Journal of Thrombosis and Haemostasis最新文献

{"title":"In situ pulmonary thrombosis and pulmonary embolus are distinct thrombotic phenotypes in critically ill patients with COVID-19 Acute Respiratory Distress Syndrome","authors":"Daniël G. Aynekulu Mersha ,&nbsp;Boaz Lopuhaä ,&nbsp;Hester A. Gietema ,&nbsp;Jim Smit ,&nbsp;Anne E. Wind ,&nbsp;Anne-Marije Hulshof ,&nbsp;Katrijn Daenen ,&nbsp;Jessica Khyali ,&nbsp;Bas C.T. van Bussel ,&nbsp;Matthijs F.M. van Oosterhout ,&nbsp;Hazra S. Moeniralam ,&nbsp;Eva K. Kempers ,&nbsp;Marieke J.H.A. Kruip ,&nbsp;Frederikus A. Klok ,&nbsp;Virgil A.S.H. Dalm ,&nbsp;Henrik Endeman ,&nbsp;Eric C.M. Van Gorp ,&nbsp;Willem A. Dik ,&nbsp;Jan H. von der Thüsen ,&nbsp;Nicole P. Juffermans","doi":"10.1016/j.jtha.2025.10.021","DOIUrl":"10.1016/j.jtha.2025.10.021","url":null,"abstract":"<div><h3>Background</h3><div>Pulmonary embolism (PE) is thought to originate from distal thrombosis. However, in hyperinflammatory conditions, such as COVID-19, thrombosis in the lung vasculature may occur independently of peripheral thrombosis, denoted as <em>in situ</em> thrombosis (IST).</div></div><div><h3>Objectives</h3><div>We hypothesize that IST results from a dysregulated immune response involving both T-helper type 1 (Th1) and non-Th1 cell upregulation and can be distinguished from PE by histologic, serologic, and radiologic features.</div></div><div><h3>Methods</h3><div>This study included critically ill patients who succumbed to COVID-19 and from whom pulmonary histopathological examination was obtained. Patients were categorized based on histologic characteristics as either IST (thrombus originating from the vessel wall, with a disorganized structure) or PE (centrally in the vessel, with a layered structure) or as controls (without any pulmonary thrombosis). Inflammation, endothelial activity, and hemostasis biomarkers were measured in blood, and computed tomography scans were analyzed.</div></div><div><h3>Results</h3><div>Of 21 included patients, <em>n</em> = 6 were categorized as IST, <em>n</em> = 8 as PE, and <em>n</em> = 7 as controls (those who did not have pulmonary thrombosis). Radiologic features of IST included irregular filling defects along vessel walls in smaller arteries in areas with infiltrates. Patients with IST had higher levels of interleukin [IL]-17, IL-18 and IL-33 than those with PE and controls, indicating upregulation of both Th1 and non-Th1 cell pathways.</div></div><div><h3>Conclusion</h3><div>IST and PE are distinct forms of pulmonary thrombosis. IST originates from the pulmonary vessel wall and is characterized by skewing from an effective immune response to upregulation of Th1, Th2, and Th17 cell pathways.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 662-671"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452099","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":"Pain diagnostics in people with hemophilia – pain pressure thresholds and influence of age and joint status","authors":"Thomas Hilberg ,&nbsp;Alexander Schmidt ,&nbsp;Andreas C. Strauss ,&nbsp;Johannes Oldenburg ,&nbsp;Georg Goldmann ,&nbsp;Natascha Marquardt ,&nbsp;Fabian Tomschi","doi":"10.1016/j.jtha.2025.09.044","DOIUrl":"10.1016/j.jtha.2025.09.044","url":null,"abstract":"<div><h3>Background</h3><div>Pain is a burden for people with hemophilia (PwH) and is often underdiagnosed. Therefore, it is crucial to develop accurate tools for pain assessment.</div></div><div><h3>Objectives</h3><div>Pain pressure thresholds (PPTs) are valuable in the diagnosis of pain sensitivity. The meaning and influencing factors in PwH were evaluated in this study.</div></div><div><h3>Methods</h3><div>We investigated PPTs in 327 PwH and 121 healthy controls to compare differences, examine the influence of age on PPT testing, and explore correlations between PPTs and numeric rating scale (NRS) categories or joint status. PPTs were measured bilaterally at hemophilia-specific joints (elbow/knee/ankle) and reference landmarks (sternum/forehead). Joint status was assessed via the Hemophilia Joint Health Score. NRS categories were used to evaluate current, mean, and maximum pain over the last 4 weeks.</div></div><div><h3>Results</h3><div>PPTs varied significantly across hemophilia-specific joints, such as the knees and ankles, compared with controls (<em>P</em> &lt; .001), but showed no significant differences at the elbows (<em>P</em> ≥ .123) or at reference landmarks (<em>P</em> ≥ .621). Age did not influence PPTs in either group. In contrast, age-related effects were observed across nearly all NRS categories (current/mean/maximum) in both groups. Correlations between PPTs and NRS categories were low (<em>r</em> ≤ −.212), indicating that they measure different dimensions of pain.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that PPT measurement is an important method of pain assessment in PwH. Joint-specific PPT values are independent of age and correlate with the presence of affected joints, potentially reflecting the local joint condition, while NRS categories likely represent the overall pain status. Therefore, PPT is a useful tool for pain assessment in PwH, particularly for the diagnosis of joint-specific pain sensitivity.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 470-482"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459062","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 mitochondrial calcium uniporter regulates calcium dynamics to drive platelet function, bioenergetics, and thrombosis","authors":"Madankumar Ghatge ,&nbsp;Gagan D. Flora ,&nbsp;Rakesh B. Patel ,&nbsp;Manasa K. Nayak ,&nbsp;Mariia Kumskova ,&nbsp;Tam Nguyen ,&nbsp;Yuriy M. Usachev ,&nbsp;Anil K. Chauhan","doi":"10.1016/j.jtha.2025.10.019","DOIUrl":"10.1016/j.jtha.2025.10.019","url":null,"abstract":"<div><h3>Background</h3><div>The mitochondrial calcium uniporter (MCU), a selective intracellular calcium (Ca²⁺) channel, mediates mitochondrial Ca²⁺ uptake, supporting Ca²⁺ homeostasis and mitochondrial bioenergetics. While cytosolic Ca²⁺ flux from the dense tubular system (DTS) and store-operated Ca²⁺ entry are known to drive platelet activation, the role of mitochondrial Ca²⁺ handling in platelet function and thrombosis is not well understood.</div></div><div><h3>Objectives</h3><div>This study examined whether targeting MCU-dependent Ca²⁺ flux could attenuate platelet activation and arterial thrombosis.</div></div><div><h3>Methods</h3><div>Susceptibility to arterial thrombosis was assessed using the FeCl₃-induced carotid injury model in wild-type and MCU^−/− mice. Mitochondrial and cytosolic Ca²⁺ levels were measured in Rhod-2– and Fura-2–loaded platelets by fluorometry, and platelet bioenergetics were analyzed using a Seahorse extracellular flux analyzer.</div></div><div><h3>Results</h3><div>Genetic ablation of MCU inhibited agonist-induced platelet functions, including aggregation, fibrinogen binding to integrin α_IIbβ₃, granule secretion, and spreading on fibrinogen. MCU^−/− mice were less susceptible to <em>in vivo</em> arterial thrombosis with unaltered tail bleeding time, suggesting normal hemostasis. Mechanistically, these effects were associated with disruption of Ca²⁺ homeostasis mediated by reduced mitochondrial Ca²⁺ uptake, altered release of Ca²⁺ from dense tubular system, and impaired store-operated Ca²⁺ entry in agonist-stimulated MCU^−/− platelets. Consistent with this, Ca²⁺-dependent glycoprotein VI signaling events such as phospholipase γ2 and protein kinase C substrate phosphorylation were significantly reduced in collagen-stimulated MCU^−/− platelets. Furthermore, disruption of mitochondrial Ca²⁺ uptake significantly impaired mitochondrial respiration and associated adenosine triphosphate production in agonist-stimulated MCU^−/− platelets.</div></div><div><h3>Conclusion</h3><div>MCU facilitates platelet activation and thrombosis by regulating calcium flux (mitochondrial and cytosolic), thereby establishing its potential as a target for antithrombotic therapeutic intervention.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 716-731"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459100","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":"Engineering a membrane-independent human prothrombinase through parsimonious mutation of factor Xa","authors":"Fatma Işık Üstok,&nbsp;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}

{"title":"Additional oxerutin therapy to promote deep vein thrombus resolution (RESOLVE-DVT): a randomized controlled pilot trial","authors":"Aaron F.J. Iding ,&nbsp;Ruben D. Hupperetz ,&nbsp;Rutger J.B. Brans ,&nbsp;Hugo ten Cate ,&nbsp;Daan J.L. van Twist ,&nbsp;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}

{"title":"Preclinical safety and bleeding evaluation in swine for a small interfering RNA-lipid nanoparticle that prevents excess fibrinogen synthesis","authors":"Monica S. Seadler ,&nbsp;Francesca Ferraresso ,&nbsp;Halen M. Turner ,&nbsp;Laura M. Ketelboeter ,&nbsp;Youjie Zhang ,&nbsp;Katherine Badior ,&nbsp;William G. Hayssen ,&nbsp;Taylor Chen ,&nbsp;Amber L. Haugen ,&nbsp;Massimo F. Cau ,&nbsp;Madelaine Robertson ,&nbsp;Chad Skaer ,&nbsp;Muskan Bansal ,&nbsp;Patrick B. Murphy ,&nbsp;Marc de Moya ,&nbsp;Mitchell R. Dyer ,&nbsp;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 &gt; 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}

{"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 ,&nbsp;Anjali Sharathkumar ,&nbsp;Riten Kumar ,&nbsp;Fernando F. Corrales-Medina ,&nbsp;Heleen van Ommen ,&nbsp;Mihir Bhatt ,&nbsp;Smita Dandekar ,&nbsp;Maua Mosha ,&nbsp;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 &lt;.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}

{"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 ,&nbsp;Shogo Tamura ,&nbsp;Atsuo Suzuki ,&nbsp;Nobuaki Suzuki ,&nbsp;Takeshi Kanematsu ,&nbsp;Naruko Suzuki ,&nbsp;Masashi Tomita ,&nbsp;Fumihiko Hayakawa ,&nbsp;Akira Katsumi ,&nbsp;Hitoshi Kiyoi ,&nbsp;Tetsuhito Kojima ,&nbsp;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&gt;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}

{"title":"Protein S as a therapeutic target","authors":"Raja Prince Eladnani ,&nbsp;Rim Diab ,&nbsp;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}

{"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 ,&nbsp;Anwar E. Ahmed ,&nbsp;Barbara A. Konkle ,&nbsp;Jill M. Johnsen ,&nbsp;Andrew Frank ,&nbsp;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}