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European Congress on Thrombosis and Haemostasis ABSTRACT BOOK European Congress on Thrombosis and Haemostasis ABSTRACT BOOK 28 – 30 September 2016 0 TABLE OF CONTENT 1 SCIENCE, FAST AND FUROUS 2 2 FOCUS SYMPOSIA ABSTRACTS 11 3 INTEGRATED SYMPOSIA ABSTRACTS 24 4 ORAL COMMUNICATIONS 35 5 POSTER SESSIONS ABSTRACTS (incl. board No) 84 6 POSTER VIEW & DISCUSSION ABSTRACTS (incl. Board No) 146 1 1 SCIENCE, FAST AND FUROUS Platelets ECTH-299 Characterization of two novel RASGRP2 variants leading to defective CalDAG-GEFI- mediated RAP1 activation and platelet dysfunction Jose Rivera, María Luisa Lozano* 1, Aaron Cook2, José María Bastida3, David S Paul4, Iruin Gemma5, Ana Rosa Cid6, Rosa Adan Pedroso5, José Ramón González Porras3, Jesús María Hernández Rivas3, Sara J Fletcher7, Ben Johnson7, Neil Morgan7, Francisca Ferrer1, Vicente Vicente1, John Sondek8, Steve P Watson7, Wolfgang Bergmeier9 1Centro Regional de Hemodonación, Murcia, Spain, 2Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States, 3IBSAL-Hopsital Univeristario de Salamanca, Salamanca , Spain, 4McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States, 5Hospital de Cruces, Bilbao, 6Hospital Universitario Politécnico de la Fe, Valencia, Spain, 7Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom, 8Department of Pharmacology, 9Department of Biochemistry and Biophysics, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Background: In addition to mutations in ITG2B or ITGB3 genes causing defective aIIbb3 expression/function in Glanzmann’s thrombasthenia patients, platelet dysfunction can be due to genetic variability in proteins mediating inside-out activation of aIIbb3. The RASGRP2 gene encodes the Ca2+ and diacylglycerol-regulated guanine nucleotide exchange factor 1 (CalDAG-GEFI). This protein is strongly expressed in platelets and neutrophils, where it facilitates the activation of the small GTPase Rap1 and subsequent activation of integrins. To date, only three siblings with platelet dysfunction caused by a RASGRP2 variant have been reported. Aims: Functional and molecular characterization of three patients from two unrelated families, with bleeding tendency and impaired platelet aggregation, but no mutations in ITG2B or ITGB3. Methods: A 9yr-old Chinese child and two Spanish siblings, a 55yr-old woman and 46yr-old man, with suspicion of inherited platelet disorder, were studied. Blood cell counts, platelet function (platelet aggregation and secretion, glycoproteins expression and platelet activation by flow cytometry, clot retraction and platelet spreading), and integrin activation in neutrophils were assessed. DNA from the Chinese boy and the Spanish siblings was analyzed by next generation sequencing (NGS) and whole exome sequencing (WES), respectively. Expression of CalDAG-GEFI protein was quantified by immunoblotting. The GEF activity of purified wild type and mutant CalDAG-GEFI was compared by an in vitro Rap1B activation assay with Bodipy FL GDP. Results: Patients displayed moderate bleeding tendency, normal platelet count and volume, and mild anemia. Platelet phenotyping showed prolonged PFA-100 closure times and reduced platelet aggregation in response to ADP and low dose collagen. Aggregation with high concentrations of PAR1, collagen, arachidonic acid, or PMA was unaffected. Platelet surface receptor expression was normal. NGS identified a homozygous change c.1142C>T in RASGRP2, leading to a p.Ser381Phe substitution in CalDAG-GEFI in the Chinese patient. WES revealed a homozygous c.337C>T (p.Arg113X) mutation in the RASGRP2 gene of the Spanish siblings. Expression of CalDAG-GEFI, but not Rap1 or the Rap-GAP Rasa3, was markedly reduced in platelets from all patients. Consistent with the aggregation defect, aIIbb3 activation was markedly impaired in patient platelets. Only minor defects were observed in granule secretion, clot retraction or spreading on fibrinogen. Patient neutrophils showed normal b2 integrin and reduced b1 integrin expression. b2 integrin activation in patient neutrophils stimulated with fMLP, PMA, or Mn2+ was impaired. Neutrophil granule secretion was not affected. Structural modeling suggested that the p.Ser381Phe substitution causes a conformational change affecting both protein stability and nucleotide exchange activity in CalDAG-GEFI. Consistently, purified CalDAG-GEFI p.Ser381Phe protein showed markedly reduced exchange activity towards Rap1B in vitro. Summary/Conclusion: We report three patients with platelet dysfunction resulting from novel mutations in RASGRP2 that affect the synthesis and/or function of CalDAG-GEFI and cause an impaired platelet aggregation response to select agonists. These findings strengthen the molecular heterogeneity of RASGRP2 as a cause of inherited platelet disorders. 2 ISCIII PI14/01956 & CB15/00055; BHF RG/ PG/13/36/30275 & RG/09/007; NIH P01 HL120846 &R01 HL121650. 3 Platelets ECTH-471 Light sheet fluorescence microscopy (LSFM) and subsequent quantitative structural analysis of megakaryocytes in intact murine bone Mari Gorelashvili* 1, David Stegner1, Judith van Eeuwijk2, Oğuzhan Angay3, Jürgen Pinnecker3, Harald Schulze4, Bernhard Nieswandt1, 2, Katrin Heinze3 1Department of Experimental Biomedicine, University Hospital Würzburg, 2Department of Experimental Biomedicine, 3Bioimaging Center, Rudolf Virchow Center, University of Würzburg, 4Department of Experimental Biomedicine, University of Würzburg, Würzburg, Germany Background: Megakaryocytes (MKs) are large polyploid cells residing in the bone marrow (BM) which are the progenitors of anucleate blood platelets. According to the current concept, MK development progresses spatially from the endosteal niche in the BM to the vascular niche, where terminal maturation and platelet release into sinusoids occur. However, experimental evidence supporting this concept is limited due to two-dimensionality of avaliable techniques (such as tissue sectioning) as well as unexplored in silico investigation of MK behaviour in BM. Aims: We aimed to study the distribution of MKs in their native environment in 3D by combining light sheet fluorescence microscopy (LSFM) and computer simulations. Methods: Sterna were antibody-stained for MKs and endothelial cells, paraformaldehyde-fixed, chemically cleared and imaged by light-sheet fluorescence microscopy (LSFM), allowing MK visualization in intact bones. This approach allowed us to quantify MK volume, localization and number in the BM. Based on ex vivo data obtained by LSFM, MK distribution in the BM was studied in silico using the real vasculature and cell geometries as templates. Further on, two photon microscopy was used to investigate MK motility in vivo. Results: Unexpectedly, in ex vivo 3D LSFM we visualized a homogeneous and extremely dense network of blood vessels in the BM, revealing an unexpected spatial limitation for MK migration. LSFM based in silico studies on MK localization in BM showed only a minor vessel bias and an essentially random distribution of non-vessel associated cells. Enhanced stimulation of megakaryopoiesis upon induced thrombocytopenia (with the use of anti-GPIb antibodies) had no significant effect on MK number or localization. Further, MK migration was not observed by in vivo microscopy, neither before nor after platelet depletion. Summary/Conclusion: In conclusion, our novel method of imaging intact BM by LSFM complements current in situ and ex vivo techniques and enables realistic in silico studies. The high quality 3D experimental data, combined with in vivo and in silico studies, challenge the current concept of MK migration and give an in-depth insight into the environmental regulation of MKs and the functional relevance of MK migration for thrombopoiesis. 4 Clotting ECTH-370 Risk prediction of recurrent venous thrombosis: validation of three models in a large unselected population Jasmijn F Timp*, Saskia le Cessie1, 2, Astrid van Hylckama Vlieg1, Frits R Rosendaal1, Suzanne C Cannegieter1, 3 1Clinical Epidemiology, 2Medical Statistics, 3Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, Netherlands Background: After a first venous thrombotic event the lifetime risk of recurrence is considerable. Because the bleeding risk associated with anticoagulant treatment is high as well, the decision on its optimal duration is challenging. Accurate assessment of an individual’s recurrence risk is therefore essential. Previously, three prediction models for recurrent venous thrombosis have been published, but external validation has hardly been performed, which hampers their practical usefulness. Aims: To externally validate previously published prediction models for recurrent venous thrombosis (HERDOO2, Vienna, DASH score). Methods: We used data from the MEGA follow-up study, in which 4731 consecutive patients with a first venous thrombotic event (DVT, PE or both), aged 18-70 years, were followed for recurrence between 1999 and 2010. Until June 2002 blood was sampled approximately three months after discontinuation of anticoagulant treatment (blood available in ~50% of the patients). Missing values on laboratory measurements and other variables were multiply imputed and results were pooled according to Rubin’s rules. For the validation analysis we selected patients with an unprovoked first event (i.e. without cancer in the five years before the event, without surgery, trauma, plaster cast, pregnancy or immobilization in the three months
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