[This corrects the article DOI: 10.1016/j.rpth.2026.103364.].

Abstract: Phase 3 trials evaluating inhibitors of coagulation factor XI (FXI) and/or its activated form (FXIa) as novel anticoagulant drugs are ongoing. These agents include parenteral monoclonal antibody (abelacimab) and oral small molecules (milvexian, asundexian). We investigated the extent to which standard and specialized coagulation assays are affected by FXI(a) inhibitors in a multicenter study involving 23 laboratories. FXI(a) inhibitors were spiked into pooled normal plasma at concentrations covering those observed in phase 2/3 clinical trials: 50 to 2000 ng/mL for milvexian and asundexian, and 1 to 30 μg/mL for abelacimab. Actual plasma concentrations were measured by high-performance liquid chromatography–tandem mass spectrometry. Assays were performed blindly using 5 to 11 different combinations of reagent/analyzer depending on the assay. Prothrombin time, Clauss fibrinogen, and clotting activity of FII, FV, FVII, and FX were not affected in a clinically relevant manner. Activated partial thromboplastin time (aPTT) was prolonged in a concentration-dependent manner, with milvexian having the greatest impact followed by abelacimab and asundexian. Clotting activity of FVIII, FIX, FXI, and FXII was underestimated. Such interference was prevented by high plasma dilution (up to 1:160) before the test, except for abelacimab: FXI clotting activity remained decreased, even at low concentration (2.5 μg/mL). FXI(a) inhibitors did not affect lupus anticoagulant (LA) testing using dilute Russell viper venom time but may lead to false-negative result with LA-sensitive aPTT reagents. Protein C anticoagulant activity was overestimated, whereas no impact on protein S anticoagulant activity was observed. This study provides a comprehensive laboratory framework for interpreting clotting assays in future patients receiving FXI(a) inhibitors.

To evaluate the incidence of bleeding and thrombotic events in children with congenital or acquired heart disease (CAHD) receiving direct oral anticoagulants by rivaroxaban, and identify associated covariates. This prospective cohort study included children with CAHD treated with rivaroxaban between September 2023 and March 2025, excluding venous thromboembolism. Patients were anticoagulant-naïve or switched from antithrombotic therapy. Serious adverse events (SAE) included significant bleeding events (major bleeding (MB) and clinically relevant non-major bleeding (CRNMB)) and thrombotic events. Cox proportional hazards models were used, with sensitivity analyses excluding patients with prior events under previous antithrombotic therapy. 125 patients were included with: 88(70.4%) patients with Fontan physiology. Seventy-two (58%) patients were switched to rivaroxaban from previous antithrombotic therapy. Median age at initiation was 9.3(IQR:5.5–13.9) years with a median follow-up of 8.5(IQR:3.9–13) months. Twenty SAEs were recorded (3 MB, 13 CRNMB, 4 thrombotic events). The incidences of significant bleeding events and thrombosis event were of 13.9%(95%CI[7,9%–24,4%]) and 4.2%(95%CI[1.6%–11,2%]) per patient year, respectively. At 12 months, 88.9%(95%CI[79.8%–94%]) of patients were free of significant bleeding events. Multivariable analysis identified female gender (HR = 13.2(95%CI[2.8–62.4])) and age > 12 years (HR = 7.1(95%CI[1.9–26.3])) as risk factors for significant bleeding events. Abnormal uterine bleeding accounted for 56.2% of significant bleeding events. Sensitivity analyses yielded similar results. Rivaroxaban therapy appears feasible in children with CAHD, but was associated with higher bleeding and thrombotic events than previously reported in clinical trials. Particular attention should be given to teenage girls at higher risk of abnormal uterine bleeding.

Background: Platelet dense granule defect (DGD) is a frequent inherited disorder that is underdiagnosed due to its complexity and poor standardization of diagnostic tools. Objectives: To assess the prevalence of DGD in a large real-life French cohort of patients with an abnormal bleeding score. Methods: Patients with abnormal International Society on Thrombosis and Haemostasis Bleeding Assessment Tool scores, but no deficiency of coagulation or von Willebrand factor, and platelet counts > 100 × 109/L, were recruited between December 2019 and March 2023 across 8 French expert centers. At the first visit, platelet function testing included light transmission aggregometry, whole-mount transmission electron microscopy, the mepacrine assay, and evaluation of CD63 expression. Patients with suspected DGD, based on prior testing, were included directly at the confirmatory visit (V2). DGD was defined by abnormal results on whole-mount transmission electron microscopy, mepacrine assay, or CD63 assay, and was considered confirmed if abnormalities were reproducible across both visits. Results: Of the 119 patients included at the inclusion visit, 66 had at least 1 abnormal dense granule test, including 19 with ≤2. Among the 54 patients seen at confirmatory visit , 40 had confirmed abnormalities, including 8 with at least 2 abnormal tests. Depending on diagnostic criteria, DGD prevalence ranged from 7.5% (≥2 abnormalities) to 37.4% (≥1 abnormality). Among 46 patients included at confirmatory visit, 30 had a confirmed DGD, including 11 with at least 2 abnormalities. No significant differences in age, sex, International Society on Thrombosis and Haemostasis Bleeding Assessment Tool scores, or bleeding history were observed between patients with or without DGD. Conclusion: DGD diagnosis in clinical practice depends on the criteria used. Standardized guidelines and repeated testing are essential for improving diagnostic accuracy.

INTRODUCTION:According to the new In Vitro Diagnostic Medical Device Regulation (EU) (IVDR) an In Vitro Medical Device (IVD) is considered as a laboratory developed test (LDT) if used outside of intended use. It is therefore essential that the information given by the manufacturer about the intended use is clear, precise, and well documented. For now, the only source of information for laboratories is the instructions for use (IFU). Our primary aim was to analyze the IFU provided by several manufacturers for a large panel of coagulation assays. The secondary objective was to provide a list of minimum information that must be accessible to clinical laboratories. METHODS:We analyzed 195 IFU for the main assays used in European hemostasis clinical laboratories commercialized by 12 manufacturers. RESULTS:The "intended use" section appears in almost all IFU, but the information given in this section is very heterogeneous. We observed disagreement for each of the assays assessed with some intended uses not supported by guidance or guidelines. Some indications in use by clinical laboratories are not provided by the manufacturers. We only found information on clinical performance for a limited number of assays. For some assays, data are available in the literature but are not reported in the IFU. The matrix and the importance of a pre-test probability are not systematically mentioned. CONCLUSIONS:We urgently request access to the necessary information to know the intended use of a reagent according to the IVDR. We define the minimum information that should be available to laboratories. We call for joint discussions to maintain innovation and ensure the quality, safety, and accessibility of innovative diagnostics.

Background: Several anti-FXI(a) agents with distinct mechanisms of action and pharmacological properties are currently under clinical development. While these anticoagulants are not yet available, there is a need to address bleeding risk management for patients already enrolled in phase III trials. These patients may face elective or unplanned invasive procedures and bleeding events in anticipation of marketing authorization.Experience from managing patients with inherited FXI deficiency, along with data from early clinical trials, suggests that the bleeding risk associated with anti-FXI(a) is likely to be low but can vary depending on the clinical situation. Anti-FXI(a) reversal options include tranexamic acid, FXI concentrates, and recombinant activated factor VII. However, these options may not always be suitable, can be expensive, and may carry a thrombotic risk. Objectives: The French Working Group on Perioperative Haemostasis (Groupe d’Intérêt en Hémostase Péri-opératoire (GIHP)) and the French Society of Thrombosis and Haemostasis (SFTH) aimed to develop proposals to manage bleeding and invasive procedures in patients treated with anticoagulants targeting Factor XI or XIa (anti-FXI(a)). Methods: Literature review and development of practical guidelines by an expert panel. Results: We propose pragmatic recommendations for optimizing safety in patients treated with anti-FXI(a), considering bleeding and thrombosis risks, the drug’s mechanism of action, and available reversal options. Conclusion: These proposals will be re-evaluated as more data becomes available. The implementation of a registry for managing anti-FXI(a) anticoagulants in patients undergoing invasive procedures or experiencing bleeding complications is needed.

Antifactor (F)XI/FXIa anticoagulants under development include antisense oligonucleotides, monoclonal antibodies, and small molecules. They do not require routine monitoring, but knowledge of their impact on coagulation tests is essential in view of their expected widespread use. A concentration-dependent prolongation of activated partial thromboplastin time has been shown but varies according to reagents, and the lack of comprehensive data makes interpretation of this test difficult. Measurement of FXI clotting activity is relevant only in case of treatment with antisense oligonucleotides. Measurement of contact pathway factors, if required, should be performed after multiple dilutions of the plasma sample to overcome any inhibitory effect of the anticoagulant. All other tests used in clinical trials (FXIa, FXI antigenic method, and specific thrombin generation assay) are not implemented in clinical laboratories.More comprehensive information on the effect of anti-FXI/FXIa anticoagulants on coagulation tests is urgently needed to anticipate the use of these drugs once they are approved.

OBJECTIVE:The Société Française de Médecine d'Urgence (SFMU), the Société Française d'Anesthésie et de Réanimation (SFAR), the Groupe d'Intérêt en Hémostase Péri-opératoire (GIHP) and the Société Française de Thrombose et d'Hémostase (SFHT) have collaborated to propose a set of guidelines on the management of anticoagulants in an emergency setting. DESIGN:A group of French and Belgian experts from the French Societies of Emergency Medicine (SFMU), Anaesthesia and Intensive Care (SFAR), the working group on Perioperative Haemostasis (GIHP) and the French Society of Thrombosis and Haemostasis (SFHT) was convened. Any potential conflicts of interest were officially declared at the start of the recommendation development process, which was conducted independently of any industry funding. The authors used the GRADE ("Grading of Recommendations Assessment, Development and Evaluation") methodology to assess the level of evidence in the literature. METHODS:Five areas were defined: (1) The role of laboratory testing in determining anticoagulant use and the level of anticoagulation; (2) Management of anticoagulant-associated bleeding; (3) Management of asymptomatic overdoses; (4) Management of non-elective invasive procedures on anticoagulants; and (5) Thrombolysis for acute ischaemic stroke on anticoagulants. For each field, the aim of the recommendations was to answer a certain number of questions formulated by the experts according to the PICO model ("Population, Intervention, Comparison, Outcome"). Based on these questions, an extensive bibliographic search from 1990 onwards was carried out using predefined key words according to the PRISMA recommendations. Data quality was analysed using the GRADE method. Recommendations were formulated using the GRADE method and then voted on by all the experts using the GRADE grid method. RESULTS:The experts' summary work and application of the GRADE method resulted in 103 recommendations concerning 21 questions. After two rounds of voting and several amendments, strong agreement was reached on 97 recommendations. Out of these recommendations, 19 have a high level of evidence (19 GRADE 1), 35 have a low level of evidence (35 GRADE 2), and 48 are expert opinions. Finally, for one question, no recommendation could be made. CONCLUSIONS:There was strong agreement among the experts to provide recommendations for clinicians to provide up-to-date management of patients on anticoagulants in an emergency setting.

INTRODUCTION:Discrepancies in factor IX activity (FIX:C) measurements between one-stage clotting assays (OSAs) have been observed following infusion with recombinant factor IX extended half-life concentrates (EHL-rFIX) in the treatment of haemophilia B. These variations, primarily due to differences in activated partial thromboplastin time (APTT) reagents, complicate clinical decision-making. OBJECTIVES:The aim of this study was to evaluate whether drug-specific calibrations for albumin-fused recombinant FIX (rFIX-FP) and Fc-fused recombinant FIX (rFIX-Fc) could reduce inter-reagent discrepancies. METHODS:In a multicentre field study involving 20 laboratories, plasma samples spiked with rFIX-FP, rFIX-Fc or standard rFIX were tested using different APTT reagents. FIX:C was measured with usual and drug-specific calibration. Data were analysed for compliance (target range: 80%-120% of expected values), interlaboratory variability and intralaboratory reproducibility. RESULTS:Usual calibration resulted in significant discrepancies among reagents, with compliance rates varying widely. Drug-specific calibration significantly improved compliance for all reagents tested, except for one concentration with rFIX-Fc. Interlaboratory variability decreased markedly, with coefficients of variation dropping from 19.4%-36.0% (usual calibration) to 6.0%-12.4% (specific calibration). Intralaboratory reproducibility was consistent whatever the type of calibration. CONCLUSION:Drug-specific calibration for EHL-rFIX reduces reagent-related variability in OSA FIX assays, ensuring reliable and standardised results. This approach facilitates monitoring with a single reagent system, improving laboratory efficiency. Wider availability of validated calibrators remains crucial for broader adoption and standardisation.

Medical biology is a medical specialty shared by medical doctor (MD) and pharmacists (PharmD), and Hemostasis is one of its disciplines. Since 2007, physicians have lost interest in medical biology. In haemostasis, the regulatory heterogeneity of status between medical biologists/MDs and medical biologists/PharmDs in a strained health system raises two major issues: (i) with demographic change, optimal patient care may no longer be guaranteed, (ii) medical biologists/PharmDs are sometimes forced to go beyond the scope of their regulatory field of practice. We conducted a survey in 2022 to examine hemostasis advice and consultation practices: 152 professionals responded, including 99 pharmacist-biologists (65.1%), 42 physician-biologists (27.6%) and 11 clinicians (7.2%). Of the practitioners questioned, 91.9% gave diagnostic advice and 75.0% therapeutic advice. 41% of respondents carried out haemostasis consultations, including 24.2% of pharmacists. Our survey reveals a little-known role for medical biologists specialized in haemostasis, particularly pharmacists, and calls for a global reflection on a possible regulated and supervised evolution of their field of practice, to enable them to pursue their mission in complete safety.

Chromogenic anti-Xa assay is currently used in the management of patients on unfractionated heparin (UFH). It has been shown that inter-assay variability in anti-Xa levels can be explained in part by the presence or absence of dextran sulfate (DXS) in the reagents. DXS has the ability to dissociate UFH from neutralizing proteins, including platelet factor 4 (PF4). Investigate whether PF4 plasma levels along with the presence/absence of DXS in anti-Xa reagents are associated with variations in UFH anti-Xa levels in different clinical situations. In the prospective multicenter study DEXHEP-NCT04700670, critically ill patients on UFH therapy (four groups) were recruited. Blood was collected into citrate and CTAD tubes. Chromogenic anti-Xa levels were assessed using seven reagent/analyzer combinations including two without DXS. Plasma PF4 was measured by ELISA (Zymutest-PF4-Hyphen-Biomed). A total of 144 patients were analyzed: average PF4 levels in citrate plasma samples were consistently higher than in CTAD ones (206 vs. 46 ng/mL, p < 10−4), regardless of the patient group. Using a linear mixed-effect model, we found a significant effect of both DXS and PF4 on anti-Xa level, with a significant interaction term (p < 10−4). Considering the 0.3 to 0.7 IU/mL therapeutic range, agreement between anti-Xa values (Liquid-anti-Xa/DXS-free vs. Biophen-LRT/DXS) was observed in roughly two-thirds of the patients. PF4 levels slightly affects anti-Xa levels, the use of CTAD tubes minimizing the effect. However, PF4 levels do not fully explain the differences of anti-Xa levels observed in the presence or absence of DXS, which has a greater effect. Anti-Xa assays require better standardization.

OBJECTIVES:Glycogen storage disease type I (GSD-I) is a metabolic disease associated with a bleeding tendency. Although decreased von Willebrand factor (VWF) and/or impaired platelet function have been reported in this condition, no direct link with bleeding has been demonstrated. The aim of this retrospective study was to assess the correlation between primary hemostasis abnormalities and haemorrhagic diathesis in a cohort of 19 GSD-I patients. METHODS:A Standardized International Society of Thrombosis and Hemostasis Bleeding Assessment Tool (ISTH-BAT) score was calculated for all patients to assess their bleeding history. Primary hemostasis was investigated by platelet closure time, VWF activity and antigen levels, and platelet aggregation. RESULTS:Seven of the 19 patients (37 %) had a positive ISTH-BAT score for age. Bleeding symptoms were essentially mucocutaneous. Thirteen patients (76 %) had a prolonged closure time with no significant difference whether ISTH-BAT was positive (ISTH-BATpos group) or negative (ISTH-BATneg group) (p = 0.60). Two patients in the ISTH-BATpos group had a moderate decrease in VWF levels. However, no statistical difference was observed between ISTH-BATpos and ISTH-BATneg groups regarding VWF activity (p = 0.40) or antigen (p = 0.82) levels either. Four patients had defective platelet aggregation, mainly in response to ADP agonist, with no significant difference between the two groups (p = 0.12). CONCLUSION:As expected, GSD-I was found to be associated with an increased risk of mucocutaneous haemorrhage. However, no correlation was observed between primary hemostasis impairment and bleeding tendency in the present study.

Emicizumab is an antibody that mimics the function of factor (F)VIII and has been approved for prophylaxis in hemophilia A patients. However, the development of anti-drug antibodies (ADA) against emicizumab, although rare, can impair its efficacy. In cases with low drug levels or bleeding events, differentiating between ADA- and adherence-related issues can be challenging.We aimed at evaluating the effectiveness of a modified bridging ELISA (Valsecchi et al, JTH 2021) in detecting ADA in patients suspected of developing this response. Clinical and laboratory data were retrospectively collected from six patients with suspected ADA and one with a confirmed case. The modified ELISA was performed blindly to identify potential ADA presence. After a new ADA case was confirmed, it was characterized by assessing its expression over time and neutralizing effect.Five patients had emicizumab levels ≤1 µg/mL, while two had higher levels (13 and 15 µg/mL). Among the patients, two experienced spontaneous bleeding, and four had traumatic bleeding. ADA was detected in two patients, including the one with a known ADA. In ADA-negative patients, emicizumab levels increased following adjustments for compliance or administration issues. The newly identified ADA was neutralizing, blocking emicizumab's binding to factors IX and X. Its pattern of expression was similar to that of the known ADA case, peaking 3 months after the loss of emicizumab efficacy and remaining positive for over a year after emicizumab discontinuation.In bleeding patients with low emicizumab levels, the modified bridging ELISA may effectively differentiate ADA patients from those with other issues leading to decreased emicizumab concentration.

Background:Factor (F)XI deficiency is a rare bleeding disorder with a poor correlation between bleeding tendency and FXI level. Management of pregnant women with FXI deficiency is not clearly established, especially regarding neuraxial analgesia (NA). Objectives:A retrospective multicenter observational study was conducted in French hemostasis centers on pregnant women with FXI of <60 IU/dL. Methods:Data to report were (i) FXI levels before pregnancy and at time of delivery, (ii) type of NA and delivery management modalities, and (iii) possible complications related to NA and bleeding complications. Results:Three hundred fourteen pregnancies in patients with FXI deficiency of <60 IU/dL were reported (from 20 centers); among them, 199 NA procedures have been completed (137 epidurals and 61 spinals, 1 had both). The period of childbirth was mostly from 2014 to 2020 (281/314; 89.5%). Congenital FXI deficiency was established with certainty by investigators in 32.8% patients (n = 103). Previous bleedings were described in 20.4% of the patients (64/314; 45.3% cutaneous, 31.3% gynecologic, and 15.6% postsurgical). Thirteen deliveries had an NA procedure with FXI of <30 IU/dL, 42 with FXI of 30-40 IU/dL, and 118 with FXI of 40-60 IU/dL. Median FXI levels at delivery in the epidural and spinal groups were not significantly different but were significantly lower in the group without NA by medical staff contraindications. There were no complications related to NA. A 17.5% postpartum hemorrhage or excessive postpartum bleeding incidence was reported, which is consistent with previous data. Conclusion:Our data support the use of a 30 IU/dL FXI threshold for NA, as suggested by the French proposals published in August 2023.