Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.015
Fatma Işık Üstok, James A. Huntington
Background
Thrombin is generated from its precursor prothrombin by sequential cleavage at Arg320 and Arg271 by the prothrombinase complex, composed of factor (F)Xa and FVa on phospholipid (PL) surfaces. The affinity of human FXa for FVa is low in the absence of PL. However, FXa orthologs from the venom of group D snakes bind to FVa with high affinity, forming an active complex without PL. We previously characterized the properties of the FXa ortholog hopsarin D (HopD) from Hoplocephalus stephensii.
Objectives
In this study, we set out to create a PL-independent human prothrombinase by making mutations to FXa, guided by a model of the prothrombinase complex and the sequence differences between human FXa and HopD.
Methods
We assessed the contribution of individual domains of FXa to its binding to FVa by swapping each with the corresponding domain of HopD. We then chose 3 loops in the serine protease domain predicted to be in contact with FVa to swap to those of HopD. Eventually, 10 residues from the 3 loops in the serine protease domain and 7 from the epidermal growth factor 2 domain were selected for mutation.
Results
The resulting M17 FXa variant bound to FVa with a dissociation constant of 21 nM, similar to HopD, and together efficiently processed prothrombin through the meizothrombin intermediate in the absence of PL.
Conclusion
We conclude that the role of PL membranes in prothrombinase assembly and function is limited to improving the affinity of FXa for FVa and that the M17-FVa complex is likely to be structurally equivalent to human prothrombinase.
背景：凝血酶是由其前体凝血酶原在磷脂（PL）表面上由因子(f) Xa和fVa组成的凝血酶原复合物在Arg320和Arg271处连续切割而产生的。在没有PL的情况下，人类fXa对fVa的亲和力较低。然而，D组蛇毒中的fXa同源物与fVa结合的亲和力很高，形成了一个没有PL的活性复合物。我们之前表征了来自stefan Hoplocephalus的fXa同源物Hopsarin D （HopD）的性质。目的：在这里，我们开始通过对fXa进行突变来创建一个pl独立的人类凝血酶原，在凝血酶原复合物模型和人类fXa和HopD之间的序列差异的指导下。方法：通过与HopD的相应结构域交换，我们评估了fXa的各个结构域对其与fVa结合的贡献。然后，我们选择了三个丝氨酸蛋白酶（SP）结构域中预测与fVa接触的环，以交换到HopD的环。最终，从SP结构域的3个环中选出10个残基，从EGF2结构域选出7个残基进行突变。结果：得到的M17 fXa变体与fVa结合，Kd值为21 nM，与HopD相似，并且在没有PL的情况下通过减数凝血酶中间体有效地加工凝血酶原。结论：我们得出PL膜在凝血酶原组装和功能中的作用仅限于提高fXa对fVa的亲和力，并且M17-fVa复合物可能在结构上与人凝血酶原相当。
{"title":"Engineering a membrane-independent human prothrombinase through parsimonious mutation of factor Xa","authors":"Fatma Işık Üstok, James A. Huntington","doi":"10.1016/j.jtha.2025.10.015","DOIUrl":"10.1016/j.jtha.2025.10.015","url":null,"abstract":"<div><h3>Background</h3><div>Thrombin is generated from its precursor prothrombin by sequential cleavage at Arg320 and Arg271 by the prothrombinase complex, composed of factor (F)Xa and FVa on phospholipid (PL) surfaces. The affinity of human FXa for FVa is low in the absence of PL. However, FXa orthologs from the venom of group D snakes bind to FVa with high affinity, forming an active complex without PL. We previously characterized the properties of the FXa ortholog hopsarin D (HopD) from <em>Hoplocephalus stephensii</em>.</div></div><div><h3>Objectives</h3><div>In this study, we set out to create a PL-independent human prothrombinase by making mutations to FXa, guided by a model of the prothrombinase complex and the sequence differences between human FXa and HopD.</div></div><div><h3>Methods</h3><div>We assessed the contribution of individual domains of FXa to its binding to FVa by swapping each with the corresponding domain of HopD. We then chose 3 loops in the serine protease domain predicted to be in contact with FVa to swap to those of HopD. Eventually, 10 residues from the 3 loops in the serine protease domain and 7 from the epidermal growth factor 2 domain were selected for mutation.</div></div><div><h3>Results</h3><div>The resulting M17 FXa variant bound to FVa with a dissociation constant of 21 nM, similar to HopD, and together efficiently processed prothrombin through the meizothrombin intermediate in the absence of PL.</div></div><div><h3>Conclusion</h3><div>We conclude that the role of PL membranes in prothrombinase assembly and function is limited to improving the affinity of FXa for FVa and that the M17-FVa complex is likely to be structurally equivalent to human prothrombinase.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 458-469"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459048","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.018
Aaron F.J. Iding , Ruben D. Hupperetz , Rutger J.B. Brans , Hugo ten Cate , Daan J.L. van Twist , Arina J. ten Cate-Hoek
Background
Postthrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT), with residual venous obstruction (RVO) as a key contributing factor. Oxerutin, a venoactive drug, has the potential to promote DVT resolution, thereby reducing RVO and possibly preventing PTS.
Objectives
This pilot study aimed to estimate the effect of oxerutin therapy on RVO.
Methods
A single-center, patient-unblinded, physician-blinded, assessor-blinded, randomized controlled trial was conducted in adults with acute proximal DVT. Patients were randomized within 48 hours to receive 2-month oxerutin therapy plus standard treatment or standard treatment alone. The primary outcome was RVO at 3 months, defined as a transversal diameter ≥2mm on compressive ultrasound, with sensitivity analysis at ≥4 mm. Secondary outcomes included PTS at 3 months and biomarkers at 5 timepoints. The study was approved by the ethics committee. All patients gave written informed consent.
Results
A total of 44 patients were randomized to oxerutin or standard treatment. At 3 months, the proportion of RVO was lower in the oxerutin group, both for ≥2 mm (42.9% vs 59.1%; odds ratio [OR], 0.34; 95% CI, 0.08-1.28) and ≥4 mm (28.6% vs 54.5%; OR, 0.21; 95% CI, 0.04-0.85), adjusted for DVT extent. A lower proportion of PTS was observed in the oxerutin group (28.6% vs 40.9%; OR, 0.38; 95% CI, 0.08-1.53). Biomarker levels of intercellular adhesion molecule-1 and interleukin-6 were persistently lower in the oxerutin group.
Conclusion
Oxerutin therapy might reduce RVO by promoting DVT resolution. These preliminary findings support further investigation in a large-scale trial to assess the long-term prevention of PTS.
背景：血栓形成后综合征（Post-thrombotic syndrome， PTS）是深静脉血栓形成（deep vein thrombosis， DVT）的一种慢性并发症，其中残余静脉阻塞（residual venous梗阻，RVO）是主要致病因素。Oxerutin是一种静脉活性药物，具有促进DVT消退的潜力，从而降低RVO并可能预防PTS。目的：本初步研究旨在评估奥施罗汀治疗对RVO的影响。方法：对成人急性近端深静脉血栓形成患者进行单中心、非盲法、医师盲法、评估盲法随机对照试验。患者在48小时内随机接受两个月的奥施罗汀治疗加标准治疗或单独标准治疗。主要终点是3个月时的RVO，定义为压缩超声的横径≥2mm，敏感性分析≥4mm。次要终点包括3个月时的PTS和5个时间点的生物标志物。这项研究得到了伦理委员会的批准。所有患者均给予书面知情同意。结果：44例患者随机分为奥施罗汀组和标准组。在3个月时，奥赛芦丁组的RVO比例较低，≥2mm （42.9% vs 59.1%；比值比[OR] 0.34； 95%可信区间[CI] 0.08-1.28）和≥4mm (28.6% vs 54.5%; OR 0.21; 95% CI 0.04-0.85)，根据DVT程度进行调整。奥赛芦丁组PTS发生率较低（28.6% vs 40.9%; OR 0.38; 95% CI 0.08-1.53）。oxerutin组细胞间粘附分子-1和白细胞介素-6的生物标志物水平持续降低。结论：奥施罗汀治疗可能通过促进DVT消退而降低RVO。这些初步发现支持在大规模试验中进一步调查以评估PTS的长期预防。
{"title":"Additional oxerutin therapy to promote deep vein thrombus resolution (RESOLVE-DVT): a randomized controlled pilot trial","authors":"Aaron F.J. Iding , Ruben D. Hupperetz , Rutger J.B. Brans , Hugo ten Cate , Daan J.L. van Twist , Arina J. ten Cate-Hoek","doi":"10.1016/j.jtha.2025.10.018","DOIUrl":"10.1016/j.jtha.2025.10.018","url":null,"abstract":"<div><h3>Background</h3><div>Postthrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT), with residual venous obstruction (RVO) as a key contributing factor. Oxerutin, a venoactive drug, has the potential to promote DVT resolution, thereby reducing RVO and possibly preventing PTS.</div></div><div><h3>Objectives</h3><div>This pilot study aimed to estimate the effect of oxerutin therapy on RVO.</div></div><div><h3>Methods</h3><div>A single-center, patient-unblinded, physician-blinded, assessor-blinded, randomized controlled trial was conducted in adults with acute proximal DVT. Patients were randomized within 48 hours to receive 2-month oxerutin therapy plus standard treatment or standard treatment alone. The primary outcome was RVO at 3 months, defined as a transversal diameter ≥2mm on compressive ultrasound, with sensitivity analysis at ≥4 mm. Secondary outcomes included PTS at 3 months and biomarkers at 5 timepoints. The study was approved by the ethics committee. All patients gave written informed consent.</div></div><div><h3>Results</h3><div>A total of 44 patients were randomized to oxerutin or standard treatment. At 3 months, the proportion of RVO was lower in the oxerutin group, both for ≥2 mm (42.9% vs 59.1%; odds ratio [OR], 0.34; 95% CI, 0.08-1.28) and ≥4 mm (28.6% vs 54.5%; OR, 0.21; 95% CI, 0.04-0.85), adjusted for DVT extent. A lower proportion of PTS was observed in the oxerutin group (28.6% vs 40.9%; OR, 0.38; 95% CI, 0.08-1.53). Biomarker levels of intercellular adhesion molecule-1 and interleukin-6 were persistently lower in the oxerutin group.</div></div><div><h3>Conclusion</h3><div>Oxerutin therapy might reduce RVO by promoting DVT resolution. These preliminary findings support further investigation in a large-scale trial to assess the long-term prevention of PTS.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 644-653"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459059","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.09.032
Ziad Hijazi , Johan Lindbäck , Jonas Oldgren , John H. Alexander , Alexander P. Benz , David D. Berg , Anthony P. Carnicelli , John W. Eikelboom , Robert P. Giugliano , Shinya Goto , Christopher B. Granger , Renato D. Lopes , Christian T. Ruff , Agneta Siegbahn , David A. Morrow , Lars Wallentin
Background
Oral anticoagulation (OAC) reduces stroke in patients with atrial fibrillation (AF), but increases bleeding.
Objectives
This study aimed to evaluate an updated version of the Age, Biomarkers, and Clinical history of bleeding in AF (ABC-AF)-bleeding score (2.0) including consideration of OAC type (direct oral anticoagulant [DOAC] or warfarin) and compare its performance with other bleeding risk scores in 25 962 patients from the COMBINE AF cohort.
Methods
The COMBINE AF biomarker cohort contains individual participant data from patients with AF enrolled in 3 pivotal randomized trials comparing DOACs with warfarin. The biomarkers in the ABC-AF-bleeding score (growth differentiation factor 15, hemoglobin, and troponin-T) were analyzed in baseline samples. The biomarker-based ABC-AF-bleeding score was updated (version 2.0) by incorporating OAC type into the model (DOAC or warfarin). Discrimination was assessed by Harrell C-index and compared with clinically based bleeding scores; HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol), DOAC, and ORBIT (Older age, Reduced haemoglobin/haematocrit or history of anaemia, Bleeding history, Insufficient renal function, Treatment with antiplatelet agents).
Results
During follow-up, 1321 patients (5.1%) had an International Society on Thrombosis and Haemostasis major bleeding event, including 480 gastrointestinal, and 248 intracranial hemorrhages. The ABC-AF-bleeding 2.0 risk score showed better discrimination and calibration than the original version and provided superior discrimination than clinical risk scores for all outcomes. The ABC-AF-bleeding score 2.0 C-indices for major bleeding were 0.69 (95% CI, 0.68-0.71); gastrointestinal bleeding, 0.72 (95% CI, 0.69-0.74); and intracranial bleeding, 0.66 (95% CI, 0.63-0.70). The ABC-AF-bleeding score 2.0 also provided consistent superior discrimination in clinically relevant subgroups.
Conclusion
The updated ABC-AF-bleeding score 2.0 provided better discrimination and calibration for the risk of major bleeding than clinical risk scores, which was consistent across multiple subgroups. These findings support the utility of the ABC-AF-bleeding score for advancing precision medicine in AF.
背景：腹侧抗凝（OAC）可减少房颤（AF）患者的卒中，但会增加出血。本研究旨在评估AF患者年龄、生物标志物和出血的临床史(ABC-AF)-出血评分（2.0）的更新版本，包括OAC类型（直接口服抗凝剂[DOAC]或华法林），并将其与其他出血风险评分进行比较。方法：COMBINE房颤生物标志物队列包含了3项比较DOACs与华法林的关键随机试验中房颤患者的个体参与者数据。在基线样本中分析abc - af出血评分中的生物标志物（生长分化因子15、血红蛋白和肌钙蛋白- t）。通过将OAC类型（DOAC或华法林）纳入模型，更新了基于生物标志物的abc - af出血评分（2.0版）。采用Harrell c指数评估辨别性，并与临床出血评分进行比较；ha -出血（高血压、肾/肝功能异常、中风、出血史或易感、INR不稳定、老年人、药物/酒精）、DOAC和ORBIT（年龄较大、血红蛋白/红细胞压积降低或贫血史、出血史、肾功能不足、抗血小板药物治疗）。结果随访期间，1321例（5.1%）患者发生国际血栓与止血学会大出血事件，其中胃肠道出血480例，颅内出血248例。与原始版本相比，abc - af -出血2.0风险评分具有更好的辨别和校准能力，并且在所有结果上都比临床风险评分具有更好的辨别能力。abc - af -出血评分2.0 c -大出血指数为0.69 (95% CI, 0.68-0.71)；胃肠道出血，0.72 (95% CI, 0.69-0.74)；颅内出血，0.66 （95% CI, 0.63-0.70）。abc - af -出血评分2.0在临床相关亚组中也提供了一致的优势区分。结论更新后的abc - af -出血评分2.0比临床风险评分能更好地区分和校准大出血风险，且在多个亚组中是一致的。这些发现支持abc -AF出血评分在推进房颤精准医学方面的应用。
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Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.09.012
Monica S. Seadler , Francesca Ferraresso , Halen M. Turner , Laura M. Ketelboeter , Youjie Zhang , Katherine Badior , William G. Hayssen , Taylor Chen , Amber L. Haugen , Massimo F. Cau , Madelaine Robertson , Chad Skaer , Muskan Bansal , Patrick B. Murphy , Marc de Moya , Mitchell R. Dyer , Christian J. Kastrup
Background
Fibrinogen levels can drastically increase from inflammation, trauma, or surgery, which increases risk of venous thromboembolism (VTE). We developed small interfering RNA (siFibrinogen) that decreased fibrinogen production and thrombosis in rodent models, which became effective hours after administration and knockdown lasted over a week. Here, we tested whether knockdown of fibrinogen was feasible and safe in a preclinical large animal model. We hypothesized that fibrinogen could be controllably knocked down to levels that still enable hemostasis and avoid limitations of the current standard of care agent, low-molecular-weight heparin (LMWH).
Objectives
This study evaluated the preclinical safety and feasibility of a novel therapy for VTE prophylaxis for complications in trauma and surgical patients.
Methods
Female Yorkshire/cross swine (7-15 kg) were infused with small interfering RNA targeting fibrinogen (siFibrinogen), LMWH, or a vehicle control. Hemostasis was assessed in an established model of hemorrhagic shock. Reversibility was evaluated by administering fibrinogen concentrate.
Results
Circulating fibrinogen concentrations decreased in swine in a dose-dependent manner, lasting over a week from 1 injection of siFibrinogen. Fibrinogen reduction to levels > 0.4 g/L did not impair hemostasis during hemorrhagic shock when compared with LMWH or vehicle control. The effects of siFibrinogen were reversed by the administration of fibrinogen concentrate. No infusion-related reactions or toxicity was observed.
Conclusion
siFibrinogen represents a promising novel approach for VTE prophylaxis, avoiding limitations of LMWH. siFibrinogen administered early in patient care could decrease fibrinogen in a sustained and predictable manner to prevent thrombosis while preserving hemostasis.
{"title":"Preclinical safety and bleeding evaluation in swine for a small interfering RNA-lipid nanoparticle that prevents excess fibrinogen synthesis","authors":"Monica S. Seadler , Francesca Ferraresso , Halen M. Turner , Laura M. Ketelboeter , Youjie Zhang , Katherine Badior , William G. Hayssen , Taylor Chen , Amber L. Haugen , Massimo F. Cau , Madelaine Robertson , Chad Skaer , Muskan Bansal , Patrick B. Murphy , Marc de Moya , Mitchell R. Dyer , Christian J. Kastrup","doi":"10.1016/j.jtha.2025.09.012","DOIUrl":"10.1016/j.jtha.2025.09.012","url":null,"abstract":"<div><h3>Background</h3><div>Fibrinogen levels can drastically increase from inflammation, trauma, or surgery, which increases risk of venous thromboembolism (VTE). We developed small interfering RNA (siFibrinogen) that decreased fibrinogen production and thrombosis in rodent models, which became effective hours after administration and knockdown lasted over a week. Here, we tested whether knockdown of fibrinogen was feasible and safe in a preclinical large animal model. We hypothesized that fibrinogen could be controllably knocked down to levels that still enable hemostasis and avoid limitations of the current standard of care agent, low-molecular-weight heparin (LMWH).</div></div><div><h3>Objectives</h3><div>This study evaluated the preclinical safety and feasibility of a novel therapy for VTE prophylaxis for complications in trauma and surgical patients.</div></div><div><h3>Methods</h3><div>Female Yorkshire/cross swine (7-15 kg) were infused with small interfering RNA targeting fibrinogen (siFibrinogen), LMWH, or a vehicle control. Hemostasis was assessed in an established model of hemorrhagic shock. Reversibility was evaluated by administering fibrinogen concentrate.</div></div><div><h3>Results</h3><div>Circulating fibrinogen concentrations decreased in swine in a dose-dependent manner, lasting over a week from 1 injection of siFibrinogen. Fibrinogen reduction to levels > 0.4 g/L did not impair hemostasis during hemorrhagic shock when compared with LMWH or vehicle control. The effects of siFibrinogen were reversed by the administration of fibrinogen concentrate. No infusion-related reactions or toxicity was observed.</div></div><div><h3>Conclusion</h3><div>siFibrinogen represents a promising novel approach for VTE prophylaxis, avoiding limitations of LMWH. siFibrinogen administered early in patient care could decrease fibrinogen in a sustained and predictable manner to prevent thrombosis while preserving hemostasis.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 508-519"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275102","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.007
Rukhmi Bhat , Anjali Sharathkumar , Riten Kumar , Fernando F. Corrales-Medina , Heleen van Ommen , Mihir Bhatt , Smita Dandekar , Maua Mosha , Neil A. Goldenberg
Background
Prognostic factors for residual thrombosis (RT) and complete veno-occlusion (CVO) after 6 weeks of anticoagulation in pediatric acute VTE remain unknown.
Objectives
This study assessed the frequency and predictors of RT and CVO through a prespecified secondary analysis of the Kids-DOTT randomized clinical trial.
Methods
Per trial protocol, RT and CVO were radiologically assessed 6 weeks after acute VTE diagnosis. Univariate logistic regression analyses were performed for both outcomes, and variables with a P value of .05 were included in a multivariable models, where a P value of <.05 denoted statistical significance.
Results
Among 532 enrolled patients, 28.8% demonstrated RT and 12.6% CVO after 6 weeks of treatment. Age and gender distributions did not differ significantly by RT and CVO status. In multivariable analysis, cerebral venous sinus location of VTE (odds ratio [OR], 2.52; 95% CI, 1.22-5.21; P = .01) and comorbid infection (OR, 1.61; 95% CI, 1.00-2.58; P = .049) were independently associated with RT. Internal jugular vein (OR, 3.97; 95% CI, 1.26-12.48; P = .02) and lower extremity VTE (OR, 2.28; 95% CI, 1.01-5.15; P = .046) were independently associated with CVO.
Conclusion
Approximately 29% of young patients developed RT, and 13% CVO, after 6 weeks of anticoagulation. VTE location and comorbid infection were identified as predictors for RT and CVO. These findings highlight the need for further studies on long-term outcomes of RT and CVO, particularly their impact on postthrombotic syndrome development and quality-of-life measures in pediatric VTE.
{"title":"Frequency of, and prognostic factors for, residual thrombosis and complete veno-occlusion following anticoagulation for provoked venous thromboembolism in patients <21 years: findings from the Kids-DOTT Multinational Trial","authors":"Rukhmi Bhat , Anjali Sharathkumar , Riten Kumar , Fernando F. Corrales-Medina , Heleen van Ommen , Mihir Bhatt , Smita Dandekar , Maua Mosha , Neil A. Goldenberg","doi":"10.1016/j.jtha.2025.10.007","DOIUrl":"10.1016/j.jtha.2025.10.007","url":null,"abstract":"<div><h3>Background</h3><div>Prognostic factors for residual thrombosis (RT) and complete veno-occlusion (CVO) after 6 weeks of anticoagulation in pediatric acute VTE remain unknown.</div></div><div><h3>Objectives</h3><div>This study assessed the frequency and predictors of RT and CVO through a prespecified secondary analysis of the Kids-DOTT randomized clinical trial.</div></div><div><h3>Methods</h3><div>Per trial protocol, RT and CVO were radiologically assessed 6 weeks after acute VTE diagnosis. Univariate logistic regression analyses were performed for both outcomes, and variables with a <em>P</em> value of .05 were included in a multivariable models, where a <em>P</em> value of <.05 denoted statistical significance.</div></div><div><h3>Results</h3><div>Among 532 enrolled patients, 28.8% demonstrated RT and 12.6% CVO after 6 weeks of treatment. Age and gender distributions did not differ significantly by RT and CVO status. In multivariable analysis, cerebral venous sinus location of VTE (odds ratio [OR], 2.52; 95% CI, 1.22-5.21; <em>P</em> = .01) and comorbid infection (OR, 1.61; 95% CI, 1.00-2.58; <em>P</em> = .049) were independently associated with RT. Internal jugular vein (OR, 3.97; 95% CI, 1.26-12.48; <em>P</em> = .02) and lower extremity VTE (OR, 2.28; 95% CI, 1.01-5.15; <em>P</em> = .046) were independently associated with CVO.</div></div><div><h3>Conclusion</h3><div>Approximately 29% of young patients developed RT, and 13% CVO, after 6 weeks of anticoagulation. VTE location and comorbid infection were identified as predictors for RT and CVO. These findings highlight the need for further studies on long-term outcomes of RT and CVO, particularly their impact on postthrombotic syndrome development and quality-of-life measures in pediatric VTE.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 672-681"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431339","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}
von Willebrand factor (VWF) propeptide (VWFpp) located in the D1-D2 domain of pro-VWF, is essential for multimerization and intracellular storage of VWF. Pathogenic variants of VWFpp cause various subtypes of von Willebrand disease, such as type 1, type 2A, type 2N, and type 3. In heterozygotes of these variants, VWFpp derived from the normal allele can rescue the abnormalities observed in the homozygote. This rescue effect may highlight the phenotypic difference between heterozygotes and homozygotes.
Objectives
We investigated the molecular pathogenesis of a novel missense variant of VWFpp, VWF c.1322 C>A (p.T441N), identified in a heterozygous 20-year-old woman.
Methods
The VWF gene was analyzed using whole-exome sequencing and Sanger sequencing. Recombinant VWF (rVWF) and VWF propeptide (rVWFpp) were overexpressed in HEK293 cells. rVWF production was measured using an in-house enzyme-linked immunosorbent assay and multimer analysis. The morphology of pseudo-Weibel–Palade bodies (WPBs) and WPBs in endothelial colony-forming cells were observed by immunocytochemistry.
Results
In the patient’s plasma, the VWF antigen level was in the normal range, but VWF ristocetin cofactor activity was slightly decreased, by 0.38 IU/mL, and high-molecular-weight and intermediate-molecular-weight multimers were decreased. Pseudo-WPBs were also shortened and rounded, corresponding with patient-derived endothelial colony-forming cells. These abnormalities were partially rescued by coexpression of wild-type rVWFpp on separate vectors.
Conclusion
VWF-T441N results in impaired multimerization and deformed WPBs. In heterozygous VWF-T441N, these abnormalities are partially rescued by VWFpp derived from the normal allele. The observed rescue effect provides further insights for understanding the phenotypic heterogeneity of VWFpp variants.
{"title":"von Willebrand factor-T441N, a novel missense variant in the von Willebrand factor D2 domain, exhibits impaired multimerization and deformed Weibel-Palade bodies","authors":"Shuichi Okamoto , Shogo Tamura , Atsuo Suzuki , Nobuaki Suzuki , Takeshi Kanematsu , Naruko Suzuki , Masashi Tomita , Fumihiko Hayakawa , Akira Katsumi , Hitoshi Kiyoi , Tetsuhito Kojima , Tadashi Matsushita","doi":"10.1016/j.jtha.2025.10.017","DOIUrl":"10.1016/j.jtha.2025.10.017","url":null,"abstract":"<div><h3>Background</h3><div>von Willebrand factor (VWF) propeptide (VWFpp) located in the D1-D2 domain of pro-VWF, is essential for multimerization and intracellular storage of VWF. Pathogenic variants of VWFpp cause various subtypes of von Willebrand disease, such as type 1, type 2A, type 2N, and type 3. In heterozygotes of these variants, VWFpp derived from the normal allele can rescue the abnormalities observed in the homozygote. This rescue effect may highlight the phenotypic difference between heterozygotes and homozygotes.</div></div><div><h3>Objectives</h3><div>We investigated the molecular pathogenesis of a novel missense variant of VWFpp, <em>VWF</em> c.1322 C>A (p.T441N), identified in a heterozygous 20-year-old woman.</div></div><div><h3>Methods</h3><div>The <em>VWF</em> gene was analyzed using whole-exome sequencing and Sanger sequencing. Recombinant VWF (rVWF) and VWF propeptide (rVWFpp) were overexpressed in HEK293 cells. rVWF production was measured using an in-house enzyme-linked immunosorbent assay and multimer analysis. The morphology of pseudo-Weibel–Palade bodies (WPBs) and WPBs in endothelial colony-forming cells were observed by immunocytochemistry.</div></div><div><h3>Results</h3><div>In the patient’s plasma, the VWF antigen level was in the normal range, but VWF ristocetin cofactor activity was slightly decreased, by 0.38 IU/mL, and high-molecular-weight and intermediate-molecular-weight multimers were decreased. Pseudo-WPBs were also shortened and rounded, corresponding with patient-derived endothelial colony-forming cells. These abnormalities were partially rescued by coexpression of wild-type rVWFpp on separate vectors.</div></div><div><h3>Conclusion</h3><div>VWF-T441N results in impaired multimerization and deformed WPBs. In heterozygous VWF-T441N, these abnormalities are partially rescued by VWFpp derived from the normal allele. The observed rescue effect provides further insights for understanding the phenotypic heterogeneity of VWFpp variants.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 483-497"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452109","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.024
Raja Prince Eladnani , Rim Diab , Anne Angelillo-Scherrer
Protein S (PS) is a key anticoagulant with additional roles in cell signaling through its interaction with Tyro3-Axl-MerTK family receptor tyrosine kinases Tyro3 and MerTK. Therapeutic targeting of PS—either enhancing or inhibiting its activity—has emerged as a promising strategy to modulate coagulation and inflammation. Approaches include nanobodies, monoclonal antibodies, and RNA interference, aiming to restore hemostatic balance or prevent bleeding, depending on the clinical context. Severe PS deficiency (homozygous or compound heterozygous) causes life-threatening conditions such as disseminated intravascular coagulation and purpura fulminans. Heterozygous deficiency is associated with an elevated venous thromboembolic risk. These insights highlight the need for tailored modulation of PS activity. A PS-enhancing nanobody has demonstrated potent antithrombotic effects in murine models, establishing proof-of-concept for a novel, safe anticoagulant strategy. Conversely, PS inhibition is being pursued to treat bleeding disorders such as von Willebrand disease and hemophilia. Both monoclonal antibodies and small-interfering RNAs targeting PS have shown safety and efficacy in preclinical models. Notably, a monoclonal antibody has demonstrated safety and preliminary efficacy in a phase 1/2 trial in patients with von Willebrand disease. Beyond coagulation, PS exerts protective effects on joint and bone tissues via Tyro3 and MerTK receptor signaling, further broadening its therapeutic potential. These findings support the continued development of PS-targeted therapies, with implications for both thrombotic and bleeding disorders, as well as for mitigating tissue damage in chronic bleeding conditions.
{"title":"Protein S as a therapeutic target","authors":"Raja Prince Eladnani , Rim Diab , Anne Angelillo-Scherrer","doi":"10.1016/j.jtha.2025.10.024","DOIUrl":"10.1016/j.jtha.2025.10.024","url":null,"abstract":"<div><div>Protein S (PS) is a key anticoagulant with additional roles in cell signaling through its interaction with Tyro3-Axl-MerTK family receptor tyrosine kinases Tyro3 and MerTK. Therapeutic targeting of PS—either enhancing or inhibiting its activity—has emerged as a promising strategy to modulate coagulation and inflammation. Approaches include nanobodies, monoclonal antibodies, and RNA interference, aiming to restore hemostatic balance or prevent bleeding, depending on the clinical context. Severe PS deficiency (homozygous or compound heterozygous) causes life-threatening conditions such as disseminated intravascular coagulation and purpura fulminans. Heterozygous deficiency is associated with an elevated venous thromboembolic risk. These insights highlight the need for tailored modulation of PS activity. A PS-enhancing nanobody has demonstrated potent antithrombotic effects in murine models, establishing proof-of-concept for a novel, safe anticoagulant strategy. Conversely, PS inhibition is being pursued to treat bleeding disorders such as von Willebrand disease and hemophilia. Both monoclonal antibodies and small-interfering RNAs targeting PS have shown safety and efficacy in preclinical models. Notably, a monoclonal antibody has demonstrated safety and preliminary efficacy in a phase 1/2 trial in patients with von Willebrand disease. Beyond coagulation, PS exerts protective effects on joint and bone tissues via Tyro3 and MerTK receptor signaling, further broadening its therapeutic potential. These findings support the continued development of PS-targeted therapies, with implications for both thrombotic and bleeding disorders, as well as for mitigating tissue damage in chronic bleeding conditions.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 354-367"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459097","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.08.040
Sara Contente , Anwar E. Ahmed , Barbara A. Konkle , Jill M. Johnsen , Andrew Frank , Kathleen P. Pratt
Background
An earlier analysis of the “My Life, Our Future” Repository indicated the risk of individuals with severe hemophilia A (HA) developing neutralizing antifactor (F)VIII antibodies (inhibitors) was (1) higher in Black and Hispanic cohorts and (2) similar in intron-22 inversion mutations vs other large structural changes in the F8 gene.
Objectives
This study determined whether specific human leukocyte antigen (HLA) alleles or haplotypes indicate either risk of or protection from inhibitor development in severe HA and if such associations correlate with race/ethnicity or F8 variant type.
Methods
HLA haplotypes were obtained from whole genome sequence data for 1841 subjects with severe HA and their racial/ethnic categories verified by principal component analysis. Pairwise and multivariable logistic regression analyses were performed for subcohorts of HLA alleles/haplotypes defined by HA mutation type and race/ethnicity.
Results
HLA-DRB1∗15:01, DQB1∗06:02, and DQA1∗01:02 and B∗07:02 were higher-risk alleles for the White/non–Hispanic cohort, while HLA-DRB∗14:01, DQB1∗05:03, DQB1∗03:01, B∗38:01, B∗44:02, and C∗05:01 were lower-risk alleles. HLA-B∗15:03 and B∗58:01 were higher-risk alleles for the Black/non–Hispanic cohort, while HLA-A∗33:03 was a lower-risk allele. Additional alleles were associated with inhibitor risk across the following cohorts: all (N = 1841), intron-22 inversion (n = 836), missense (n = 288), not-missense (n = 1553). No associations of HLA with inhibitor risk were seen for the Hispanic/White cohort. Analysis of subjects carrying both higher-risk and lower-risk alleles revealed combinations affecting the risks associated with individual alleles.
Conclusion
Our results implicate both innate and adaptive immune mechanisms, possibly including multiallelic HLA-associated effects on FVIII processing/presentation or signaling pathways in the development of inhibitors vs peripheral tolerance to FVIII.
{"title":"Human leukocyte antigen alleles associated with inhibitor development in severe hemophilia A: analysis of the “My Life, Our Future” hemophilia A cohort","authors":"Sara Contente , Anwar E. Ahmed , Barbara A. Konkle , Jill M. Johnsen , Andrew Frank , Kathleen P. Pratt","doi":"10.1016/j.jtha.2025.08.040","DOIUrl":"10.1016/j.jtha.2025.08.040","url":null,"abstract":"<div><h3>Background</h3><div>An earlier analysis of the “My Life, Our Future” Repository indicated the risk of individuals with severe hemophilia A (HA) developing neutralizing antifactor (F)VIII antibodies (inhibitors) was (1) higher in Black and Hispanic cohorts and (2) similar in intron-22 inversion mutations vs other large structural changes in the <em>F8</em> gene.</div></div><div><h3>Objectives</h3><div>This study determined whether specific human leukocyte antigen (HLA) alleles or haplotypes indicate either risk of or protection from inhibitor development in severe HA and if such associations correlate with race/ethnicity or <em>F8</em> variant type.</div></div><div><h3>Methods</h3><div>HLA haplotypes were obtained from whole genome sequence data for 1841 subjects with severe HA and their racial/ethnic categories verified by principal component analysis. Pairwise and multivariable logistic regression analyses were performed for subcohorts of HLA alleles/haplotypes defined by HA mutation type and race/ethnicity.</div></div><div><h3>Results</h3><div><em>HLA-DRB1∗15:01</em>, <em>DQB1∗06:02</em>, and <em>DQA1∗01:02</em> and <em>B∗07:02</em> were higher-risk alleles for the White/non–Hispanic cohort, while <em>HLA-DRB∗14:01</em>, <em>DQB1∗05:03</em>, <em>DQB1∗03:01</em>, <em>B∗38:01</em>, <em>B∗44:02</em>, and <em>C∗05:01</em> were lower-risk alleles. <em>HLA-B∗15:03</em> and <em>B∗58:01</em> were higher-risk alleles for the Black/non–Hispanic cohort, while <em>HLA-A∗33:03</em> was a lower-risk allele. Additional alleles were associated with inhibitor risk across the following cohorts: all (<em>N</em> = 1841), intron-22 inversion (<em>n</em> = 836), missense (<em>n</em> = 288), not-missense (<em>n</em> = 1553). No associations of HLA with inhibitor risk were seen for the Hispanic/White cohort. Analysis of subjects carrying both higher-risk and lower-risk alleles revealed combinations affecting the risks associated with individual alleles.</div></div><div><h3>Conclusion</h3><div>Our results implicate both innate and adaptive immune mechanisms, possibly including multiallelic HLA-associated effects on FVIII processing/presentation or signaling pathways in the development of inhibitors vs peripheral tolerance to FVIII.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 443-457"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102579","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.07.040
Eva Soler-Espejo , María Pilar Ramos-Bratos , José Miguel Rivera-Caravaca , Eduardo González-Lozano , Francisco Marín , Vanessa Roldán , Gregory Y.H. Lip
Background
Patients with atrial fibrillation (AF) often require oral anticoagulation (OAC), but predicting bleeding risk remains challenging. Classic risk scores such as HAS-BLED and ORBIT, along with newer models such as DOAC and AF-BLEED, exhibit only modest predictive performance.
Objectives
In this study, we compared these 4 scores in patients with AF on OAC to evaluate their predictive accuracy and clinical utility.
Methods
We included patients with AF starting OAC between January 2016 and November 2021. Endpoints assessed were major bleeding, major bleeding/clinically relevant nonmajor bleeding (CRNMB), and intracranial hemorrhage (ICH). Score performance was assessed through discrimination, calibration, reclassification (net reclassification improvement), decision curve analysis, and accuracy over a 2-year follow-up period.
Results
In total, 3259 patients with AF were included (median age, 77 years; IQR, 70-83 years; 52.8% female). Over 2 years’ follow-up, 196 patients (6.35%/year) experienced major bleeding, 413 (10.3%/year) major bleeding/CRNMB, and 32 (0.5%/year) experienced ICH. All risk scores performed modestly for major bleeding (c-indexes, <0.7), with ORBIT (c-index, 0.664) and HAS-BLED (c-index, 0.651) performing the best. All 4 scores demonstrated good discriminatory ability (log-rank P < .001). The ORBIT score showed a slight improvement in net reclassification improvement for major bleeding compared with HAS-BLED, with a modest increase in discrimination, while no other score outperformed HAS-BLED. Calibration showed that HAS-BLED and ORBIT outperformed the DOAC and AF-BLEED scores for major bleeding and CRNMB. The Brier index indicated high accuracy across all scores.
Conclusion
All bleeding-risk scores only had modest predictive ability. None demonstrated clear superiority in predicting major bleeding, major bleeding/CRNMB, or ICH.
{"title":"A comparative analysis of HAS-BLED, ORBIT, DOAC, and AF-BLEED bleeding-risk scores in anticoagulated patients with atrial fibrillation: a report from the prospective Murcia atrial fibrillation project III (MAFP-III) cohort","authors":"Eva Soler-Espejo , María Pilar Ramos-Bratos , José Miguel Rivera-Caravaca , Eduardo González-Lozano , Francisco Marín , Vanessa Roldán , Gregory Y.H. Lip","doi":"10.1016/j.jtha.2025.07.040","DOIUrl":"10.1016/j.jtha.2025.07.040","url":null,"abstract":"<div><h3>Background</h3><div>Patients with atrial fibrillation (AF) often require oral anticoagulation (OAC), but predicting bleeding risk remains challenging. Classic risk scores such as HAS-BLED and ORBIT, along with newer models such as DOAC and AF-BLEED, exhibit only modest predictive performance.</div></div><div><h3>Objectives</h3><div>In this study, we compared these 4 scores in patients with AF on OAC to evaluate their predictive accuracy and clinical utility.</div></div><div><h3>Methods</h3><div>We included patients with AF starting OAC between January 2016 and November 2021. Endpoints assessed were major bleeding, major bleeding/clinically relevant nonmajor bleeding (CRNMB), and intracranial hemorrhage (ICH). Score performance was assessed through discrimination, calibration, reclassification (net reclassification improvement), decision curve analysis, and accuracy over a 2-year follow-up period.</div></div><div><h3>Results</h3><div>In total, 3259 patients with AF were included (median age, 77 years; IQR, 70-83 years; 52.8% female). Over 2 years’ follow-up, 196 patients (6.35%/year) experienced major bleeding, 413 (10.3%/year) major bleeding/CRNMB, and 32 (0.5%/year) experienced ICH. All risk scores performed modestly for major bleeding (c-indexes, <0.7), with ORBIT (c-index, 0.664) and HAS-BLED (c-index, 0.651) performing the best. All 4 scores demonstrated good discriminatory ability (log-rank <em>P</em> < .001). The ORBIT score showed a slight improvement in net reclassification improvement for major bleeding compared with HAS-BLED, with a modest increase in discrimination, while no other score outperformed HAS-BLED. Calibration showed that HAS-BLED and ORBIT outperformed the DOAC and AF-BLEED scores for major bleeding and CRNMB. The Brier index indicated high accuracy across all scores.</div></div><div><h3>Conclusion</h3><div>All bleeding-risk scores only had modest predictive ability. None demonstrated clear superiority in predicting major bleeding, major bleeding/CRNMB, or ICH.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 431-442"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958920","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}
Background: Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening thrombotic microangiopathy, with a substantial risk of relapse despite advances in therapy. Robust biomarkers to predict relapse are urgently needed to inform risk-adapted management. This study represents the first application of bone marrow proteomic profiling in TTP to explore relapse-associated biomarkers.
Methods: We conducted a retrospective cohort study involving 123 patients diagnosed with TTP at a single center. Clinical and laboratory variables at initial presentation were analyzed to identify potential predictors of relapse using Cox proportional hazards models. To explore molecular correlates of relapse, bone marrow paraffin-embedded samples from 18 patients were subjected to quantitative proteomic profiling. Machine learning algorithms were applied to identify candidate relapse-associated proteins. Selected proteins were subsequently validated by immunohistochemistry (IHC) on corresponding tissue sections.
Results: Age ≤30 years and severe neuropsychiatric symptoms were independently associated with increased relapse risk, but demonstrated only moderate predictive performance (AUC = 0.706). Proteomic profiling revealed TMEM109 as a relapse-associated protein with superior discriminative capacity (AUC = 0.929). IHC analysis confirmed reduced TMEM109 expression in relapsed patients (p < 0.0001).
Conclusions: TMEM109 is a promising biomarker for predicting TTP relapse. While clinical factors such as age and neuropsychiatric symptoms provide valuable prognostic information, TMEM109 may enhance relapse risk stratification, offering potential for individualized monitoring and therapeutic decision-making. These findings underscore the value of proteomic profiling in complementing clinical evaluation in TTP.
{"title":"Bone Marrow Proteomic Profiling Reveals TMEM109 as a Biomarker for Relapse in Thrombotic Thrombocytopenic Purpura.","authors":"Qing Wen, Jia Chen, Ting Sun, Xiyan Wang, Mankai Ju, Xiaofan Liu, Huiyuan Li, Rongfeng Fu, Wei Liu, Feng Xue, Huan Dong, Xinyue Dai, Wentian Wang, Ying Chi, Renchi Yang, Yunfei Chen, Lei Zhang","doi":"10.1016/j.jtha.2026.01.003","DOIUrl":"https://doi.org/10.1016/j.jtha.2026.01.003","url":null,"abstract":"<p><strong>Background: </strong>Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening thrombotic microangiopathy, with a substantial risk of relapse despite advances in therapy. Robust biomarkers to predict relapse are urgently needed to inform risk-adapted management. This study represents the first application of bone marrow proteomic profiling in TTP to explore relapse-associated biomarkers.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study involving 123 patients diagnosed with TTP at a single center. Clinical and laboratory variables at initial presentation were analyzed to identify potential predictors of relapse using Cox proportional hazards models. To explore molecular correlates of relapse, bone marrow paraffin-embedded samples from 18 patients were subjected to quantitative proteomic profiling. Machine learning algorithms were applied to identify candidate relapse-associated proteins. Selected proteins were subsequently validated by immunohistochemistry (IHC) on corresponding tissue sections.</p><p><strong>Results: </strong>Age ≤30 years and severe neuropsychiatric symptoms were independently associated with increased relapse risk, but demonstrated only moderate predictive performance (AUC = 0.706). Proteomic profiling revealed TMEM109 as a relapse-associated protein with superior discriminative capacity (AUC = 0.929). IHC analysis confirmed reduced TMEM109 expression in relapsed patients (p < 0.0001).</p><p><strong>Conclusions: </strong>TMEM109 is a promising biomarker for predicting TTP relapse. While clinical factors such as age and neuropsychiatric symptoms provide valuable prognostic information, TMEM109 may enhance relapse risk stratification, offering potential for individualized monitoring and therapeutic decision-making. These findings underscore the value of proteomic profiling in complementing clinical evaluation in TTP.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093426","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}
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