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This document is a letter to the editor discussing a French field study on the cross-reactivity of human anti-FVIII antibodies to porcine rFVIII. The study aimed to validate the modified Nijmegen method used in French laboratories for the titration of anti-porcine FVIII inhibitors. The study compared the stability of rpFVIII in different dilution media and assessed the cross-reactivity of plasma samples from patients with AHA and congenital hemophilia A with inhibitors. The results showed a decrease in rpFVIII activity after incubation, but no statistical difference between dilution media. The study provides valuable information for the laboratory assessment of rpFVIII in the treatment of AHA. Another study discussed in the letter found that cross-reactivity with rpFVIII was detected in 26% of AHA samples and 75% of PWA samples, but high cross-reactivity above 20 BU/mL was rare and not observed in the AHA population. The study confirmed the feasibility of using imidazole buffer to detect anti-rpFVIII antibodies. [Extracted from the article]

Introduction Factor XIII ( FXIII) deficiency is a rare hemorrhagic disorder whose early diagnosis is crucial for appropriate treatment and prophylactic supplementation in cases of severe deficiency. International guidelines recommend a quantitative FXIII activity assay as first-line screening test. FXIII antigen measurement may be performed to establish the subtype of FXIII deficiency ( FXIIID) when activity is decreased. Methods The aim of this multicenter study was to evaluate the analytical and diagnostic levels of performance of a new latex immunoassay, K-Assay® FXIII reagent from Stago, for first-line measurement of FXIII antigen. Results were compared to those obtained with the Berichrom® FXIII chromogenic assay for measurement of FXIII activity. Of the 147 patient plasma samples, 138 were selected for analysis. Results The accuracy was very good, with intercenter reproducibility close to 7%. Five groups were defined on FXIII activity level (<5% ( n = 5), 5%-30% ( n = 23), 30%-60% ( n = 17), 60%-120% ( n = 69), above 120% ( n = 24)), without statistical differences between activity and antigen levels ( P value >0.05). Correlation of the K-Assay® with the Berichrom® FXIII activity results was excellent (r = 0.919). Good agreement was established by the Bland and Altman method, with a bias of +9.4% on all samples, and of −1.4% for FXIII levels lower than 30%. One patient with afibrinogenemia showed low levels of Berichrom® FXIII activity but normal antigen level and clot solubility as expected. Conclusions The measurement of FXIII antigen using the K-Assay® is a reliable first-line tool for detection of FXIII deficiency when an activity assay is not available. [ABSTRACT FROM AUTHOR]

We present here a 63-year old woman with a long history of immune thrombocytopenia. She was hospitalized for a traumatic intracranial hemorrhage with thrombocytopenia. Following inefficient treatment of four platelet transfusions, immunoglobulins, and corticosteroids, we initiated treatment with a thrombopoietin (TPO) receptor agonist (eltrombopag 25 mg/d) with a good efficacy. Her mother and sister also had chronic thrombocytopenia. Clinical history, hemostasis results, and gene analysis revealed von Willebrand disease (VWD) type 2B with the mutation (c.3946G>A; p.V1316M), which combines a von Willebrand factor defect with severe thrombocytopenia, as well as a thrombocytopathy. The efficacy of TPO receptor agonists appears to counterbalance, at least to some extent, the thrombocytopathy associated with this mutation. As such, the use of TPO receptor agonists could represent an alternative therapeutic approach in cases of VWD type 2B with severe thrombocytopenia. [ABSTRACT FROM PUBLISHER]

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.

Abstract: Antithrombin (AT) is a natural anticoagulant and serine protease inhibitor. Hereditary AT deficiencies are uncommon and are associated with a higher risk of venous thrombo-embolism (VTE) compared to other thrombophilias. They are either quantitative (type I) or qualitative (type II) and various mutations have been reported. The II HBS deficiency is caused by a defect in the heparin-binding region (HBS) of AT. This homozygous deficiency increases the risk of VTE. The association with arterial thrombosis is weak but a few cases have been reported. We report a 20-year-old female with recurring arterial thrombosis associated with an AT type II HBS deficiency, due to a homozygous mutation Leu99Phe. In young patients, with recurrent and unexplained arterial thrombosis, a biologic thrombophilia has to be comprehensively searched. [Copyright &y& Elsevier]

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]

Abstract: Purpose: Acquired haemophilia A (AHA) is a rare bleeding disorder, due to the presence of an inhibitor directed against factor VIII (FVIII). About 50% of the AHA are idiopathic, while the remaining 50% are related to an underlying disorder or condition (autoimmune diseases, malignancies, postpartum, etc.). Patients and methods: We report on a monocentric retrospective cohort of 39 patients with AHA. Data were collected and compared to recent published data. Results: Thirty-nine patients were admitted for AHA between 1993 et 2011. Mean age at diagnosis was 71.3 years, and we noted a marked male predominance. Although the majority of patients presented a bleeding event at diagnosis (94.9%), the hemorrhagic mortality was low (2.6%). On the contrary, immunosuppressive morbidity and mortality were high in this elderly population. There was a clear correlation between initial FVIII inhibitor titer and complete remission delay. We did not identify prognostic factor for global survival. Conclusion: AHA is a rare but potentially fatal disorder. Rapidity of diagnosis and treatment initiation is crucial. Morbidity and mortality, particularly of infectious cause, due to immunosuppressive treatment, should lead to consider other available therapeutical options. [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.)