EASL Clinical Practice Guidelines on prevention and management of bleeding and thrombosis in patients with cirrhosis

: The prevention and management of bleeding and thrombosis in patients with cirrhosis poses several difficult clinical questions. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics, including current views on haemostasis in liver disease, controversy regarding the need to correct thrombocytopenia and abnormalities in the coagulation system in patients undergoing invasive procedures, and the need for thromboprophylaxis in hospitalised patients with haemostatic abnormalities. Multiple recommendations in this document are based on interventions that the panel feels are not useful, even though widely applied in clinical practice

Syndrome des antiphospholipides et thrombopénie induite par l'héparine : à propos d'un cas (revue de la littérature et implications thérapeutiques)

Nous rapportons l'observation d'une thrombopénie induite par l'héparine de type II (TIH) chez une jeune femme traitée par héparine non fractionnée (HNF) pour une embolie pulmonaire grave révélatrice d'un syndrome des antiphospholipides (SAPL). Le SAPL est aujourd'hui défini par des manifestations thrombotiques et/ou obstétricales associées à la présence d'anticorps dirigés contre des phospholipides membranaires. Une revue actualisée des données épidémiologiques, diagnostiques, biologiques, physiopathologiques et thérapeutiques sur le SAPL montre que des incertitudes persistent tant sur la compréhension du SAPL que sur la prise en charge thérapeutique optimale des patients atteints. La TIH est aujourd'hui relativement bien connue mais reste un diagnostic d'exclusion. Sa prévalence est estimée à 1% lors de l'utilisation d' HNF à doses curatives alors qu'elle est évaluée à moins de 0,1% en cas d'usage d' HBPM. C'est une entité clinico-biologique associant une baisse du chiffre des plaquettes et/ou de nouvelles complications thromboemboliques. Ce diagnostic est confirmé biologiquement par la mise en évidence d'anticorps anti-PF4/héparine par tests d'agrégation plaquettaire et/ou ELISA. Evoquer la TIH au cours d'un SAPL est particulièrement difficile car cette complication peut mimer un SAPL (association thrombose et thrombopénie). Certains auteurs évoquent une incidence plus importante des anticorps anti-PF4/héparine dans le SAPL mais ces données sont issues de l'analyse d'effectifs de très petites tailles. A notre connaissance, seuls quelques rares cas d'association de SAPL et TIH ont été rapportés. Ainsi, dans la mesure où il existe des cohortes de suivi de patients ayant un SAPL, une enquête de prévalence des anticorps anti-PF4/héparine pourrait être menée. De même, une étude prospective ayant pour but de déterminer l'incidence de la TIH chez ces patients lors d'un traitement par héparine (en particulier s'il est fait usage d' HNF) pourrait permettre d'établir le risque de TIH au sein de cette population.PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Response to Wiewel-Verschueren S. et al. : gynaecologial and obstetrical bleeding in women with factor XI deficiency : a systematic review

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Prevention and treatment of atherosclerosis in haemophilia - how to balance risk of bleeding with risk of ischaemic events

Life expectancy for patients with haemophilia (PWH) has significantly increased in the last decades, due to improvement of clotting factor replacement therapy. However, despite a lower cardiovascular mortality rate and contrasting prevalence for non-fatal ischaemic heart disease (IHD), cardiovascular diseases are increasing in PWH. The prevalence of cardiovascular risk factors in PWH is as prevalent as in the general population, whereas an increased risk of hypertension has been observed in some studies. Furthermore, PWH are not protected against atherosclerosis. Coronary artery disease treatment is extremely challenging in PWH. Two institutional' guidelines for the management of IHD in PWH have been published. Since these recommendations, the use of new drugs such as prasugrel, ticagrelor, bivalirudin, new oral anticoagulants and new drug-eluting stents have been recommended in the general population but should be evaluated in PWH. Some questions arise: which trough level during long-term single or dual antiplatelet treatment (DAT) is really needed? The clinical role of platelet testing remains ill defined but may be considered in selected patients. A multidisciplinary approach is necessary for the management of IHD in PWH in order to treat the patient as any patient according to the cardiological guidelines during the acute phase, and long-term management should be discussed

Targeting protease nexin-1, a natural anticoagulant serpin, to control bleeding and improve hemostasis in hemophilia

International audienceHemophilia A and B, diseases caused by the lack of factor VIII (FVIII) and factor IX (FIX) respectively, lead to insufficient thrombin production, and therefore to bleeding. New therapeutic strategies for hemophilia treatment that do not rely on clotting factor replacement, but imply the neutralization of natural anticoagulant proteins, have recently emerged. We propose an innovative approach consisting of targeting a natural and potent thrombin inhibitor, expressed by platelets, called protease nexin-1 (PN-1). By using the calibrated automated thrombin generation assay, we showed that a PN-1-neutralizing antibody could significantly shorten the thrombin burst in response to tissue factor in platelet-rich plasma (PRP) from patients with mild or moderate hemophilia. In contrast, in PRP from patients with severe hemophilia, PN-1 neutralization did not improve thrombin generation. However, after collagen-induced platelet activation, PN-1 deficiency in F8-/-mice or PN-1 blocking in patients with severe disease led to a significantly improved thrombin production in PRP, underlining the regulatory role of PN-1 released from platelet granules. In various bleeding models, F8-/-/PN-1-/- mice displayed significantly reduced blood loss and bleeding time compared with F8-/-mice. Moreover, platelet recruitment and fibrin(ogen) accumulation were significantly higher in F8-/-/PN-1-/- mice than in F8-/-mice in the ferric chloride-induced mesenteric vessel injury model. Thromboelastometry studies showed enhanced clot stability and lengthened clot lysis time in blood from F8-/-/PN-1-/- and from patients with hemophilia A incubated with a PN-1-neutralizing antibody compared with their respective controls. Our study thus provides proof of concept that PN-1 neutralization can be a novel approach for future clinical care in hemophilia

A focus on dominant negative variants in a series of 170 heterozygous FXI-deficient patients

International audienceINTRODUCTION: Dominant-negative effects have been described for 10 F11 variants in the literature. AIM: The current study aimed at identifying putative dominant-negative F11 variants. MATERIAL AND METHODS: This research consisted in a retrospective analysis of routine laboratory data. RESULTS: In a series of 170 patients with moderate/mild factor XI (FXI) deficiencies, we identified heterozygous carriers of previously reported dominant-negative variants (p.Ser243Phe, p.Cys416Tyr, and p.Gly418Val) with FXI activities inconsistent with a dominant-negative effect. Our findings also do not support a dominant-negative effect of p.Gly418Ala. We also identified a set of patients carrying heterozygous variants, among which five out of 11 are novel, with FXI activities suggesting a dominant-negative effect (p.His53Tyr, p.Cys110Gly, p.Cys140Tyr, p.Glu245Lys, p.Trp246Cys, p.Glu315Lys, p.Ile421Thr, p.Trp425Cys, p.Glu565Lys, p.Thr593Met, and p.Trp617Ter). However, for all but two of these variants, individuals with close to half normal FXI coagulant activity (FXI:C) were identified, indicating an inconstant dominant effect. CONCLUSION: Our data show that for some F11 variants recognized has having dominant-negative effects, such effects actually do not occur in many individuals. The present data suggest that for these patients, the intracellular quality control mechanisms eliminate the variant monomeric polypeptide before homodimer assembly, thereby allowing only the wild-type homodimer to assemble and resulting in half normal activities. In contrast, in patients with markedly decreased activities, some mutant polypeptides might escape this first quality control. In turn, assembly of heterodimeric molecules as well as mutant homodimers would result in activities closer to 1:4 of FXI:C normal range

Management of rare inherited bleeding disorders: Proposals of the French Reference Centre on Haemophilia and Rare Coagulation Disorders

Introduction: The rare coagulation disorders may present significant difficulties in diagnosis and management. In addition, considerable inter-individual variation in bleeding phenotype is observed amongst affected individuals, making the bleeding risk difficult to assess in affected individuals. The last international recommendations on rare inherited bleeding disorders (RIBDs) were published by the United Kingdom Haemophilia Centre Doctors' Organisation in 2014. Since then, new drugs have been marketed, news studies on surgery management in patients with RIBD have been published, and new orphan diseases have been described. Aim: Therefore, the two main objectives of this review, based on the recent recommendations published by the French Reference Centre on Haemophilia and Rare Bleeding Disorders, are: (i) to briefly describe RIBD (clinical presentation and diagnostic work-up) to help physicians in patient screening for the early detection of such disorders; and (ii) to focus on the current management of acute haemorrhages and long term prophylaxis, surgical interventions, and pregnancy/delivery in patients with RIBD.</p