - University Hospital, Hematology, hemorrhagic phenotypes showed that the Lag-time and Palermo (4) - Kedrion SpA, Research&Innovation, Lucca (5) TTP seem to be able to differentiate the severe patients Background. Different scores have been created to with high bleeding from everyone else, while the same define the haemorrhagic phenotype in people with cannot be affirmed for the remaining two parameters, FVII deficiency: Mariani score, ISTH/SSC bleeding ETP and thrombin Peak. All parameters resulted instead assessment score, and Di Minno classification. All these inadequate to distinguish a patient with moderate tools are equally easy to use, but not all have the same bleeding from one with mild bleeding or from a non- accuracy. In addition to scores, the use of Thrombin bleeder. Generation Assay (TGA) to describe the hemorrhagic Conclusions. Preliminary results showed that the phenotype of these patients can be an interesting option Thombin Generation Assay could be an analytical method for the clinicians. Aim of this study was o define the useful to assess the bleeding risk in severe haemorrhagic correlation between three different bleeding scores and phenotype FVII deficiency patients. TGA results in assessing the hemorrhagic phenotype among a group of patients presenting different FVII plasma concentrations and severity degrees of FVII deficiency. Methods. FVII deficiency patients coming to four different Italian Hemophilia Centers (Roma, Pavia, Palermo, Padova) with different bleeding phenotype were enrolled in this study. The severity of FVII deficiency was classified following the “Consensus Definitions in Rare Bleeding Disorders of the Factor VIII/Factor IX ISTH-SSC” (severe: FVII level ≤10%; moderate: FVII level 10–20%; mild FVII level > 20%). The bleeding phenotype has been evaluated by the three different bleeding scores and the plasma of patients was analyzed by the TGA assay. The following TGA parameters has been considered: Lag-Time (time needed to detect© the thrombin SIMTIPRO formation onset); Srl Endogenous Thrombin Potential (ETP - amount of thrombin formed in a defined period); Peak thrombin (the maximum amount of thrombin reached during the thrombogram formation); time to Peak (TTP - time needed to reach the maximum amount of thrombin). The statistical correlation between TGA parameters Vs the bleeding phenotype and the FVII% has been evaluated by Anova and Tukey test.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s363 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT

܁܁ gum bleed. Prophylaxis was not modified and 3.03 - VON WILLEBRAND FACTOR AND VON ibrutinib was temporarily held; WILLEBRAND DISEASE ܁܁ post minor surgery bleed without previous pdFVIII/ VWF (no hematological consultancy). Ibrutinib was ABS56 - Efficacy and safety of Ibrutinib temporarily held and pdFVIII/VWF was infused for in a patient with Waldenström’s 3 consecutive days; Macroglobulinemia and Von Willebrand disease: a case report ܁܁ post BMB hematoma, on ibrutinib and af ter pdFVIII/ Jacopo Agnelli Giacchello (1) - Irene Dogliotti (2) - Cristina VWF. Ibrutinib and prophylaxis were continued. Dainese (1) - Alessandra Valpreda (1) - Enrico Dosio (1) - LTA and VWF recovery before and during stable ibrutinib (2) (2) Daniele Grimaldi - Federica Cavallo - Alessandra therapy were performed. According with literature data, (1) Borchiellini non-pathological lower amplitude and longer lag phase University Hospital City of Health and Science, Regional Center Hemorrhagic and Thrombotic diseases, Hematology Unit, Turin (1) - in collagen-mediated LTA were found. No differences University Hospital City of Health and Science, Hematology Unit, in Arachidonic Acid, Ristocetin and VWF recovery were Turin (2) found. In January 2020, after 7 cycles of ibrutinib, BMB Background. Von Willebrand disease (VWD) is an showed partial response. inherited bleeding disorder characterized by Von Conclusions. No difference in ABR before and after Willebrand Factor (VWF) deficiency (Type 1/3) or ibrutinib plus standard prophylaxis were found; 2 out of 3 disfunction (type 2). Waldenström’s Macroglobulinemia bleeds on ibrutinib were post-procedural (one performed (WM) is a lymphoplasmacytic lymphoma with bone without pdFVIII/VWF). According with published data, marrow (BM) pathological involvement and IgM non-pathological alteration in collagen mediated LTA monoclonal component. Bruton Kinase (BTK) inhibitor were found. As far as we know, this is the first report ibrutinib is a highly effective treatment for WM. regarding the use of ibrutinib in inherited bleeding BTK is involved in the signaling of several platelet disorders. In this case, standard prophylaxis added to receptors, with platelets disfunction and bleeding. Light ibrutinib has not modified prior bleeding phenotype. transmission Aggregometry (LTA) is considered the best Given the association of the 2 rare hematological tool for platelets function evaluation on ibrutinib. We diseases, collaboration between experts is suggested to describe a 77 years old woman with type 2 VWD and guarantee safety and efficacy of both therapies. relapsed WM treated with ibrutinib. Case Report. VWD was diagnosed in 2001 with ABS57 - Type 3 von Willebrand disease VWF:Antigen (VWFAg) 14%, VWF Ricof (VWFRCO) associated with an homozygous splice site 3% and Factor VIII (FVIII:C) of 22%. Previous VWF mutation Federica Riccardi (1) - Gianna Franca Rivolta (1) - Gabriele gene analysis showed 2 mutations, probably in 2 Quintavalle (1) - Annalisa Matichecchia (1) - Antonio different alleles: c.2435delC (frameshift, truncated and Coppola (1) - Annarita Tagliaferri (1) nonfunctional protein) and c.253T>C (missense). ISTH Haemophilia Centre, University Hospital, Parma (1) Bleeding score Assessment Tool (ISTH-BAT) was 23. Desmopressin test was performed, with a good response Background. Type 3 von Willebrand disease (VWD) is but poor tolerance. Annual Bleeding Rate (ABR) before associated with a severe quantitative defect or virtual WM diagnosis was© 3. In August SIMTIPRO 2017, WM was diagnosed absence of von Willebrand Factor Srl (VWF) in plasma and by BM biopsy (BMB) performed due to pancytopenia. In consequently very reduced levels of Factor VIII (FVIII), February 2019 WM relapsed after first line treatment; resulting from its accelerated proteolysis. Type 3 VWD is MYD88 L265P mutation on BM aspirate was detected. inherited in an autosomal recessive pattern, being caused Considering the hemorrhagic phenotype and the high by homozygous or compound heterozygous mutation in efficacy in MYD88L265P WM, reduced dose ibrutinib the gene encoding von Willebrand factor (VWF), which (280mg/d) and standard prophylaxis with plasma maps to chromosome 12p13. The majority of type 3 VWD derived FVIII/VWF (pdFVIII/VWF) were started. ABR mutations are small deletions and insertions, nonsense on ibrutinib plus prophylaxis was 3: or other mutations interfering with VWF synthesis and

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s364 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ABSTRACT secretion. However, approximately 10-15% of VWF gene mutations affects consensus splice sites, conserved nucleodites in intron-exon boundaries that regulate the splicing mechanism. This process provide for intron removal and exon ligation in pre-mRNA transcripts and precedes traslation. Here we report the case of a type 3 VWD patient, referred to Hemophilia Centre of Parma, carrying an homozygous splice site mutation. Methods. Bleeding symtoms, laboratory tests (VWF:RCo and FVIII:C) and family tree were retrieved by the patient’s clinical records. Blood samples for genetic test were collected from the proband, his parents and his brother. VWF gene coding sequence and exon- intron boudaries were analyzed with Next Generation Sequencing approach. Gene variants were confirmed with direct sequencing. Splice site variant effect was analyzed with NetGene2 an in silico tool (http://www. cbs.dtu.dk/services/NetGene2/). Results. Consistent with the diagnosed VWD type (VWF:RCo and VWF-Ag <1 IU/dL, FVIII 5 IU/dL), the index case had recurrent bleeding manifestations (bruising, epistaxis, hemarthrosis with severe arthropathy at physical and ultrasound evaluation). His relatives showed low-normal VWF:RCo levels and no bleeding symptoms. We identified a VWF gene variant, c.3108+5G>A (rs61748495), in homozygosis in the index case. The same variant was, then, confirmed in heterozygosis in the proband’s relatives (both parents, consanguineous, and the brother). This variant is reported in the ClinVar database with an uncertain significance, whereas is described as pathogenetic in the VWD mutation database (https:// databases.lovd.nl/shared/genes/VWF ), in which it is reported three times. Allele frequency, according to the Genome Aggregation Database (gnomAD), was 0.00000398 (benign frequency cut-off is 0.0057, as reported in Varsome, https://varsome.com/gene/VWF). NetGene2 analysis ©predicts the SIMTIPROdisruption of the native Srl intron 23 donor splice site. Thus, this variant likely affects pre-mRNA splicing. Conclusions. Clinical and genetic features of the patient here described and of his family confirm that splice site mutations in heterozygosis, frequently associated with mild forms of VWD (Corrales et al., JTH 2011), when found in homozygous state, are phenotypically associated with type 3 VWD, with severe clinical symptoms. In vitro studies would be advisable.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s365 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite Milano, 8-11 ottobre 2020

PREMI AICE PER I GIOVANI RICERCATORI*

Premio AICE per il miglior abstract su tematiche inerenti alle innovazioni terapeutiche A next-generation rFVIIa fusion protein with enhanced half-life as a novel by-passing tool in hemophilia Alessio Branchini (Ferrara)

Premi AICE in memoria del Prof. Raffaello de Biasi con il supporto di CSL Behring^ Migliori abstract su aspetti genetici, immunologici, di laboratorio e di ricerca di base dell’emofilia e delle MEC An in vitro sensitive system unravels traces of full-length factor VIII from the majority of F8 nonsense mutations Maria Francesca Testa (Ferrara) Non-canonical F8 variants causing mild hemophilia A Annalisa Maticecchia (Parma) Prediction markers for development of persistent inhibitors in previously untreated patients with severe hemophilia A Syna Miri (Milano) Comparison between three different bleeding scores and the Thrombin Generation Assay (TGA) to assess the haemorrhagic phenotype in patients with different degrees of FVII deficiency Marta Milan (Padova) Investigation of possible correlation between clinical and laboratory phenotype in congenital dysfibrinogenemia/hypodysfibrinogenemia: preliminary results from a single center Antonietta Ferretti (Roma)

Aspetti clinici e della gestione multidisciplinare dell’emofilia e delle MEC Impact of comorbidities and comedication in adult/elderly hemophilic patients Gabriele Quintavalle (Parma) Psycho-emotional SPHERE and functional status of elderly patients with haemophilia: the multicenter S+PHERA study Silvia Riva (Milano) Adherence to prophylaxis in Italian patients with haemophilia: results from a multicentre study Mariasanta Napolitano (Palermo) Telerehabilitation and “Zoomtherapy” during SARS-CoV-2 pandemic Valentina Begnozzi (Milano) Emergency care pathway in haemophilia: the model of Cesena Congenital Bleeding Disorder centre Tiziano Martini© (Cesena) SIMTIPRO Srl Von Willebrand disease and Factor XI deficiency: report of four cases Mariapia Falbo (Catanzaro)

*Due bandi per i migliori abstract presentati al XVII Convegno Triennale da primo autore di età inferiore a 40 anni (https://aiceonline.org/?p=13654). I premi sono stati attribuiti da una Commissione presieduta dal Presidente Reggente AICE, Angiola Rocino, e costituita dai membri del Comitato Scientifico AICE (Massimo Morfini, Presidente; Giancarlo Castaman, Massimo Franchini, Gabriella Gamba, Hamisa Jane Hassan, Maria Gabriella Mazzucconi, Alberto Tosetto). ^Premi banditi e assegnati da AICE con il contributo incondizionato di CSL Behring.

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s366 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite Milano, 8-11 ottobre 2020

Elenco Autori

A Biasoli Chiara ABS21 Cassone Cristina ABS18 Aaen Kristin Hovden ABS27 Biasoli Chiara ABS37 Castaman Giancarlo ABS08 Abbonizio Francesca RE02 Biasoli Chiara RE09 Castaman Giancarlo ABS13 Acquila Maura RE14 Biasoli Chiara RE18 Castaman Giancarlo ABS28 Agliastro Giuseppe ABS20 Biguzzi Eugenia ABS01 Castaman Giancarlo ABS30 Agnelli Giacchello Jacopo ABS04 Biguzzi Eugenia ABS02 Castaman Giancarlo ABS32 Agnelli Giacchello Jacopo ABS23 Biguzzi Eugenia ABS03 Castaman Giancarlo ABS33 Agnelli Giacchello Jacopo ABS24 Biguzzi Eugenia ABS05 Castaman Giancarlo ABS37 Agnelli Giacchello Jacopo ABS44 Biguzzi Eugenia ABS52 Castaman Giancarlo ABS38 Agnelli Giacchello Jacopo ABS56 Bissolotti Luciano ABS36 Castaman Giancarlo RE08 Agosti Pasquale ABS49 Boccalandro Elena Anna ABS14 Castaman Giancarlo RE14 Ambaglio Chiara ABS55 Bocchicchio Raffaele ABS54 Catalano Alberto ABS29 Andersen Jan Terje ABS26 Borchiellini Alessandra ABS04 Cavallo Federica ABS56 Andersen Jan Terje ABS27 Borchiellini Alessandra ABS21 Ceresi Nicola ABS15 Andretta Margherita ABS11 Borchiellini Alessandra ABS23 Chairi Sonia ABS36 Antolino Agostino ABS41 Borchiellini Alessandra ABS24 Chilà Diego ABS25 Aprile Simona Michela ABS54 Borchiellini Alessandra ABS44 Chistolini Antonio ABS54 Arcieri Romano RE02 Borchiellini Alessandra ABS56 Cigolini Luisa ABS36 Artoni Andrea ABS49 Boscarino Marco ABS09 Cimino Ernesto ABS40 Boscarino Marco ABS22 Cipolla Antonino ABS19 B Boscolo Massimo ABS52 Cisiano Carola ABS42 Bailon Mariagiulia ABS44 Bosio Caterina ABS18 Clerici Marigrazia ABS52 Baldacci Erminia ABS41 Bowen Joel ABS10 Colpani Paola ABS02 Baldacci Erminia ABS54 Braham Simon ABS01 Colpani Paola ABS03 Balestra Dario ABS38 Braham Simon ABS03 Colpani Paola ABS05 Barello Serena ABS18 Braham Simon ABS05 Coluccia Antonella RE12 Baronciani Luciano ABS02 Braham Simon ABS52 Coluccio Valeria ABS39 Baronciani Luciano ABS03 Branchini Alessio ABS13 Coppens Michiel ABS28 Baronciani Luciano ABS05 Branchini Alessio ABS26 Coppola Antonio ABS06 Barone Francesco ABS54 Branchini Alessio ABS27 Coppola Antonio ABS12 Batur Muhammed ABS10 Branchini Alessio ABS37 Coppola Antonio ABS15 Begnozzi Valentina ABS14 Branchini Alessio ABS38 Coppola Antonio ABS21 Belvini Donata ABS13 Bucciarelli Paolo ABS22 Coppola Antonio ABS34 Belvini Donata ABS37 Bulla Anna ABS19 Coppola Antonio ABS39 Belvini Donata RE13 Buzzi Andrea ABS18 Coppola Antonio ABS43 Bern Malin ABS26 Buzzi Andrea ABS51 Coppola Antonio ABS57 Bern Malin ABS27 Coppola Antonio RE03 Bernardi Francesco© ABS13SIMTIPROC Coppola Antonio Srl RE06 Bernardi Francesco ABS37 Cabibbo Sergio ABS19 Coppola Antonio RE07 Bernardi Francesco ABS38 Camire Rodney ABS26 Coppola Antonio RE14 Bernardi Francesco RE14 Campello Elena RE11 Cortesi Paolo Angelo ABS15 Bernardi Stefano ABS36 Cantori Isabella ABS21 Cortesi Paolo Angelo ABS40 Bertolotti Marina ABS42 Carulli Christian ABS30 Cozzi Giovanna ABS02 Biasoli Chiara ABS12 Carulli Christian ABS32 Cozzi Giovanna ABS03 Biasoli Chiara ABS15 Carulli Christian ABS33 Cozzolino Paolo ABS15 Biasoli Chiara ABS18 Cassone Cristina ABS15 Cucuzza Francesco ABS15

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s369 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ELENCO AUTORI

Cultrera Dorina ABS19 Fjerza Rajmonda ABS30 Leebeek Frank W.G. ABS28 Cultrera Dorina ABS37 Fornari Arianna ABS15 Leo Francesca ABS07 Forneris eleonora ABS35 Leo Francesca ABS48 D Fragomeno Anna ABS15 Leo Francesca ABS53 Dainese Cristina ABS04 Frusconi Sabrina ABS38 Leombruni Paolo ABS44 Dainese Cristina ABS23 Leonardi Andrea ABS31 Dainese Cristina ABS24 G Lessi Marilena ABS16 Dainese Cristina ABS44 Gatteri Vincenzo ABS36 Linari Silvia ABS08 Dainese Cristina ABS56 Gemmati Donato ABS37 Linari Silvia ABS30 Dallari Francesca Lyda ABS39 Giacomini Elisa ABS11 Linari Silvia ABS32 Davidson Robert ABS26 Giampaolo Adele RE02 Linari Silvia ABS38 De Luca Maria Lucia ABS54 Giermasz Adam ABS28 Lombardi Silvia ABS13 Degli Esposti Luca ABS11 Giuffrida Gaetano ABS40 Lombardi Silvia ABS26 Demartis Francesco ABS21 Gomez Esteban ABS28 Lombardi Silvia ABS27 Demartis Francesco ABS30 Graffigna Guendalina ABS18 Losio Maria ABS43 Di Cocco Maria Luisa ABS29 Gresele Paolo ABS37 Luciani Matteo ABS21 Di Gregorio Patrizia ABS29 Grimaldi Daniele ABS56 Luise Francesca ABS25 Di Laura Danilo ABS40 Grippa Veronica ABS45 Luise Francesca ABS51 Di Minno Giovanni ABS40 Gualtierotti Roberta ABS01 Lunghi Barbara ABS38 Di Minno Matteo Nicola Dario RE16 Gualtierotti Roberta ABS03 Dogliotti Irene ABS56 Gualtierotti Roberta ABS05 M Dosio Enirco ABS04 Gualtierotti Roberta ABS09 Maino Alberto ABS49 Dosio Enrico ABS23 Gualtierotti Roberta ABS52 Malizia Raniero ABS29 Dosio Enrico ABS24 Guida Elena ABS18 Malori Alessandra ABS43 Dosio Enrico ABS56 Gut Robert ABS28 Mancini Ilaria ABS49 Mannucci Pier Mannuccio ABS22 E H Mannucci Pier Mannuccio ABS50 Elia Lucia Concetta ABS07 Hermans Cedric ABS20 Mansueto Maria Francesca ABS20 Elia Lucia Concetta ABS48 Mansueto Maria Francesca ABS46 Elia Lucia Concetta ABS53 I Mantovani Lorenzo Giovanni ABS15 Iannaccaro Piergiorgio ABS07 Mantovani Lorenzo Giovanni ABS40 F Iannaccaro Piergiorgio ABS48 Marchesini Emanuela ABS50 Facchetti Rita ABS15 Iannaccaro Piergiorgio ABS53 Marchetti Giovanna ABS38 Falbo Mariapia ABS07 Innocenti Massimo ABS30 Marietta Marco ABS39 Falbo Mariapia ABS48 Innocenti Massimo ABS32 Marino Renato ABS40 Falbo Mariapia ABS53 Innocenti Massimo ABS33 Marino Renato ABS41 Feola Giulio ABS45 Iorio Alfonso ABS50 Martinelli Ida ABS01 Ferrarese Mattia© ABS13SIMTIPROMartinelli IdaSrl ABS03 Ferrarese Mattia ABS26 K Martinelli Ida ABS05 Ferrarese Mattia ABS27 Kampmann Peter ABS28 Martinelli Ida ABS09 Ferrari Barbara ABS49 Key Nigel S. ABS28 Martinelli Ida ABS52 Ferretti Antonietta ABS54 Klamroth Robert ABS28 Martinelli Ida Marianna ABS14 Ferrini Anna Chiara ABS16 Martinelli Marco ABS36 Ferrini Anna Chiara ABS17 L Martinelli Nicola ABS38 Fjerza Rajmonda ABS08 Lattimore Susan ABS28 Martini Tiziano ABS16

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 s370 All rights reserved - For personal use only No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ELENCO AUTORI

Martini Tiziano ABS17 Oriana Vincenzo ABS25 Poggiani Chiara ABS11 Matichecchia Annalisa ABS06 Oriana Vincenzo ABS51 Poletto Francesco RE11 Matichecchia Annalisa ABS12 Poli Ilaria ABS36 Matichecchia Annalisa ABS34 P Pollio Berardino ABS21 Matichecchia Annalisa ABS39 Padovan Lidia ABS52 Pollio Berardino ABS35 Matichecchia Annalisa ABS57 Pagliarino Mauro ABS35 Pollio Berardino ABS42 Mazzucconi Maria Gabriella ABS54 Pagliarino Mauro ABS42 Polo Raul Marco ABS34 Meijer Kathleen ABS28 Palla Roberta ABS09 Prejano Simona ABS07 Meijer Piet RE05 Palla Roberta ABS10 Prejano Simona ABS48 Melchiorre Daniela ABS08 Palla Roberta ABS22 Prejano Simona ABS53 Menegatti Marzia ABS10 Paolini Fabrizio ABS29 Preti Daniele ABS15 Messina Dora ABS51 Pasca Samantha ABS21 Miesbach Wolfgang ABS28 Pasca Samantha ABS40 Q Milan Marta ABS55 Pasca Samantha ABS41 Quintavalle Gabriele ABS06 Miniotti Marco ABS44 Pasca Samantha ABS47 Quintavalle Gabriele ABS12 Miri Syna ABS22 Pasca Samantha ABS55 Quintavalle Gabriele ABS34 Modafferi Bruno ABS25 Passeri Valter Emilio ABS36 Quintavalle Gabriele ABS39 Molinari Angelo Claudio ABS21 Pasta Gianluigi RE09 Quintavalle Gabriele ABS43 Molinari Angelo Claudio ABS37 Pasta Gianluigi RE16 Quintavalle Gabriele ABS57 Molinari Angelo Claudio RE04 Pasta Gianluigi RE17 Morfini Massimo ABS37 Pedrazzi Paola ABS16 R Morfini Massimo ABS38 Pedrazzi Paola ABS17 Radossi Paolo ABS13 Mori Filippo ABS55 Perrone Valentina ABS11 Radossi Paolo ABS37 Peyvandi Flora ABS01 Radossi Paolo RE13 N Peyvandi Flora ABS02 Rampi Nicolò ABS01 Nakar Charles ABS10 Peyvandi Flora ABS03 Rampi Nicolò ABS05 Nannizzi Silvia ABS55 Peyvandi Flora ABS05 Ranalli Paola ABS39 Napolitano Mariasanta ABS20 Peyvandi Flora ABS09 Raso Simona ABS20 Napolitano Mariasanta ABS37 Peyvandi Flora ABS10 Raso Simona ABS46 Napolitano Mariasanta ABS41 Peyvandi Flora ABS14 Recht Michael ABS28 napolitano mariasanta ABS46 Peyvandi Flora ABS22 Ricca Irene ABS35 Napolitano Marisanta ABS55 Peyvandi Flora ABS49 Ricca Irene ABS41 Natali Letizia ABS55 Peyvandi Flora ABS52 Ricca Irene ABS42 Natesirinilkul Rungrote ABS10 Pieri Lisa ABS08 Riccardi Federica ABS06 Nicolò Giovanna Maria ABS51 Pieri Lisa ABS30 Riccardi Federica ABS12 Nicolò Giovanna Maria ABS25 Pieri Lisa ABS33 Riccardi Federica ABS34 Nicolosi Daniela ABS40 Pinotti Mirko ABS13 Riccardi Federica ABS39 Nilsen Jeannette ©ABS26 SIMTIPROPinotti Mirko ABS26 Riccardi Federica Srl ABS57 Nilsen Jeannette ABS27 Pinotti Mirko ABS27 Riccardi Federica RE14 Novembrino Cristina ABS01 Pinotti Mirko ABS37 Riva Silvia ABS49 Novembrino Cristina ABS02 Pinotti Mirko RE10 Riva Silvia ABS50 Pipe Steve W. ABS28 Rivolta Gianna Franca ABS06 O Piromalli Angela ABS25 Rivolta Gianna Franca ABS12 Oliovecchio Emily ABS50 Piromalli Angela ABS51 Rivolta Gianna Franca ABS34 Oliovecchio Emily RE01 Pivetti Stefania ABS36 Rivolta Gianna Franca ABS39

Blood Transfus 2020; 18 (Suppl 3) DOI 10.2450/2020.S3 All rights reserved - For personal use only s371 No other use without premission XVII Convegno Triennale sui Problemi Clinici e Sociali dell’Emofilia e delle Malattie Emorragiche Congenite ELENCO AUTORI

Rivolta Gianna Franca ABS43 Santoro Rita Carlotta ABS40 Tagliaferri Annarita ABS43 Rivolta Gianna Franca ABS57 Santoro Rita Carlotta ABS48 Tagliaferri Annarita ABS57 Roberson Christopher ABS10 Santoro Rita Carlotta ABS53 Tagliaferri Annarita RE03 Rocino Angiola ABS09 Santoro Rita Carlotta RE04 Testa Maria Francesca ABS13 Rocino Angiola ABS15 Sartori Maria Teresa ABS31 Thukral Neelam ABS10 Rocino Angiola ABS41 Sawyer Eileen K. ABS28 Tofani Lorenzo ABS08 Rocino Angiola ABS47 Scalambrino Erica ABS52 Torres Marcela ABS10 Rocino Angiola RE14 Schiavone Lucia ABS22 Tosetto Alberto ABS11 Roopenian Derry ABS26 Schutgens Roger ABS28 Tosini Rossella ABS36 Roopenian Derry ABS27 Scita Giacomo ABS34 Tripodi Armando ABS52 Rosendaal Frits ABS22 Serino Maria Luisa ABS37 Rossi Federica ABS02 Shapiro Amy D. ABS10 V Rossi Rossana ABS39 Siboni Simona Maria ABS01 Valdrè Lelia ABS12 Rossio Raffaella ABS01 Siboni Simona Maria ABS02 Valeri Federica ABS23 Ruenes Ruben Dario ABS39 Siboni Simona Maria ABS03 Valeri Federica ABS24 Siboni Simona Maria ABS05 Valpreda Alessandra ABS04 S Siboni Simona Maria ABS10 Valpreda Alessandra ABS23 Sabatino Vincenzo ABS45 Siboni Simona Maria ABS52 Valpreda Alessandra ABS24 Salvatore Franco ABS29 Simioni Paolo RE11 Valpreda Alessandra ABS56 Salviato Roberta ABS37 Siragusa Sergio ABS20 Valsecchi Carla ABS22 Salviato Roberta RE13 Siragusa Sergio ABS46 Vegetti Walter RE15 Sandlie Inger ABS26 Sirocchi Davide ABS20 Verna Sandra ABS29 Sandlie Inger ABS27 Sottilotta Gianluca ABS25 Villa Maria Rosaria ABS47 Sangiorgi Diego ABS11 Sottilotta Gianluca ABS51 Von Drygalski Annette ABS28 Santagostino Elena ABS21 Spiezia Luca RE11 Santoro Cristina ABS21 Z Santoro Cristina ABS37 T Zanon Ezio ABS21 Santoro Cristina ABS54 Tagliaferri Annarita ABS06 Zanon Ezio ABS40 Santoro Cristina ABS55 Tagliaferri Annarita ABS12 Zanon Ezio ABS47 Santoro Rita Carlotta ABS07 Tagliaferri Annarita ABS21 Zanon Ezio ABS55 Santoro Rita Carlotta ABS21 Tagliaferri Annarita ABS34 Zanon Ezio RE06 Santoro Rita Carlotta ABS37 Tagliaferri Annarita ABS39 © SIMTIPRO Srl