SIMTI Servizi Srl

Official journal of

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Società Italiana di Medicina Trasfusionale e Immunoematologia - SIMTI Associazione Italiana dei Centri Emofilia - AICE Hrvatsko društvo za hematologiju i transfuzijsku medicinu - HDHTM Sociedad Española de Transfusión Sanguínea y Terapia Celular - SETS Società Italiana per lo Studio dell'Emostasi e della Trombosi - SISET

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LECTURES AND ABSTRACT BOOK XXIV National Congress of the Italian Society for Thrombosis and Hemostasis - SISET

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Abano Terme (PD), Italy 9-12 November 2016 Guest Editor: Anna Falanga

Blood Transfus 14, Supplement no. 5, October 2016 - ISSN 1723-2007

w w w. b l o o d t r a n s f u s i o n . i t Edizioni SIMTI Blood Transfus DOI 10.2450/2012.00?????? © SIMTI Servizi Srl

All rights reserved - For personal use only No other use without premission

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Sr l zi Se rv i TI SI M © All rights reserved - For personal use only No other use without premission

ISSN 1723-2007

Edizioni SIMTI © SIMTI Servizi Srl

Official journal of:

Società Italiana di Medicina Trasfusionale e Immunoematologia, SIMTI Associazione Italiana dei Centri Emofilia, AICE Hrvatsko društvo za hematologiju i transfuzijsku medicinu, HDHTM Sociedad Española de Transfusión Sanguinea y Terapia Celular, SETS Società Italiana per lo Studio dell'Emostasi e della Trombosi, SISET

Affiliated Societies of the journal:

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International Editorial Board Jean-Pierre Allain, United Kingdom Giuseppe Aprili, Italy Michael Auerbach, United States of America John Barbara, United Kingdom Lydia Blanco, Spain Ines Bojanić, Croatia Pietro Bonomo, Italy Dialina Brilhante, Portugal Maria Domenica Cappellini, Italy Jean-Pierre Cartron, France Giancarlo Castaman, Italy Valerio De Stefano, Italy Josè António Duran, Portugal Willy A Flegel, United States of America Gilles Folléa, The Netherlands Zulmira Fonseca, Portugal Gabriella Girelli, Italy Giuliano Grazzini, Italy Ana Hećimović, Croatia Giancarlo Icardi, Italy Syria Laperche, France Luis Larrea, Spain Franco Locatelli, Italy Aurelio Maggio, Italy Michael Makris, United Kingdom Rossella Marcucci, Italy Maurizio Margaglione, Italy Ivanka Mihaljević, Croatia Manuel Muñoz, Spain Mario Muon, Portugal Alessandro Nanni Costa, Italy Salvador Oyonarte, Spain Arturo Pereira, Spain Flora Peyvandi, Italy Paolo Rebulla, Italy Angiola Rocino, Italy Elena Santagostino, Italy Dorotea Šarlija, Croatia Erhard Seifried, Germany Paolo Simioni, Italy Paul FW Strengers, The Netherlands Jonathan H Waters, United States of America Alessandro Zanetti, Italy

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Editor-in-Chief Giancarlo M Liumbruno [email protected] Senior Editor-in-Chief Claudio Velati Associate Editors Walter Ageno Giovanni Di Minno Anna Falanga Massimo Franchini Joan R Grífols Irena Jukić Pier Mannuccio Mannucci Daniele Prati Roberto Reverberi Luisa Romanò Giuseppe Tagariello Tomislav Vuk Alberto Zanella Affiliated Society Editors Anna Falanga, SISET Maria Helena Gonçalves, APIH Alice Maniatis, HSBT Massimo Morfini, AICE Eduardo Muñiz-Diaz, SETS Ana Planinc Peraica, HDHTM Executive Director Stefano Antoncecchi Founder Lorenzo Lapponi Past Editors-in-Chief Lorenzo Lapponi, 1956-1964 Carlo Alberto Lang, 1965-1966 Roberto Venturelli, 1967-1968 Rosalino Sacchi, 1969-1978 Giorgio Reali, 1979-2006 Editorial Office Luisa Stea and Francesca Fermi SIMTI Servizi Srl Via Desiderio, 21 - 20131 Milano Website www.bloodtransfusion.it Printing Grafica Briantea Srl Via per Vimercate, 25/27 - 20040 Usmate (MI)

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Associação Portuguesa de Imuno-Hemoterapia, APIH - Hellenic Society of Blood Transfusion, HSBT

The journal is indexed in PubMed-MEDLINE, Google Scholar, Embase and Scopus and PubMed Central

Tribunale di Milano - Authorisation n° 380, 16th June 2003 This number is published in 700 copies. Printed in October 2016 Euro 5,00 each

Blood Transfusion articles are indexed in Journal of Citation Reports (JCR) for Impact Factor determination. All rights reserved - For personal use only Impact Factor 2015: 1.514. No other use without premission

Associated with USPI Unione Stampa Periodica Italiana


Index Lectures s645

LE01 - Incidental venous thromboembolism Dentali F., Fantoni C.

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LE02 - Management of venous thromboembolism in cancer patients Falanga A., Russo L.

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Educational Session 2 - Arterial thrombosis

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LE03 - Risk and benefit of combined antiplatelet and anticoagulant therapies Marcucci R., Grifoni E.

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Educational Session 1 - Controversies in VTE management

Educational Session 3 - Controversies in thrombophilia diagnosis and management

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LE04 - Family history is a first-aid tool in primary care to assess the individual risk for VTE Margaglione M., Grandone E.

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Educational Session 4 - Management of hemorrhagic patient

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LE06 - Postpartum haemorrhage Marietta M., Romagnoli E., Luppi M.

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LE05 -Thrombophilia and risk of recurrent venous thromboembolism De Stefano V., Rossi E.

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LE08 - Direct oral anticoagulants: new perspectives on reversal agents Imberti D., Fontana M., Benedetti R.

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State of the art - New therapeutic advances in inherited bleeding disorders

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LE09 - Molecular mechanisms and therapeutic approaches for restoration of mRNA transcription, maturation and translation in inherited coagulation factor deficiencies Balestra D., Bovolenta M., Branchini A., Pinotti M., Bernardi F.

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State of the art - Hot topics in coagulation

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LE10 - Reversal agents for the direct oral anticoagulants Ageno W.

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LE11 - Management of hemostasis abnormalities in cirrhosis: from bench to bedside Tripodi A., Chantarangkul V., Primignani M.

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LE07 - Management of bleeding with point-of-care testing: doubts and certainties Campello E., Spiezia L, Maggiolo S., Simioni P.

Blood Transfus 2016; 14 Suppl 5 DOI 10.2450/2016.S5 © SIMTI Servizi Srl All rights reserved - For personal use only No other use without premission

Oral Communications PLEANARY SESSION 1 OC001 - The carboxyl-terminal region is not essential for secreted and functional levels of coagulation factor X Branchini A., Baroni M., Burini F., Mari R., Gemmati D., Puzzo F., Bernardi F., Pinotti M. OC002 - Role of PCSK9 in platelet activation Rossetti L., Ferri N., Ricci C., Canciani B., Trabattoni D., Santilli F., Davì G., Tremoli E., Camera M. OC003 - Carotid atherosclerotic plaque matrix metalloproteinase-2 predicts adverse outcome in patients undergoing endarterectomy Gubbiotti G., Isernia G., Falcinelli E., Guglielmini G., Lenti M., Gresele P.

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OC004 - Metabolomics by nmr identifies patients with high risk of death within two years after a cardiovascular event: the case of the amiflorence ii study Tenori L., Giusti B., Vignoli A., Gori A.M., Luchinat C., Grifoni E., Barchielli A., Balzi D., Marchionni N., Marcucci R.

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OC005 - Low-dose aspirin is associated with reduced cancer mortality: prospective results from the mOLI-SANI study Costanzo S., Persichillo M., Bonaccio M., De Curtis A., Rago L., Olivieri M., Di Castelnuovo A., Cerletti C., De Gaetano G., Donati M.B., Iacoviello L.

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Plenary Session 2

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OC006 - Biomarkers for the prediction of venous thromboembolism in metastatic cancer patients enrolled in the hypercan study Marchetti M., Verzeroli C., Giaccherini C., Labianca R., Mandalà M., Merelli B., Masci G., Santoro A., De Braud F., Celio L., Gasparini G., Sarmiento R., Tartari C.J., Gamba S., Rio F., Vignoli A., Russo L., Malighetti P., Spinelli D., Iacoviello L., Falanga A.

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OC007 - Risk of venous thromboembolism in hospitalized patients with malignant lymphoma: risk factors and proposal of a lymphoma-specific risk score Hohaus S., Tisi M.C., Bartolomei F., Cuccaro A., Maiolo E., Alma E., De Stefano V.

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OC008 - Real-life use of non-vitamin K antagonist oral anticoagulants in patients with cancer associated venous thromboembolism: a prospective cohort Vedovati M.C., Mancuso A., Pierpaoli L., Paliani U., Conti S., Filippucci E., Ascani A., Radicchia S., Galeotti G., Agnelli G., Becattini C. OC009 - Identification of the platelet surface receptor for active MMP-2 Sebastiano M., Momi S., Falcinelli E., Bury L., Hoylaerts M., Gresele P. OC010 - Trend of circulating microparticles in pregnant patients with antiphospholipid antibody syndrome Campello E., Radu C.M., Mattia E., Tonello M., Bulato C., Hoxha A., Kuzenko A., Ruffatti A., Simioni P. OC011 - Recurrences after splanchnic venous thrombosis: risk factors and effect of different treatments in a retrospective monocenter cohort of 160 patients De Stefano V., Bartolomei F., Ciminello A., Betti S., Za T, Chiusolo P., Rossi E. OC012 - Predictive value of circulating microparticles signature in coronary artery bypass graft patency Canzano P., Brambilla M., Rossetti L., Zara C., Cavallotti L., Parolari A., Veglia F., Tremoli E., Camera M.

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Blood Transfus 2016; 14 Suppl 5: III-XI All rights reserved - For personal use only No other use without premission

Session 1 - Atherothrombosis and arterial thromboembolism OC013 - The generation of platelet micropraticles is modulated by antiplatelet agents Giacomazzi A., Degan M., Calabria S., Meneguzzi A., Minuz P. OC014 - Role of lipoprotein-associated phospholipase a2 in ischemic stroke patients treated with tpa thrombolysis: the magic study Gori A.M., Giusti B., Piccardi B., Innocenti E., Nencini P., Nesi M., Palumbo V., Sereni A., Pracucci G., Abbate R., Inzitari D. OC015 - Sirt1 activation by resveratrol rescues the pro-thrombotic phenotype of bdnfmet/met mice Amadio P., Sandrini L., Lee F.S., Tremoli E., Barbieri S.S. OC016 - Prevalence of cardiovascular risk factors in young and elderly italian population: findings from the inhes Study Persichillo M., Bonanni A., Bracone F., Olivieri M., Costanzo S., Cerletti C., Donati M.B., De Gaetano G., Iacoviello L., Di Castelnuovo A.

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OC017 - Lifestyle and dietary determinants of low-grade inflammation: findings from the mOLI-SANI Study Bonaccio M., Di Castelnuovo A., Pounis G., De Curtis A., Costanzo S., Persichillo M., De Lucia F., Cerletti C., Donati M.B., De Gaetano G., Iacoviello L.

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OC018 - Higher adherence to mediterranean diet is associated with lower levels of d-dimer: findings from the moli-sani study Di Castelnuovo A., Bonaccio M., De Curtis A., Costanzo S., Persichillo M., Bracone F., De Gaetano G., Donati M.B., Iacoviello L. OC019 - Mean platelet volume and risk of all-cause mortality: prospective results from the mOLI-SANI Study Bonaccio M., Di Castelnuovo A., Costanzo S., De Curtis A., Persichillo M., Cerletti C., Donati M.B., De Gaetano G., Iacoviello L.

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OC020 - Residual vein thrombosis in subjects with proximal dvt: an association with subclinical atherosclerosis. The veritas Study Prandoni P., Ciammaichella M., Mumoli N., Zanatta N., Visonà A., Avruscio G., Bucherini E., Bova C., Imberti D., Rossetto V., Camporese G., Noventa F., Milan M.

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OC021 - High on-treatment platelet reactivity and adverse cardiovascular events: any role for gender? Results from the reclose2-acs Study Gori A.M., Giusti B., Grifoni E., Paniccia R., Valenti R., Parodi G., Migliorini A., Antoniucci D., Gensini G.F., Abbate R., Marcucci R.

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Session 2 - Anticoagulant therapy and management of complications OC022 - Direct oral anticoagulants in patients affected by high risk atrial fibrillation with history of intracranial hemorrhage Arioli D., Barillari G., Leone M.C., Romagnoli E., Casali A., Antonucci E., Tittl L., Beyer-Westendorf J., Palareti G., Dentali F. OC023 - Use of reduced dose of non-vitamin K antagonist oral anticoagulants for non-valvular atrial fibrillation in clinical practice: data from a prospective cohort Vedovati M.C., Giustozzi M., Verdecchia P., Pierpaoli L., Conti S., Verso M., Filippucci E., Ascani A., Marchesini E., Agnelli G., Becattini C. OC024 - AF patients on VKAs: heart failure is associated with worst quality of anticoagulation and higher bleeding risk. Results from the start register Poli D., Antonucci E., Migliaccio L., Testa S., Pengo V., Marongiu F., Tripodi A., Palareti G. OC025 - FCSA-START study: bleeding and thrombotic events in an italian prospective cohort of patients treated with DOAC Antonucci E., Migliaccio L., Marongiu F., Pengo V., Poli D., Testa S., Tripodi A., Guazzaloca G., Moia M., Palareti G. Blood Transfus 2016; 14 Suppl 5: III-XI All rights reserved - For personal use only No other use without premission

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OC026 - Management and outcomes of patients with gastrointestinal bleeding related to new oral anticoagulants: findings from prospective cohort Study Verso M., Pierini P., Vinci A., Fedele M., Germini F., Agnelli G.

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OC027 - Fluctuations of inr in anticoagulated patients receiving psychotropic drugs: results from farmamico Milesi V., Gualandris F., Martini G., Bettoni D., Russo L., Falanga A.

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OC028 - VKA treatment and bleeding rate of patients aged older than 90 years: results from a prospective multicentre start register study Poli D., Antonucci E., Fumagalli S., Marongiu F., Testa S., Tripodi A., Palareti G.

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OC029 - The management of patients treated with vka in fcsa Centers 20 years after the iscoat Study: the iscoat-2016 Study Palareti G., Antonucci E., Erba N., Marongiu F., Pengo V., Poli D., Tosetto A., Tripodi A., Moia M.

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OC030 - Management of major bleeding and outcomes in patients treated with doac: results from the start-event register Testa S., Walter A., Antonucci E., Pengo V., Poli D., Beyer-Westendorf J., Righini M., Wang T., Verhamme P., Rojnuckarin P., Caramelli B., Angchaisuksiri P., Paciaroni M., Grifoni E., Guazzaloca G., Sivera P., Grandone E., Turrini A., Rupoli S., Tosetto A., Palareti G.

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Session 3 - Congenital and acquired bleeding disorders (I)

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OC031 - Intracranial haemorrhage in haemophilia patients: the retrospective-prospective italian registry (Emo.R.E.C) Zanon E., Demartis F., Tagliaferri A., Schinco P., Cantori I., Milan M., Molinari A.C., Biasoli C., Coppola A., Castaman G., Luciani M., Sottilotta G., Santagostino E.

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OC032 - Bleeding risk of surgery in patients with inherited platelet disorders. The surgery in platelet disorders and therapeutic approach (SPATA) Study Orsini S., Noris P., Bury L., Heller P., Santoro C., Kadir R., Butta N., Falcinelli E., Cid A., Fabris F., Foussier M., Miyazaki K., Rivera J., Mezzano D., Flaujac C., Podda G., Bermejo N., Favier R., Henskens Y., De Maistre E., De Candia E., Mumford A., Ozdemir N., Eker I., Nurden P., Bayart S., Lambert M., Bussel J., Zieger B., Tosetto A., Melazzini F., Balduini C., Cattaneo M., Schlegel N., Gresele P.

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OC033 - Short and long-term outcome in hemophilia patients with inhibitors undergoing orthopedic prosthetic surgery Linari S., Carulli C., Rizzo A., Felici I., Demartis F., Innocenti M., Castaman G.

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OC034 - Investigation of possible correlation between clinical and laboratory phenotype in congenital fxi deficiency: results from a single center Santoro C., Barone F., Ferrara G., Bochicchio A.R., Bicocchi M.P., Acquila M., Baldacci E., Paoloni F., Ferretti A., Mattone P.F., Porrazzo M., Mazzucconi M.G. OC035 - Safety and effectiveness of desmopressin for the management of mild-moderate von willebrand disease: results of the international Prospective Study in 225 patients Federici A.B., Castaman G. OC036 - The bone disease in haemophilia: the role of von willebrand factor, factor viii and thrombin Lancellotti S., Battafarano G., Sacco M., Arcovito A., De Cristofaro R., Del Fattore A. OC037 - Pharmacokinetics of a novel extended half-life glycopegylated factor ix, nonacog beta pegol (n9-gp) in previously treated adult, adolescent, and paediatric patients with haemophilia b - results from two phase 3 trials Santagostino E., Tiede A., Abdul-Karim F., Carcao M., Persson P., Clausen W., Colberg T., Lapecorella M., Kearney S., Matsushita T., Negrier C., Oldenburg J., Young G. OC038 - Prevalence of disorders of hemostasis in adolescent girls with abnormal uterine bleeding Linari S., Bruni V., Paladino E., Bucciantini S., Castaman G.

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OC039 - Once-weekly dosing with a long-acting glycopegylated factor ix, nonacog beta pegol (n9-gp), maintains time with high mean trough levels in previously treated adult, adolescent, and paediatric patients with severe/moderate haemophilia b - results from two phase 3 clinical trials Santagostino E., Young G., Abdul-Karim F., Carcao M., Colberg T., Clausen W., Persson P., Kearney S., Lapecorella M., Matsushita T., Negrier C., Oldenburg J., Tiede A.

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Session 4 - Laboratory diagnosis OC040 - Thrombin generation in lymphoproliferative diseases at diagnosis Vaccarino A., Stella S., Pagliaro M., Montaruli B., Roccatello D., Bazzan M.

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OC042 - Neosynthesis of Dicer1 in thrombin activated platelets modulates miRNAs profile and mRNA translation Manni G., Bury L., Marturano A., Piselli E., Gresele P.

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OC043 - Changes in thrombin generation parameters induced by addition of reversible inhibitors to normal platelet poor plasma: a direct comparison of Dabigatran, Apixaban and Rivaroxaban Pozzi L., Della Valle P., Pattarini E., D'Angelo A.

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OC041 - Impact of somatic mutations on cellular origin and patterns of plasma microparticles (MP) in patients with myeloproliferative neoplasms (MPN) Tartari C.J., Marchetti M., Lacroix R., Russo L., Gamba S., Finazzi G., Rambaldi A., Falanga A.

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OC044 - Pharmacogenetics of Apixaban interindividual variability Dimatteo C., D'Andrea G., Vecchione G., Paoletti O., Tiscia G., Santacroce R., Correale M., Brunetti N., Grandone E., Testa S., Margaglione M. OC045 - Comparison of two anti-xa assays for rivaroxaban levels determination with or without exogenous antithrombin Cini M., Legnani C., Carraro P., Cosmi B., Dellanoce C., Marcucci R., Paniccia R., Paoletti O., Pengo V., Poli D., Testa S., Tripodi A., Palareti G.

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OC046 - Pharmacokinetics and -dynamics of dabigatran etexilate and rivaroxaban in short bowel syndrome patients requiring parenteral nutrition (the PDER PAN Study) Barco S., Cheung Y.W., Coppens M., Mathot R., Van Den Dool E., Stroobants A., Serlie M., Middeldorp S. OC047 - Thrombin generation in patients with non valvular atrial fibrillation and venous thromboembolism treated with DOAC and VKA Paoletti O., Dellanoce C., Bassi L., Beati C., Cancellieri E., Morandini R., Stramezzi M., Tala M., Zambelli S., Zimmermann A., Testa S.

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OC048 - Two novel mutations in italian family with protein c/protein s deficiency Favuzzi G., D'Andrea G., Tiscia G.L., Cappucci F., Fischetti L., Chinni E., Vergura P., Grandone E., Margaglione M.

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Session 5 - Congenital and acquired bleeding disorders (II) OC049 - Prophylactic efficacy of nonacog beta pegol once weekly in adult and pediatric patients with hemophilia b: a pooled analysis Santagostino E., Escobar M., Young G., Oldenburg J., Mahlangu J., Lapecorella M., Carcao M., Colberg T., Khodaie M., Shima M. OC050 - Genotype and bleeding symptoms in fxi deficiency Quintavalle G., Riccardi F., Rivolta G.F., Tagliaferri A. OC051 - Activated prothrombin complex concentrate in acquired haemophilia a: an italian registry-the F.A.I.R. study Zanon E., Mazzucconi M.G., Milan M., Gamba G., Rocino A., Siragusa S., Cantori I., Mameli L.A., Giuffrida G., Falanga A., Federici A., Lodigiani C., Santoro R.


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OC052 - Responsiveness of hemophilia b-causing nonsense mutations to ribosome readthrough-inducing drugs strictly depends on the nucleotide and protein context Ferrarese M., Branchini A., Campioni M., Mari R., Castaman G., Bernardi F., Pinotti M.

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OC053 - An Exon specific U1snRNA rescues different haemophilia b -causing splicing-defective factor ix variants in mice Balestra D., Scalet D., Franco P., Bernardi F., Pinotti M.

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OC054 - An engineered tale-transcription factor rescues f7 promoter activity impaired by mutations causing severe factor vii deficiency Barbon E., Pignani S., Branchini A., Bernardi F., Pinotti M., Bovolenta M.

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OC055 - Neuromedin u potentiates adp- and epinephrine-induced human platelet aggregation Grippi C., Izzi B., Gianfagna F., Donati M.B., Hoylaerts M., Cerletti C., Iacoviello L., De Gaetano G. OC056 - Modulation of hemostatic parameters in cancer patients undergoing antithrombotic therapy for venous thromboembolism (vte) with low molecular weight heparin (LMWH) D'Alessio A., Marchetti M., Tartari C.J., Russo L., Cecchini S., Resta D., Falanga A.

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OC057 - Hemostatic abnormalities in patients with ehlers-danlos syndrome Artoni A., Abbattista M., Lecchi A., Bassotti A., La Marca S., Marinelli B., Clerici M.G., Martinelli I.

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Session 6 - Venous thromboembolism: clinical and diagnostic aspects (I)

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OC058 - High prevalence of pulmonary embolism in patients hospitalized for syncope Prandoni P., Lensing A., Prins M., Ciammaichella M., Perlati M., Mumoli N., Bucherini E., Visonà A., Bova C., Imberti D., Campostrini S., Barbar S.

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OC060 - Recurrent venous thromboembolism during pregnancy in women with quantitative antithrombin deficiency with or without antithrombotic prophylaxis Passamonti S.M., Artoni A., Bucciarelli P., Gianniello F., Martinelli I.

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OC059 - Extensive computed tomography versus limited screening for detection of occult cancer in unprovoked venous thromboembolism: a multicenter, controlled, randomized clinical trial Prandoni P., Bernardi E., Dalla Valle F., Visonà A., Tropeano P.F., Bova C., Bucherini E., Islam S., Piccioli A.

OC061 - High recanalization rate in patients with proximal-vein thrombosis treated with the new direct oral anticoagulants Prandoni P., Ageno W., Mumoli N., Zanatta N., Imberti D., Visonà A., Ciammaichella M., Simioni L., Cappelli R., Bucherini E., Di Nisio M., Avruscio G., Parisi R., Cuppini S., Sarolo L.

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OC062 - Comparison of strategies for preventing venous thromboembolism in high risk pregnant women according to National and International Guidelines: results of a prospective cohort Study Valdrè L., Lambertini I., Palareti G., Cosmi B. OC063 - The safety of age-adjusted d-dimer to rule out dvt: findings from the palladio algorithm Ageno W., Camporese G., Riva N., Iotti M., Bucherini E., Righini M., Kamphuisen P., Verhamme P., Douketis J., Tonello C., Prandoni P. OC064 - Long-term recurrence of venous thromboembolism after short-term treatment of symptomatic isolated distal deep vein thrombosis: a cohort study Donadini M.P., Dentali F., Pegoraro S., Pomero F., Brignone C., Guasti L., Steidl L., Ageno W. OC065 - Droplet digital PCR: a new promising approach for absolute quantification of the JAK2 V617F mutation in patients with splanchnic venous thrombosis Colaizzo D., Amitrano L., Guardascione M.A., Sgherza N., Chinni E., Favuzzi G., Fini E., Fischetti L., Cappucci F., Cascavilla N., Margaglione M., Grandone E. OC066 - Home parenteral nutrition-associated thromboembolic and bleeding events: results of a cohort Study of 236 individuals Barco S., Heuschen C., Salman B., Brekelmans M., Serlie M., Middeldorp S., Coppens M.

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Session 7 - Fibrinolysis and endothelium: clinical and laboratory OC067 - Fibrinolytic changes precede thrombocytopenia and predict outcome in patients with severe sepsis. Findings from the albios trial Semeraro F., Masson S., Caironi P., Ammollo C.T., Semeraro N., Panigada M., Tognoni G., Gattinoni L., Latini R., Colucci M. OC068 - Hyperfibrinolysis during liver transplantation detected by classical parameters and thromboelastometry Maggiolo S., Campello E., Spiezia L., Tredese A., Saggiorato G., Gavasso S., Feltracco P., Simioni P. OC069 - Multicenter trial on efficacy and safety of human plasma derived plasminogen eye drops for the treatment of ligneous conjunctivitis due to congenital plasminogen deficiency Sartori M.T., Shapiro A., Jeng B., Di Pasquale I., Leonardi A., Nakar C., Price F., Thukral N., Pucci N., Secci J., Bergman G., Lotti Suffredini A., Caputo R.

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OC070 - D-dimer and fibrinolytic activity in patients with liver cirrhosis and ascites Grifoni E., Cellai A.P., Romanelli R.G., Alessandrello Liotta A., Rogolino A.A., Cesari F., Prisco D., Laffi G., Marcucci R.

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OC071 - Grape intake enhances plasma fibrinolysis and reduces thrombin generation by decreasing the procoagulant activity of circulating microparticles Ammollo C.T., Semeraro F., Milella R.A., Antonacci D., Incampo F., Semeraro N., Colucci M.

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OC073 - Prostacyclin prevents venous thrombosis in COX-2 knockout mice: a new role of monocyte Annexin A2 (ANXA2) Sandrini L., Amadio P., Tarantino E., Tremoli E., Barbieri S.S.

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OC074 - Endothelial dysfunction in idiopathic thromboembolism investigated through gene expression profiling of endothelial colony forming cells Lodigiani C., Calcaterra F., Carenza C., Ferrazzi P., Librè L., Mavilio D., Della Bella S.

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OC072 - Thromboelastometry parameters of fibrinolysis: distinction between increased enzymatic fibrinolysis and reduced clot strength Sampietro F., Baraldini V., Pattarini E., Riccipetitoni G., D'Angelo A.

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OC075 - Extracellular histones enhance platelet-mediated clot retraction and fibrinolytic resistance Ammollo C.T., Semeraro N., Colucci M., Semeraro F.

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Session 8 - Hemostasis , inflammation and immunity

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OC076 - Monocyte-derived macrophages from coronary artery disease patients show a proinflammatory and prothrombotic profile Eligini S., Fiorelli S., Cosentino N., Camera M., Fabbiocchi F., Niccoli G., Crea F., Marenzi G., Tremoli E. OC077 - Low molecular weight heparins prevent the formation of neutrophil extracellular traps Manfredi A.A., Rovere-Querini P., D'Angelo A., Maugeri N. OC078 - Progenitor endothelial cells and endothelial mature cells in systemic sclerosis: possible markers of endothelial damage and regeneration in the early stages of connective disease Cesari F., Fabbri A., Rogolino A., Grifoni E., Gori A.M., Guiducci S., Matucci Cerinic M., Marcucci R., Moggi Pignone A., Abbate R. OC079 - The role of circulating microparticles in subjects with thrombofilic associated autoimmune disorders: a new cytofluorimetric approach Niccolai E., Ricci F., Squatrito D., Emmi G., Silvestri E., Emmi L., Ciucciarelli L., Manganaro D., Prisco D., Amedei A. OC080 - Lipoprotein-associated phospholipase a2 circulating levels in the general population of the montignoso study Gori A.M., Sereni A., Kura A., Galora S., Marcucci R., Giusti B., Sofi F., Chiappino D., Della Latta D., Abbate R., Gensini G.F. Blood Transfus 2016; 14 Suppl 5: III-XI All rights reserved - For personal use only No other use without premission

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OC081 - The emerging role of neutrophils in thrombus formation Becatti M., Emmi G., Silvestri E., Vaglio A., Squatrito D., Mannucci A., Taddei N., Marcucci R., Emmi L., Prisco D., Fiorillo C.

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OC082 - Role of whole blood thromboelastometry in patients with sepsis Maggiolo S., Campello E., Spiezia L., Consolaro E., Bulato C., Sartorello F., Simioni P.

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OC083 - Lack of endothelial nitric oxide synthase (enos) induces a pro-thrombotic phenotype in mice Momi S., Guglielmini G., Falcinelli E., Gresele P.

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OC084 - Increased interleukin-6 levels at the time of acute pulmonary embolism are associated with short- and long-term adverse outcomes Barco S., Barbar S., Kirschner Y., Kaeberich A., Hobohm L., Keller K., Hasenfuss G., Wild P., Konstantinides S., Lankeit M.

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Session 9 - Venous thromboembolism: clinical and diagnostic aspects (II)

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OC085 - External validation of the dash prediction model: the trip (Thrombosis Research Italian Partnership) collaboration Tosetto A., Ageno W., Nichele I., Martinelli I., Bucciarelli P., Poli D., Testa S., Tala M., Dentali F., De Stefano V., Bartolomei F., Cosmi B., Lodigiani C., Palareti G.

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OC087 - Incidence and case fatality rate of cerebral vein thrombosis: a population-based Study Dentali F., Ageno W., Fantoni C., Pomero F., Squizzato A., Bonzini M.

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OC086 - Clinical and therapeutic management of splanchnic venous thrombosis Canafoglia L., Rupoli S., Svegliati Baroni G., Gironella M., Micucci G., Federici I., Da Lio L., Scortechini A.R., Leoni P.

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OC088 - The impact of increased systolic pulmonary artery pressure on the late outcome of patients with pulmonary embolism Pesavento R., Filippi L., Prandoni P.; for the SCOPE Investigators

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OC090 - Thrombophilic and cardiovascular risk factors in retinal vein occlusion Bucciarelli P., Passamonti S.M., Gianniello F., Artoni A., Martinelli I.

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OC089 - Obstetrical history of women with cerebral vein thrombosis Poli D., Cenci C., Testa S., Paoletti O., Grifoni E., Maggini N., Antonucci E.

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OC091 - Incidence rates and case fatality rates of portal vein thrombosis and budd-chiari syndrome in northwestern Italy Ageno W., Dentali F., Pomero F., Fenoglio L., Squizzato A., Bonzini M.

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OC092 - Hemostatic profile in women with history of recurrent pregnancy loss: evidence of an underlying prothrombotic status Romagnuolo I., Cozzolino M., Attanasio M., Paladino E., Castaman G., Coccia M.E., Fatini C.

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OC093 - Independent role of white blood cells in predicting the short term outcome in patients with acute pulmonary embolism Pagani G., Martinelli A., Conte G., Bertù L., Turato S., Grazioli S., Guasti L., Grandi A.M., Ageno W., Dentali F.

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Poster Sessions s765

Session 2 - Hemostasis, inflammation and immunity

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Session 3 - Anticoagulant therapy and management of complications (I)

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Session 4 - Congenital and acquired bleeding disorders (I)

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Session 5 - Platelets: congenital and acquired disorders (I)

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Session 6 - Laboratory diagnosis in hemostasis and thrombosis

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Session 7 - Venous thromboembolism: clinical and diagnostic aspects (I)

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Session 8 - Atherothrombosis and arterial thromboembolism (II)

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Session 9 - Anticoagulant therapy and management of complications (II)

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Session 10 - Congenital and acquired bleeding disorders (II)

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Session 11 - Acquired hemostasis disorders: clinical and laboratory

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Session 12 - Platelets: congenital and acquired disorders (II)

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Session 13 - Venous thromboembolism: clinical and diagnostic aspects (II)

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Session 14 - Venous thromboembolism: clinical and diagnostic aspects (III)

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Session 1 - Atherothrombosis and arterial thromboembolism (I)

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Authors Index


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XXIV National Congress of the Italian Society for Thrombosis and Hemostasis - SISET Lectures

XXIV National Congress of the Italian Society for Thrombosis and Hemostasis (SISET) Abano Terme (PD), Italy 9-12 November 2016

SCIENTIFIC ADVISORY BOARD Anna Falanga (Bergamo), Walter Ageno (Varese), Armando D'Angelo (Milano), Giancarlo Castaman (Firenze), Giovanni Davì (Chieti), Maurizio Margaglione (Foggia), Sophie Testa (Cremona), Paolo Prandoni (Padova), Erica De Candia (Roma), Valerio De Stefano (Roma), Marcello Di Nisio (Chieti), Rossella Marcucci (Firenze), Marco Marietta (Modena), Alberto Tosetto (Vicenza)

Bergamo Firenze Foggia Modena Cagliari Milano Milano Genova Bologna Padova Milano Pavia Firenze Padova Roma Milano Alessandria Roma Otranto (LE) Padova Palermo Varese Cremona Padova Milano Vicenza Milano Pordenone Perugia Roma

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Marchetti Marina Marcucci Rossella Margaglione Maurizio Marietta Marco Marongiu Francesco Martinelli Ida Moia Marco Molinari Angelo Claudio Palareti Gualtiero Pengo Vittorio Peyvandi Flora Piovella Franco Poli Daniela Prandoni Paolo Rossi Elena Santagostino Elena Santi Roberto Santoro Cristina Schiavoni Mario Simioni Paolo Siragusa Sergio Squizzato Alessandro Testa Sophie Tormene Daniela Toschi Vincenzo Tosetto Alberto Tripodi Armando Tropeano Pietro Vedovati Maria Cristina Violi Francesco

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Firenze Varese Pavia Torino Perugia Milano Milano Firenze Milano Bari Alessandria Napoli Milano Chieti Roma Roma Roma Varese Napoli Chieti Pozzilli (IS) Bergamo Milano Pavia Firenze Foggia Perugia Pozzilli (IS) Piacenza Bologna

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REVIEWERS Abbate Rosanna Ageno Walter Balduini Carlo Bazzan Mario Becattini Cecilila Bucciarelli Paolo Camera Marina Castaman Giancarlo Cattaneo Marco Colucci Mario Contino Laura Coppola Antonio D'angelo Armando Davì Giovanni De Candia Erica De Cristofaro Raimondo De Stefano Valerio Dentali Francesco Di Minno Giovanni Di Nisio Marcello Donati Maria Benedetta Falanga Anna Federici Augusto Gamba Gabriella Giusti Betti Grandone Elvira Gresele Paolo Iacoviello Licia Imberti Davide Legnani Cristina

Blood Transfus 2016; 14 Suppl 5 All rights reserved - For personal use only No other use without premission

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XXIV National Congress of the Italian Society for Thrombosis and Hemostasis - SISET

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Abano Terme (PD), Italy 9-12 November 2016

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Lectures




Incidence of unsuspected VTE and major risks factors Regarding incidental pulmonary embolism (PE), a bulk of data is available in literature. Conversely, less information is available about silent deep vein thrombosis (DVT) or abdominal deep vein thrombosis (ADVT). In a systematic review and meta-analysis of twelve studies including 10,289 patients, we found a weighted prevalence of unsuspected asymptomatic PE of 2.6% (95% CI 1.9, 3.4), with high risk in inpatients and cancer patients4. In this study the prevalence of PE was higher using a CT scan with 75 years • Female gender • Low body weight • Major bleeding in the previous 6 months • Previous hemorrhagic stroke • Gastrointestinal or genitourinary lesions at risk of bleeding • Malignancies at risk of bleeding • Uncontrolled systemic hypertension • Severe renal failure • Severe liver diseases


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4) Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for cardiothoracic surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35: 2541-619. 5) Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double blind, phase II trial. Eur Heart J 2011; 32: 2781-9. 6) Alexander JH, Becker RC, Bhatt DL, et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009; 119: 2877-85. 7) Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; 365: 699-708. 8) Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009; 374: 29-38. 9) Gibson CM, Mega JL, Burton P, et al. Rationale and design of the Anti-Xa Therapy to Lower cardiovascular events in Addition to standard therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS-ACS 2 TIMI 51) trial: A randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome. Am Heart J 2011; 161: 815-21. 10) Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9-19. 11) Bayer Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS). Available at: https://clinicaltrials.gov/ ct2/show/NCT01776424. 12) Bayer. A Study to Compare the Safety of Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome (GEMINI ACS 1). Available at: https:// clinicaltrials.gov/ct2/show/NCT02293395. 13) Dentali F, Douketis JD, Lim W, et al. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med 2007; 167: 117-24.   14) Paikin JS, Wright DS, Eikelboom JW. Effectiveness and safety of combined antiplatelet and anticoagulant therapy: a critical review of the evidence from randomized controlled trials. Blood Rev 2011; 25: 123-9. 15) Warfarin Antiplatelet Vascular Evaluation Trial Investigators, Anand S, Yusuf S, et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007; 357: 217-27. 16) Anonymous. Adjusted-dose warfarin versus low-intensity fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-8. 17) Gullov AL, Koefoed BG, Petersen P. Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Atrial Fibrillation Aspirin and Anticoagulation. Arch Intern Med 1999; 159: 1322-8.

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contrast with dabigatran and edoxaban, which have been tested in two different dose regimens in a randomized fashion and in sufficiently powered cohorts of AF patients, the lower dosages of rivaroxaban and apixaban have only been used with a dose adjustment strategy in a smaller number of patients, according to baseline characteristics, such as reduced renal function, advanced age and low body weight. Phase III trials investigating DOACs compared with warfarin in patients with AF undergoing PCI are ongoing. PIONEER AF-PCI is an open-label, randomized, multicenter, study evaluating the safety of two different rivaroxaban treatment strategies and one VKA treatment strategy in addition to various combination of DAPT or low-dose aspirin or P2Y12 inhibitors (i.e., clopidogrel, ticagrelor, or prasugrel) among patients non-valvular AF undergoing PCI with stent implantation29,30. RE-DUAL PCI is a trial with the aim of comparing a dual antithrombotic strategy of dabigatran etexilate (110 mg bid or 150 mg bid) plus clopidogrel or ticagrelor with a TT combination of dose-adjusted warfarin plus aspirin (≤100 mg od) plus clopidogrel or ticagrelor31. AUGUSTUS is a randomized, controlled trial in non-valvular AF patients with either a recent ACS or undergoing PCI, in which patients are put on a P2Y12 inhibitor and aspirin on the first day of ACS or PCI, and then randomized to either a VKA or apixaban, with subsequent randomization to aspirin (TT) or placebo (an anticoagulant plus P2Y12 inhibition only)32. The results of these trials could offer in the near future new possibilities of combining antiplatelets and anticoagulant agents. In the setting of concomitant ACS and AF the option of switching clopidogrel to a novel antiplatelet agent aims to enhance the net clinical benefit rather than reducing the risk of bleeding. Novel antiplatelet drugs, such as prasugrel and ticagrelor, are more effective at reducing recurrent myocardial infarction, stroke, and death than clopidogrel in patients with ACS, but they are also associated with an increased risk of bleeding. The use of prasugrel in the contest of TT was evaluated in a study by Sarafoff et al.33 When compared with clopidogrel, the treatment with prasugrel in addition to aspirin and warfarin for a 6-month regimen was associated with a significant increase in the rate of bleeding (28.6 vs 6.7%; p=0.03), without significant difference in the combined ischemic secondary end-points. Although ticagrelor has not been studied to date in TT, it is likely to expose patients to a higher risk of bleeding as well. Therefore, prasugrel and ticagrelor are generally not recommended as a part of a TT10,34. In conclusion, pending further evidence on the role of novel oral anticoagulants and antiplatelets in TT, at present, the best strategy for managing patients with AF who also need DAPT in addition to oral anticoagulants seems to choose the optimal duration of DAPT on an individual basis after a careful assessment of the thromboembolic and bleeding risks.

References 1) Weitz JI. Insights into the role of thrombin in the pathogenesis of recurrent ischaemia after acute coronary syndrome. Thromb Haemost 2014; 112: 924-31. 2) De Caterina R, Goto O. Targeting thrombin long-term after an acute coronary syndrome: opportunities and challenges. Vascular Pharmacology 2016; 81:1-14. 3) Rothberg MB, Celestin C, Fiore LD, et al. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med 2005; 143: 241-50.

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treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). Am Heart J 2015; 169: 472-8 e5. 31) Boehringer Ingelheim. Evaluation of dual therapy with dabigatran vs. triple therapy with warfarin in patients with AF that undergo a PCI with stenting (REDUAL-PCI). Available at: https://clinicaltrials.gov/ct2/show/NCT02164864. 32) Bristol-Myers Squibb. Study Apixaban to Vitamin K Antagonist for the Prevention of Stroke or Systemic Embolism and Bleeding in Patients With Non-valvular Atrial Fibrillation and Acute Coronary Syndrome/Percutaneous Coronary Intervention. Available at https://clinicaltrials.gov/ ct2/show/NCT02415400. 33) Sarafoff N, Martischnig A, Wealer J, et al. Triple therapy with aspirin, prasugrel, and vitamin K antagonists in patients with drug-eluting stent implantation and an indication for oral anticoagulation. J Am Coll Cardiol 2013; 61: 2060-6. 34) Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation, Europace 2015; 17: 1467-507.

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18) Rubboli A, Faxon DP, Airaksinen JKE, et al. The optimal management of patients on oral anticoagulation undergoing coronary artery stenting. The 10th anniversary overview. Thromb Haemost 2014; 112: 1080-7. 19) Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation 2012; 126: 1185-93. 20) Bavishi C, Koulova A, Bangalore S, et al. Evaluation of the efficacy and safety of dual antiplatelet therapy with or without warfarin in patients with a clinical indication for DAPT and chronic anticoagulation: A meta-analysis of observational studies. Catheter Cardiovasc Interv 2016; 88: E12-22. 21) Patti G, Di Sciascio G. Antithrombotic strategies in patients on oral anticoagulant therapy undergoing percutaneous coronary intervention: a proposed algorithm based on individual risk stratification. Catheter Cardiovasc Interv 2010; 75: 128-34. 22) Lip GY, Windecker S, Huber K, et al. P. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS), Eur Heart J 2014; 35: 3155-79. 23) Dewilde WJM, Oirbans T, Verheugt FWA, et al; WOEST study investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an openlabel, randomised, controlled trial. Lancet 2013; 381: 1107-15. 24) Fiedler KA, Maeng M, Mehilli J, et al. Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug-Eluting Stent Implantation: The ISAR-TRIPLE Trial. J Am Coll Cardiol 2015; 65: 1619-29. 25) Rubboli A, Agewall S, Huber K, et al. New-onset atrial fibrillation after recent coronary stenting: Warfarin or nonvitamin K-antagonist oral anticoagulants to be added to aspirin and clopidogrel? A viewpoint. Int J Cardiol 2015; 196: 133-8. 26) Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013; 127: 634-40. 27) Alexander JH, Lopes RD, Thomas L, et al. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2014; 35: 224-32. 28) Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093-104. 29) Janssen Scientific Affairs LLC. A study exploring two strategies of rivaroxaban and one of oral vitamin K antagonist in patients with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). Available at: http://clinicaltrials.gov/ct2/show/NCT01830543. 30) Gibson CM, Mehran R, Bode C, et al. An open-label, randomized, controlled, multicenter study exploring two Blood Transfus 2016; 14 Suppl 5


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Abstract VTE is a complex disorder that is affected by many interacting genetic and non-genetic factors. A positive family history of venous thrombosis may reflect the presence of genetic risk factors in a family. The use of family history for predicting the risk of disease and for personalizing preventive care has led, mainly in Western countries, to a marked increase of easy genetic tests has set-up to investigate the presence of sporadic mutations. The family history is an underused tool and barriers to the appropriate collection and use exist. There is compelling evidence that persons from a different genetic background often carry a significant different VTE risk, suggesting that geographically prevalent susceptibility alleles play a pivotal role. Knowledge of ancestry increases the ability of family history to capture information that allows for the identification of individuals at risk for VTE. Even in the "-omics" era, the family history still plays a very important role, being a proxy mainly for genetic risks of VTE. The family history can be used to allow for a risk stratification, leading to interventions to ameliorate the risk, as laboratory testing for thrombophilic risk factors and a consideration of tailored prophylactic treatment. Keywords: venous thromboembolism, family history, ancestry, genetics, prevention.

The multifactorial model Since its introduction, the multifactorial threshold model has been widely applied in genetic counselling for qualitative (discrete) traits8-10. The multifactorial model includes the influence of many genetic and environmental factors, the risk does not change as drastically with the presence or the absence of one of them. This implies that the susceptibility to VTE is largely accounted for by the clustering of several, possibly inherited, risk factors. Hyperhomocysteinaemia is a mild cause of VTE and provides an excellent example of the interaction among genetic (MTHFR 677TT genotype) and acquired factors (vitamins intake) affecting an intermediate phenotype11. As the cause for VTE, a multifactorial nonMendelian inheritance model was recently formally proposed, while a model postulating a purely environmental cause was rejected6. Usually, geneticists admit that in a multifactorial disease several, but not an unlimited number, loci are involved in the expression of the trait; there is no classical (Mendelian) dominance or recessivity at each of these loci; the loci act in concert in an additive fashion, each adding or detracting a small amount from the phenotype; and the environment interacts with the genotype to produce the final phenotype. None of them is neither necessary nor sufficient for the disease to occur but makes it more likely that one will become ill. This means that liability to develop the disease is continuously distributed in the population because of the additive effects of genetic and environmental factors. Our current thinking is that only the individuals whose liability exceeds a certain threshold will manifest the disorder. However, because the phenotype alone may not be able to distinguish different sub-groups, genetic heterogeneity may affect the ability to identify genetic risk factors associated with the disease.

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LE04 FAMILY HISTORY IS A FIRST-AID TOOL IN PRIMARY CARE TO ASSESS THE INDIVIDUAL RISK FOR VTE Margaglione M.1, Grandone E.2 1 Genetica Medica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Foggia; 2Unità di Aterosclerosi e Trombosi, I.R.C.C.S. "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Italy

60%5,6. In addition, the overall contribution of genetic factors to VTE was further strengthened in male twin pairs. Data from the Danish Twin Registry and from family studies provided substantial evidence for the genetic transmission of VTE. The odds ratio for the second twin to have VTE if one twin had an event was 13.5 and 3.8 for monozygotic and dizygotic twins, respectively7.

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Educational Session 3 Controversies in thrombophilia diagnosis and management

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Targeting individuals with increased risk for common disease can improve the efficiency and efficacy of preventive efforts and increase the quality of public health, and at the same time contain health care costs. Venous thromboembolism (VTE) is the third most common cardiovascular disease after ischaemic heart disease and stroke1. Deep-vein thrombosis (DVT), the most frequent presentation of VTE, is associated with significant morbidity and mortality. The most serious complication of DVT, pulmonary embolism (PE), is a life-threatening condition with short-term survival of less than 60%2. VTE is a common multifactorial disease resulting from the interaction of genetic and/or environmental predisposing risk factors3. In addition to circumstantial predisposing factors, genetic abnormalities of components of the coagulation pathway leading to hypercoagulability have been found in subjects who have suffered from thromboembolic disease4. While both acquired and inherited factors play important roles in the pathogenesis of VTE, risk varies greatly from one individual to another, and the causes for many cases remain unidentified. The involvement of genetic factors to an increased risk for VTE was confirmed in family-based studies among Spanish and Caucasian-American families that estimated a heritability of thrombosis up to about

Genetic heterogeneity of VTE Familial clustering is extensively documented and genetic predisposition due to molecular abnormalities of components of the coagulation pathway have been found in subjects who had had thromboembolic disease. Among the three major causes of thrombosis, postulated by Virchow in 185612; blood hypercoagulability plays a major role in VTE development. Reports on families in which a high number of VTE events suggested a familial hypercoagulability emerged as early as 190513,14. Inherited VTE risk factors, resulting from singlegene defects, have been known since 196515-18. Actually, abnormalities within the gene loci encoding for natural anticoagulants (antithrombin, protein C and protein S). Then, a large array of gene mutations was suggested to modulate such risk and, mainly in patients of European ancestry, common gain-of-function mutations within the gene of the coagulation factor V (FV Leiden mutation) and the factor II (FII A20210 allele) gene have been shown to account for a large number of cases of VTE19. Nevertheless, it is well known that genetic susceptibility to VTE is complex,




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Family history for VTE as a tool for improving health To fully understand, and use, the information achieved it is mandatory to clarify the role of the family history, its validity in the primary care setting, and its effect on individual and population health outcomes. From a practical point of view, family history can be considered the single best ‘genetic test' available to primary care. Certainly it is the most readily accessible and cheapest. In addition to capture information about genetic susceptibilities, family history has the potential to record information on shared environmental exposures, lifestyles, and behaviors. Thus, family history represents the integration of risk within a family deriving from clustering of genetic and non-genetic risk factors. Strictly dependent on this, information derived from collection of family history represents a potentially important step in personalizing health care. Indeed, it is routinely used in determining who might benefit from genetic testing and in the interpretation of genetic test results. In primary care, family history is an inexpensive, non-invasive aid for diagnosis and risk-assessment in medical genetics43,44. Awareness that a healthy person has a family history of VTE can lead to an emphasis on interventions that are known to ameliorate such risk, including dietary to reduce overweight, as well as to early laboratory testing for thrombophilic risk factors and a consideration of tailored prophylactic use of heparins. Of course, knowledge of individual risk does not always lead to better health. On the other hand, it is crucial that, to be of value in clinical decision making, information provided by patients when gathering family history must be accurate. An accurate family history has been shown to be both sensitive (correctly identifying disease in relatives) and specific (correctly identifying lack of disease in relatives). However, a higher accuracy was observed for specificity (absence of disease in relatives) than for sensitivity (correctly reporting relatives who have been affected). A great variation was observed in how family history was captured. In addition to the difficult features of VTE (silent events, other causes mimicking, etc.), limitations of patient knowledge, a deliberate lack of truthful disclosure, and provider time constraints are known factors that can affect the value of collecting family history. Patients may have difficulty to distinguish thrombosis events in their families (i.e. arterial vs. venous), may be unaware of what led to disease or hospitalization of their closest relatives or may incorrectly attribute. Notwithstanding there is ample evidence that the family history is underused45,46. collection of family history represents a powerful tool not only to identify at risk individuals but also to recognize private gene mutations representing a high risk factor for VTE. Refs Finally, through taking a family history, individuals at high risk can be identified and referred for genetic testing that, though costly, is more cost-effective than diagnosing and treating VTE in this setting.

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Family history for VTE as an independent risk factor A careful collection of medical conditions and inherited diseases occurring in a family has long been recognized as an important part of a complete medical assessment. Family history allows to identify patients and families who are at increased risk of specific disorders, including those caused by single gene mutations (such as hemophilia or vonWillebrand disease) or by multifactorial inheritance (such as cardiovascular disease or VTE). A positive family history of venous thrombosis may reflect the presence of genetic risk factors in a family. Carriers of a genetic risk factor are at increased risk of a first venous thrombosis, particularly when exposed to environmental triggers. For example, factor V Leiden synergistically increases the risk of venous thrombosis among oral contraceptive users21. Because universal screening is not cost-effective22,23, research efforts are focused on selection criteria that may be used to increase the chance of finding a genetic risk factor. Overall, family history may provide information on the influence of genetic variants which, collectively, act to increase or decrease disease susceptibility, and on other familial factors which alter such risk (such as shared behaviors and lifestyles). Epidemiologic evidence shows associations between family history and risk for many common chronic diseases24-30. Thus, family history is an evident candidate. Family history information might aid in assessing risk for a condition, even in the absence of an understanding of the molecular cause of that condition and even for disorders that do not follow a distinct Mendelian inheritance pattern. Several authors have addressed more in-depth the value of family history as a surrogate of known genetic risk factors for venous thrombosis using familial aggregation of thrombosis to measure the extent of genetic disposition31–38. These found that mainly first-degree relatives (i.e., parents, siblings, children) of venous thromboembolism cases are also at increased risk. Although thrombosis occurs more often in the first-degree relatives of patients with VTE than in the general population31,37,39-42, a positive family history does not reflect always the presence and the segregation of a known genetic risk factor. The increased risk for thrombosis in relatives is incompletely explained by the presence of known thrombophilias, as the risk for thrombosis in firstdegree relatives is increased even if patients do not have a

detectable defect. These studies have shown that the family history cannot be used to identify genetic risk factors because positive predictive value and sensitivity are low. Indeed, it increases more than 2-fold the risk of venous thrombosis, regardless of the inherited risk factors and strongly suggests an additional and independent value in predicting an individual's risk31. In particular, the number of affected relatives, and the young age of the affected relatives, more strongly indicated a predisposition to develop venous thrombosis.

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multifactorial, and heterogeneous. From a clinical point of view, multifactorial diseases as VTE are the result of a large collection of a number, even high, of common and rare, private, genetic and acquired risk factors. Usually, genetic heterogeneity refers to the presence of a variety of different genetic mechanisms, due to different mutations in the same gene or occurring in different unrelated loci, which lead to the same clinical disease, a finding common to many human diseases including VTE. Because most of these gene mutations give rise to a hypercoagulability state, one can refers to them as "thrombophilias". Thus, genetic thrombophilia can be defined as the tendency to develop blood clots as a result of a genetic/inherited molecular defect20. On the population level, the effect of each of them may be considerate moderate at most, and clearly, genetics is not the only factor contributing to this phenotype. By contrast, in some families, genetic factors may dominate the risk for VTE. Thus, family history is one of the best tools that we have for the moment, and risk estimates based on family history may help to improve our understanding of genes responsible for VTE in the near future.


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structure reflecting recent admixture with American Indian and African populations62. As a consequence, they carry a high frequency of O blood group, which is known to be associated with a lower VTE risk, and intermediate frequency of sickle cell trait. Although genetic diversity among populations is lower than that existing within populations63,64, depending on the particular combination of mutations present, each population carries its own risk for VTE. Knowledge of ancestry can be clinically important providing information on specific risk factors as other personal information gathered when collecting family history, such as sex and age. In addition to genetic structure, ancestry may capture relevant cultural habits and environmental determinants shared by specific population groups. It has to be carefully taken into account that understanding of the human genome does not support the existence of discrete boundaries between populations: each person represents a unique combination of alleles65. Keeping this information in mind, knowledge about individual genetic background may be useful and further increase the ability of family history to identify individuals at risk for VTE66.

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Family history in the "-omics" era With the huge amount of new data we continually get from genomics, proteomics, transcriptomics, and all other –omics, is reasonable to wonder whether the family history eventually will become an old tool that will be replaced by more "modern" methods. Today, sequencing a patient's genome may cost few hundreds of euros. It is still worthwhile to waste time to obtain the less precise information contained in a family history, instead of using more powerful tools? Although expectations are mounting that advances in human genomics and related fields will lead to enhanced personalized health care and disease prevention, we still do not fully know how gene products interact each other and with environmental factors in health and disease. At least until we will completely understand human molecular pathways, it will be most effective to integrate information from family history with clinical and laboratory data to individualize health care. In a time of "-omics" era, family history remains a cornerstone of the concept of truly personalized medicine – and seems likely to be only more useful, not less, in the near future. Future solutions need to focus on creating time-effective ways to collect and analyze the family history, and on developing innovative methods of educating medical providers at all levels of training as to how to apply the family history in clinical practice.

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Family history and ancestry The incidence of VTE varies widely among different groups of population from settings with a distinct genetic background, and disparities in VTE burden may be attributable to differences in genetic risk factors not strictly belonging to the coagulation pathway. Ancestry can be applied to roughly have a measure of such genetic differences. Actually, the term "ancestry" better describes the genetic distance or variation among different populations than terms as "race" and "ethnicity", which are biologically meaningless because populations do not present genetic boundaries. However, the definition is arbitrary because ancestry refers also to shared cultural and environmental characteristics. Result of a series of investigations strongly supports that the incidence and rate of VTE varies among populations from different genetic backgrounds. These studies were performed in communities where a remarkable diversity in genetic background is present47-49. The most notable finding was a significantly lower incidence of both total and idiopathic VTE among the Asian/Pacific-Islanders and Hispanics compared to both Caucasians and African-Americans. Overall, the findings of these studies document that there is the highest incidence of VTE among individuals of African ancestry, a significantly higher incidence among Caucasians, a somewhat lower incidence among Hispanics and American Indians, and a very low incidence among individuals of Asian ancestry. Circumstantial and acquired thrombophilic risk factors may interact with each other and, at least in part, well explain different VTE incidences. In Caucasian unselected patients presenting with VTE the aggregate prevalence of deficiencies of the endogenous anticoagulant proteins antithrombin, protein C, and protein S is approximately 5-7%4,19,20. At variance with this, deficiencies of natural anticoagulants were consistently reported to be significantly higher in Chinese, Thai, and Japanese patients with VTE50-58. FV Leiden and FII 20210A mutations are almost absent in African populations despite they show a VTE risk and a prevalence of family history of VTE at least comparable to Caucasians1,47–49,59. More, although lower than in Caucasians, a familial clustering of the risk has been documented in other settings5. Thus, according to different ancestries, a positive family history may account for a different prevalence of known inherited thrombophilic risk factors as well as a number of other different prothrombotic mutations, which are likely to be present in non-Caucasian populations. Well-known thrombophilic risk factors, mainly FV Leiden and FII A20210 alleles, confer a susceptibility to disease in Caucasians. In persons from African ancestry, the main source of the genetic risk appears to be sickle cell trait and compound heterozygous haemoglobinopathies. The situation is more puzzling in Asia where distribution of the haemoglobinopathies is high in the Middle East (sickle cell trait), parts of the Indian sub-continent (sickle cell trait and HbE) and throughout South-East Asia (HbE). On the contrary, they are relatively rare in northeast Asia and Japan, where the VTE incidence appear to be low. In the latter geographical regions, the most represented genetic risk factor for VTE is a deficiency of natural coagulation inhibitors. Epidemiological data suggest that American Indians and Hispanics have an intermediate VTE risk. American Indians have an Asian origin60, although current non European-derived populations in the Americas show higher levels of African and European genetic admixture61. Hispanics possess a complex genetic

References 1) Kniffin WD, Baron JA, Barrett J, et al. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994; 154: 861-6. 2) Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based, cohort study. Arch Intern Med 1998; 158: 585-93. 3) Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-73. 4) De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia. Pathogenesis, clinical syndromes and management. Blood 1996; 87: 3531-44. 5) Souto JC, Almasy L, Borrell M, et al. Genetic susceptibility to thrombosis and its relationship to physiological risk Blood Transfus 2016; 14 Suppl 5

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27) Meigs JB, Cupples LA, Wilson PW. Parental transmission of type 2 diabetes: the Framingham Offspring Study. Diabetes 2000; 49: 2201-7. 28) Millar WJ, Young TK. Tracking diabetes: prevalence, incidence and risk factors. Health Rep 2003; 14: 35-47. 29) Molyneaux L, Constantino M, Yue D. Strong family history predicts a younger age of onset for subjects diagnosed with type 2 diabetes. Diabetes Obes Metab 2004; 6: 187-94. 30) Nakanishi S, Yamane K, Kamei N, et al. Relationship between development of diabetes and family history by gender in Japanese-Americans. Diabetes Res Clin Pract 2003; 61: 109-15. 31) Bezemer ID, van der Meer FJ, Eikenboom JC, et al. The value of family history as a risk indicator for venous thrombosis. Arch Intern Med 2009; 169: 610-15. 32) Briët E, van der Meer FJM, Rosendaal FR, et al. The family history and inherited thrombophilia. Br J Haematol 1994; 87: 348-52. 33) Cosmi B, Legnani C, Bernardi F, et al. Value of family history in identifying women at risk of venous thromboembolism during oral contraception: observational study. BMJ 2001; 322: 1024-5. 34) Lensen RP, Bertina RM, de Ronde H, Vandenbroucke JP, Rosendaal FR. Venous thrombotic risk in family members of unselected individuals with factor V Leiden. Thromb Haemost 2000; 83: 817-21. 35) Aznar J, Mira Y, Vaya A, et al. Is family history sufficient to identify women with risk of venous thromboembolism before commencing the contraceptive pill? Clin Appl Thromb Hemost 2002; 8: 139-41. 36) Caprini JA, Goldshteyn S, Glase CJ, Hathaway K. Thrombophilia testing in patients with venous thrombosis. Eur J Vasc Endovasc Surg 2005; 30: 550-5. 37) van Sluis GL, Söhne M, El Kheir DY, et al. Family history and inherited thrombophilia. J Thromb Haemost 2006; 4: 2182-7. 38) Hron G, Eichinger S, Weltermann A, et al. Family history for venous thromboembolism and the risk for recurrence. Am J Med 2006; 119: 50-3. 39) Segal JB, Brotman DJ, Necochea AJ, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA 2009; 301: 2472-85. 40) Couturaud F, Kearon C, Leroyer C, et al. Groupe d'Etude de la Thrombose de Bretagne Occidentale (G.E.T.B.O) Incidence of venous thromboembolism in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. Thromb Haemost 2006; 96: 744-749. 41) Sørensen HT, Riis AH, Diaz LJ, et al. Familial risk of venous thromboembolism: a nationwide cohort study. J Thromb Haemost 2011; 9: 320-4. 42) Couturaud F, Leroyer C, Julian JA, et al. Factors that predict risk of thrombosis in relatives of patients with unprovoked venous thromboembolism. Chest 2009; 136: 1537-45. 43) Rich EC, Burke W, Heaton CJ, et al. Reconsidering the family history in primary care. J Gen Intern Med 2004; 19: 273-80. 44) Wolpert CM, Speer MC. Harnessing the power of the pedigree. J Midwifery Womens Health 2005; 50: 189-96. 45) Fuller M, Myers M, Webb T, et al. Primary care providers' responses to patient-generated family history. J Genet Couns 2010; 19: 84-96.

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factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia. Am J Hum Genet 2000; 67: 1452-9. 6) Heit JA, Phelps MA, Ward SA, et al. Familial segregation of venous thromboembolism. J Thromb Haemost 2004; 2: 731-6. 7) Larsen TB, Sørensen HT, Skytthe A, et al. Major genetic susceptibility for venous thromboembolism in men: a study of Danish twins. Epidemiology 2003; 14: 328-32. 8) Crittenden LB. An interpretation of familial aggregation based on multiple genetic and environmental factors. Ann NY Acad Sci 1961; 91: 769-80. 9) Falconer DS. The inheritance of liability to certain diseases estimated from the incidence among relatives. Ann Hum Genet 1965; 29: 51-76. 10) Smith C. Recurrence risks for multifactorial inheritance. Am J Hum Genet 1971; 23: 578-88. 11) Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. J Thromb Haemost 2005; 3: 292-9. 12) Virchow R. Phlogose und Thrombose im Gefäßsystem. Gesammelte Abhandlungen zur Wissenschaftlichen Medizin. Frankfurt, Germany: Staatsdruckerei; 1856. 13) Briggs JB. Recurrent phlebitis of obscure origin. John Hopkins Hosp Bull 1905: 16: 228-33. 14) Jordan FLJ, Nandorff A. The familial tendency in thromboembolic disease. Acta Med Scand 1956; 156: 267-75. 15) Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13: 516-30. 16) Egeberg O. Inherited fibrinogen abnormality causing thrombophilia. Thromb Diath Haemorrh 1967; 17: 176-87. 17) Griffin JH, Evatt B, Zimmerman TS, et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-3.   18) Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-8.   19) Franco RF, Reitsma PH. Genetic risk factors of venous thrombosis. Hum Genet 2001; 109: 369-84.   20) Lane DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia: Part 1. Thromb Haemost 1996; 76: 651-62.   21) van Vlijmen EF1, Veeger NJ, Middeldorp S, et al. Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception. Blood 2011; 118: 2055-61. 22) Vandenbroucke JP, van der Meer FJM, Helmerhorst FM, Rosendaal FR. Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ 1996; 313: 1127-30. 23) Wu O, Robertson L, Twaddle S, et al. Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis. Br J Haematol 2005; 131: 80-90. 24) Williams RR, Hunt SC, Heiss G, et al. Usefulness of cardiovascular family history data for population-based preventive medicine and medical research (the Health Family Tree Study and the NHLBI Family Heart Study). Am J Cardiol 2001; 87: 129-35. 25) Hawe E, Talmud PJ, Miller GJ, Humphries SE; Second Northwick Park Heart Study. Family history is a coronary heart disease risk factor in the Second Northwick Park Heart Study. Ann Hum Genet 2003; 67: 97-106. 26) Melbostad E, Eduard W, Magnus P. Determinants of asthma in a farming population. Scand J Work Environ Health 1998; 24: 262-9. Blood Transfus 2016; 14 Suppl 5


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63) Bamshad M, Wooding S, Salisbury BA, Stephens JC. Deconstructing the relationship between genetics and race. Nat Rev Genet 2004; 5: 598-609. 64) Witherspoon DJ, Wooding S, Rogers AR, et al. Genetic similarities within and between human populations. Genetics 2007; 176: 351-9. 65) Schwartz RS. Racial profiling in medical research. N Engl J Med 2001; 344: 1392-3. 66) Margaglione M, Grandone E. Population genetics of venous thromboembolism. A narrative review. Thromb Haemost. 2011; 105: 221-31.

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46) Acheson LS, Wiesner GL, Zyzanski SJ, et al. Family historytaking in community family practice: implications for genetic screening. Genet Med 2000; 2: 180-5. 47) White RH, Zhou H, Romano PS. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California. Ann Intern Med 1998; 128: 737-40. 48) Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asians/Pacific Islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med 2004; 116: 435-42. 49) White RH, Zhou H, Murin S, Harvey D. Effect of ethnicity and gender on the incidence of venous thromboembolism in a diverse population in California in 1996. Thromb Haemost 2005; 93: 298-305. 50) Angchaisuksiri P, Atichartakarn V, Aryurachai K, et al. Risk factors of venous thromboembolism in Thai patients. Int J Hematol 2007; 86: 397-402. 51) Chen TY, Su WC, Tsao CJ. Incidence of thrombophilia detected in southern Taiwanese patients with venous thrombosis. Ann Hematol 2003; 82: 114-7. 52) Shen MC, Lin JS, Tsay W. Protein C and protein S deficiencies are the most important risk factors associated with thrombosis in Chinese venous thrombophilic patients in Taiwan. Thromb Res 2000; 99: 447-52. 53) Ho CH, Chau WK, Hsu HC, et al. Causes of venous thrombosis in fifty Chinese patients. Am J Hematol 2000; 63: 74-8. 54) Shen MC, Lin JS, Tsay W. High prevalence of antithrombin III, protein C and protein S deficiency, but no factor V Leiden mutation in venous thrombophilic Chinese patients in Taiwan. Thromb Res 1997; 87: 377-85. 55) Suehisa E, Nomura T, Kawasaki T, Kanakura Y. Frequency of natural coagulation inhibitor (antithrombin III, protein C and protein S) deficiencies in Japanese patients with spontaneous deep vein thrombosis. Blood Coagul Fibrinolysis 2001; 12: 95-9. 56) Kinoshita S, Iida H, Inoue S, et al. Protein C and protein S gene mutations in Japanese deep vein thrombosis patients. Clin Biochem 2005; 38: 908-15. 57) Tang L1, Jian XR, Hamasaki N, et al. Molecular basis of protein S deficiency in China. Am J Hematol 2013; 88: 899-905. 58) Tang L1, Guo T, Yang R, et al. Genetic background analysis of protein C deficiency demonstrates a recurrent mutation associated with venous thrombosis in Chinese population. PLoS One 2012; 7: e35773. 59) Dowling NF, Austin H, Dilley A, et al. The epidemiology of venous thromboembolism in Caucasians and AfricanAmericans: the GATE Study. J Thromb Haemost 2003; 1: 80-7. 60) O'Rourke DH, Raff JA. The human genetic history of the Americas: the final frontier. Curr Biol 2010; 20: R202-7. 61) Kayser M, Brauer S, Schädlich H, et al. Y chromosome STR haplotypes and the genetic structure of U.S. populations of African, European, and Hispanic ancestry. Genome Res 2003; 13: 624-34. 62) Bryc K, Velez C, Karafet T, et al. Colloquium paper: genomewide patterns of population structure and admixture among Hispanic/Latino populations. Proc Natl Acad Sci USA 2010; 107 (Suppl 2): 8954-61.




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Abstract Optimal duration of secondary prophylaxis with vitamin K-antagonists or direct oral anticoagulants after a first episode of venous thromboembolism (VTE) should balance the risk of bleeding with that of a recurrent VTE event. A number of independent factors predicting recurrence have been identified as decision-making tools to modify duration of therapy after VTE. The overall effect of thrombophilia on the risk of recurrent VTE is small, and the usefulness of laboratory testing to predict the likelihood of future events is questioned. However, there is consistent evidence that there is a risk gradient among inherited thrombophilic abnormalities, higher in carriers of antithrombin, protein C or S deficiencies, homozygosity for factor V Leiden (FVL) or prothrombin (PT) 20210A, and multiple abnormalities (severe thrombophilia) than in heterozygotes for FVL or PT20210A (mild thrombophilia). In most studies the risk of recurrent VTE among the rare patients with severe thrombophilia is difficult to estimate because it is diluted by the weak effect of the much more frequent mild thrombophilia. However, carriers of severe thrombophilia were reported to be more prone to recurrent VTE in retrospective and prospective investigations and although the quality of the evidence is low, they are potential candidates for long-term oral anticoagulation after a first unprovoked VTE. Patients with antiphospholipid antibodies are at increased risk of recurrence but the strength of the association is uncertain; patients "triple positive" for a lupus anticoagulant, an anticardiolipin, and an antibeta2 glycoprotein 1 antibody are likely candidates to long-term treatment. However, prediction of recurrent VTE should be based on an overall evaluation including both clinical and laboratory factors, and decision about life-long anticoagulant treatment should be carefully tailored for individual patients, considering also risk factors for bleeding and patient's informed preference. Keywords: thrombophilia, venous thromboembolism, recurrence.

influence risk of recurrent VTE after stopping VKA4. Among patients with VTE provoked by a reversible factor, the risk of recurrence is much lower if the provoking factor was recent surgery compared with a nonsurgical trigger (eg, estrogen therapy, pregnancy, leg injury, flight of >8 hours)2,5. In patients with proximal deep venous thrombosis (DVT) and pulmonary embolism (PE), the estimated cumulative risk of recurrent VTE after stopping anticoagulant therapy is as follows: VTE provoked by surgery, 1% after 1 year and 3% after 5 years; VTE provoked by a nonsurgical reversible risk factor, 5% after 1 year and 15% after 5 years; and unprovoked VTE, 10% recurrence after 1 year and 30% after 5 years4. Additional factors considered strong enough to modify duration of therapy after VTE are: isolated calf DVT versus proximal DVT (relative risk, RR, approximately 0.5); one or more previous episodes of VTE (RR, approximately 1.5)4. Other additional factors predicting the risk of recurrent VTE include: negative d-dimer 1 month after withdrawal of VKA (RR, approximately 0.4); presence of antiphospholipid antibodies (APLA) (RR, approximately 2); inherited thrombophilia (RR, approximately 1.5); males vs females (RR, approximately 1.6); Asian ethnicity (RR, approximately 0.8); residual thrombosis in the proximal veins (RR, approximately 1.5)4. Guidelines from the ISTH suggest that the following factors may favor long-term anticoagulation in patients with a first unprovoked proximal DVT or PE: male gender; moderateto-severe post-thrombotic syndrome; ongoing dyspnoea (possibly related to unresolved or recurrent PE); satisfactory initial anticoagulant control; elevated D-dimer result based on individual D-dimer assay performance characteristics using a study-validated assay6. As regards thrombophilia, testing for inherited thrombophilic abnormalities is not considered useful to predict likelihood of thrombosis recurrence after a first episode of VTE and for this reason is not routinely required6,7. However, testing for inherited thrombophilia in selected patients, such as those with a strong family history of unprovoked recurrent thrombosis, may influence decisions regarding duration of anticoagulation.6 Some clinical prediction models have been proposed to assess the risk of recurrent VTE, but thrombophilia scoring is not included in any of them8-10.

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LE05 Thrombophilia and risk of recurrent venous thromboembolism De Stefano V., Rossi E. Institute of Hematology, Catholic University School of Medicine, Rome, Italy

Introduction After a first episode of venous thromboembolism (VTE), the duration of secondary prophylaxis with vitamin K-antagonists (VKA) or direct oral anticoagulants (such as dabigatran, rivaroxaban, apixaban or edoxaban) should be decided balancing the risk of hemorrhagic complications with that of a novel VTE. The cumulative rate of recurrence is as high as 40% within 10 years from the first VTE1, being lower in patients with VTE associated with transient risk factors and maximal in those with unprovoked VTE1-3. Risk factors for recurrent venous thromboembolism American College of Chest Physicians (ACCP) guidelines for long-term treatment of VTE identifies as primary factors for estimating risk of recurrence: presence of a reversible provoking risk factor, unprovoked VTE, and presence of active cancer, which are the most important factors that

Role of inherited thrombophilia in predicting recurrent venous thromboembolism Inherited thrombophilia can be caused by two main mechanisms: the loss-of-function of endogenous anticoagulants (including deficiency or dysfunction of antithrombin [AT], protein C [PC], protein S [PS]) and gain-of-function of procoagulant factors. The latter include not only factor V Leiden (FVL) and prothrombin (PT) 20210A, but also high plasma levels of factor VIII (FVIII), fibrinogen, factor IX (FIX), X (FX), XI (FXI), of which the genetic determinants are only partially known. In rare instances, hypofibrinolysis may be a mechanism of thrombophilia11. Family studies, conducted among individuals with the same genetic background, indicate consistently that there is a risk gradient for VTE, higher in AT, PC, PS deficiencies, homozygous FVL or PT20210A and multiple abnormalities than in heterozygotes for FVL or PT20210A11. Accordingly, the former abnormalities are commonly identified as severe thrombophilia and the latter as mild thrombophilia. Carriers of AT, PC or PS deficiencies have a 4- to 30-fold increased risk of VTE than non-carriers, the highest incidence of 0.9 to


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Mild inherited thrombophilia and risk of recurrent venous thromboembolism As aforementioned, inherited thrombophilia is considered to play a minor role in predicting recurrence after a first VTE4,6. In fact, inherited thrombophilia has been reported to have little impact on the risk of recurrence in prospective studies2,3. As expected, in such investigations the most represented abnormalities are FVL and PT20210A (mild thrombophilia), which are present in nearly one third of patients with VTE2,3. Studies specifically aimed to investigate the risk of recurrence in carriers of either mutations gave conflicting results. The risk of recurrent VTE among heterozygous carriers of either FVL or PT20210A has been recently revised by at least three meta-analyses12-14. One estimated that patients with a first VTE and FVL or PT20210A have significant 1.4-fold and 1.7-fold increases in the risk of recurrence, respectively12. In a second meta-analysis restricted to prospective studies, the risk of recurrent VTE conferred by heterozygous FVL was increased by 1.4-fold, whereas the risk found among heterozygotes for PT20210A was lower13. Finally, a third systematic review found that heterozygosity for FVL was associated with a 1.6-fold increase in risk of recurrent VTE in probands, whereas heterozygosity for PT20210A was not predictive of recurrence14. However, the magnitude of the risk is modest, and the hemorrhagic risk related to the indication for long-term anticoagulation could be not justified in the majority of cases. Moreover, in a large retrospective case-control study, laboratory investigation for inherited thrombophilia in patients with a first VTE did not reduce the incidence of recurrence15. Anyhow the value of laboratory investigation for the outcome of recurrence should be investigated in a trial in which the participants tested for thrombophilia should have predetermined consequences, such as a prolongation of the duration of anticoagulant treatment or a higher intensity of anticoagulation; such a trial has never been performed16. Nevertheless, in a prospective cohort of 599 patient with a first VTE, the presence of inherited thrombophilia was associated with a 1.8-fold increase in risk of recurrence, and in patients with inherited thrombophilia measurement of D-dimer identified a subset with low risk of recurrence (4.2% after 1.4 years of follow-up in the presence of normal D-dimer levels), and a subset with high risk of recurrence (27.1% in the presence of altered D-dimer levels, with a hazard ratio of 8.3-fold in comparison with the subset with low risk)17. Those findings suggest that thrombophilia cannot be considered as a whole and that further efforts are needed to clarify the role of mild thrombophilia in the interaction with other predictors of recurrent VTE and to identify subsets of patients at higher risk of recurrence.

treatment4,6. However, it can be expected that the risk of recurrent VTE among the rare patients with a deficiency of a natural anticoagulant AT, PC, or PS is difficult to determine in most studies because it is diluted by the weak effect of the much more frequent polymorphisms FVL and PT20210A. In older family studies the rate of recurrent VTE was higher in carriers of PC or PS deficiency in comparison with their noncarrier relatives18-20. In a retrospective controlled investigation, AT deficiency was associated with a significant 1.9-fold increase in risk of recurrence in the absence of anticoagulation in comparison with patients with no thrombophilia; deficiencies of PC or PS were associated with a lower risk of recurrence (1.4-fold)21. In a prospective cohort of unselected patients, those with an AT deficiency had a 2.6-fold increase in risk of recurrence, yet the result is likely not significant due to the small number of cases2. Moreover, in probands and their deficient relatives belonging to the EPCOT prospective cohort the incidence of recurrent VTE was 10.5 % per patient-year in patients with AT deficiency and 3.5 % per patient-year in carriers of FVL22. In a retrospective investigation on proband patients with a deficiency of natural anticoagulants and their deficient relatives, the incidence of recurrent VTE was confirmed to be high, resulting in 7.7 % per patient-year (10% for AT deficiency, 6% for PC deficiency, and 8.4% for PS deficiency)23. There is convincing evidence that patients with multiple defects are more prone to recurrent VTE24-27. A retrospective study demonstrated that homozygotes for FVL showed a higher risk of recurrent VTE than heterozygotes28. In a systematic review, homozygosity for FVL was associated with a 2.6fold increased risk of recurrent VTE14. A recent retrospective study claimed that the rate of recurrence after a first VTE did not differ between homozygotes and heterozygotes for FVL; indeed, such results should be interpreted with caution, since long-term anticoagulation (>6 months) was prescribed more frequently to homozygotes than to heterozygotes 71% vs 41%)29. In conclusion, although the quality of the evidence in this area is low and does not allow firm recommendations, patients with AT deficiency, homozygosity for FVL, multiple defects, and perhaps PC or PS deficiency could be more prone to recurrence and therefore potential candidates for long-term oral anticoagulation after a first unprovoked VTE.

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4.0/100 person-years being observed in AT deficiency. On the other hand, carriers of mild thrombophilia have a 2- to 7-fold increased risk, with a much lower incidence of events than carriers of severe thrombophilia, i.e., 0.14 to 0.67/100 person-years for FVL and 0.05 to 0.42/100 persons-year for PT20210A11.

Severe inherited thrombophilia and risk of recurrent venous thromboembolism International guidelines do not consider patients with AT, PC, or PS deficiency or multiple gene alterations (high-risk thrombophilia) different from all the other patients with inherited thrombophilia regarding the duration of anticoagulant

Laboratory screening for inherited thrombophilia On the whole, given the low absolute number of recurrent VTE events among carriers of mild thrombophilia, laboratory screening is of little usefulness in the clinical management of the large majority of patients with VTE. However, it cannot be overlooked that severe thrombophilia is detected in the non-trivial proportion of at least 10% of all VTE cases, and that these patients are at a much higher risk of VTE recurrence11. This has been accepted by an International Consensus Statement in 200530 and, more recently, by the French consensus guideline on testing for thrombophilia in VTE31, which recommend laboratory investigations in patients with VTE occurred at young age and/or in those with unprovoked events. Nevertheless, the British and American guidelines do not consider routine testing to be justified among patients with VTE4,7,32,33. A possible exception could be testing patients with a family history of VTE4,33, particularly testing targeting patients with a deficiency of natural anticoagulants and if anticoagulant treatment is to be Blood Transfus 2016; 14 Suppl 5

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Conclusions In patients with VTE inherited thrombophilia is not scored as a determinant of recurrence, playing a minor role in the decision of prolonging anticoagulation; indeed, a few guidelines consider testing worthwhile to identify carriers of severe thrombophilia (i.e., deficiency of natural anticoagulants, homozygosity, multiple abnormalities), particularly those with a family history of VTE34. The evidence for prescribing indefinite anticoagulation after a first VTE to patients with APLA has been questioned42, but patients "triple positive" are likely candidates to long-term treatment43. However, it should be emphasized that prediction of recurrent VTE should be based on an overall evaluation including multiple risk factors besides the presence of an inherited or acquired thrombophilic abnormality: previous VTE events, circumstances of the first or subsequent VTE events

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Antiphospholipid antibodies and risk of recurrent venous thromboembolism APLA (i.e. lupus anticoagulant, anticardiolipin antibodies or anti-beta2 glycoprotein 1 antibodies) have been associated with arterial and venous thrombosis37,38. Patients are defined as having the antiphospholipid syndrome if they have had one or more thrombotic events and have a positive APLA test on more than one occasion at least 12 weeks apart39. The syndrome can also be defined by certain obstetrical events39. On the basis of a randomized controlled trial published in 199840, it is often recommended that these patients receive indefinite anticoagulant therapy after a first VTE because of an increased rate of recurrences after VKA discontinuation41. In order to assess whether this practice is fully justified, a recent systematic review included 8 prospective studies that met prespecified design criteria42. There were 109 recurrent VTE in 588 patients with APLA and 374 recurrent VTE in 1914 patients without APLA (relative risk 1.41; 95% confidence

interval [CI], 0.99 to 2.36). The unadjusted risk ratio for recurrent VTE after stopping anticoagulant therapy in patients with an anticardiolipin antibody was 1.53 (95% CI, 0.76-3.11), and with a lupus anticoagulant was 2.83 (95% CI, 0.83-9.64). All studies had important methodologic limitations and the overall quality of the evidence was very low. It is concluded that although a positive APLA test appears to predict an increased risk of recurrence in patients with a first VTE, the strength of this association is uncertain because the available evidence is of very low quality. A retrospective observational study suggests that being positive for a lupus anticoagulant, an anticardiolipin, and an anti-beta2 glycoprotein 1 antibody (i.e., "triple positive") confers a high risk of recurrent thrombosis. This was significantly higher in those patients not taking oral anticoagulants as compared with those on treatment (hazard ratio=2.4 95% CI 1.3-4.1; P50 years) Yes, in patients with a single unprovoked proximal DVT and/or PE A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genet Med 2011; 13: 67-76. 33) NICE. Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. Clinical guideline 144. London: National Institute for Health and Clinical Excellence, published June 2012, updated November 2015. 34) De Stefano V, Rossi E. Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives. A review of the Guidelines from Scientific Societies and Working Groups. Thromb Haemost 2013; 110: 697-705. 35) Einhäupl K, Stam J, Bousser MG, et al.; European Federation of Neurological Societies. EFNS guideline on the treatment of cerebral venous and sinus thrombosis in adult patients. Eur J Neurol 2010; 17: 1229-35. 36) DeLeve LD, Valla DC, Garcia-Tsao G; American Association for the Study Liver Diseases. Vascular disorders of the liver. Hepatology 2009; 49: 1729-64. 37) Petri M. Thrombosis and systemic lupus erythematosus: the Hopkins Lupus Cohort perspective. Scand J Rheumatol 1996; 25: 191-3. 38) Pengo V, Ruffatti A, Legnani C, et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood 2011; 118: 4714-8. 39) Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295-306. 40) Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med 1998; 104: 332-8. Blood Transfus 2016; 14 Suppl 5


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Epidemiology Rates of PPH vary according to the definition4. The rate of PPH based on hospital discharge data from the United States, Canada and New South Wales, Australia is between 3% and 6% of pregnancies; the rate of severe PPH requiring transfusion is approximately 1%, and the rate of a major obstetric hemorrhage resulting in coagulopathy is half a percent or less7. In a Scottish population, a severe form of PPH, with estimated blood loss >2,500 ml or needing transfusion of >5 units of blood or needing treatment for coagulopathy during the acute event, has been reported in 3.7 in 1,000 pregnancies8. In some developed countries, however, the rate of PPH appears to be increasing. Reasons for the rise in the rate of PPH are not clear, but the increase cannot be explained only by changes in rates of cesarean delivery, induction of labor or by increases in maternal age or maternal body mass index (BMI), factors associated with PPH which are increasing in developed countries. In developed countries, the number of deaths from obstetric haemorrhage is relatively small, with 14 maternal deaths as a result of haemorrhage reported in the 2003 to 2005 triennium in the UK, corresponding to a maternal mortality rate of 0.66/100,000 maternities9. This data shoud be compared to a maternal mortality ratio of 14.7/100,000 for PPH reported in the most recent South Africa triennium, 2005 to 200710. Despite such a relatively low mortality rate, at least in developed countries, PPH remains the principal cause of severe maternal morbidity, and the most common obstetric cause of admission to the intensive care unit11. Moreover, it exposes women to long-term sequelae, such as the complications of transfusion, resuscitation, and to infertility if hysterectomy is required.

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Abstract Despite susbstantial improvements in its management over last years, major obstetric haemorrhage (MOH) still remains a major health problem, being the leading cause of maternal mortality in every part or the world. The management of such a life-threatening emergency is complex, and requires a multidisciplinary approach cohordinated between obstetrician, anaesthetist, clinical haematologist, blood bank and laboratory staff, and other disciplines as needed, such as interventional radiologists and vascular surgeons. Moreover, evidence on the management of MOH is surprisingly scarce, and current guidelines are largely based on expert consensus, which in turn often relies on data referring to the treatment of massive bleeding in other clinical scenarios, such as surgery or trauma, hardly transferable to the specific setting of MOH. Aim of this paper is to perform a comprehensive review of the literature about the topic of MOH, with a special focus on its peculiar pathophysiology and on the haematological aspects of its management. Keywords: major obstetric haemorrhage, postpartum haemorrhage, massive bleeding, massive transfusion, fibrinogen.

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LE06 Postpartum haemorrhage Marietta M.1, Romagnoli E.2, Luppi M.1 1 Department of Oncology, Hematology and Respiratory Diseases, Azienda Ospedaliero-Universitaria Policlinico di Modena, Italy; 2 Department of Internal Medicine, Ospedale di Pavullo nel Frignano, Azienda AUSL Modena

Approximately half of the cases of APH are of unknown origin. Cases with abnormal placentation, usually placenta previa or placental abruption, can result in serious complications for mother and the fetus3,4. The most common form of major obstetric haemorrhage (MOH) is primary postpartum haemorrhage (PPH). The traditional definition of primary PPH is the loss of 500 mL or more of blood from the genital tract within 24 hours of the birth4-6. PPH can be minor (500-1,000 mL) or major (more than 1,000 mL); major PPH could further be divided to moderate (1,000-2,000 mL) or severe (more than 2,000 mL). Secondary PPH is defined as abnormal or excessive bleeding from the birth canal between 24 hours and 12 weeks postnatally.

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Educational Session 4 Management of hemorrhagic patient

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Background Despite substantial improvements in maternal survival in the last decades, worldwide about 300,000 women still die annually during pregnancy and childbirth1. Obstetric haemorrhage is one of the leading causes of maternal death: across the globe, more than 70,000 women die every year from haemorrhage due to childbirth, mainly in resource-poor countries, but an unacceptable number of these women die also in resourcerich countries. Many deaths occur because of a poor clinical response to massive bleeding, not only due to a scarcity of resources, trained personnel and access to basic health care, but also to a failure in coordinating the already available resources. For instance, in the 2003-2005 report of the UK Confidential Enquiries into Maternal Deaths, haemorrhage was the third highest direct cause of maternal death (6.6 deaths/million maternities) with a rate similar to the previous triennium2. The majority of these maternal deaths due to haemorrhage were preventable, and 58% cases were judged to have received "major substandard care"2 even in a high-income country such as UK.

Definition The term obstetric haemorrhage encompasses both antepartum (APH) and postpartum (PPH) haemorrage, and indicates any bleeding occurring between the 20th gestation week and the delivery.APH accounts for about 20% of obstetric haemorrhages; it is often benign and usually it doesn't lead to maternal or fetal morbidity, but a few cases it can result in PPH.

Haemostatic changes in pregnancy Normal pregnancy and childbirth are associated with relevant haemostatic changes, which create a procoagulant state, possibly in preparation for the haemostatic challenge of delivery. The concentration of the majority of clotting factors (including fibrinogen, factors VII [FVII], VIII [FVIII], X [FX], XII [FXII] and von Willebrand factor [VWF]) increases, and there is a decrease in physiological anticoagulants, including thrombomodulin and protein C inhibitor12,13. The increase is generally more marked for factor FVIII and VWF. Levels of factor II [FII], factor V [FV] and factor IX [FIX] are either slightly increased or remain unchanged during normal pregnancy13, whereas reports on the change in factor XI [FXI] levels in pregnancy are inconsistent. From a clinical practice point of view, the most important haemostatic change is the increase in fibrinogen levels during




Uterine atony inhibits this physiological process predisposing to as well as worsening intractable bleeding. Uterine atony is the most common reason for PPH, accounting for almost 80% of cases. Risk factors for postpartum haemorrhage (PPH) Many factors, either presenting antenatally or becoming apparent during labour and delivery, are significantly associated with the risk of developing PPH (Table I).

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The Four T's As Table I shows, all risk factors for PPH refer to one or more of four basic pathophysiologic mechanisms involved in the genesis of PPH: Tone, Trauma, Tissue, Thrombin (the four T's'). Tone refers to uterine atony, which is responsible for the majority of cases of PPH. Trauma refers to genital tract trauma, which is responsible for about 20% of cases of PPH. Genital tract trauma includes trauma to the broad ligament, uterine rupture, uterine inversion as well as cervical, vaginal and perineal tears. Tissue refers to retained placental tissue, which prevents effective uterine contraction, accounting for about 10% of cases of PPH. Thrombin refers to coagulation disorders, either acquired or inherited. Acquired coagulopathy, with the clinical picture of DIC preceding the development of PPH, can be initiated by placental abruption, pre-eclampsia, septicaemia and intrauterine sepsis, retained dead foetus, amniotic fluid embolus, incompatible blood transfusion, abortion with hypertonic saline. The coagulopathy of massive bleeding is related to consumption of coagulation, factors, activation of fibrinolysis, haemodilution by resuscitation fluids, hypothermia, acidosis and hypocalcaemia and can further exacerbate a PPH, no matter how generated. Women with Inherited Bleeding Disorders (IBD), including carriers of haemophilia A and B, pose special clinical challenge in pregnancy and during delivery16,17 (please refer to the "Prevention of PPH in women with inherited bleeding disorders" section).

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gestation, especially through the third trimester. At term, fibrinogen plasma levels normally increase to values of 4-6 g/l, thus an apparently normal non-pregnant fibrinogen of 2 g/l in a PPH will reflect that significant bleeding has occurred. Moreover, in women with PPH a fibrinogen level below 2 g/l at the time of diagnosis of PPH is independently and significantly associated with the worsening of bleeding14. Antithrombin levels in pregnant women remain stable during pregnancy, delivery, and the postpartum period at levels slightly lower than the non-pregnant reference interval13. Protein C remains stable within the non-pregnant reference interval during pregnancy and increases slightly at delivery and during the postpartum period. Some women tend to have values in the upper end of the non-pregnant reference interval around delivery. Protein S activity decreases steadily during pregnancy reaching the lowest values at delivery. Already at weeks 13-20, about half of the pregnant women have protein S levels below the non-pregnant reference value. This portion increases to approximately 80% late in pregnancy13. The concentration of the plasminogen activators, tissue plasminogen activator (t-PA) and urinary plasminogen activator (u-PA) increase in pregnancy, and these changes are balanced by a several-fold increase in plasminogen activator inhibitor-1 (PAI-1) levels and the production by the placenta of large quantities of an inhibitor similar to PAI-1, called PAI-2. The two plasminogen activator inhibitors successfully depress fibrinolytic activity in pregnancy, but after placental separation maternal fibrinolytic activity increases rapidly. High levels of fibrin degradation products seen in the latter part of pregnancy run counter to the concept of depressed fibrinolysis, but this finding probably reflects the overall upregulation of the haemostatic system seen in pregnancy. The D-dimer concentration increases progressively throughout the pregnancy and peaks at the first postpartum day. As early as weeks 13-20, more than 25% of pregnant women without any complications have D-dimer levels at or above 0.5 mg/L, the conventional cut-off point for thromboembolism, and therefore D-dimer analysis has a very limited value for diagnosing venous thromboembolism in pregnancy13. Relevant to this, D-dimer test was excluded from a recently developed Disseminated Intravascular Coagulation (DIC) SCORE specific for pregnancy15. The Authors mae this decision In light of the changes in the maternal concentrations of D-dimer during pregnancy, the lack of its clinical utility during gestation, and the small number of D-dimer tests performed at our medical center, this marker was not included in our score. Despite the lack of this parameter, this DIC score performed well, resulting sensitive as well as specific in the specific setting of pregnancy. Uterine blood flow changes in pregnancy Placental blood vessels progressively dilate as pregnancy advances, to shunt blood from nonplacental to placental tissues. Maternal spiral arteries, originating from the uterine arteries, undergo remodelling, whereby they lose their vascular resistance because of the loss of smooth muscle and elastic lamina from the vessel wall. By term, 80% to 90% of total uterine blood flow is passing through the placenta, with a flow rate of more than 600 ml per minute and a pressure of 70 mm Hg. Such an impressive blood flow must be stopped almost immediately at placental separation, and this is accomplished in part by the "procoagulant state" already described, but mainly by the contraction of uterine muscle fibres, causing compression of the spiral arteries and mechanical haemostasis.

Diagnosis By definition, the diagnosis of MOH relies on the assessment of the amount of blood loss during pregnancy (APH) and/or labour and delivery (PPH). However, reliable assessment of blood loss is a well-known problem because visual assessment notoriously underestimates large blood loss volumes (>1,000 mL) and significantly overestimates low volumes (35) Anaemia (Hb12 hours) Big baby (>4 kg) Pyrexia in labour Age (>40 years, not multiparous)

Treatment of PPH Organizational aspects-key principles Although a substantial reduction in morbidity and mortality of PPH has been reported, at least in high-income countries, a Confidential Enquiries into Maternal Deaths performed in UK a few years ago showed that substandard care was still a risk factor in two thirds of PPH-related deaths9. PPH should be managed by a skilled "PPH team", organized according to the trauma team model6,25, formed by a consultant obstetrician, anaesthetist and midwifery with early involvement of an expert on haemostasis and thrombosis and other disciplines as needed (i.e., interventional radiologists and vascular surgeons). The PPH team should be rapidly available and should operate according to shared local protocol based on the best available evidences and regularly updated. Robust systems are also needed for early alert and ongoing communication between PPH team members as well as with laboratory teams and the portering staff. All professionals which are likely to deal with PPH should be adequately trained, and the acquired skills should periodically be reassessed.

MINOR PPH (blood loss 500-1000 ml, no clinical shock) Perform: • group and screen • full blood count • coagulation screen including fibrinogen • Point-of-Care viscoelastic test if available Full blood count Measurement of haemoglobin (Hb) or haematocrit (Ht) during PPH are poor indicators of the actual amount of the acute blood loss27, as they can start to decline some hours after acute bleeding, with the peak drop occurring 2-3 days later. Blood Transfus 2016; 14 Suppl 5

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3. 4. 5. 6. 7. 8.

(blood loss 500-1000 ml, no clinical shock)

(blood loss more than 1000 ml and continuing to bleed OR clinical shock):

Alert the midwife-in-charge Alert first-line obstetric and anaesthetic staff trained in the management of PPH Estimate blood loss Ensure two intravenous access (16-14-gauge cannula) Record pulse and blood pressure Check airway patency and provide adequate ventilation if needed Insert an urinary catheter Perform: a. group and screen b. full blood count c. coagulation screen including fibrinogen d. Point-of-Care viscoelastic test if available Perform arterial blood analysis Prevent or correct acidosis Prevent or correct hypothermia Start crystalloid infusion Explore uterus and lower genital tract to assess the cause of PPH (4T’s)

ALL THE ABOVE, PLUS: 1. Alert the PPH team 2. Monitor temperature every 15 minutes. 3. Monitor continuously pulse, blood pressure recording and respiratory rate (using oximeter, electrocardiogram and automated blood pressure recording). 4. Give Oxygen by mask at 10-15 litres/minute 5. Until blood is available, infuse up to 3.5 litres of warmed crystalloid Hartmann’s solution (2 litres) and/or colloid (1-2 litres) as rapidly as possible 6. Transfuse blood product as soon as possible (see text for details) 7. Record parameters on a flow chart (ie, MEOWS chart) 8. Document fluid balance, blood, blood products and procedures.

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MAJOR PPH

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1. 2.

MINOR PPH

Figure 1 - Suggested strategies for the treatment of PPH according to its severity.

women in their ninth month of pregnancy29. Conversely, they demonstrated that a platelet count G in 5'UTR in ANKRD26 gene. - one with deletion in exon 1 of the ANKRD26 gene (c.60_62del AGA). - 3 subjects with different mutations of RUNX1 gene: one missense mutation with a modification in the amino acid polarity in exon 4 (c.76C>G), one deletion (c.934del A) in exon 8 and finally one insertion (c.1214_1215insTG) in exon 9. - one subject with a deletion in intron 1 of the ETV6 gene (c.28+192delC). All six mutations found were not present in public databases. Conclusions The data demonstrated that mutations in the ANKRD26, RUNX-1 and ETV6 genes were present in patients with MDS and prevalent thrombocytopenia. Even if the involvement of these genes in megacaryopoiesis is well known, the exact mechanism responsible for thrombocytopenia is not yet clear. As the pathology is extremely rare, it is difficult to find data for genotype-phenotype analyses. However we hypothesized that these mutations are responsible for the low platelet counts in patients with myelodysplasia. Greater knowledge about the pathogenesis of these forms of thrombocytopenia will facilitate finding new therapies for them. This will have important clinical implications since platelet transfusion is the only therapeutic option for these patients. Defining the molecular mechanism of thrombocytopenia in these patients could constitute the first step on the path leading to new therapeutic possibilities with TPO mimetics as has been demonstrated in hereditary form of thrombocytopenia.

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Background Neonatal alloimmune thrombocytopenia (NAIT) is a disorder caused by specific maternal immunization against human platelet antigens (HPAs) and represents the most frequent cause of severe isolated fetal or neonatal thrombocytopenia. Clinical neonatal manifestations ranges from mild asymptomatic to severe thrombocytopenia that can lead to spontaneous intracranial hemorrage. Since this syndrome presents high recurrence and greater severity in subsequent pregnancies, there is a consensus on antenatal management with maternal first-line therapy using intravenous immunoglobulins (IVIG) and steroids. Case report A 35-year-old woman, was referred to our Haemostasis and Thrombosis Center. Her medical history consisted of 1 miscarriage at gestational week 6, 1 pregnancy complicated by NAIT with severe thrombocytopenia (Plts=5000mmc) and minor bleeding symptoms (petechiae). Serological tests confirmed the presence of maternal anti-HPA1b, anti-HPA-5a and anti-HLA-class1 antibodies. The analysis of amniotic liquid showed HPA-1a/1a and HPA-5a/5b antigenic profile. Maternal antibodies were monitored every two weeks and an increase of anti-HPA-1b antibodies was observed from week 16. From week 18 she started immunosuppressive therapy with prednisone 0.5 mg/Kg/die and IVIG 1 gr/kg/iv per week. The sequential maternal anti-HPA-1b quantifications was performed from the beginning of IVIG therapy to delivery every 2 weeks, showing a progressive reduction in the Ab titre. From week 32, IVIG dose was increased to 2 gr/kg/iv per week until delivery. The strict obstetrical and ultrasound monitoring confirmed the normal fetal growth and cesarean section was performed at week 38. The newborn, a male with a body mass =3,280 gr; didn't show major or minor bleeding manifestations. The platelet count was normal and anti HPA-1b were negative. He was monitored during the first week: platelet count were always in normal range and he didn't showed any clinical significant manifestation. After one week newborn and mother were discharged and the follow up at 6 months showed no complications. Conclusions NAIT, resulting from maternal immunization against human platelet antigens (HPA), can appear during the first pregnancy. At present no screening test on platelet antigen profile on both parents is indicated before a first pregnancy but it is recommended in case of a previous NAIT. This case showed a successfull management of NAIT during a second pregnancy and the necessity of increase general knowledge on this condition.

PO121 THE STUDY OF GENETIC MUTATIONS THAT INFLUENCES THROMBOPOIESIS IN PATIENTS WITH MYELODYSPLASIA: THE ROLES OF ANKRD26, RUNX-1 AND ETV6 Ferrari S.(1), Vianello F.(2), Lombardi A.M.(1), Cortella I.(1), Barzon I.(1), Fabris F.(1) (1) Department of Medicine DIMED, University of Padua, Padua; (2) Ematology Unit, University of Padua, Padua

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PO120 MANAGEMENT OF FETAL ALLOIMMUNE THROMBOCYTOPENIA: A CASE REPORT Paoletti O.(1), Lanza F.(2), Pecoroni L.(3), Cavalli P.(4), Crotti M.(3), Franchini M.(5), Marchitelli G.(6), Morandini R.(1), Poggiani C.(7), Paccapelo C.(8), Riccardi A.(6), Zimmermann A.(1), Testa S.(1) (1) Haemostasis and Thrombosis Center, Department of Laboratory Medicine, ASST, Cremona; (2) Department of Haematology, ASST, Cremona; (3) Blood Transfusion Department, ASST, Cremona; (4) Medical Genetics, ASST, Cremona; (5) Department of Transfusion Medicine and Haematology, ASST Mantova, Mantova; (6) Department of Obstetrics and Gynaecology, ASST, Cremona; (7) Department of Pediatrics, ASST, Cremona; (8) Laboratorio di Immunoematologia di Riferimento, Fondazione IRCCS Ospedale Maggiore Policlinico di Milano, Milano



XXIV National Congress of the Italian Society for Thrombosis and Hemostasis - SISET Poster Sessions

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Background Heparin-induced trombocytopenia (HIT) is caused by antibodies that recognize platelet factor 4 (PF4) bound to heparin. Some heparin-naive patients can generate anti-PF4/ heparin IgG (anti-H/PF4) within 4 days of heparin treatment, suggesting a possible pre-immunization by antigens mimicking H/PF4 complexes. Anti-H/PF4 were seen to be induced by previous bacterial infections. Circulating microparticles (MPs) have been described both in HIT and in sepsis, as markers of platelets activation. Aims of our study were 1) to evaluate antiPF4/H development in acute septic patents, and 2) to investigate the possible association between these antibodies and both total circulating MPs and platelets-derived PF4 bearing MPs. Methods 34 patients admitted for sepsis (cases), 12 acute inpatients treated with heparin without infection (non septic patients), and 65 healthy controls were enrolled. In all subjects, the titre of anti-H/PF4 expressed by optical density (OD) was assayed by ELISA method (Immunocor gamma), and total MPs (Annexin V+) and platelets-derived PF4 bearing MPs (CD61+/ PF4+) were measured using flow cytometry. In septic patients anti-H/PF4 and MPs were measured at admission (T0) and 7 days later (T1). Septic patients were classified by DIC, NEWS, and SOFA scores, and platelets count, CRP, lactic acid were measured. Results Septic patients showed a significant decrease in NEWS and SOFA scores, CRP and lactic acid levels without significant changes of platelets count at T1 compared to T0. Anti-H/ PF4 median levels showed a non significant increasing trend between T0 and T1 in septic patients, and were slightly higher in cases as compared with both control groups (median OD in septic patients 0.110 and 0.126 at T0 and T1, respectively: in healthy controls 0.114; in non septic patients 0.087). Annexin V+ MPs median levels in cases were significantly increased respect to healthy controls (p

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