Search

The article offers information on a study conducted by the authors on discrepancies between chromogenic substrate assay and one stage assay in patients who are treated with coagulation factor VIII. Topics discussed include evaluation of the ReFacto antihemophilic factor in clinical practice, testing of plasma samples of the patients, and mentions the need for guidelines to be followed for postinfusion monitoring and pharmacokinetic assessment of coagulation factor FVIII concentrates.

PURPOSE: Review of the frequency, clinical and biological features and treatment of type II heparin-induced thrombocyopenia.METHODS: Case report and literature review.RESULTS: A 65 years old woman received as antithrombotic prophylaxis low molecular weight heparin (LMWH) after prosthetic knee replacement. Day 8, asymptomatic deep vein thrombosis was discovered after systematic echodoppler examination. Curative anticoagulation was started with LMWH. A fall in the platelet count (17 G/L) was noted day 12. Danaparoid was immediately introduced and heparin discontinued. However, day 16 a massive pulmonary embolism occurred which required transfer to an intensive care unit. Danaparoid was changed for lepirudin the same day. It took longer than three weeks for platelet count to return to normal value after heparin discontinuation. The suspicion of heparin-induced thrombocyopenia was confirmed by specific tests.DISCUSSION: HIT type II are rare but life-threatening and thrombosis events are the most frequent complications. The diagnosis is a high probability proved by both clinical and biological patterns. The treatment consists in alternative thrombin inhibitors such as danaparoid and lepirudin. The platelet count usually requires less than ten days to recover normal values after heparin withdrawal. Cases in which the delay to a normal platelet count exceeds 3 weeks have been reported specially after LMWH therapy.CONCLUSION: Type II HIT are rare but life-threatening events can occur. The platelet count check-up during heparin therapy must be systematic. [Copyright &y& Elsevier]

Purpose.– Moderate hyperhomocysteinemia is a risk factor for deep venous thrombosis. The homozygous C677T methylenetetrahydrofolate reductase (MTHFR) mutation is associated with increased level of total plasma homocysteine. The association between homozygous C677T mutation and deep venous thrombosis is still controversial.Method. – In order to evaluate this association, we studied the prevalence of C677T mutation in 168 patients with confirmed deep venous thrombosis; 31 with an idiopathic deep venous thrombosis (group A) and 137 with thromboembolic event explained by one or more clinical and/or biological risk factors (group B).Results.– The distribution of genotypes was different between group A and B [++/+ –/– –(n(%))] : 9(29)/10(32)/12(39) vs 16(12)/57(42)/64(46) (χ2 : 6.03 ; P: 0.049). The comparison between homozygotes and the two other genotypes showed significant statistical relationship between homozygous genotype and idiopathic character of deep venous thrombosis (χ2 : 6.01 ; P : 0.014 ; OR : 3.09 [IC 95% : 1.06–8.53]).Conclusion. – These results suggest that homozygous C677T methylenetetrahydrofolate reductase mutation could be considered as a genetic risk factor for venous thrombosis. [Copyright &y& Elsevier]

We report the case of a preterm infant presenting a thrombosis, discovered on ultrasound at 22 weeks of gestational age and confirmed at birth following additional examinations. We describe the anticoagulant treatment of this patient by intravenous enoxaparin, tinzaparin and rivaroxaban, from questioning to practice., Competing Interests: Competing interests: S P-L is an associate editor for EJHP., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Type 2 Normandy von Willebrand disease (VWD2N) is usually perceived as a mild bleeding disorder that can be treated with desmopressin (DDAVP). However, VWD2N patients can be compound heterozygous or homozygous for different variants, with p.Arg854Gln (R854Q) being the most frequent causative one. There are limited data about the impact of 2N variants on VWD2N phenotype and DDAVP response., Objectives: This study aims to describe the phenotype of VWD2N, including DDAVP response, according to genotype., Methods: VWD2N patients with a complete genotype/phenotype characterization by the French reference center for VWD, including MCMDM-1VWD bleeding score, were eligible to be included in the study. Results of the DDAVP trial were also collected., Results: A total of 123 VWD2N patients from the French registry were included in this study. Results were stratified according to the presence (R854QPos, n = 114) or absence (R854QNeg, n = 9) of at least 1 R854Q allele. Three R854QPos subgroups were further individualized: patients homozygous (R854QHmz, n = 55), compound heterozygous for R854Q and a null allele (R854Q/3, n = 48), or compound heterozygous for R854Q and another 2N variant (R854Q/2N, n = 11)., Fviii: C levels were significantly lower in R854QNeg and R854Q/3 patients compared with R854QHmz ones (P < .001 and P < .0001, respectively). R854QNeg patients were diagnosed earlier due to bleeding symptoms and had a higher bleeding score than R854QPos patients (P < .001). In DDAVP trial, FVIII:C survival was lower in VWD type 2N than in type 1 patients. R854QPos patients had a heterogeneous DDAVP response, which was best predicted by baseline FVIII:C level., Conclusion: The heterogeneous genetic background of VWD2N drives different bleeding phenotypes and response patterns to DDAVP, underlining the clinical relevance of DDAVP trial to identify patients potentially eligible to alternative therapeutic options., Competing Interests: Declaration of competing interests F.V. has received honoraria for consultancy, board, or oral presentations from CSL/Behring, LFB, Roche/Chugai, Takeda, Pfizer, and Sobi. Y.R. has received research support outside this work from Stago, Roche-Chugai, CSL Behring, and LFB and received Honoria for lectures or consultancy from Sobi, LFB, Octapharma, Roche-Chugai, CSL Behring, and Shire-Takeda. C.V.D. and P.J.L. are inventors on patents related to VWF. P.J.L. receives research support to institute from BioMarin, Sanofi, Sobi, and Roche. S.S. has received research support outside this work from CSL Behring, Roche-Chugai, Stago, and Siemens Healthineers and received honoraria for lectures or consultancy from BioMarin, Bioverativ, CSL Behring, Hemosonics, LFB, Novo Nordisk, Roche/Chugai, Sanofi, Siemens Healthineers, Shire-Takeda, and Sobi. The other authors have no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Introduction: Acquired von Willebrand syndrome (AVWS) is a rare haemorrhagic disorder. The prophylaxis and treatment of bleeding before surgery are complex. Since 2018, a new recombinant VWF (rVWF) concentrate that contains no factor VIII (FVIII) but a high amount of high molecular weight VWF multimers has been available in France., Aim: To describe the real-world experience of using rVWF in non-surgical bleeding and surgical procedures in patients with AVWS., Methods: Fifteen bleeding episodes in seven patients and 16 surgeries in 10 patients were retrospectively analysed in t French haemostasis centres., Results: During bleeding, the median number of infusions was only 1 (range 1-27) with a median loading dose of 58 IU/kg (range 17-116) rVWF and a total median dose of 65 IU/kg (range 35-1488) rVWF. Bleeding control was rated markedly effective in 73% (11/15) of the cases and ineffective in 27% (4/15). During surgeries, the median number of infusions was 3 (range 1-8) with a preoperative loading dose of 60 IU/kg (range 23-118) rVWF and a total median dose of 123 IU/kg (range 31-542). The overall clinical efficacy was qualified as excellent, good and poor (ISTH criteria) in respectively 7 (43%), 6 (38%) and 3 (19%) procedures. There was no accumulation of VWF or FVIII during postoperative monitoring. No thromboembolic events nor adverse events were reported., Conclusion: This French 'real-world' experience shows that rVWF could be of interest in the treatment and prophylaxis of bleeding in patients with AVWS, with no clinically significant safety concern., (© 2024 John Wiley & Sons Ltd.)

Introduction: The entity entitled bleeding disorder of unknown cause (BDUC) qualifies individuals displaying a mild haemorrhagic profile but normal routine coagulation tests. This study was designed to evaluate whether collagen-binding assay for von Willebrand Factor (VWF) measurement (VWF:CB) could allow to diagnose VW disease in such patients., Methods: A large screening was conducted prospectively in two University Hospitals, using the bleeding assessment tool (BAT) recommended by the International Society of Thrombosis and Hemostasis. Patients with an abnormal BAT were confirmed to have a normal complete hemostatic evaluation. A large range of VWF assays was then carried out on a new blood sample for the 68 individuals (91% women) thus identified. Of note, five VWF:CB using different types of collagen were performed, as well as a comprehensive sequencing of the VWF gene., Results: Of this cohort, only 3 individuals (all blood group O), had a VWF:CB between 40 and 50 IU/dL. No unknown anomaly of the VWF gene was disclosed. Of note, 54% of these patients had unexplained abnormal occlusion times on PFA-200., Conclusion: This study identified 68 cases of BDUC, after screening of a large population, indicating a low incidence. Only 3 cases were potentially confirmed as displaying moderate von Willebrand disease. VWF:CB tests were globally normal in the 65 other patients of the cohort., Trial Registration: ClinicalTrials.gov identifier: NCT0279220., (© 2024 John Wiley & Sons Ltd.)

Treatment of type 3 von Willebrand disease by infusion of von Willebrand factor (VWF) and factor VIII (FVIII) concentrates may lead to the development of anti-VWF antibodies, challenging haemostasis management. The systematic review of the literature presented here retrieved 15 such cases (surgery n  = 11, bleeding n  = 4). The heterogeneous patient management mostly involved continuous infusion of FVIII, or recombinant FVIIa together with various other strategies. Off-label infusion of the bispecific monoclonal antibody emicizumab was prescribed in three cases and in a complex local case, ultimately well-controlled with emicizumab. This illustrates the fact that emicizumab appears as a therapeutic option in this context of allo-immunisation., Competing Interests: Aurélie Briane and Marianne Sigaud declare they have no conflicts of interest. Marc Trossaërt has received research funding from NovoNordisk, Octapharma and Takeda, and acted as a paid consultant and received honoraria for participation in advisory boards for NovoNordisk, Roche, Sobi and Takeda. Valérie Horvais has received honoraria as speaker from Sobi. Nicolas Drillaud has received research funding from NovoNordisk, honoraria for participation in advisory boards for Roche and Octapharma and as speaker for Sobi. Catherine Ternisien has acted as a paid consultant and received honoraria for participation in advisory boards for LFB, Roche‐Chugaï and Takeda. Marc Fouassier has received research funding from Sobi, NovoNordisk and Takeda, has acted as a paid consultant and received honoraria for participation in advisory boards for Sobi, Takeda, CSL Behring and Roche‐Chugaï. Antoine Babuty has received research funding from Takeda and Bayer and acted as a paid consultant for Sobi., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder. However, studies of hospitalisation patterns with replacement treatment are scarce., Objectives: The aim of this study was to investigate the current therapeutic management of VWD and determine the key drivers of coagulation factor uses in patients during hospitalisation., Methods: Hopscotch-WILL was a multi-centric retrospective study conducted over a 48-month period in any patients with VWD. The data were collected from the BERHLINGO Research Database and the French Hospital database., Results: A total of 988 patients were included; 153 patients (15%) were hospitalised during 293 stays requiring treatment with von Willebrand factor (VWF) concentrates-pure or in association with Factor VIII (FVIII). Their median basal concentrations of VWF and FVIII were significantly lower than in untreated patients: VWF antigen < 30 IU/dL, VWF activity < 20 IU/dL and FVIII:C < 40 IU/dL. The median (interquartile range) concentrate consumption was similar between highly purified VWF or VWF combined with FVIII (72 [110] vs 57 [89] IU/kg/stay, p = 0.154). The use of VWF was highly heterogeneous by VWD type; type 3 had a particularly high impact on VWF consumption in non-surgical situations. The main admissions were for ear/nose/throat, hepato-gastroenterology, and trauma/orthopaedic conditions, besides gynaecological-obstetric causes in women., Conclusions: The use of VWF concentrates is mostly influenced by low basal levels of VWF and FVIII, but also by VWD type or the cause for hospitalisation. These results could inform future studies of newly released recombinant VWF., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Turoctocog alfa is a recombinant Factor VIII used in patients with hemophilia A. The aim is to assess the real-life evidence of turoctocog alfa in surgery., Study Design and Methods: Data were extracted from a national database., Results: Turoctocog alfa was used for 86 surgeries (49 major and 37 minor) in 56 patients. The results are expressed as medians (interquartile range). Six (10.7%) patients had severe hemophilia A, four (7.1%) moderate, and 46 (82.2%) mild. For patients who underwent major surgeries, basal plasma FVIII coagulant activity (FVIII:C) levels were 15 IU.dL -1 (8-22). Eight (5-14) infusions were given, at a preoperative loading dose of 40.0 (35.0-45.5) IU.kg -1 and a total dose of 253.3 (125.0-507.0) IU.kg -1 . In patients who underwent minor surgeries, basal FVIII:C levels were 18 IU.dL -1 (9-31). Two (1-3) infusions were required, at a preoperative loading dose of 34.0 (28.8-38.5) IU.kg -1 and a total dose of 73.7 (37.6-122.1) IU.kg -1 . The overall clinical efficacy was judged excellent/good in 77 procedures (89.5%) and fair/poor in nine (10.5%). The fair/poor efficacy concerned seven patients (six mild hemophilia and one severe), for four urological surgeries, two dermatological procedures, one heart surgery, one ear-nose-throat procedure, and one dental avulsion in the patient with severe hemophilia. Three out of those seven patients received antiplatelet therapy. No thromboembolic events, anti-FVIII antibodies, or adverse events were reported., Discussion: The efficacy and safety of turoctocog alfa were confirmed for the management of surgery in patients with hemophilia A. No adverse events were observed and overall efficacy was good., (© 2023 AABB.)

Background: The bleeding risk of patients with mild platelet function disorders is difficult to assess and their phenotype remains ill-explored., Aim: This study was designed to establish a comprehensive biological phenotype of patients with mild platelet function disorders., Methods: Twenty patients were included with persistent abnormal light transmission aggregometry (LTA). The ISTH bleeding assessment tool (ISTH-BAT) was assessed to identify laboratory analyses associated with an abnormal hemorrhagic score., Results: The majority of patients had defects that might affect Gαi protein signaling pathways or minor abnormalities. No LTA nor flow cytometry parameters were associated with an above-normal hemorrhagic score. However, prothrombin consumption, which corresponds to the ratio of serum residual factor II to plasma residual factor II, was significantly higher (p = .006) in the abnormal ISTH-BAT group (mean = 14%, SD = 6) compared with the normal ISTH-BAT group (mean = 8%, SD 4). Prothrombin consumption was significantly associated with ISTH-BAT score (r = .5287, IC 95% 0.0986-0.7924, p = .0165)., Conclusion: In this group of patients, there was an association between a pathological bleeding score and increased prothrombin consumption. This test could be used as an additional indicator of platelet function abnormality liable to be related to bleeding risk., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Cerebral venous sinus thrombosis (CVST) is a rare disease with highly variable clinical presentation and outcomes. Clinical studies suggest a role of inflammation and coagulation in CVST outcomes. The aim of this study was to investigate the association of inflammation and hypercoagulability biomarkers with CVST clinical manifestations and prognosis., Methods: This prospective multicenter study was conducted from July 2011 to September 2016. Consecutive patients referred to 21 French stroke units and who had a diagnosis of symptomatic CVST were included. High-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR), D-dimer, and thrombin generation using calibrated automated thrombogram system were measured at different time points until 1 month after anticoagulant therapy discontinuation., Results: Two hundred thirty-one patients were included. Eight patients died, of whom 5 during hospitalization. The day 0 hs-CRP levels, NLR, and D-dimer were higher in patients with initial consciousness disturbance than in those without (hs-CRP: 10.2 mg/L [3.6-25.5] vs 23.7 mg/L [4.8-60.0], respectively; NLR: 3.51 [2.15-5.88] vs 4.78 [3.10-9.59], respectively; D-dimer: 950 μg/L [520-2075] vs 1220 μg/L [950-2445], respectively). Patients with ischemic parenchymal lesions (n = 31) had a higher endogenous thrombin potential 5pM than those with hemorrhagic parenchymal lesions (n = 31): 2025 nM min (1646-2441) vs 1629 nM min (1371-2090), respectively ( P  = .0082). Using unadjusted logistic regression with values >75th percentile, day 0 hs-CRP levels of >29.7 mg/L (odds ratio, 10.76 [1.55-140.4]; P  = .037) and day 5 D-dimer levels of >1060 mg/L (odds ratio, 14.63 [2.28-179.9]; P  = .010) were associated with death occurrence., Conclusion: Two widely available biomarkers measured upon admission, especially hs-CRP, could help predict bad prognosis in CVST in addition to patient characteristics. These results need to be validated in other cohorts., (© 2023 The Authors.)

von Willebrand factor (VWF) is a multimeric protein, the size of which is regulated via ADAMTS13-mediated proteolysis within the A2 domain. We aimed to isolate nanobodies distinguishing between proteolyzed and non-proteolyzed VWF, leading to the identification of a nanobody (designated KB-VWF-D3.1) targeting the A3 domain, the epitope of which overlaps the collagen-binding site. Although KB-VWF-D3.1 binds with similar efficiency to dimeric and multimeric derivatives of VWF, binding to VWF was lost upon proteolysis by ADAMTS13, suggesting that proteolysis in the A2 domain modulates exposure of its epitope in the A3 domain. We therefore used KB-VWF-D3.1 to monitor VWF degradation in plasma samples. Spiking experiments showed that a loss of 10% intact VWF could be detected using this nanobody. By comparing plasma from volunteers to that from congenital von Willebrand disease (VWD) patients, intact-VWF levels were significantly reduced for all VWD types, and most severely in VWD type 2A-group 2, in which mutations promote ADAMTS13-mediated proteolysis. Unexpectedly, we also observed increased proteolysis in some patients with VWD type 1 and VWD type 2M. A significant correlation (r = 0.51, P < .0001) between the relative amount of high-molecular weight multimers and levels of intact VWF was observed. Reduced levels of intact VWF were further found in plasmas from patients with severe aortic stenosis and patients receiving mechanical circulatory support. KB-VWF-D3.1 is thus a nanobody that detects changes in the exposure of its epitope within the collagen-binding site of the A3 domain. In view of its unique characteristics, it has the potential to be used as a diagnostic tool to investigate whether a loss of larger multimers is due to ADAMTS13-mediated proteolysis., (© 2023 by The American Society of Hematology.)

Constitutional thrombocytopenias are rare disorders, often difficult to discriminate from acquired thrombocytopenias. More than 80 genes have been described as being at the origin of these diseases. Among them, several variants of the glycoprotein Ib platelet subunit alpha (GP1BA) and glycoprotein Ib platelet subunit beta (GP1BB) genes, coding for the GpIb-IX-V glycoprotein complex, have been reported in the literature. The study reported here aimed at describing newly identified monoallelic anomalies affecting the GP1BA and GP1BB genes on a clinical, biological and molecular level. In a cohort of nine patients with macrothrombocytopenia, eight heterozygous variants of the GP1BA or GP1BB genes were identified. Five of them had never been described in the heterozygous state. Computer modelling disclosed structure/function relationships of these five variants., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Competing Interests: The authors declare that they have no conflict of interest.

Background:  The way by which 1-deamino-8-D-arginine vasopressin (DDAVP) acts on platelets remains unclear. Data from the literature tend to show that there is no definite effect on platelet activation, but recent work has suggested that a subtype of platelets, activated by the combined action of collagen and thrombin, was triggered by DDAVP. Moreover, platelet microparticles (PMPs), which have been shown to be procoagulant, have rarely been studied in this context. The goal of this study was to analyze the effects of DDAVP on PMPs' release through platelet activation., Methods:  Fifteen out of 18 consecutive patients undergoing a therapeutic test with DDAVP were included. They were suffering from factor VIII deficiency or from von Willebrand disease. The expression of P-selectin and PAC-1 binding on platelets and the numbers of circulating PMPs were evaluated ex vivo before and after DDAVP infusion. Peripheral blood was collected on CTAD to limit artifactual platelet activation., Results:  DDAVP induced a significant decrease of platelet counts and volume. Only small changes of P-selectin expression and PAC-1 binding were observed. Considering PMPs, two populations of patients could be defined, respectively, with (120%, n  = 6) or without (21%, n  = 7) an increase of PMPs after DDAVP. The decrease in platelet counts and volume remained significant in the group of responders., Conclusion:  This study shows that DDAVP induces the generation/release of PMPs in some patients with factor VIII deficiency and von Willebrand disease 1 hour after DDAVP infusion., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Introduction: Cerebral venous thrombosis (CVT) is a rare disease with highly variable clinical presentation and outcome. Etiological assessment may be negative. The clinical and radiological presentation and evolution can be highly variable. The mechanisms involved in this variability remain unknown. Objective: The aim of this multicenter French study registered on ClinicalTrials.gov (NCT02013635) was therefore to prospectively recruit a cohort of patients with cerebral venous thrombosis (FPCCVT) in order to study thrombin generation and clot degradation, and to evaluate their influence on clinical radiological characteristics. The first part of the study was to compare our cohort with a reference cohort. Methods: This prospective, multicenter, French study was conducted from July 2011 to September 2016. Consecutive patients (aged >15 years) referred to the stroke units of 21 French centers and who had a diagnosis of symptomatic CVT were included. All patients gave their written informed consent. The diagnosis of CVT had to be confirmed by imaging. Clinical, radiological, biological, and etiological characteristics were recorded at baseline, at acute phase, at 3 months and at last follow-up visit. Thrombophilia screening and the choice of treatment were performed by the attending physician. All data were compared with data from the International Study on CVT published by Ferro et al. Results: Two hundred thirty-one patients were included: 117 (50.6%) had isolated intracranial hypertension, 96 (41.5%) had focal syndrome. During hospitalization, 229 (99.1%) patients received anticoagulant treatment. Median length of hospital stay was 10 days. Five patients died during hospitalization (2.2%). At 3 months, 216 patients (97.0%) had follow-up with neurological data based on an outpatient visit. The mean duration of antithrombotic treatment was 9 months, and the mean time to last follow-up was 10.5 months. At the end of follow-up, eight patients had died, and 26 patients were lost to follow-up. At least one risk factor was identified in 200 patients. Conclusions: We demonstrated that the FPCCVT cohort had radiological, biological, and etiological characteristics similar to the historical ISCVT cohort. Nevertheless, the initial clinical presentation was less severe in our study probably due to an improvement in diagnostic methods between the two studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Triquenot Bagan, Crassard, Drouet, Barbieux-Guillot, Marlu, Robinet-Borgomino, Morange, Wolff, Grunebaum, Klapczynski, André-Kerneis, Pico, Martin-Bastenaire, Ellie, Menard, Rouanet, Freyburger, Godenèche, Allano, Moulin, Mourey, Derex, Berruyer, Runavot, Trichet, Viader, Le Querrec, Husein, Cluet-Dennetiere, Macian-Montoro, Donnard, Guillon, Ternisien, Zuber, Laplanche, Tassan, Peeltier, Canaple, Roussel, Gaillard, Scavazza and Le Cam Duchez.)

Introduction: To date, there is no specific recommendation or evaluation of the morbidity of prostate surgery in patients with haemophilia (PWH) although this surgery is common and at high risk of bleeding., Aim: To assess the post-operative morbidity of benign prostate hyperplasia (BPH) surgeries and of oncological prostate interventions in patients with mild haemophilia A or B., Methods: We performed a monocentre, epidemiological, in real life study. Data were collected between 1 January, 1997 and 1 September, 2020 and focused on prostate biopsy, radical prostatectomy, prostate radiotherapy, simple prostatectomy, transurethral resection of prostate (TURP) and laser-vaporisation in patients with mild haemophilia A or B., Results: Between 1 January, 1997 and 1 September, 2020, 51 interventions were performed on 30 patients with mild haemophilia. Haemophilia A represented 93.33% of the population and haemophilia B 6.67%. For prostate biopsies (n = 24), median length of hospitalisation was 4 days and only one patient needed a blood transfusion. No patient needed re-admission. For prostatectomy (n = 10), one patient presented with intra-operative and post-operative bleeding. Two patients required re-admission. The other patients did not present any significant haemorrhagic symptoms. For radiotherapy (n = 4), two patients presented a grade II complication (radiocystitis and radiorectitis). For BPH surgeries, during hospitalisation, laser-vaporisation (n = 5) was less haemorrhagic than TURP (n = 5) but after hospital discharge, 60% of patients presented a haemorrhagic complication with two readmissions and one surgical re-explorations., Conclusion: Performed in a specialised centre, prostate surgeries and interventions in patients with mild haemophilia is feasible with acceptable morbidity., (© 2021 John Wiley & Sons Ltd.)

Background: Despite their usefulness in perioperative and acute care settings, factor-Xa inhibitor-specific assays are scarcely available, contrary to heparin anti-Xa assay. We assessed whether the heparin anti-Xa assay can (1) be used as a screening test to rule out apixaban, rivaroxaban, fondaparinux, and danaparoid levels that contraindicate invasive procedures according to current guidelines (>30 ng·mL-1, >30 ng·mL-1, >0.1 µg·mL-1, and >0.1 IU·mL-1, respectively), (2) quantify the anticoagulant level if found significant, that is, if it exceeded the abovementioned threshold., Methods: In the derivation cohort then in the validation cohort, via receiver operating characteristics (ROC) curve analysis, we evaluated the ability of heparin anti-Xa assay to detect levels of factor-Xa inhibitors above or below the abovementioned safety thresholds recommended for an invasive procedure (screening test). Among samples with relevant levels of factor-Xa inhibitor, we determined the conversion factor linking the measured level and heparin anti-Xa activity in a derivation cohort. In a validation cohort, the estimated level of each factor-Xa inhibitor was thus inferred from heparin anti-Xa activity. The agreement between measured and estimated levels of factor-Xa inhibitors was assessed., Results: Among 989 (355 patients) and 756 blood samples (420 patients) in the derivation and validation cohort, there was a strong linear relationship between heparin anti-Xa activities and factor-Xa inhibitors measured level (r = 0.99 [95% confidence interval {CI}, 0.99-0.99]). In the derivation cohort, heparin anti-Xa activity ≤0.2, ≤0.3, <0.1, <0.1 IU·mL-1 reliably ruled out a relevant level of apixaban, rivaroxaban, fondaparinux, and danaparoid, respectively (area under the ROC curve ≥0.99). In the validation cohort, these cutoffs yielded excellent classification accuracy (≥96%). If this screening test indicated relevant level of factor-Xa inhibitor, estimated and measured levels closely agreed (Lin's correlation coefficient close to its maximal value: 95% CI, 0.99-0.99). More than 96% of the estimated levels fell into the predefined range of acceptability (ie, 80%-120% of the measured level)., Conclusions: A unique simple test already widely used to assay heparin was also useful for quantifying these 4 other anticoagulants. Both clinical and economic impacts of these findings should be assessed in a specific study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 International Anesthesia Research Society.)

Background: Despite a high prevalence of angiodysplasia, no specific guidelines are available for the modalities of endoscopic exploration of gastrointestinal (GI) bleeding in von Willebrand disease (VWD). Whether VWD patients could benefit from video capsule endoscopy (VCE) looking for angiodysplasia eligible to endoscopic treatment or at high risk of bleeding is unknown., Objectives: To assess the diagnostic efficacy for angiodysplasia and the prognostic value of VCE on top of conventional endoscopy in VWD patients with GI bleeding., Patients/methods: A survey was sent to the 30 centers of the French-network on inherited bleeding disorders to identify VWD patients referred for endoscopic exploration of GI bleeding from January 2015 to December 2017. Data obtained included patient characteristics, VWD phenotype/genotype, GI bleeding pattern, results of endoscopic investigations, and medical management applied including endoscopic therapy. We assessed by Kaplan-Meier analysis the recurrence-free survival after the first GI bleeding event according to endoscopic categorization and, in patients with angiodysplasia, to the presence of small-bowel localizations on VCE exploration., Results: GI bleeding source localization was significantly improved when including VCE exploration (P < .01), even in patients without history of angiodysplasia (P < .05). Patients with angiodysplasia had more GI bleeding recurrences (P < .01). A lower recurrence-free survival was observed in patients with angiodysplasia (log-rank test, P = .02), and especially when lesions were located in the small bowel (log-rank test, P < .01), even after endoscopic treatment with argon plasma coagulation (log-rank test, P < .01)., Conclusion: VCE should be more systematically used in VWD patients with unexplained or recurrent GI bleeding looking for angiodysplasia eligible to endoscopic treatment or at high risk of relapse., (© 2020 International Society on Thrombosis and Haemostasis.)

Emicizumab, a bispecific humanised monoclonal antibody restoring to some extent the function of activated FVIII deficient in haemophilia A, represents a major therapeutic advance in the management of haemophilia A patients. No dosage adjustment is required, which leads to a major change for patients used to regular biological monitoring which is particularly burdensome in the case of substitution therapy. In some circumstances, such as before an invasive procedure or in case of bleeding, biological monitoring will be necessary and emicizumab's interference with haemostasis tests, particularly those based on an activated partial thromboplastin times (aPTT), must be known to best interpret the tests and to select the most appropriate methods to guide therapy. The normalisation of aPTT in patients treated with emicizumab is not sufficient to consider haemostasis as normalised. In the event of administration of FVIII to a patient receiving emicizumab, the determination of FVIII should use a chromogenic method using non-human reagents. Coagulation global tests have been proposed to evaluate the biological response when using bypassing agents in patients treated with emicizumab, but the usefulness must be confirmed. The French group BIMHO presents proposals for biological monitoring of a patient treated with emicizumab according to clinical situations., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: With current molecular diagnosis, about 1 to 5% of haemophilia A (HA) patients remain genetically unresolved. In these cases, deep intronic variation or structural variation disrupting the F8 gene could be causal., Aim: To identify the causal variation in four genetically unresolved mild-to-severe HA patients using an F8 mRNA analysis approach., Methods: Ectopic F8 mRNA analysis was performed in four unrelated HA patients. An in vitro minigene assay was performed in order to confirm the deleterious splicing impact of each variation identified., Results: In all probands, mRNA analysis revealed an aberrant splicing pattern, and sequencing of the corresponding intronic region found a deep intronic substitution. Two of these were new variations: c.2113+601G>A and c.1443+602A>G, while the c.143+1567A>G, found in two patients, has previously been reported. The c.1443+602A>G and the c.143+1567A>G variants both led to the creation of a de novo acceptor or donor splice site, respectively. Moreover, the c.143+1567A>G was found in 3/6 patients with genetically unresolved moderate HA registered in our laboratory. Haplotype analysis performed in all patients carrying the c.143+1567A>G variation suggests that this variation could be a recurrent variation. The c.2113+601G>A led to the exonization of a 122-bp antisense AluY element by increasing the strength of a pre-existing cryptic 5' splice site. For each point variation, in vitro splicing analysis confirmed its deleterious impact on splicing of the F8 transcript., Conclusion: We identified three deep intronic variations, leading to an aberrant mRNA splicing process as HA causing variation., (© 2020 John Wiley & Sons Ltd.)

Replacement therapy with plasma-derived or recombinant FVIII and FIX (pdFVIII/pdFIX or rFVIII/rFIX) concentrates is the standard of treatment in patients with haemophilia A and B, respectively. Measurement of factor VIII (FVIII:C) or factor IX (FIX:C) levels can be done by one-stage clotting assay (OSA) or chromogenic substrate assay (CSA). The French study group on the Biology of Hemorrhagic Diseases (a collaborative group of the GFHT and MHEMO network) presents a literature review and proposals for the monitoring of FVIII:C and FIX:C levels in treated haemophilia A and B patients, respectively. The use of CSA is recommended for the monitoring of patients treated with pdFVIII or rFVIII including extended half-life (EHL) rFVIII. Except for rFVIII-Fc, great caution is required when measuring FVIII:C levels by OSA in patients substituted by EHL-rFVIII. The OSA is recommended for the monitoring of patients treated with pdFIX or rFIX. Large discordances in the FIX:C levels measured for extended half-life rFIX (EHL-rFIX), depending on the method and reagents used, must lead to great attention when OSA is used for measuring FIX:C levels in patients substituted by EHL-rFIX. Data of most of recent studies, obtained with spiked plasmas, deserve to be confirmed in plasma samples of treated patients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background:  Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatments, and only a few large patient cohorts have been reported. In this study, biological and clinical data from 144 French patients with HIT were analyzed in comparison with the literature., Methods:  The diagnosis of HIT was confirmed in all patients by an immunoassay combined with serotonin release assay. In the literature, only cohorts of at least 20 HIT patients published from 1992 were selected for a comparative analysis., Results:  Two-thirds of patients were hospitalized in surgery and most were treated with unfractionated heparin (83.2% vs. 16.8% with low molecular weight heparin only). Thrombotic events in 54 patients (39.7%) were mainly venous (41/54). However, arterial thrombosis was more frequent after cardiac surgery (13.2% vs. 2.4% in other surgeries, p  = 0.042) with a shorter recovery time (median = 3 vs. 5 days, p  < 0.001). The mortality rate was lower in our series than in the 22 selected published studies (median = 6.3% vs. 15.9%). Three genetic polymorphisms were also studied and homozygous subjects FcγRIIA RR were more frequent in patients with thrombosis (37.8 vs. 18.2% in those without thrombosis, p  = 0.03)., Conclusion:  This study shows that the mortality rate due to HIT has recently decreased in France, possibly due to earlier diagnosis and improved medical care. It also confirms the strong association between polymorphism FcγRIIA H131R and thrombosis in HIT., Competing Interests: Y.G.: Consulting and/or travel fees from Octapharma, Shire, CSL Behring, Novo Nordisk, Bayer, LFB, and Léo Pharma. J.R.: Travel fees from Octapharma, Shire, and CSL Behring. C.V.: Travel fees from Sobi, Roche, Shire, and CSL Behring. D.F.: Consulting and/or travel fees from Aspen, Boehringer, Werfen, Stago, and Léo Pharma. A.B.: Travel fees from Aspen, Boehringer, Werfen, Pfizer, and LFB. A.L.: Consulting and/or travel fees from Bayer, LFB, Pfizer, Sobi, and Octapharma. E.D.M.: Travel fees from Sobi, Bayer, Novo Nordisk, and Pfizer. B.T.P.: Consulting and/or travel fees from Sobi, Bayer, Shire, CSL Behring, and Pfizer. I.E.: Consulting and/or travel fees from BMS, Aspen, Léo Pharma, Daiichi Sankyo, Pfizer, Sanofi-Aventis, and Shire. C.L.B.: Travel fees from Sobi, Octapharma, CSL Berhing, and Novo Nordisk. C.M.: Consulting and/or travel fees from BMS, Aspen, Pfizer, and Bayer. C.B.: Consulting and/or travel fees from CSL, Sobi, Bayer, and Novo Nordisk. C.T.: Consulting and travel fees from Sobi, Roche, Octapharma. F.N.G.: Travel fees from Sobi, Bayer, BMS, and Boehringer. J.D.: Travel fees from CSL and Novo Nordisk. T.B.A.: Travel fees from Servier and MSD. E.D.R.: Consulting and/or travel fees from Shire, Alexion, Sobi, Bayer, and Novo Nordisk. I.G.T.: Consulting and/or travel fees from Bayer, MSD, Pfizer, Sanofi-Aventis, and BMS. L.R.: Consulting and/or travel fees from CSL, LFB, Novo Nordisk, Sobi, and Bayer. B.T.: Consulting and/or travel fees from Sobi, Bayer, Novo Nordisk Aspen, CSL Behring, and Pfizer. C.P.: Consulting and/or travel fees from Sobi, Roche, Novo Nordisk, and CSL Behring. P.W., M.A.G., S.V., V.G.G., J.P., and B.G. have no conflict to disclose. All the authors did not receive any personal honorarium or funds related to the study reported in this manuscript. Y.G. reports grants from Ministère de la Santé (Government), during the conduct of the study; personal fees and nonfinancial support from CSL Behring, personal fees and nonfinancial support from Octapharma, nonfinancial support from Shire, personal fees from Léo Pharma, personal fees and nonfinancial support from LFB, nonfinancial support from Bayer, nonfinancial support from Novo Nordisk, outside the submitted work., (Georg Thieme Verlag KG Stuttgart · New York.)

Competing Interests: Declaration of Competing Interest The authors stated that they had no interests which might be perceived as posing a conflict or bias.

The use of enhanced half-life (EHL) FVIII has improved the quality of prophylaxis in haemophilia A, but with a benefit that may vary from one patient to another. We analysed the pharmacokinetic data obtained with efmoroctocog alfa (rFVIII-Fc) in 114 patients and, in 47 cases, compared them to those previously measured with non-EHL FVIII. The in vivo recovery (IVR) of rFVIII-Fc measured with one stage clotting assay (OSA) and chromogenic assay (CSA) was 2.2 and 2.8 IU/mL per IU/kg, respectively. The median half-life (T 1/2 ) of rFVIII-Fc was 14.5 hours whatever the FVIII:C assay used, but variable and correlated with preinfusion VWF:Ag levels (r = .76). Both IVR and T 1/2 were lower in patients under 12 years old (2.4 IU/mL per IU/kg and 11.1 hours, respectively; CSA). PK study of rFVIII-Fc vs non-EHL FVIII showed a T 1/2 ratio of 1.4 in favour of rFVIII-Fc, regardless of the patient's age. However the relative increase in T 1/2 with rFVIII-Fc was lower than 30% in one-third of patients evaluated, particularly when the previous FVIII administered was a BHK-derived product. This study therefore suggests that analysis of individual PK profile in response to a specific FVIII concentrate is potentially useful before a switch in haemophilia A patients., (© 2020 John Wiley & Sons Ltd.)

Patients with type 2B von Willebrand disease (vWD) (caused by gain-of-function mutations in the gene coding for von Willebrand factor) display bleeding to a variable extent and, in some cases, thrombocytopenia. There are several underlying causes of thrombocytopenia in type 2B vWD. It was recently suggested that desialylation-mediated platelet clearance leads to thrombocytopenia in this disease. However, this hypothesis has not been tested in vivo The relationship between platelet desialylation and the platelet count was probed in 36 patients with type 2B von Willebrand disease (p.R1306Q, p.R1341Q, and p.V1316M mutations) and in a mouse model carrying the severe p.V1316M mutation (the 2B mouse). We observed abnormally high elevated levels of platelet desialylation in both patients with the p.V1316M mutation and the 2B mice. In vitro , we demonstrated that 2B p.V1316M/von Willebrand factor induced more desialylation of normal platelets than wild-type von Willebrand factor did. Furthermore, we found that N-glycans were desialylated and we identified αIIb and β3 as desialylation targets. Treatment of 2B mice with sialidase inhibitors (which correct platelet desialylation) was not associated with the recovery of a normal platelet count. Lastly, we demonstrated that a critical platelet desialylation threshold (not achieved in either 2B patients or 2B mice) was required to induce thrombocytopenia in vivo In conclusion, in type 2B vWD, platelet desialylation has a minor role and is not sufficient to mediate thrombocytopenia., (Copyright© 2019 Ferrata Storti Foundation.)

Background: Accurate determination of coagulation factor VIII activity (FVIII:C) is essential for effective and safe FVIII replacement therapy., Fviii: C can be measured by one-stage and chromogenic substrate assays (OSAs and CSAs, respectively); however, there is significant interlaboratory and interassay variability., Aims: This international comparative field study characterized the behaviour of OSAs and CSAs used in routine laboratory practice to measure the activity of Nuwiq ® (human-cl rhFVIII, simoctocog alfa), a fourth-generation recombinant human FVIII produced in a human cell line., Methods: FVIII-deficient plasma was spiked with Nuwiq ® or Advate ® at 1, 5, 30 and 100 international units (IU)/dL. Participating laboratories analysed the samples using their routine procedures and equipment. Accuracy, inter- and intralaboratory variation, CSA:OSA ratio and the impact of different OSA and CSA reagents were assessed., Results: Forty-nine laboratories from 9 countries provided results. Mean absolute FVIII:C was comparable for both products at all concentrations with both OSA and CSA, with interproduct ratios (Nuwiq ® :Advate ® ) of 1.02-1.13. Mean recoveries ranged from 97% to 191% for Nuwiq ® , and from 93% to 172% for Advate ® , with higher recoveries at lower concentrations. Subgroup analyses by OSA and CSA reagents showed minor variations depending on reagents, but no marked differences between the two products. CSA:OSA ratios based on overall means ranged from 0.99 to 1.17 for Nuwiq ® and from 1.01 to 1.17 for Advate ® ., Conclusions: Both OSAs and CSAs are suitable for the measurement of FVIII:C of Nuwiq ® in routine laboratory practice, without the need for a product-specific reference standard., (© 2019 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Introduction: Acquired haemophilia A (AHA) is a rare autoimmune bleeding disorder caused by the presence of autoantibodies against coagulation factor VIII (FVIII). The mortality rate remains high. International recommendations define complete remission as undetectable inhibitor (<0.6 Bethesda Units [BU]) and normal FVIII activity (FVIII:C) that persists after immunosuppressive therapy stopped. For patients achieving remission, the risk of relapse reaches 20%. The risk factors for this relapse are not well known., Aim: In this study, we examined the accuracy of the FVIII/W ratio (FVIII:C/von Willebrand Factor Antigen (VWF:Ag) ratio) to predict relapse in 64 consecutive patients with AHA., Results: In this cohort, all patients had a very low FVIII/W ratio at the time of diagnosis, and this value progressively increased in the first weeks of immunosuppressive treatment. In our study, 9/55 (14%) did not achieve complete remission. Twenty-seven patients were followed long enough (more than a year) to show that in the 22 patients who did not relapse, the FVIII/W ratio remained durably normalized. By contrast, in the five patients who relapsed during follow-up, we noted either no normalization of the FVIII/W ratio, or a secondary decrease to an abnormal value of <0.7 after initial normalization. In all patients who relapsed, the ratio was the first abnormal biological result to be observed, always preceding changes in the activated partial thromboplastin time (aPTT), FVIII:C and anti-FVIII reappearance., Conclusion: These data suggest that the FVIII/W ratio could be considered a sensitive biological marker to predict recovery and/or relapse in AHA., (© 2019 John Wiley & Sons Ltd.)