Journal of Thrombosis and Haemostasis最新文献

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.

Background: Postthrombotic syndrome (PTS) is a serious complication of deep vein thrombosis (DVT), linked to persistent inflammation and impaired thrombus resolution. Enhanced formation of neutrophil extracellular traps (NETs) is involved in DVT pathogenesis.

Objectives: We investigated whether increased NET formation, associated with an unfavorable fibrin clot phenotype, predisposes to the development of PTS.

Methods: We studied 179 patients with DVT. Three months after diagnosis and initiation of anticoagulant therapy, citrullinated histone H3 (H3cit), thrombin generation, clot permeability, clot lysis time, and inflammatory markers were measured. PTS severity was assessed at 12 to 14 months by the Villalta score. During a median 53-month follow-up, we recorded recurrent venous thromboembolism and venous ulcers.

Results: Patients with PTS (n = 43, 24.0%) had 68.8% higher H3cit levels compared with those without PTS (P < .001). In the whole group, H3cit showed a positive association with Villalta scores (R = .596; P < .001). Higher H3cit was linked to denser fibrin clots (ie, clot permeability; R = -.352; P < .001), slower fibrinolysis (ie, clot lysis time; R = .287; P < .001), and higher interleukin 6 (R = .429; P < .001), but not C-reactive protein or thrombin generation. In multivariable analysis, higher H3cit per 1 ng/mL at 3 months was independently associated with PTS (odds ratio, 5.50; 95% CI, 2.52-12.01). Patients with recurrent venous thromboembolism (n = 43, 24.0%) had 37.8% higher H3cit concentrations compared with those without recurrence (P < .001). Venous ulcer formation was not related to this marker.

Conclusion: This study is the first to show that enhanced NET formation following DVT may contribute to PTS and its severe forms, at least in part through unfavorable fibrin clot properties.

Background: Anthrax, caused by Bacillus anthracis, leads to severe sepsis due to multiple virulence factors, including toxins and bacterial cell wall components, which disrupt immune responses and induce cytotoxic effects. However, the relative contributions of toxins vs bacterial overload during systemic disease remain unclear.

Objectives: We aimed to investigate the differential effects of toxigenic B anthracis Sterne strains and nontoxigenic ΔSterne strains on coagulation, complement activation, immune response, endothelial function, and organ damage in a baboon model of anthrax.

Methods: Healthy baboons were intravenously infused with a sublethal dose (1 × 10⁸ colony-forming units/kg) of either B anthracis Sterne or ΔSterne strains. Animals were monitored for 7 days and assessed for vital signs, hematologic parameters, coagulation markers, endothelial dysfunction, complement activation, and proteomic profiles.

Results: The toxigenic Sterne strain induced more severe systemic effects than the ΔSterne strain, including prolonged bacterial persistence, enhanced coagulopathy, increased complement activation, endothelial dysfunction, neutrophil activation, and neutrophil extracellular trap formation. Coagulopathy was evidenced by elevated protease-antithrombin complexes, prolonged clotting times, fibrinogen consumption, and thrombocytopenia. Proteomic analysis of plasma revealed stronger upregulation of proteins involved in innate immunity, metabolism, coagulation, and cell death pathways in Sterne animals compared with ΔSterne-challenged animals.

Conclusion: Our findings suggest that anthrax toxins contribute to the exacerbation of pathological host responses during anthrax sepsis, including coagulopathy, complement activation, endothelial dysfunction, and organ injury. These observations provide insight into the role of toxins in intensifying disease severity beyond bacterial burden alone. Therapeutic strategies targeting coagulation and complement pathways, while preserving endothelial function, may help mitigate anthrax-induced sepsis.

Background: 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 in situ thrombosis (IST).

Objectives: 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.

Methods: 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.

Results: Of 21 included patients, n = 6 were categorized as IST, n = 8 as PE, and n = 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.

Conclusion: 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.

Background: 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.

Malignant brain tumors, including both primary brain cancer and metastatic brain cancer, are associated with a markedly increased risk of venous thromboembolism (VTE). Anticoagulation is challenging in this population, as these patients are not only at risk of thrombotic complications but also at high risk of bleeding. In this review, we examine current knowledge on the incidence, risk factors, pathophysiology, and management of brain cancer-associated VTE. In primary brain cancer, particularly in glioblastoma, expression of the procoagulant proteins podoplanin and tissue factor by tumor cells was found to be an important pathophysiological driver of hypercoagulability. Expression of these prothrombotic factors was found to be dependent on the genetic profile of the brain tumor. Clinical data on the treatment of VTE in brain cancer are limited and mostly based on observational studies. The risk of intracranial hemorrhage during anticoagulation remains a key concern. Data from retrospective studies suggest that direct oral anticoagulants may be associated with a lower bleeding risk than low-molecular-weight heparins. Pharmacological thromboprophylaxis in the ambulatory setting is not routinely recommended, largely due to the lack of trial data in this population. Future studies are needed to improve risk prediction, to clarify the underlying mechanisms of brain cancer-associated VTE, and to define safe and effective treatment strategies.