OBJECTIVES:Diffuse alveolar haemorrhage (DAH) is a rare and poorly understood manifestation of antiphospholipid (AP) syndrome (APS). This study describes the clinical presentation, treatment and prognosis of DAH in APS with or without catastrophic APS (CAPS). METHODS:A retrospective multicentre French study includes all APS patients diagnosed according to the Sydney criteria with a history of definite DAH. RESULTS:Of the 26 patients included, 15 (58%) were female (median age, 45.5 years; 95% CI, 35-58.1); 23 (88%) patients had a history of thrombotic events (6 arterial), and 13 (50%) had CAPS. Twenty (77%) were triple-positive for APL antibodies, 5 (19%) had systemic lupus erythematosus, and DAH was inaugural for 7 (27%) patients. Twenty-two patients (85%) were treated with anticoagulants, 22 (85%) with steroids and 8 (31%) with immunosuppressive therapy. Complete remission was achieved in 18 (69%) cases. DAH relapses occurred in 14 patients (54%) after a median of 1.8 (95% CI 1.1-3.6) years. Risk factors for DAH relapse were histories of arterial thrombosis (hazard ratio (HR) 4.6, 95% CI 1.2-17), transient ischaemic attack or stroke (HR 7.8, 95% CI 2.2-28), mechanical ventilation during DAH episode (HR 6.1, 95% CI 0.99-37) and triple APL positivity. Multivariate analysis showed a higher risk of DAH relapse in patients without (vs with) CAPS (HR 6.8, 95% CI 1.0-45.3; P = 0.048). Overall mortality was higher in patients with CAPS (7.7% at 1 year and 37.1% at 5 years); no patients without CAPS died. CONCLUSION:The immediate prognosis of DAH, mainly treated with anticoagulants and steroids, was good. Patients with CAPS had a higher mortality rate in the long-term follow-up. Triple-positive and/or arterial phenotype patients more frequently experienced DAH relapses even when treated with anticoagulants.

ABSTRACT:Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody intended for once-daily subcutaneous prophylactic treatment for people with hemophilia A or B with and without inhibitors. Results from the phase 3 explorer7 study confirmed superiority of concizumab prophylaxis over no prophylaxis in reducing the annualized bleeding rate (ABR) in people with hemophilia A or B with inhibitors (HAwI/HBwI). Male patients aged ≥12 years were randomized 1:2 to no prophylaxis (group 1) or concizumab prophylaxis (group 2), or nonrandomly allocated to concizumab prophylaxis (groups 3 and 4). After ≥24 weeks of treatment, patients in group 1 could switch to concizumab prophylaxis. At the 56-week cutoff (defined as when all patients in groups 2-4 had completed the visit at 56 weeks or permanently discontinued treatment), bleed-related efficacy, pharmacokinetics and pharmacodynamics, and safety were assessed. Of the 133 patients enrolled (HAwI, n = 80; HBwI, n = 53), 114 received concizumab prophylaxis (groups 2-4) and 19 were randomized to no prophylaxis (group 1). After ≥24 weeks, 13 patients from group 1 switched to concizumab. Median ABR for treated spontaneous and traumatic bleeding episodes in patients receiving concizumab was 0.8 (interquartile range [IQR], 0.0-3.2) at the 56-week cutoff, consistent with the low bleeding rates (median ABR, 0.0; IQR, 0.0-3.3) at the 32-week cutoff. Concizumab and free-TFPI concentration remained stable over time. No new safety concerns were reported. Longer-term (≥1 year) efficacy and safety results of concizumab prophylaxis for HAwI/HBwI were consistent with the 32-week cutoff results in explorer7. This trial was registered at www.clinicaltrials.gov as #NCT04083781.

The sthemO 301 is a new hemostasis analyzer developed by Diagnostica Stago, combining simultaneously three different methodologies (i.e. clotting, chromogenic and immunological assays) on a single platform. The objective of this evaluation was to assess the analytical performances of the sthemO 301 and to compare it with the STA R Max on a selection of 20 hemostasis parameters (PT, aPTT with two reagents, Clauss fibrinogen, thrombin time, D-dimer, anti-Xa, factors II, V, VII, X, VIII, IX and XI, antithrombin, protein C and protein S). Within-run and inter-laboratory precisions have been evaluated using quality controls. Method comparisons were performed using a minimum of 100 plasma samples, collected across multiple sites, and compared to the STA R Max analyzer. Reference intervals were determined or verified based on published data. Within-run and inter-laboratory precisions were respectively below 5.2 and 7.6% whatever the parameter and the sample used. Pearson correlation coefficient was above 0.976 for all assays and slopes ranged from 0.94 to 1.07 for all but thrombin time, which was at 0.86. Bias at levels of interest were less than 6% for most routine coagulation parameters, coagulation factors and inhibitors. We reported the precision, accuracy and reference intervals of 20 parameters on the sthemO 301, half of these being reported for the first time, which include anti-Xa, factors II, V, VII, X, VIII, IX, XI, protein S free antigen and activity. The sthemO 301 analyzer offers satisfactory analytical performance and a good comparability with the STA R Max for all parameters.

Background:During the last few years, the small, oral, activated factor XI inhibitor, asundexian, has been investigated in different cardiovascular disorders. However, little is known about its impact on laboratory coagulation assays. Objectives:To describe the effects of asundexian on a panel of laboratory coagulation assays. Methods:The following assays were performed in normal pooled plasma spiked with increasing concentrations of asundexian (0-2000 ng/mL): activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen quantification (PT-derived and Clauss method), one-stage aPTT and PT-based coagulation factor assays, chronometric protein C and immunoturbidimetric protein S assays, reptilase time, chromogenic ecarin assay, dilute Russell's viper venom time assays, thrombin generation assay initiated by tissue factor (1, 5, and 20 pM) and ellagic acid (0.42 μM), rotational thromboelastometry intrinsically- and extrinsically-triggered assays, kaolin-activated clotting time, and glass bead-activated clotting time. This latter assay was also carried out in whole blood. Results:Asundexian up to 2000 ng/mL impacted aPTT and one-stage aPTT-based coagulation factor assays, with high variability between reagents and methodologies. Asundexian reduced thrombin generation triggered by ellagic acid and 1 or 5 pM tissue factor. The rotational thromboelastometry intrinsically-triggered assays and kaolin- and glass bead-activated clotting time assays were affected by asundexian 2000 ng/mL, while overall, no significant interference was observed with any of the remaining assays. Conclusion:Despite this study including a comprehensive panel of coagulation assays, asundexian may still affect other coagulation assays not assessed here. Further investigations in patients treated with asundexian are therefore warranted.

Background The Hemophilia Functional Ability Scoring Tool (Hemo-FAST), consisting of a patient-reported outcome (PRO) part and a clinician-reported outcome (ClinRO) part, was developed as a rapid and effective tool to assess functional mobility in clinical practice. This study (NCT04731701) aimed to validate the psychometric properties of Hemo-FAST for assessment of joint health in people with haemophilia (PwH). Methods PwH A or B aged ≥18 years completed questionnaires including the PRO part of Hemo-FAST and the short-form 36 health survey (SF-36) during one study visit. Clinicians completed the Haemophilia Joint Health Score (HJHS) and the ClinRO part of Hemo-FAST at the same visit. Validation was performed using reliability, construct validity, and structure validity assessments. Results The study enrolled 180 PwH A or B from 14 centres across France. Estimated time to complete the PRO part was mean (standard deviation) 4.6 (5.4) minutes. PRO items showed good test–retest reliability (intraclass correlation coefficient value ≥0.70). Inter-rater values were >0.70 for 7/9 ClinRO items, indicating good reliability. All items (15 PRO; 9 ClinRO) had high internal consistency (Cronbach's coefficient alpha: 0.97). Hemo-FAST demonstrated convergent construct validity with HJHS and the SF-36 physical component and discriminant construct validity with the SF-36 mental health component. Hemo-FAST scores distinguished between subgroups of people with expected differences in joint health status, including by haemophilia severity (p < 0.0001). Conclusion This study successfully validated Hemo-FAST as a rapid and reliable tool for the functional assessment of joint health in adults with haemophilia, both in clinical practice and clinical research settings.

Centrifugation is a critical step in sample preparation and accounts for an important part of turnaround time. This step is further critical for hemostasis, which requires a low platelet count to produce reliable results. For automated laboratories, centrifugation can represent a bottleneck and thus a shorter centrifugation time would benefit tube flow and turnaround time. We compared a rapid centrifugation protocol (4000 g 4 min) with the recommended protocol (2200 g 15 min) at two different centers, after one or two centrifugation cycles. The effect of each protocol was assessed on the platelet count at every step to verify the capacity of the protocol to yield platelet-poor plasma (PPP). Results on 16 coagulation parameters were compared to verify the reliability of rapid centrifugation. In one center, a consecutive two-cycle centrifugation had been tested on platelet count. A single centrifugation cycle, using the rapid protocol, produced plasma with increased residual platelets compared with the Groupe Etude sur l'Hémostase et la Thrombose (GEHT) protocol. Despite this difference, the coagulation results were interchangeable between the protocols. In addition, a second centrifugation cycle produces plasma with a mean residual platelet less than or equal to 10 × 10 9 /l. A single cycle of rapid centrifugation can be used to assess prothrombin time (PT), activated partial thromboplastin time (aPTT), aPTT kaolin, thrombin time (TT), fibrinogen, antithrombin (AT), D-dimers, anti-Xa, factor II (FII), factor V (FV), factor VII (FVII), and factor X (FX). For frozen plasmas, a double-cycle followed by a third cycle should be performed to ensure that 100% of samples contain less than 10 × 10 9 /l platelets.

BACKGROUND:Preanalytical conditions, particularly centrifugation protocols, are critical for producing high-quality platelet-poor plasma in hemostasis testing. Centrifuge braking is debated due to its potential impact on platelet remixing. OBJECTIVES:To evaluate the effect of centrifuge braking on residual platelet counts and a broad panel of hemostasis assays using both fresh and double-centrifuged plasma. METHODS:Fifty-six adult patients provided surplus citrate plasma samples. Three centrifugation protocols were assessed: 2000 g for 15 min with braking (B+/2000/15), 2500 g for 10 min with braking (B+/2500/10), and 2500 g for 10 min without braking (B-/2500/10). Routine assays were performed on fresh plasma. Specialized assays (factors VIII, IX, XI, XII, VWF, protein C, protein S, antithrombin, APC resistance, DRVVT, antiphospholipid antibodies) were performed on frozen plasma after double-centrifugation. Platelet counts and assay concordance were evaluated. RESULTS:Residual platelet counts were significantly higher in the B+/2500/10 protocol (9 [6-13] × 109/L) compared to B-/2500/10 (2 [2-4] × 109/L, p < 0.001) and B+/2000/15 (3 [2-4] ×109/L, p < 0.01). All frozen samples had platelet counts < 10 × 109/L. Routine coagulation assays were unaffected by protocol choice, except for a slight but statistically significant increase in factor V with braking. Specialized assays showed no meaningful differences across protocols, with the exception of a minor DRVVT confirmation time reduction in the braking group. CONCLUSION:Braking during centrifugation reduces processing time but modestly increases residual platelet counts. Nonetheless, it does not compromise the performance of hemostasis assays when protocols are appropriately validated. These findings support the use of braking in clinical laboratories.

Available data on the potential use of thrombin generation (TG) assays in clinical practice is promising but larger studies involving several centers are needed to confirm this added-value for clinical purposes. The objective of this evaluation was to assess the analytical performances of the ST Genesia using STG-ThromboScreen, STG-BleedScreen, and STG-DrugScreen reagents across three centers to support its use in multicenter studies. Repeatability and reproducibility have been evaluated using commercial plasmas and quality control (QC) samples. Accuracy was assessed by calculating QC biases from the manufacturer's assigned values. Frozen plasma samples from healthy donors and patients having thrombophilia, hemorrhagic disorders, or taking anticoagulants allowed the comparison of TG parameters between the analyzers from two French centers. Repeatability and reproducibility CVs were respectively below 5% and 10% whatever the reagent and the sample used. The later fell under 6% after normalization. Mean biases between observed and assigned QC values provided by the manufacturer were less than 5% for most TG parameters. We found a good agreement for all TG parameters between the two evaluating centers. Relative bias was below 5% for all combination of parameters and reagents except for Peak height (+14.2%), ETP (+7.3%), and ETP inhibition (-12.0%) using STG-ThromboScreen. We found satisfactory repeatability, reproducibility, accuracy, and inter-laboratory variability for TG parameters using the three available reagents across three centers, supporting the use of ST Genesia in multicenter clinical trials.

INTRODUCTION:There are few data on healthcare resource use and related costs of French haemophilia A (HA) and B (HB) patients. AIMS:This study aimed to describe the profile of HA and HB patients, current disease management, clinical burden and costs. METHODS:Data related to haemophilia patients of all ages alive on 1/1/2022 were extracted from the nationwide French claims database (SNDS). Patients were divided into four treatment groups: on-demand or prophylaxis with or without inhibitors. Haemophilia patients were compared with a control group (ratio 1:3) matched for age, gender and region using risk ratios (RR [95% confidence interval]). The annual direct health care costs per person were estimated. RESULTS:A total of 5,577 (HA) and 1,332 (HB) patients were included (mean age: 36.4 years). Most patients were treated on-demand (HA: 72.8%; HB: 76.6%) and a few had inhibitors (HA: 3.6%; HB: 1.1%). Overall, haemophilia clinical burden was significantly higher than among controls, in particular, mortality (RR:1.42 [1.04-1.92]), work disability (RR: 2.71 [2.22-3.30]), hospitalisation for major bleeding (RR:12.06 [8.67-16.80]), orthopaedic surgery (RR: 2.97 [2.65-3.32]) and hospitalisation all causes (RR: 2.44 [2.31-2.58]). This burden was more important in patients with inhibitors or treated in prophylaxis and was close for HA and HB patients. The annual per-person costs were €282,560 and €181,566 for HA and HB in prophylaxis without inhibitors, respectively. The population with inhibitors, although limited, had even much higher costs. CONCLUSION:The clinical burden and costs of haemophilia treatments may be very high especially in patients in prophylaxis and/or with inhibitors.

BACKGROUND:Haemophilia management aims to prevent bleeding and preserve joint function. Changes in patients' joint health may influence physicians' decisions to adjust treatment. The Haemophilia Joint Health Score (HJHS) and Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score assess joint health but are not routinely used. AIM:To evaluate whether systematic joint examination with HJHS and/or HEAD-US had an impact on treatment management decisions in France, using final data from the A-MOVE study. METHODS:A-MOVE (NCT04133883) was a 12-month prospective, multicentre study, which enrolled persons with haemophilia A (all severities, aged 6-40 years) treated prophylactically or on demand with standard/extended half-life FVIII replacement. At baseline, 6 and 12 months, HJHS/HEAD-US and changes in patients' management were assessed. RESULTS:Eighty-six patients from 20 sites were included in the final analysis; 68 had HJHS/HEAD-US assessments at 12 months. Over 12 months, 24.4% (n = 21/86) of patients experienced an impact on their haemophilia management due to HJHS/HEAD-US scores; these decisions were impacted by HJHS in about half of the patients (52.4%, n = 11/21) and HEAD-US in almost all patients (95.2%, n = 20/21). Both assessments contributed to a change in management decisions in about half of the patients (47.6%, n = 10/21). Twenty-nine patients (33.7%) had haemophilia management decisions impacted by factors other than HJHS/HEAD-US, including physical examination findings (n = 9) and the occurrence of bleeding episodes (n = 8). CONCLUSIONS:Final data from the A-MOVE study show that systematic joint assessments, through functional/physical examination (HJHS) and ultrasound (HEAD-US), may impact treatment management decisions in persons with haemophilia A.

[This corrects the article DOI: 10.1016/j.rpth.2025.102950.].

Bleeding during oral anticoagulant therapy is currently codified by expert guidelines. Monitoring coagulation during bleeding events remains challenging. This study aimed to assess viscoelastic hemostatic assays (VHAs) using the Quantra analyzer (HemoSonics) in dabigatran-treated patients with International Society on Thrombosis and Haemostasis major bleeding. We conducted a prospective, multicenter study at 2 university hospitals from January 2021 to December 2023. VHA were evaluated using whole blood sample collected upon emergency admission and 30 minutes after reversal therapy. Six dabigatran-treated patients with major bleeding were included in this study and received idarucizumab: 4 patients with an intracranial bleeding and 2 with gastrointestinal major bleeding. Prior to reversal therapy, clot time (CT) and clot time with heparinase coagulation time (CTH) were prolonged beyond normal range for all patients but clot stiffness (CS) was notably low, indicating a hypocoagulable state. After idarucizumab administration, both CT (median [interquartile range], 179.5 s [169.3-238.5 s] vs 126 s [96-135.5 s]; P = .002) and CTH (181.5 s [166.3-224.3 s] vs 118.5 s [99.5-121.3 s], P = .002) significantly decreased, whereas CS increased significantly (median [interquartile range], 18 hPa [12.3-24.3 hPa] vs 26.6 hPa [25.5-33.8 hPa]; P = .03), all values falling within the normal range. Median anti-IIa activity at emergency arrivals decreased under 30 ng/mL 30 minutes, 6 hours, and 24 hours after idarucizumab administration (P = .0008). No complications were reported during follow-up. After idarucizumab administration, VHA demonstrated significant reductions in CT and CTH, with a corresponding increase in CS within normal ranges. These findings suggest that VHA using the Quantra analyzer may be a valuable tool in assessing the presence of dabigatran and the efficacy of idarucizumab reversal in patients with major bleeding. SIGNIFICANCE STATEMENT: This study highlights viscoelastic hemostatic assays using the Quantra analyzer to monitor reversal therapy in dabigatran-treated patients with major bleeding. It demonstrates the efficacy of idarucizumab in restoring coagulation parameters, offering insights into clinical management.

Acquired haemophilia A (AHA) is a rare haemorrhagic disease characterised by new-onset haemorrhagic symptoms associated with a dramatic decrease in factor VIII levels and an anti-factor VIII neutralising autoantibody concentration >0.6 Bethesda units. Elderly people are often affected, whereas children are rarely affected; the paediatric incidence reported in the literature is about 0.045 case/million/year. For some time, the paediatric standard of care has been that for adults, but clinicians have often reported poor outcomes. Here, we describe the largest retrospective paediatric AHA cohort assembled to date, including eight patients diagnosed in France from 2000 to 2020.

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.

OBJECTIVES:To assess the real-world efficacy and safety of recombinant factor IX albumin fusion protein (rIX-FP) in patients with hemophilia B (HB) in France. METHODS:Data on dosing frequency, weekly consumption, and bleeds before-and-after switching to rIX-FP, were collected from December 2021 to February 2024. Annualized (spontaneous) bleeding rates [A(s)BRs] were calculated only in patients on prophylaxis with a follow-up ≥ 6 months. RESULTS:This interim analysis focused on 77 patients ≥ 12 years; 62 (81%) had severe HB. After switching to rIX-FP, the infusion interval was 14 (7-14) days. Weekly consumption was 43 (35.5-53) IU/kg. ABRs and AsBRs were 0.5 (0-1.9) and 0 (0-0.7) (n = 63) at 18.2 (12.3-21.9) months of follow-up. Prophylactic efficacy of rIX-FP was considered 'Excellent'/'Good' in 65/68 (95%) patients. Among the 43 patients previously treated with rFIXFc, 21 increased the infusion interval from 7 (7-11) days with rFIXFc to 14 (7-14) days with rIX-FP; 33/43 (77%) reduced weekly factor IX (FIX) consumption from 59.95 (46.35-77.93) to 42.5 (35.88-50.25) IU/kg. Patients maintained good protection against bleeds. CONCLUSION:This analysis confirmed that switching to rIX-FP allows for reducing injection frequency and FIX consumption while maintaining good bleed protection.

The phase 3 OCEANIC-AF trial (NCT05643573) of the investigational oral activated factor XI (FXIa) inhibitor asundexian (Bayer, Leverkusen, Germany) tested at the dose of 50 mg has been stopped early due to an inferior efficacy of asundexian versus the control arm (apixaban) for the prevention of strokes and systemic embolisms in patients with atrial fibrillation (AF). This decision is based on the recommendation of the study's independent data monitoring committee (IDMC) as part of ongoing surveillance [ [1] Bayer OCEANIC-AF study stopped early due to lack of efficacy. https://www.bayer.com/media/en-us/oceanic-af-study-stopped-early-due-to-lack-of-efficacy/Date: 2023 Date accessed: November 19, 2023 Google Scholar ]. No additional details were available when this manuscript was written. The Phase 3 trial LIBREXIA-AF (NCT05757869), a randomized, double-blind study that evaluates the efficacy and safety of milvexian versus apixaban in AF is ongoing. Results are expected in 2027.