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An International Registry of Patients with Plasminogen Deficiency

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An International Registry of Patients with Plasminogen Deficiency REVIEW ARTICLE An international registry of patients with Ferrata Storti Foundation plasminogen deficiency (HISTORY) Amy D. Shapiro, 1 Marzia Menegatti, 2 Roberta Palla, 3 Marco Boscarino, 2 Christopher Roberson, 1 Paolo Lanzi, 4 Joel Bowen, 5 Charles Nakar, 1 Isaac A. Janson 1 and Flora Peyvandi 2,3 1Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA; 2Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy; 3Università degli Studi di Haematologica 2020 4 Milano, Department of Pathophysiology and Transplantation, Milan, Italy; Misto s.r.l., Volume 105(3):554-561 Milan, Italy and 5Rho, Inc., Durham, NC, USA ABSTRACT lasminogen deficiency is an ultra-rare multisystem disorder charac - terized by the development of fibrin-rich pseudomembranes on Pmucous membranes. Ligneous conjunctivitis, which can result in vision impairment or loss, is the most frequent symptom reported. Affected systems may also include the respiratory tract, oropharynx, female reproductive tract, gingiva, middle ear, renal collecting system, skin and central nervous system. Untreated, plasminogen deficiency may result in significant reduction in quality of life and morbidity with poten - tial life-threatening complications. Non-specific therapies are inadequate and plasminogen concentrates are not commercially available. The cur - rent understanding of plasminogen deficiency and management of disease symptoms and its progression are based on case reports/series and two small clinical trials. To date there has never been a comprehensive, inter - national study to examine the natural history or optimal therapeutic inter - Correspondence: vention; knowledge gaps include identification of contributing factors and triggers of disease manifestations, inability to predict disease course, and AMY D. SHAPIRO insufficient real-world data for use of therapeutics. We have created an [email protected] international, observational study (HISTORY) in a large cohort of persons with plasminogen deficiency and first-degree family members to address Received: October 22, 2019. these gaps and to advance knowledge and care. HISTORY will build upon Accepted: January 20, 2020. the established relationship between the Indiana Hemophilia and Thrombosis Center and the Fondazione Angelo Bianchi Bonomi, IRCCS Pre-published: January 30, 2020. Ca’ Granda Ospedale Maggiore Policlinico - University of Milan and will utilize a modified version of the Prospective Rare Bleeding Disorders doi:10.3324/ haematol.2019.241158 Database (PRO-RBDD). A biorepository containing samples from sub - jects with plasminogen deficiency will be established. This article Check the online version for the most updated describes the rationale behind the study and efforts towards its goals. information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/554 Introduction ©2020 Ferrata Storti Foundation Diseases are defined as rare if they affect fewer than 200,000 people in the Material published in Haematologica is covered by copyright. United States of America (USA) or fewer than 1 in 2,000 in the European Union; All rights are reserved to the Ferrata Storti Foundation. Use of there are estimated to be approximately 6,500 clinically distinct rare diseases published material is allowed under the following terms and 1 conditions: across all medical specialties. Given the large number of diseases meeting this https://creativecommons.org/licenses/by-nc/4.0/legalcode. broad classification, the term ‘ultra-rare disease’ has emerged to describe the rarest Copies of published material are allowed for personal or inter - of these disorders; this phrase is not well defined, but in the United Kingdom (UK) nal use. Sharing published material for non-commercial pur - it has come to mean fewer than 1,000 patients in that country (approximately 1 in poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, 65,000). These diseases pose unique considerations for the researcher, clinician sect. 3. Reproducing and sharing published material for com - and patient; these range from an understanding of the natural history of the dis - mercial purposes is not allowed without permission in writing ease and accurate diagnosis, to safe and effective treatment options and availabil - from the publisher. ity of knowledgeable specialists. Randomized and large prospective clinical trials are often not feasible for ultra- rare diseases as the limited number of eligible patients and phenotypic hetero - 554 haematologica | 2020; 105(3) HISTORY, a plasminogen deficiency registry geneity affect recruitment, interpretation of data and epidemiological study performed in the UK observed a applicability of conclusions to the larger real-world popu - 0.26% prevalence of asymptomatic heterozygous PLGD; 4-6 lation of patients; in many cases it may not be possible to similar prevalences of heterozygous PLGD have been design a clinical trial accurately because of insufficient reported in other countries. 7-9 The UK data suggest that the knowledge of the disease. 2 Instead clinicians have often prevalence of individuals with symptomatic PLGD relied on personal experience, case studies/series and (homozygous/compound heterozygous) is 1.6 per million patient registries to understand the natural history of population; 10,11 there are estimated to be 500 symptomatic these diseases and to collect data on therapeutic interven - people with PLGD in the USA and 12,000 worldwide. tions and patient outcomes. Patient registries may be Based on experience with other rare bleeding disorders, a national, regional or international, each with its own higher prevalence of PLGD is likely to occur in regions advantages and disadvantages. The value of international where consanguineous marriages are more common; 11,12 for patient registries in rare diseases has long been recog - this reason, a national study would likely misstate the true nized; however, given the large number of rare diseases prevalence and phenotypic diversity of the disease. An and the small number of affected patients, funding oppor - increased number of females are reported to be sympto - tunities are frequently limited, particularly for long-term matic compared to males (ratio of 1.27-1.88:1). 12,13 maintenance. 1 People with PLGD may exhibit a multi-organ systemic Some diseases are so rare that many clinicians may disease that commonly manifests as the extravascular never see a case; for example, plasminogen deficiency accumulation of fibrin-rich, woody (ligneous) (PLGD) is an ultra-rare disease with an estimated preva - pseudomembranes on mucous membranes. PLGD is a lence of approximately 1.6 per million population. Most lifelong disease, although the most severe symptoms are commonly it presents as ligneous conjunctivitis, an observed in infants and children. 3,14 Ligneous conjunctivi - extravascular accumulation of fibrin-rich, woody (lig - tis is the most common disease symptom (81% preva - neous) pseudomembranes on the mucous membrane of lence); 3 pseudomembrane growth may be triggered by a the eye; it can also manifest on other mucous mem - local infection or injury and can result in impairment or branes, and as a life-long, systemic disease impacting loss of vision if untreated and/or persistent. 3,11 multiple systems either intermittently or continuously. Approximately one-third of people with PLGD have No specific therapies are approved by the Food and Drug corneal involvement with potential for blindness, 11,12 and Administration or European Medicines Agency and non - 30% present with ligneous gingivitis resulting in peri - specific treatments are inadequate. odontal destruction and tooth loss. 3,12,13 Other common Current knowledge of PLGD stems from case reports symptom locations include the respiratory tract (20%), and small series; systematic prospective data collection ears (14%), female genitourinary tract (9%), and kidneys coupled with serial biological samples collected from per - (4%). 3,11,15-18 sons with PLGD and first-degree family members has not Lesions are often inflamed and painful and can compro - been performed. Knowledge gaps include identification mise organ function, resulting in life-threatening condi - of contributing factors to and triggers of disease manifes - tions including renal and respiratory failure (e.g., tracheo - tations, inability to predict disease course, and insuffi - bronchial lesions). 11,18 Central nervous system complica - cient real-world data for individualized use of potential tions have been noted, including Dandy-Walker malfor - new therapeutics. To address unmet needs, a retrospec - mation and occlusive hydrocephalus 12 in 14% of children tive and prospective data collection system of a large due to fibrin deposition in the cerebral ventricular system; cohort of people with PLGD and their family members shunts used to drain cerebrospinal fluid are prone to has been developed to define the natural history of PLGD occlusion or poor peritoneal absorption, leading some and is entitled Hypoplasminogenemia: An International neurosurgeons to recommend ventriculocholecystic Retro Spec Tive and Pr Ospective Coho Rt Stud Y (HISTORY). shunts. 19 In women, dysmenorrhea, abnormal menses, HISTORY addresses key gaps in the knowledge about the dyspareunia, and infertility have been reported. 15 Wound natural history of PLGD and builds
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