Influence of coagulation factors and tissue factor concentration on the thrombin generation test in plasma.

International audienceThe thrombin generation test is used to study coagulation in patients with haemorrhagic diseases or with high thrombotic risk. To our knowledge, this is the first study investigating the relative influence of coagulation factors on thrombin generation in plasma. The aim was to investigate the influence of coagulant factors, anticoagulant factors, and tissue factor (TF) on three parameters: endogenous thrombin potential (ETP), peak thrombin concentration, and lag time for the appearance of thrombin. At a low TF concentration, all factors except factor XI influenced thrombin generation. At a high TF concentration, only the factors of the extrinsic pathway exerted an influence. ETP and peak thrombin were linearly correlated to factor II concentration. Factor V and factor VII effects increased hyperbolically with factor concentration. The influence of factor X on thrombin generation depended on TF concentration. In the absence of factor VIII and factor IX, ETP fell to 60-70% of the normal when peak thrombin fell to 25-30% of the normal. Fibrinogen concentration influenced ETP and peak thrombin and decreasing fibrinogen levels shortened the lag time. As expected, decreasing antithrombin concentration caused dramatic increases in thrombin generation. Protein S prolonged the lag time, especially at a low TF concentration. No effect of protein C was observed, likely due to the absence of thrombomodulin. The thrombin generation test was more sensitive to factor deficiencies at low than at high TF concentration. ETP was not the most critical parameter for studying coagulation factor deficiencies. Instead, peak thrombin was the most sensitive parameter

Statin exposure and thrombosis risk in patients with myeloproliferative neoplasms

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Outcomes of pregnancy after bariatric surgery: results of a French matched-cohort study

International audienceBackground: While the benefits of bariatric surgery (BS) on pregnancy outcomes have been demonstrated for women compared with matched controls on presurgery body mass index (pB-BMI), data are lacking and those benefits are uncertain compared with matched controls on prepregnancy BMI (pP-BMI).Objectives: Our study aimed to evaluate outcomes (obstetrical and neonatal) of single pregnancy in women previously exposed to BS compared with women unexposed to BS matched on pB-BMI and pP-BMI.Settings: Retrospective matched cohort study from 2 observational studies of pregnant women conducted in a French administrative county (Finistère).Methods: From April 1, 2015 to January 31, 2019, pregnant women with previous BS (n = 52) were included and compared with 2 different control groups as follows: group A (n = 104), matched for pB-BMI, age, and parity; and group B (n = 104), matched for pP-BMI, age, and parity.Results: In women exposed to BS, mean age was 27.1 (±4.9) years and pB-BMI was 46.0 (±4.6) kg/m2. Operated women differed significantly from group A but not from group B for pP-BMI (29.4 ± 6.1 versus 45.3 ± 4.5 group A versus 28.6 ± 6.6 group B) and gestational diabetes (12.0% versus 44.0% group A versus 17.0% group B), respectively. In the group of women exposed to BS, birth weight (g) was significantly lower (2960 ± 545 versus 3381 ± 735 group A versus 3310 ± 645 group B) and large-for-gestational-age infants less frequent (0% versus 13% group A versus 8% group B).Conclusion: Bariatric surgery reduced risks of excessive fetal growth and gestational diabetes with a trend for a higher risk of small-for-gestational-age, despite matching on pP-BMI suggesting a risk associated to BS and solely to previous surgery-induced weight loss

17 Jeunes Hématologues Association des Internes en Hématologie

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Revisiting the molecular epidemiology of factor XI deficiency: Nine new mutations and an original large 4qTer deletion in western Brittany (France).

International audienceConstitutional deficiency in factor XI (FXI) is a rare bleeding disorder in the general population, with the exception of Ashkenazi Jews. During the last decade, the detection of FXI-deficient patients has shifted from clinical screening identifying mostly severe bleeders to biological screening combining findings of prolonged activated partial thromboplastin time and FXI coagulation activity (FXI:C) below 50 U/dl. The goal of this study was to determine the molecular basis of FXI deficiency in western Brittany, France. Over the course of four years, we detected 98 FXI-deficient patients through biological screening, and 44 patients agreed to participate in this study corresponding to 25 index cases. We developed an efficient mutation detection strategy (combining direct sequencing and QFM-PCR to search for heterozygous rearrangements in a routine setting) that detected F11 mutations in 24 out of the 25 index cases. An unexpected allelic heterogeneity was found, with 14 different single point mutations being detected, among which nine are new. Moreover, a large heterozygous deletion of the entire F11 gene was detected, and was then further defined using a CGH array as a 4q34.2 telomeric deletion of 7 Mb containing 77 genes. We propose that the observed recurrent mutations may be considered as genetic tags of a population. This study highlights the importance of screening for large deletions in molecular studies of F11

rFVIII-Fc in severe haemophilia A: The incentive switch in case of high risk of joint bleedings

International audienceBackground Efmoroctocog alfa, the first recombinant factor VIII fusion protein with extended half-life (rFVIII-Fc), has been hypothesized to lower FVIII consumption in patients with severe Haemophilia A (pwSHA), without reducing clinical efficacy. What about real life? Method MOTHIF-II was a noninterventional, multicentre, before/after study, via the collection of retrospective data from July 2015 to June 2016 (called T1), and from July 2017 to June 2018 (called T2), in 7 French haemophilia treatment centres. We examined the prescriptions and dispensations of factor VIII and the Annual Bleeding Rate (ABR), in pwSHA without current inhibitors on prophylaxis, before and after the introduction of rFVIII-Fc. The data gathered from the BERHLINGO research database and from the French Healthcare claims database with a determinist pairing process based on the national unique identification number. Results A total of 156 pwSHA were included in the prescription cohort and 83 in the ABR cohort. For switched patients, the mean amounts of prescribed FVIII were significantly higher during T1 compared to T2 (4333 (2052) vs. 3921 (2029) IU/kg/year/patient, p: 0.028); a significant decrease in their ABR was also observed between T1 and T2 (6.3 (6.0) vs. 4.4 (5.4), p: 0.047). These patients had a more severe bleeding profile centred on haemarthrosis. Conclusion The results are related to those of the pivotal clinical trials for the reduction in FVIII consumption following the switch to rFVIII-Fc, with a significant improvement in the haemorrhagic phenotype for pwSHA

Biological determinants of bleeding in patients with heterozygous factor XI deficiency.

International audienceBleeding risk is not predictable in patients with factor XI (FXI; F11) deficiency. In this prospective study, our objectives were to determine the biological determinants for bleeding risk in patients with heterozygous FXI deficiency. Patients were classified as either bleeding patients or non-bleeding patients by calculating the bleeding score (BS) described for von Willebrand disease. Primary haemostasis, thrombin generation, thromboelastometry, procoagulant proteins, inhibitors, fibrinolysis, and F11 gene mutations were compared between bleeding and non-bleeding patients. Thirty-nine patients were included. BS significantly correlated with clinical assessment (P=0*001), and a score over 3 discriminated between bleeding (n=15) and non-bleeding (n=24) patients (P=0*034). Despite normal values, von Willebrand factor (VWF) and thrombomodulin (TM) plasma levels were significantly lower in bleeding patients than non-bleeding patients [ristocetin cofactor activity (VWF:RCo)=80*6±29*7 iu/dl and 101*8±29*5iu/dl respectively, P=0*043; and VWF antigen (VWF:Ag)=84*0±28*0 iu/dl and 106*3±36*1 iu/dl respectively, P=0*035; and TM=17*7±11*7ng/ml and 23*6±9*7ng/ml respectively, P=0*043]. When considering BS as a continuous variable, only VWF:RCo remained significant (P=0*042), which accounted for 11% of the variability in BS

Differences between aquagenic and non‐aquagenic pruritus in myeloproliferative neoplasms: An observational study of 500 patients

Abstract Background Pruritus is a frequent symptom experienced by patients with myeloproliferative neoplasms (MPN). Aquagenic pruritus (AP) is the most common type. The Myeloproliferative Neoplasm‐Symptom Assessment Form Total Symptom Score (MPN‐SAF TSS) self‐report questionnaires were distributed to MPN patients before consultations. Objectives The aim of this study was to assess clinical incidence (phenotypical evolution and response to treatment) of pruritus, especially AP, in MPN patients during their follow‐ups. Patients and Methods We collected 1444 questionnaires from 504 patients [54.4% essential thrombocythaemia (ET) patients, 37.7% polycythaemia vera (PV) patients, and 7.9% primary myelofibrosis (PMF) patients]. Results Pruritus was reported by 49.8% of the patients, including 44.6% of AP patients, regardless of type of MPN or driver mutations. Patients suffering from pruritus were more symptomatic and had a higher rate of evolution into myelofibrosis/acute myeloid leukaemia (19.5% vs. 9.1%, OR = 2.42 [1.39; 4.32], p = 0.0009) than MPN patients without pruritus. Patients with AP had the highest pruritus intensity values ( p = 0.008) and a higher rate of evolution (25.9% vs. 14.4%, p = 0.025, OR = 2.07) than patients with non‐AP. Disappearance of pruritus was observed in only 16.7% of AP cases, compared to 31.7% of cases with other types of pruritus ( p < 0.0001). Ruxolitinib and hydroxyurea were the most effective drugs to reduce AP intensity. Conclusions In this study, we demonstrate the global incidence of pruritus across all MPN. Pruritus, especially AP, which is a major constitutional symptom observed in MPN, should be assessed in all MPN patients due to higher symptom burden and higher risk of evolution

Gynecological and obstetric outcome in the French cohort of women with factor XIII deficiency

International audienceIntroduction: Congenital factor XIII deficiency is a very rare bleeding disorder affecting 33 patients in France. Besides its role in fibrin clot stabilization, factor XIII is involved in placental attachment. Fetal miscarriages represent a frequent and concerning issue for these patients. The aim of the present study was to describe clinical characteristics of women presenting severe congenital FXIII deficiency in France, to focus on gynecological and obstetrical events, and to report the management of these rare situations. Methods: We conducted a retrospective study in the French Hemophilia Comprehensive Care and Clinical Hemostasis Centers. Women between 15 and 65 years with factor XIII activity < 10 IU dL(-1) were included. Biological, clinical and therapeutic events that occurred to these patients during their gynecological and obstetrical period were recorded.Results: Among 31 centers, eleven patients were included. The median age at diagnosis was 1.5 years (range: 0-35), and at inclusion it was 30 years (range: 15-63). Fetal miscarriage was the primary manifestations in 2 (18%) patients, the remaining were diagnosed during hemorrhage. Menorrhagias were reported by 2 women (27%), 13 pregnancies were reported by 9 women including one abortion. Every pregnancy was conducted under factor XIII substitution, no hemorrhagic episode was reported. Four patients (36%) experienced at least one fetal miscarriage with a total amount of 30 miscarriages with 6 occurring during substitution.Conclusion: Altogether, our data confirmed the high incidence of miscarriage in women with factor XIII deficiency. Good outcome of pregnancies required prophylaxis in accordance with international guidelines

Factors associated with poor fetal outcome in placental abruption

International audienceObjectives: We aimed at describing placental abruption in our county and at evaluating factors associated with poor fetal outcome.Study design: In this case-control study, women with placental abruption were identified from two databases of Brest University Hospital between January 2013 and December 2018.Main outcome measures: Placental histological findings, course of pregnancies, maternal and fetal characteristics were described and compared between cases (placental abruption with stillbirth or neonatal death) and controls.Results: We identified 135 placental abruption, of whom 24.4% were complicated with stillbirth and 6.5% with neonatal death. Forty percent of women were smokers and 14.1% had a history of vasculoplacental disorder. Pregnancies were complicated with 42.2% of pre-eclampsia and 43% of intrauterine growth restriction. Cases were associated with more autoimmune diseases in mother (20.0% versus 3.2%, P = 0.003), more aspirin or heparin use during pregnancy (20.0% versus 6.3%, P = 0.03), less pre-eclampsia (25.0% versus 49.5%, P = 0.01) and more deliveries ≤ 34 weeks of gestation (80.0% versus 43.2%, P = 0.0001) than controls. Placentas from cases showed more placental indentation ≥ 30% (42.5% versus 5.3%, P < 0.0001) and less histological chronic inflammation, especially less chronic chorioamniotitis (2.5% versus 24.2%, P = 0.002) than controls. In multivariate analysis, factors negatively associated with poor fetal outcome were placental histological chronic inflammation (P = 0.01) and macroscopic infarcts (P = 0.01).Conclusions: Poor fetal outcome is negatively associated with certain placental histological chronic lesions, but not with pre-eclampsia, what suggests various pathophysiological processes among placental abruption