Journal of Thrombosis and Haemostasis最新文献

{"title":"The diagnostic value of the platelet function analyzer in mild to moderate bleeding disorders","authors":"Amaury Monard , Yvonne Henskens , Floor Heubel-Moenen","doi":"10.1016/j.jtha.2025.03.041","DOIUrl":"10.1016/j.jtha.2025.03.041","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 7","pages":"Pages 2116-2118"},"PeriodicalIF":5.5,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of heparins, DOACs, and FXII/FXI inhibitors on catheter-initiated thrombin generation in PRP: an in vitro study.","authors":"Hardy Michael, Thonon Henri, Douxfils Jonathan, Vassart Julie, Gouin-Thibault Isabelle, Lessire Sarah, Lecompte Thomas, Mullier François","doi":"10.1016/j.jtha.2025.06.016","DOIUrl":"10.1016/j.jtha.2025.06.016","url":null,"abstract":"<p><strong>Background: </strong>Invasive endovascular procedures often require anticoagulation to prevent device-associated thrombosis. High doses of unfractionated heparin (UFH) are the gold standard. The efficacy of factor XII(a) and XI(a) inhibitors remains unexplored.</p><p><strong>Objectives: </strong>We aim to investigate, using a validated in vitro model of catheter-initiated thrombin generation (TG) in platelet-rich plasma (PRP), the effects of garadacimab, abelacimab, asundexian, milvexian, and commonly used anticoagulants apixaban, dabigatran, fondaparinux and heparins (enoxaparin, UFH).</p><p><strong>Methods: </strong>Anticoagulants were added to PRP at six concentrations and effects compared with UFH as a reference. The impact of adding anticoagulants into collection tubes before most preanalytical contact activation was also assessed. Concentrations achieving a 50% reduction in TG peak height (PH) were determined (IC50).</p><p><strong>Results: </strong>All anticoagulants prolonged lag time (LT) and reduced PH and endogenous thrombin potential, albeit to varying extents. UFH was the only anticoagulant able to suppress TG at clinically achieved concentrations (1 U/mL). The following IC50 were found: milvexian 2,400 ng/mL, apixaban and dabigatran 175 ng/mL, fondaparinux 2.4 μg/mL, enoxaparin 0.5 U/mL and UFH 0.25 U/mL. Asundexian up to 5,000 ng/mL failed to reduce TG PH by 50%. Adding garadacimab and abelacimab to collection tubes resulted in greater efficacy than when added to PRP: LT increased by 89% and 32%, respectively; IC50 were 25 and 12.5 μg/mL, respectively.</p><p><strong>Conclusions: </strong>Heparins were by far the most effective anticoagulants in our in vitro model. Factor XIIa and XI(a) inhibitors did not adequately prevent coagulation on the studied artificial surface. DOACs and fondaparinux showed limited efficacy, aligning with clinical observations.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Basis of Thrombotic Microangiopathy.","authors":"Yuan Zhou, Joel Moake, Jing-Fei Dong","doi":"10.1016/j.jtha.2025.06.014","DOIUrl":"10.1016/j.jtha.2025.06.014","url":null,"abstract":"<p><p>Thrombotic thrombocytopenic purpura (TTP) and Hemolytic uremic syndrome (HUS) are two index conditions of thrombotic microangiopathy (TMA). While conditions classified as TMA share common clinical characteristics, their underlying causes differ significantly. TMA is challenging to diagnose but life threating without proper and timely diagnosis and treatments. In this review, we discuss recent advances in understanding of the molecular basis, clinical epidemiology, and treatments of TTP and HUS.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A First-in-Human Study of NXT007, a Next-Generation, Activated Factor VIII-Mimetic Bispecific Antibody, in Healthy Participants.","authors":"Takehiko Sambe, Takuya Miwa, Koichiro Yoneyama, Takaaki Ishida, Taigi Yamazaki, Midori Shima","doi":"10.1016/j.jtha.2025.06.013","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.06.013","url":null,"abstract":"<p><strong>Background: </strong>NXT007 is a bispecific antibody that mimics the cofactor function of activated factor (F)VIII and was engineered by modifying emicizumab. Nonclinical investigations suggested its potential to provide non-hemophilic levels of coagulation activity to people with hemophilia A (PwHA). A first-in-human, single-ascending-dose study of NXT007 was conducted in healthy Japanese male adults (Part A of the NXTAGE study).</p><p><strong>Objectives: </strong>To evaluate safety, immunogenicity, pharmacokinetics, and pharmacodynamics of NXT007.</p><p><strong>Methods: </strong>Forty participants were enrolled across five cohorts and randomized to receive a single subcutaneous injection of NXT007 (n=6 per cohort; 0.0018, 0.0054, 0.018, 0.054, or 0.18 mg/kg) or placebo (n=2 per cohort).</p><p><strong>Results: </strong>There were no dose-dependent increases in the incidence of adverse events (AEs), and no thrombotic events or injection-site reactions were reported. One serious AE of erythema was reported in a participant who received NXT007 0.0054 mg/kg, and its causality to NXT007 could not be ruled out. Nine participants developed anti-NXT007 antibodies (ADAs); all were considered to be associated with faster clearance of NXT007 without impacting safety. NXT007 exposure increased dose-dependently but less than dose-proportionally. The elimination half-life of NXT007 was approximately 10 weeks in ADA-negative participants. With ex vivo neutralization of endogenous FVIII in plasma samples, activated partial thromboplastin time was shortened and thrombin generation was promoted in a dose-dependent manner.</p><p><strong>Conclusions: </strong>A single subcutaneous injection of NXT007 was well tolerated without occurrence of thrombotic events. The long half-life, pharmacological effect, and safety profile supported study progression to the subsequent multiple-ascending-dose parts of the NXTAGE study in PwHA.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2025 focused update of the 2020 ISTH guidelines for management of thrombotic thrombocytopenic purpura.","authors":"X Long Zheng, Zainab Al-Housni, Spero R Cataland, Paul Coppo, Brian Geldziler, Federico Germini, Alfonso Iorio, Arun Keepanasseri, Camila Masias, Masanori Matsumoto, Keith R McCrae, Jo McIntyre, Reem A Mustafa, Flora Peyvandi, Lene Russell, Rawan Tarawneh, Sara K Vesely","doi":"10.1016/j.jtha.2025.06.002","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.06.002","url":null,"abstract":"<p><strong>Background: </strong>Over the past few years, new information has emerged in the management of both immune thrombotic thrombocytopenic purpura (iTTP) and congenital (or hereditary) thrombotic thrombocytopenic purpura (cTTP).</p><p><strong>Methods: </strong>In March 2024, the International Society on Thrombosis and Haemostasis (ISTH) formed a multidisciplinary panel comprising hematologists, intensivists, nephrologists, pathologists, patient representatives, and a methodology team. The panel discussed all treatment questions related to thrombotic thrombocytopenic purpura (TTP) using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method to appraise evidence and formulate recommendations.</p><p><strong>Results: </strong>For patients with cTTP in remission, a new strong recommendation was issued for the use of recombinant ADAMTS-13 over fresh frozen plasma in the context of moderate certainty evidence. The panel also revised a previous recommendation and suggested using fresh frozen plasma over a watch-and-wait approach for patients with cTTP in remission based on very low certainty evidence should recombinant. The panel reviewed and referenced new publications supporting therapeutic efficacy, potential survival benefit, and cost considerations of adding caplacizumab to therapeutic plasma exchange, corticosteroids, and rituximab, but concluded that no change was warranted to the previous recommendations in the management of iTTP. Good practice statements on the concomitant use of antithrombotic agents were marginally modified.</p><p><strong>Conclusions: </strong>For patients with iTTP, no change to 2020's recommendations. For patients with cTTP, the panel supports ADAMTS-13 replacement. Where accessible, recombinant ADAMTS-13 provides the most favorable balance of benefits and risks. Otherwise, fresh frozen plasma may still be effective. Shared decision-making should include the benefits, the potential harms, and the burden of care.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thromboembolism in transplant-ineligible multiple myeloma patients on triplet/quadruplet therapy: a post-hoc analysis of BENEFIT.","authors":"Emilie Chalayer, Corinne Frere, Elisabeth Daguenet, Thomas Lecompte, Bernard Tardy, Ilhame Bounouara, Manon Sapet, Arthur Bobin, Stephanie Harel, Olivier Decaux, Karim Belhadj, Cyrille Touzeau, Margaret Macro, Mohamad Mohty, Philippe Moreau, Jill Corre, Hervé Avet-Loiseau, Lionel Karlin, Thierry Facon, Aurore Perrot, Cyrille Hulin, Salomon Manier, Laurent Frenzel, Xavier Leleu","doi":"10.1016/j.jtha.2025.06.012","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.06.012","url":null,"abstract":"<p><strong>Background: </strong>Venous thromboembolism event (VTE) remains a major concern for patients with newly diagnosed multiple myeloma (nMM) undergoing therapy.</p><p><strong>Methods: </strong>This post hoc analysis of the randomized phase 3 BENEFIT trial (NCT04751877) evaluated the incidence and risk factors for VTE in 257 patients aged 65-79 years with transplant-ineligible (TI) nMM who received isatuximab/ bortezomib/lenalidomide/dexamethasone or isatuximab/lenalidomide/dexamethasone.</p><p><strong>Results: </strong>In the whole cohort, the 6-month cumulative incidence of VTE was 4.8% (95% CI, 2.7-8.1%); 0.8% (95% CI, 0.1-5.6%) in patients receiving low-dose direct oral anticoagulants (DOACs) compared to 5.6% (95% CI, 1. 9-16.7%) in those who received prophylactic-dose heparin and 9.8% (95% CI, 3.9-24.75 in patients receiving aspirin. Only one VTE occurred beyond the 6-month period. The most frequently used thromboprophylaxis agents were DOACs (n=127, 55.2%), low molecular weight heparins (n=54, 23.5%), and aspirin (n=40, 17.4%). We noted that one-third of patients who experienced VTE had not received thromboprophylaxis. Among the different thromboprophylaxis regimens used, only a low-dose DOAC was associated with a significant reduction in the risk of VTE. In multivariate analysis, proteinuria ≥ 0.44g/L (HR 5.8; 95% CI, 1.7-26.8) and M-protein level ≥ 22g/L (HR 4.9; 95% CI, 1.3-31.9), were significantly associated with an increased risk of VTE while low-dose DOAC was associated with a decreased risk for VTE (HR 0.13; 95 %CI, 0.007-0.67).</p><p><strong>Conclusions: </strong>In summary, the cumulative incidence of VTE remains high in patients with TI nMM. DOACs could be the most effective option for preventing VTE.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute kidney injury after cardiac surgery is associated with platelet activation.","authors":"Naomi Brown, Nikol Sullo, Nathan Tyson, Bryony Eagle-Hemming, Florence Y Lai, Sophia Sheikh, Kristina Tomkova, Lathishia Joel-David, Tracy Kumar, Hardeep Aujla, Alison H Goodall, Gavin J Murphy, Marcin J Woźniak","doi":"10.1016/j.jtha.2025.06.009","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.06.009","url":null,"abstract":"<p><strong>Background: </strong>Post-cardiac surgery acute kidney injury (AKI) is common and associated with high mortality and morbidity. Its pathogenesis remains unclear. We hypothesised that platelet activation, extracellular vesicles (EVs), and micro-RNA levels are associated with post-surgery AKI.</p><p><strong>Methods: </strong>Plasma samples from 95 MaRACAS study patients were collected before, immediately after, and 6-12, 24, and 48 hours post-surgery. Platelet responsiveness was assessed with Multiplate. Flow cytometry measured platelet and leukocyte activation and EV derivation. EV size and concentration were analysed using NanoSight. Circulating biomarkers were measured by immunoassays, and micro-RNA was analysed using TaqMan-arrays and validated by qPCR.</p><p><strong>Results: </strong>AKI occurred in 57% of patients. Platelet-derived EVs increased 24 hours post-surgery in AKI patients. Platelets were desensitised to ADP at 6-12 hours, independent of aspirin or P2Y12 antagonist use. AKI patients had more activated platelets at 6-12 hours, more platelet-granulocyte aggregates before, and at 6-12 and 24 hours post-surgery, and higher sICAM1 levels before and 48 hours post-surgery. TaqMan arrays showed miR-668 was downregulated before, and miR-92a-1, -920, -518a-3p, -133b, and -1262 were upregulated after surgery in AKI patients. qRT-PCR confirmed miR-1262 upregulation. Multivariate analysis showed that granulocyte-platelet aggregates were independently associated with AKI before, and at 6-12 and 24 hours post-surgery. Activated GPIIb/IIIa and ADP were associated with AKI at 6-12 and 24 hours, and sICAM1 at 48 hours.</p><p><strong>Conclusions: </strong>AKI is associated with platelet activation, suggesting alternative platelet inhibition may offer renoprotection. Larger studies are needed to validate these findings.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Phenotypes in Thrombotic Primary Antiphospholipid Syndrome Using Cluster Analysis: A step Towards Personalized Medicine.","authors":"Gabrielle M Santos, Paula David, Or Hen, Juan Luis Ontiveros-Austria, Rotem Liran, Sergio Rodriguez-Rodriguez, Julia Cerchiari de Godói, Yonatan Shneor Patt, Shaked Beladev, Erica Okazaki, Marina Collela, Bianca Stefanello, Gabriela G Yamaguti-Hayakawa, Cynthia Rothschild, Joyce Annichino-Bizzachi, Angel Vargas-Ruiz, Paula Prestes, Vanderson Rocha, Erich V de Paula, Omer Gendelman, Ophira Salomon, Roberta Demichelis-Gomez, Ana Barrera-Vargas, Howard Amital, Paula Villaça, Yehuda Shoenfeld, Fernanda A Orsi","doi":"10.1016/j.jtha.2025.06.010","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.06.010","url":null,"abstract":"<p><strong>Background: </strong>Thrombotic risk in primary antiphospholipid syndrome (APS) is a result of complex, yet undefined, interactions among multiple factors. While long-term anticoagulation reduces thrombotic complications, its efficacy varies, with thrombosis recurrence rates ranging from 5-20% within two years. Emerging therapies may benefit specific APS subgroups, although identifying and stratifying these groups remains a significant challenge.</p><p><strong>Objective: </strong>To identify specific phenotypic subgroups of thrombotic primary APS based on clinical and laboratory characteristics to provide insight for both personalized diagnostic and therapeutic strategies.</p><p><strong>Patients/methods: </strong>Multicenter retrospective cohort study including 663 patients with thrombotic primary APS who were followed in Brazil, Israel, and Mexico (2018-2023). Hierarchical cluster analysis categorized patients based on demographics, thrombotic characteristics, comorbidities, and laboratory data.</p><p><strong>Results: </strong>Cluster analysis identified three distinct phenotypes. Cluster 1 (n=348) included older patients (median age 43 years) with high cardiovascular risk factors (hypertension, diabetes, and dyslipidemia) and predominantly arterial thrombosis (53%, p<0.001). Cluster 2 (n=119) included younger patients (median age 35 years) with high recurrence rates (71%, p<0.001) of venous thromboembolism (80%, p<0.001) and higher anticardiolipin prevalence (29%, p<0.001). Cluster 3 (n=196) featured the youngest patients (median age 29 years), predominantly triple aPL positive (98.5%, p<0.001), with complement consumption (C3: 17%, p=0.003), thrombocytopenia (12%, p=0.05), and venous thrombosis (73%, p<0.001).</p><p><strong>Conclusion: </strong>This study identified three distinct phenotypes of thrombotic primary APS, each characterized by the predominance of cardiovascular risk factors, hypercoagulability, or immunological derangements. The findings provide a basis for developing personalized management strategies to improve patient outcomes.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating endothelial cell transduction and hexon:PF4 binding of ChAdOx1 in the context of VITT.","authors":"Charlotte Lovatt, Lars Frängsmyr, Emma A Swift, Rosie M Mundy, Alan L Parker","doi":"10.1016/j.jtha.2025.06.006","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.06.006","url":null,"abstract":"<p><strong>Background: </strong>Vaccines against SARS-CoV2 have been essential in controlling COVID-19 related mortality and have saved millions of lives. Adenoviral (Ad) based vaccines been integral part in this vaccine campaign, with licensed vaccines based on the simian Y25 isolate (Vaxzevria, Astrazeneca) and human Ad type 26 (Jcovden, Janssen) widely adopted. As part of the largest global vaccination programme ever undertaken, cases of vaccine-induced thrombotic thrombocytopenia (VITT) have been described in approximately 1:200,000 vaccinees administered with Ad based SARS-CoV2 vaccines.</p><p><strong>Objectives: </strong>The mechanism underpinning these adverse events remain to be completely delineated, but is characterised by elevated autoantibodies against PF4 which, in complex with PF4, cluster, bind FcγRIIa on platelets and induce thrombus formation. Here we investigated the ability of ChAdOx1 to transduce and activate endothelial cells (EC).</p><p><strong>Methods: </strong>Using protein sequence alignment tools and in vitro transduction assays, the ability of ChAdOx1 to infect EC was assessed. Furthermore, the ability of ChAdOx1 infection to activate EC was determined. Finally, using surface plasmon resonance we assessed the electrostatic interactions between the ChAdOx1 hexon and PF4.</p><p><strong>Results and conclusions: </strong>Despite lacking the primary cell entry receptor, Coxsackie and Adenovirus Receptor (CAR), ChAdOx1 efficiently transduced EC in a CAR-independent manner. This transduction did not result in EC activation. Purified hexon protein from ChAdOx1 preps did, however, bind PF4 with a similar affinity to that previously reported for the whole ChAdOx1 capsid. These data confirm the need to develop non-PF4 binding adenoviral capsids and assess their potential to mitigate adverse events associated with VITT.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The genetic spectrum of rare bleeding disorders.","authors":"Samin Mohsenian, Omid Seidizadeh, Andrea Cairo, Roberta Palla, Marzia Menegatti, Flora Peyvandi","doi":"10.1016/j.jtha.2025.06.005","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.06.005","url":null,"abstract":"<p><strong>Background: </strong>Rare bleeding disorders (RBDs) account for almost 3-5% of bleeding disorders. Because of their rarity, phenotype and genotype analyses have been conducted only on a limited number of cases.</p><p><strong>Aims: </strong>To characterize the laboratory phenotype and genetic spectrum of a large international cohort of RBDs.</p><p><strong>Material and methods: </strong>A total of 807 individuals suspected to have RBDs were collected (2001-2020). The severity of RBDs was assessed based on plasma clotting factor activity levels. Gene sequencing was performed to confirm the diagnosis. Novel variants were assessed using in-silico prediction tool (CADD and REVEL scores).</p><p><strong>Results: </strong>After excluding 46 subjects with normal phenotype and genotype, 761 cases with RBDs from 19 countries were included. Of these, 526 had coagulant activity levels below the normal range with identified variants. FVII deficiency was the most frequent (23%), while FII and compound FV+FVIII (6%) deficiencies were the rarest. The majority of cases (86%) had an autosomal recessive pattern and among their heterozygous cases (22%), 8% were severely affected, suggesting that the second expected variant was not identified. No causative variant was identified in 4% of cases. Among the identified 257 unique variants, 86% were predicted to be pathogenic and 11% were novel. Missense variants were identified in 57% of cases, excluding cases of afibrinogenemia and compound FV+FVIII deficiencies. The majority (48%) affected exons encoding catalytic domains.</p><p><strong>Conclusion: </strong>In this large group of RBDs, missense variants were the most prevalent, primarily affecting the catalytic domains of proteins, except in cases of afibrinogenemia and FV+FVIII deficiencies.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}