Journal of Thrombosis and Haemostasis最新文献

{"title":"Evaluation of intracranial atherosclerotic stenosis burden, the use of dual antiplatelet therapy, and stroke recurrence in patients with minor stroke.","authors":"Tingting Liu, Yongle Wang, Kaili Zhang, Haimei Fan, Xinyi Li, Xuemei Wu, Xiaoyuan Niu","doi":"10.1016/j.jtha.2025.04.034","DOIUrl":"10.1016/j.jtha.2025.04.034","url":null,"abstract":"<p><strong>Background: </strong>Intracranial atherosclerotic stenosis (ICAS) is a primary cause of ischemic stroke, but it might not be the main predictor of stroke recurrence.</p><p><strong>Objectives: </strong>A comprehensive assessment of dual antiplatelet therapy (DAPT) effectiveness via ICAS burden (ICASB) is crucial for patients with minor stroke.</p><p><strong>Methods: </strong>This prospective, multicenter cohort study included patients with minor (National Institutes of Health Stroke Scale score ≤5) stroke. The ICASB was determined by the degree and number of ICAS occurrences. The primary efficacy outcomes were all stroke types (ischemic or hemorrhagic). Ninety-day and 1-year follow-up evaluations were conducted.</p><p><strong>Results: </strong>Among 3061 patients (age = 61.7 ± 12.0 years; males, 73.3%), 61.0% (n = 1868) received DAPT, and 39.0% (n = 1193) received single APT. Finally, 2900 and 2709 patients were included in the 90-day and 1-year outcome assessments, respectively. The primary outcome occurred in 242 patients (8.3%) at 90 days and 353 patients (13.0%) at the 1-year follow-up. In patients with high ICASB (but not those with low ICASB), compared with single APT, DAPT was associated with a lower recurrent stroke rate at the 90-day (weighted absolute risk difference, 7.3%; inverse probability of treatment weighted hazard ratio, 0.58; 95% CI, 0.39-0.87) and 1-year (weighted absolute risk difference, 3.9%; inverse probability of treatment weighted hazard ratio, 0.68; 95% CI, 0.45-1.03) follow-ups. Significant interactions were observed at the 90-day (P_interaction = .021) and 1-year (P_interaction = .086) follow-ups. Similar results were observed for the propensity score matched model.</p><p><strong>Conclusion: </strong>For minor stroke patients receiving APT, DAPT reduced stroke recurrence at 90 days in the high ICASB group but not in the low ICASB group.</p><p><strong>Trial registration: </strong>Unique identifier: ChiCTR1900025214.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094375","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":"Successful use of aflibercept for high cardiac output in hereditary hemorrhagic telangiectasia after failure of pazopanib and bevacizumab therapy","authors":"Akshay Mathavan ,&nbsp;Akash Mathavan ,&nbsp;Urszula Krekora ,&nbsp;Krunal Shukla ,&nbsp;Marc S. Zumberg ,&nbsp;Ali Ataya","doi":"10.1016/j.jtha.2025.05.007","DOIUrl":"10.1016/j.jtha.2025.05.007","url":null,"abstract":"<div><div>Hereditary hemorrhagic telangiectasia (HHT) can manifest with hepatic arteriovenous malformations, leading to a high cardiac output state and pulmonary hypertension. Bevacizumab is commonly used to treat this complication, but response is often partial and may diminish over time. We present a patient with <em>ACVRL1</em>-related HHT and high cardiac output who failed pazopanib and developed apparent bevacizumab resistance with symptom recurrence despite maintenance and reintroduced therapy. Aflibercept, a vascular endothelial growth factor and placental growth factor-binding decoy receptor, was initiated intravenously, resulting in improved dyspnea, decreased epistaxis severity, and a reduction in cardiac index from 3.92 to 2.90 L/min/m². Hemoglobin and iron indices remained stable without transfusion or iron support. This case highlights aflibercept as a potential alternative antiangiogenic agent for HHT-related high-output states following bevacizumab failure. Mechanistic distinctions between these agents and prior reports of aflibercept efficacy in other refractory vascular contexts suggest a role for broader investigation.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 8","pages":"Pages 2651-2655"},"PeriodicalIF":5.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086323","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":"Bleeding risk and performance of bleeding risk assessment models in patients with venous thromboembolism on anticoagulation: results from the prospective observational bleeding and assess long-term outcomes on health in patients with venous thromboembolism (BACH-VTE) study.","authors":"Timothy Hoberstorfer, Stephan Nopp, Daniel Steiner, Julia Deinsberger, Oliver Schlager, Ingrid Pabinger, Benedikt Weber, Cihan Ay","doi":"10.1016/j.jtha.2025.05.005","DOIUrl":"10.1016/j.jtha.2025.05.005","url":null,"abstract":"<p><strong>Background: </strong>Patients with venous thromboembolism (VTE) are at risk of bleeding during anticoagulation.</p><p><strong>Objectives: </strong>This study aimed to assess bleeding risk and the performance of risk assessment models (RAMs) VTE-PREDICT, HAS-BLED, RIETE, and VTE-BLEED in patients with acute VTE initiating anticoagulation.</p><p><strong>Methods: </strong>We used data from a prospective observational cohort study (BACH-VTE) including patients with acute VTE who initiated anticoagulation with a follow-up period of up to 2 years. Exclusion criteria were active cancer, pregnancy, and postpartum period. Major bleeding, clinically relevant nonmajor bleeding (CRNMB), and minor bleeding were recorded and their frequencies calculated. RAM performance was evaluated by discrimination and calibration. Predictors associated with clinically relevant bleeding (CRB; composite of major and CRNMB) were assessed.</p><p><strong>Results: </strong>In total, 308 patients (median age, 55 years; 42% women, 47% pulmonary embolism, 62% unprovoked VTE) were included. During a median follow-up time of 12.6 months, we observed 2 major bleedings, 41 CRNMBs, and 66 minor bleedings, corresponding to 2-year cumulative incidences (95% CI) of 0.9% (0%-2.1%), 16.2% (10.7%-21.3%), and 20.6% (15.1%-25.8%), respectively, and of 33.4% (26.7-39.5) for any bleeding. RAM discrimination was poor to moderate with C-statistics (95% CI) for CRB of 0.71 (0.61-0.80) for VTE-PREDICT, 0.59 (0.49-0.68) for HAS-BLED, 0.52 (0.41-0.62) for RIETE, and 0.56 (0.45-0.68) for VTE-BLEED. Calibration analysis revealed underestimation of bleeding risk. Female sex, lower hemoglobin, and bleeding history were associated with CRB in a univariable but not in a multivariable model.</p><p><strong>Conclusion: </strong>In patients treated with anticoagulants for VTE, we found high rates of CRB. Only the VTE-PREDICT model showed acceptable discrimination, but poor calibration.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086312","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":"Benefits of anticoagulation prophylaxis in children undergoing kidney transplant: systematic review and meta-analysis","authors":"Ahmad H. Al-Huniti ,&nbsp;Caroline Malcolmson ,&nbsp;Valerie Langlois ,&nbsp;Ashlene M. McKay ,&nbsp;Armando Lorenzo ,&nbsp;Zhen Wang ,&nbsp;Suzan Williams ,&nbsp;Chia Wei Teoh ,&nbsp;Leonardo R. Brandão","doi":"10.1016/j.jtha.2025.04.032","DOIUrl":"10.1016/j.jtha.2025.04.032","url":null,"abstract":"<div><h3>Background</h3><div>Graft thrombosis is a preventable cause of early allograft loss after pediatric kidney transplant, but the role of primary thromboprophylaxis is uncertain.</div></div><div><h3>Objectives</h3><div>This study aimed to determine the effectiveness and safety of thromboprophylaxis in preventing graft thrombosis among children (0-21 years) undergoing kidney transplant.</div></div><div><h3>Methods</h3><div>We performed a systematic literature review of MEDLINE, Embase, and Cochrane Libraries from inception until September 2024. The primary outcome assessed by meta-analysis was graft thrombosis, and the secondary outcome was major bleeding (per International Society on Thrombosis and Haemostasis criteria).</div></div><div><h3>Results</h3><div>Twenty-five observational studies (21 retrospective and 4 prospective) describing 2094 patients (1659 cases and 435 controls) met eligibility criteria. Thromboprophylaxis was used universally (ie, all kidney recipients in the study) in 64% (1055/1659) or only in high-risk patients (eg, recipient weight &lt;20 kg and age &lt;5 years) in 36% (604/1659). Compared with no preventive measures for thrombosis, thromboprophylaxis was associated with reduced risk of graft thrombosis (odds ratio, 0.31; 95% CI, 0.18-0.53). Subgroup analyses of heparinoid-only, universal thromboprophylaxis, and high risk only protocols revealed similar findings. Thromboprophylaxis was not associated with increased risk of bleeding resulting in surgical exploration or graft loss. The overall risk of bias was moderate. Studies showed high clinical and methodologic heterogeneity in study populations and thromboprophylaxis protocols.</div></div><div><h3>Conclusion</h3><div>Primary thromboprophylaxis appears effective in preventing kidney graft loss from vascular thrombosis in pediatric recipients. This benefit may be offset by the risk of bleeding, although clarity on bleeding risk factors is lacking. We identified knowledge gaps, including uncertainty about optimal thromboprophylaxis regimens and treatment duration.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 8","pages":"Pages 2568-2583"},"PeriodicalIF":5.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086306","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":"Recombinant a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS-13) for acute and prophylactic treatment of congenital thrombotic thrombocytopenic purpura in pregnancy","authors":"Taeer Avnon ,&nbsp;Anat Rabinovich ,&nbsp;Oleg Pikovsky ,&nbsp;Gali Pariente ,&nbsp;Offer Erez","doi":"10.1016/j.jtha.2025.05.006","DOIUrl":"10.1016/j.jtha.2025.05.006","url":null,"abstract":"<div><div>Thrombotic thrombocytopenic purpura (TTP) is a disorder of the absence or severe depletion of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS-13) protease, which cleaves von Willebrand factor multimers. In its absence, exposed platelet binding sites on large von Willebrand factor multimers bind and aggregate platelets, causing microangiopathic hemolytic anemia and thrombosis. The rare congenital form of TTP (cTTP) is caused by mutations in the <em>ADAMTS-13</em> gene. Pregnant cTTP patients are at very high risk of developing complications. Current recommendations for pregnant cTTP patients are prophylactic fresh–frozen plasma infusions; however, efficacy varies among patients. Recombinant ADAMTS-13 (rADAMTS-13) is a novel alternative to plasma infusions, recently reported to be effective and safe for treating nonpregnant cTTP patients. Few studies have attempted to treat pregnant cTTP patients with rADAMTS-13. We present a case of successful treatment with rADAMTS-13 for acute TTP exacerbation and maintenance during pregnancy in a cTTP patient with a history of pregnancy complications and insufficient response to plasma infusions.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 8","pages":"Pages 2598-2603"},"PeriodicalIF":5.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086318","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 factor (F)VIII K1693N mutation (FVIII-Nara) in a patient with moderate hemophilia A confers resistance to thrombin-catalyzed cleavage at Arg1689 involving P4ʹ position","authors":"Shoko Furukawa ,&nbsp;Nemekhbayar Baatartsogt ,&nbsp;Takeshi Kawamura ,&nbsp;Kaoru Horiuchi ,&nbsp;Masaaki Doi ,&nbsp;Yuji Kashiwakura ,&nbsp;Tsukasa Ohmori ,&nbsp;Keiji Nogami","doi":"10.1016/j.jtha.2025.05.002","DOIUrl":"10.1016/j.jtha.2025.05.002","url":null,"abstract":"<div><h3>Background</h3><div>Some patients with nonsevere hemophilia A (HA) are diagnosed with reduced factor (F)VIII activity (FVIII:C) relative to FVIII antigen (FVIII:Ag) and are classified as cross-reactive material-positive. We previously found a novel FVIII-Lys1693Asn (K1693N) natural mutation in a patient with HA with moderate phenotype (FVIII:C/FVIII:Ag = 1.9 IU/dL/124 IU/dL).</div></div><div><h3>Objective</h3><div>To examine the mechanism(s) involving the P₄ʹ site on thrombin cleavage site at Arg¹⁶⁸⁹ in a cross-reactive material-positive phenotype.</div></div><div><h3>Methods</h3><div>FVIII-K1693N and its comparison variant K1693A were analyzed for t thrombin-mediated activation. FVIII-K376N, listed in the HA database due to a similar Lys-to-Asn substitution, was examined with K376A as its comparison. All mutants were expressed in BHK cells.</div></div><div><h3>Results</h3><div>FVIII-K1693N showed delayed cleavage at Arg¹⁶⁸⁹ and low peak FVIII:C, while FVIII-K1693A showed mildly reduced FVIII:C after thrombin activation. Mildly reduced peak FVIII:C and similar cleavage to wild-type was illustrated, however, with the FVIII-K1693A mutation after thrombin activation. These findings indicated that the conversion to Asn at P4ʹ site mediated thrombin resistance. FVIII specific activities of FVIII-K376N and FVIII-K376A were 6.1%/3.1% (one-stage assay) of wild-type, respectively. Thrombin-catalyzed cleavage at Arg³⁷² was comparable to wild-type with both mutants, but thrombin-catalyzed FVIII activation was severely-depressed. Spontaneous decay rates of FVIIIa activity with FVIII-K376N (<em>k</em> = 0.53) and FVIII-K376A (<em>k</em> = 0.99) were greater compared to wild-type (<em>k</em> = 0.32), suggesting that cleavage of P4ʹ site following cleavage at Arg³⁷²contributed to A1-A2 domainal interaction.</div></div><div><h3>Conclusion</h3><div>Lys1693 and Lys376, both located at P₄ʹ sites, are suggested to influence FVIII function via distinct mechanisms, indicating that patient-derived mutations can reveal functional aspects of FVIII activation.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 8","pages":"Pages 2461-2472"},"PeriodicalIF":5.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078881","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":"Elevated levels of (active) von Willebrand factor during anticoagulation are associated with early recurrence of venous thromboembolism","authors":"Geke C. Poolen ,&nbsp;Rolf T. Urbanus ,&nbsp;Mark Roest ,&nbsp;Geert–Jan Geersing ,&nbsp;Bas de Laat ,&nbsp;Roger E.G. Schutgens","doi":"10.1016/j.jtha.2025.04.030","DOIUrl":"10.1016/j.jtha.2025.04.030","url":null,"abstract":"<div><h3>Background</h3><div>Venous thromboembolism (VTE) can recur shortly after stopping anticoagulation, highlighting the need for reliable biomarkers to identify high-risk patients during treatment.</div></div><div><h3>Objectives</h3><div>To determine whether platelet and endothelial markers predict VTE recurrence.</div></div><div><h3>Methods</h3><div>We used data and samples from the randomized controlled VISTA trial (2011-2015), which included patients with unprovoked VTE who were treated with vitamin K antagonists for 6 months. After treatment cessation, patients were followed for 2 years to assess recurrence. This dataset formed the basis for the current prospective analysis, in which plasma levels of von Willebrand factor (VWF), active VWF (aVWF), soluble P-selectin, soluble thrombomodulin, CXCL4, and CXCL7 were measured before and after cessation of anticoagulation. Associations between biomarker levels and recurrence were analyzed using Cox regression.</div></div><div><h3>Results</h3><div>Plasma samples from 629 patients with a first unprovoked VTE who discontinued vitamin K antagonists were analyzed. Recurrence occurred in 75 patients (12%); 11 (15%) within 1 month, 29 (39%) within 3 months, and 46 (61%) after 3 months. Elevated levels of VWF and aVWF were associated with an increased risk of recurrence per 10-unit increase (VWF: hazard ratio, 1.03; 95% CI, 1.01-1.06; aVWF: hazard ratio, 1.02; 95% CI, 1.00-1.05). Associations were stronger for early recurrence (&lt;3 months), while (a)VWF levels were not associated with late recurrence (&gt;3 months). Stratification showed that VWF and aVWF were associated with increased recurrence risk in men, but not in women.</div></div><div><h3>Conclusion</h3><div>Elevated levels of VWF and aVWF during anticoagulation were associated with early recurrence in men and might serve as biomarkers for predicting VTE recurrence.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 8","pages":"Pages 2558-2567"},"PeriodicalIF":5.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078868","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":"Chromogenic vs one-stage assay to diagnose women and girls with hemophilia A—mapping global approaches and assessing challenges: communication from the SSCs of the ISTH","authors":"Lakshmi Srivaths ,&nbsp;Joanna Larson ,&nbsp;Karin Fijnvandraat ,&nbsp;Jesus Ardila ,&nbsp;Miguel Escobar","doi":"10.1016/j.jtha.2025.05.003","DOIUrl":"10.1016/j.jtha.2025.05.003","url":null,"abstract":"<div><h3>Background</h3><div>Assay discrepancies are well recognized in diagnosing men and boys with hemophilia A (MBwHA), but are not well studied in women and girls with hemophilia A (WGwHA).</div></div><div><h3>Objectives</h3><div>To survey hemophilia providers to map global approaches/perspectives/challenges in diagnosing WGwHA with a chromogenic assay (CSA) vs one-stage assay (OSA) and other diagnostic tools to diagnose WGwHA compared with MBwHA.</div></div><div><h3>Methods</h3><div>The International Society on Thrombosis and Haemostasis Scientific and Standardization Committees on FVIII, FIX and Rare Coagulation Disorders and Pediatric and Neonatal Thrombosis and Haemostasis convened a working group, which compiled a Research Electronic Data Capture survey and disseminated it to global hemophilia providers. Descriptive statistics were applied to survey results.</div></div><div><h3>Results</h3><div>Of 174 respondents, 95% were hemophilia providers, comprising 34% adult hematologists, 58% pediatric hematologists, 2% nurse practitioners, and 0.5% nurses; 95% were providers for WGwHA and WGwHMB. The results showed that CSA with/without OSA is ordered by fewer providers in women and girls (WG, 35%) than in men and boys (MB, 61%; <em>P</em> &lt; .001). OSA is ordered by more providers (62%) in WGwHA due to various assay-related reasons. Bleeding Assessment Tool and genetic testing were not used to diagnose WGwHA by 29% and 33%, respectively.</div></div><div><h3>Conclusion</h3><div>Based on our survey results, CSA is ordered less frequently in diagnosing WGwHA compared with MBwHA, likely due to assay-related factors including cost, availability, and insurance coverage, and possibly due to some providers not considering assay discrepancies in WGwHA. Increasing global availability and improving provider consideration of assay discrepancies in WGwHA can increase use of both assays. Improved use of assays and other diagnostic tools, such as Bleeding Assessment Tool scores, will improve effective diagnoses of WGwHA.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 8","pages":"Pages 2656-2662"},"PeriodicalIF":5.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078867","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":"Basic regions of factor V and tissue factor pathway inhibitor mediate heavy chain and acidic region interactions on factor V revealed by tethered chemical cleavage","authors":"Francis Ayombil ,&nbsp;Raffaella Toso ,&nbsp;Rodney M. Camire","doi":"10.1016/j.jtha.2025.04.028","DOIUrl":"10.1016/j.jtha.2025.04.028","url":null,"abstract":"<div><h3>Background</h3><div>Factor (F)V plays a pivotal role in coagulation, having both pro- and anticoagulant functions. Conserved acidic and basic regions (AR and BR) within FVs central B-domain play a key role in regulating procoagulant function. Removing the BR (residues 963-1008) through proteolysis or splicing, as in FV-short, produces an active cofactor, which is partly regulated by tissue factor pathway inhibitor-α (TFPIα) through its C-terminal BR. Although AR2 (residues 1493-1537) is known to be involved, other FV regions that may interact with the FV-BR or TFPIα-BR have not been defined.</div></div><div><h3>Objectives</h3><div>To uncover binding interactions between the BRs and other regions on FV-short.</div></div><div><h3>Methods</h3><div>We used a unique chemical cleavage agent, FeBABE (Fe-p-bromoacetamidobenzyl-ethylenediaminetetraacetic acid) tethered to the FV-BR or TFPIα-BR (BR-FeBABE) to footprint areas of engagement with FV-short using biochemical methods and western blotting.</div></div><div><h3>Results</h3><div>BR-FeBABE bound FV-short and FV-810, another B-domainless form of FV, with high affinity and blocked procoagulant activity, similar to untethered BR. When BR-FeBABE was stimulated, it cut FV-short and FV-810 at 3 sites including the beginning of AR2, near residues 678 to 692 comprising part of AR1 (residues 659-697), and at the beginning of the A2 domain. Cleavage by BR-FeBABE was specific as untethered FV-BR, TFPIα-BR, or TFPIα blocked proteolysis, and forms of FV that do not bind BR-FeBABE, such as FV, FVa, and any form of FV lacking AR2, were not cut.</div></div><div><h3>Conclusion</h3><div>These results define areas of interaction between the BR and FV-short and advance our knowledge about how FV is regulated by the B-domain and TFPIα.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 8","pages":"Pages 2449-2460"},"PeriodicalIF":5.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078865","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":"Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of von Willebrand disease and bleeding","authors":"Rachel K. Friedman ,&nbsp;Adam S. Heath ,&nbsp;Jennifer E. Huffman ,&nbsp;James T. Baker ,&nbsp;Natalie R. Hasbani ,&nbsp;Sarah A. Gagliano Taliun ,&nbsp;Ming–Huei Chen ,&nbsp;Tom E. Howard ,&nbsp;Joshua P. Lewis ,&nbsp;Nathan Pankratz ,&nbsp;Snehal Patil ,&nbsp;Alex P. Reiner ,&nbsp;Florian Thibord ,&nbsp;Lisa R. Yanek ,&nbsp;Jie Yao ,&nbsp;Hung–Hsin Chen ,&nbsp;Joanne E. Curran ,&nbsp;Nauder Faraday ,&nbsp;Xiuqing Guo ,&nbsp;Marsha M. Wheeler ,&nbsp;Paul S. de Vries","doi":"10.1016/j.jtha.2025.04.029","DOIUrl":"10.1016/j.jtha.2025.04.029","url":null,"abstract":"<div><h3>Background</h3><div>von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (<span><math><mrow><mo>≤</mo></mrow></math></span> 50 IU/dL) in the general population is underexplored.</div></div><div><h3>Objectives</h3><div>To identify genetic variants influencing VWF:Ag levels <span><math><mrow><mo>≤</mo></mrow></math></span> 50 IU/dL.</div></div><div><h3>Methods</h3><div>We performed a genome-wide association study in 926 cases with VWF:Ag levels <span><math><mrow><mo>≤</mo></mrow></math></span> 50 IU/dL and 12 846 controls from 7 studies from the Trans-Omics for Precision Medicine program. We then examined whether significant genome-wide findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1 286 069 controls, and with 6 bleeding and thrombotic disorders in FinnGen.</div></div><div><h3>Results</h3><div>Variants at 2 loci were associated (<em>P</em> &lt; 5 × 10⁻⁹) with VWF:Ag levels <span><math><mrow><mo>≤</mo></mrow></math></span> 50 IU/dL: <em>ABO</em> and <em>VWF</em>. The <em>VWF</em> index variant, p.Tyr1584Cys, is a rare (0.22%) missense variant with odds ratio (OR) of 78.58, while the <em>ABO</em> index variant is a common intronic variant with a smaller effect (OR = 2.52). Notably, both <em>VWF</em> (OR = 7.16) and <em>ABO</em> (OR = 1.57) variants were also associated (<em>P</em> &lt; .025) with diagnosed VWD. Among p.Tyr1584Cys heterozygotes, the penetrance of VWF:Ag levels <span><math><mrow><mo>≤</mo></mrow></math></span> 50 IU/dL was 24.2% and the penetrance of diagnosed VWD was 0.3%. p.Tyr1584Cys was associated (<em>P</em> &lt; .0042) with increased odds of heavy menstrual bleeding (OR = 1.27), iron deficiency anemia (OR = 1.55), and intrapartum hemorrhage (OR = 2.20), but decreased odds of deep vein thrombosis (OR = 0.54).</div></div><div><h3>Conclusions</h3><div>Although there are currently conflicting interpretations of pathogenicity p.Tyr1584Cys, our results suggest that it is a low penetrance pathogenic variant that contributes to VWF:Ag levels <span><math><mrow><mo>≤</mo></mrow></math></span> 50 IU/dL, bleeding, and VWD.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 8","pages":"Pages 2410-2421"},"PeriodicalIF":5.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078870","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}