Thrombosis and haemostasis最新文献

Left ventricular thrombus (LVT) commonly complicates ST-segment elevation myocardial infarction (MI), and up to 30% of LVT may persist despite anticoagulation. Data linking post-MI LVT and inherited thrombophilias are sparse.A total of 148 consecutive MI patients with LVT at a mean age of 63.9 (6.9) years were referred for further workup. After 3 months of oral anticoagulation, screening for factor V Leiden (FVL) and prothrombin G20210A variant, protein S, protein C, and antithrombin deficiency was performed. Subjects with antiphospholipid syndrome were not eligible. Thrombus persistence was assessed after 3 and 6 months of anticoagulation.Inherited thrombophilias were identified in 34 (23%) patients, including 18 (52.9%) with FVL, 9 (26.5%) with prothrombin G20210A variant, 3 (8.8%) with protein C deficiency, and 4 (11.8%) with protein S deficiency. Carriers of thrombophilias were similar to non-thrombophilic subjects, except for higher fibrinogen in the former group. Inherited thrombophilias were associated with LVT persistence after 3 and 6 months post MI (25 [73.5%] vs. 50 [43.9%], p = 0.002 and 20 [58.8%] vs. 24 [21.1%], p < 0.001, respectively). Inherited thrombophilias were independently associated with an increased risk of persistent LVT 3 and 6 months post MI (OR 2.75, 95% CI 1.13-6.74, p = 0.026 and OR 4.06, 95% CI 1.57-10.51, p = 0.004, respectively).Our findings suggest that inherited thrombophilias may predispose to LVT persistence despite anticoagulation in MI survivors. Thrombophilia screening may help identify a subgroup likely to benefit from prolonged anticoagulation.

Hemophilia B is a rare inherited bleeding disorder resulting from mutations in the coagulation factor IX (factor IX) gene. While mutations in factor IX catalytic domains directly compromise clotting activity, mutations in the signal peptide and propeptide domains contribute to disease pathogenesis through more complex and indirect mechanisms. Despite not participating directly in enzymatic catalysis, the signal peptide and propeptide domains are indispensable for proper factor IX biosynthesis, structural maturation, and post-translational modifications. Research on these regions remains limited, and the precise molecular mechanisms linking mutations in the signal peptide and propeptide domains to clinical manifestations are not yet fully elucidated. In this review, we systematically catalog pathogenic mutations identified in factor IX's signal peptide and propeptide domains, organizing them by mutation types and functional consequences. We highlight how these mutations disrupt domain integrity, compromise factor IX stability, and interfere with its physiological processing. Furthermore, we discuss additional modifiers of disease severity, such as vitamin K availability, hypersensitivity to anticoagulant therapies, and inhibitor development. By integrating genetic, biochemical, and clinical perspectives, this review highlights the crucial role of factor IX's signal peptide and propeptide domains in the pathogenesis of hemophilia B and provides a foundational mechanistic framework that may inform future therapeutic development and help elucidate the molecular basis of disease heterogeneity.

Risk of venous thromboembolism (VTE) is increased in pregnancy and postpartum, and 40% of VTEs in pregnancy (Caucasians) are associated with heterozygous factor V Leiden mutation (FVL). Thrombin generation is increased in individuals with FVL and in pregnant women, and thrombin amplifies both platelet and coagulation activation. Although both contribute to VTE pathophysiology, the mechanisms of platelet activation in pregnant women, particularly with heterozygous FVL, remain poorly understood.To describe the physiological course of the platelet activation marker plasma soluble P-selectin (sP-selectin), whole blood platelet aggregation, and thromboelastography (TEG) parameters throughout pregnancy and postpartum, and assess differences between women with and without heterozygous FVL.A total of 22 pregnant women with heterozygous FVL and 22 without were enrolled. Blood samples were collected at multiple time points during and after pregnancy. Platelet activation and aggregation were evaluated using sP-selectin, multiple electrode aggregometry (MEA) with adenosine diphosphate, arachidonic acid, thrombin receptor-activating peptide-6 as agonists, and TEG.sP-selectin levels increased significantly during pregnancy, while platelet aggregation decreased in response to all agonists (P < 0.005). TEG maximum amplitude (MA) increased throughout pregnancy. No significant differences were observed between women with and without FVL.In late pregnancy, decreased platelet aggregation responses were observed alongside increased sP-selectin levels, with no differences in levels between women with and without heterozygous FVL. These findings indicate that the presence of heterozygous FVL does not significantly influence platelet function during pregnancy. The cause of the unexpected, reduced platelet aggregation remains unclear and warrants further investigation.

Platelets are among the most abundant cells in the body and play important roles in coagulation and immunity. Platelets are formed when hematopoietic stem cells proliferate and differentiate into megakaryocytes via the regulation of various cytokines. After the megakaryocytes mature in the bone marrow cavity, proplatelets are released into the blood circulation where they eventually remodel into mature platelets. Given that the production and functions of platelets involve the regulation of many factors-such as hematopoietic stem cells, the hematopoietic microenvironment, and cytokines-the causes and mechanisms of platelet-related diseases are diverse, often involving platelet production, clearance, and distribution. In this review, we examined the regulation of platelet production and summarized common disorders affecting platelet quantity, namely, thrombocytopenia and thrombocytosis. In addition, we reviewed previous clinical studies and summarized the medication strategies commonly used for the treatment of different platelet disorders in different clinical scenarios.

Coronavirus disease 2019 (COVID-19) is often associated with thrombosis. Elevated levels of soluble C-type lectin-like receptor 2 (sCLEC-2), a biomarker for platelet activation, have been reported in COVID-19. Therefore, we examined the behavior of sCLEC-2 levels and their relationship with thrombosis.The clinical course of inflammatory and thrombotic biomarkers was assessed in 271 patients with COVID-19.Inflammatory biomarkers such as C-reactive protein, procalcitonin, and presepsin levels were significantly increased in patients with COVID-19, and these behaviors differed among the clinical course or stages. The plasma D-dimer levels increased slightly and gradually. Platelet counts were within the normal range, and plasma sCLEC-2 levels were markedly increased in most patients with COVID-19. There were 17 patients with thrombosis in this study. Although there was no significant difference in various biomarkers between COVID-19 patients with and without thrombosis, the super formula of sCLEC-2xD-dimer/platelet count in patients with thrombosis was significantly higher than in those without thrombosis. Furthermore, this super formula was significantly higher in COVID-19 patients with severe or critical illness than in those with mild or moderate illness.Elevation of the super formula of sCLEC-2xD-dimer/platelet count was associated with the thrombosis in patients with COVID-19 suggesting the thrombosis in COVID-19 may be caused by the development of microthrombosis.

Protein C (PC) activation on endothelial cells is a critical antithrombotic mechanism. Hereditary PC deficiency (PCD), which is caused by mutations in the PROC gene, can predispose affected individuals to thrombophilia. Previous studies investigated activated protein C (APC) generation in PCD patients without including endothelial cells, which are essential for physiological PC activation. This study aimed to assess APC generation in PCD patients using a novel endothelial cell-based assay.Plasma samples from 21 patients with 19 heterozygous PROC mutations (median PC level 58%) and 24 healthy controls were analyzed. Endothelium-dependent APC generation was initiated by overlaying plasma on human umbilical vein endothelial cells (HUVECs) and adding tissue factor (1 pmol/L). APC levels were quantified using an oligonucleotide-based enzyme capture assay. The area under the curve (AUC) was calculated to monitor cumulative APC formation over time. A calibration curve generated from wild-type PC in PC-deficient plasma established reference ranges.Mean peak levels of APC were significantly lower in PCD patients than in healthy controls (0.75 vs. 1.83 nmol/L, p = 2 × 10^-10). The AUC APC was below the reference range in 8 of 21 (38%) patient samples, indicating disproportionately severe impairment in APC generation. The observed variability in APC generation suggests that endothelial contributions may identify functional differences undetected by standard PC activity or antigen assays.This study introduces a novel endothelial cell-based APC generation assay, demonstrating the functional consequences of PROC mutations and providing insights into the regulation of APC generation, with potential applications in thrombosis risk assessment and personalized therapy.

von Willebrand disease (VWD) type 2 arises from variants in von Willebrand factor (VWF) that disrupt its essential hemostatic functions. As per ISTH guidelines, it is classified as type 2A, 2B, 2M, and 2N based on the affected VWF roles.This population-based study aims to uncover the genotype and laboratory phenotypes in type 2 VWD, providing insights into underlying genetics and genotype-phenotype associations.Our cohort included 247 patients from 196 families. Patients were characterized through multiple VWF phenotypic assays and genetic analyses, including DNA sequencing, copy number variation evaluations, and bioinformatic assessments.A total of 86 index patients (IPs, 44%) were diagnosed with type 2A, the most prevalent subtype. Additionally, 27 IPs (14%) were diagnosed with type 2N, 24 IPs (12%) with type 2B, 17 IPs (9%) with type 2M, and 42 IPs categorized as type U VWD carried VWD-associated variants but could not be assigned to a specific subtype. VWF variants were detected in 187 out of 196 (95%) individuals. A total of 222 VWF variants were identified: 187 missense (84%), 22 null alleles (10%), 5 regulatory (2%), 6 gene conversions (3%), and 2 silent variants (1%). Many variants were recurrent in our cohort, resulting in 114 distinct variants. Of these, 45 (39%) were novel.Our data expands the spectrum of disease-associated variants in VWF, including many newly identified variants. This provides valuable insights for accurate diagnosis and personalized treatment. Additionally, the significant genetic heterogeneity among type 2 patients highlights the challenges in sub-classification.

Complement is activated after trauma, but the activation mechanism is unknown. Plasmin can directly activate C3 and C5, and four distinct fibrinolytic phenotypes have now been recognized after injury-hyperfibrinolysis, fibrinolysis shutdown, hypofibrinolysis, and nonpathologic/physiologic.We set out to investigate whether a relationship between complement activation and fibrinolysis was present in adult trauma patients (n = 56).Rapid and tPA-challenged thromboelastography (TEG) was performed in the emergency department with IRB approval, and plasma obtained for C3a, C4a, C5a, Ba, sC5b-9, Factor I, Factor H, active PAI-1, α-2 antiplasmin (A2AP), plasmin-antiplasmin complex (PAP), and tPA activity measurement via multiplex, ELISA and activity assays. Data were analyzed using ANOVA and Spearman's correlations. Significance was set at p < 0.05.C3a and sC5b-9 were significantly higher in patients with hyperfibrinolysis than with physiologic or hypofibrinolysis (p < 0.05). Elevations in C3a, C4a, and SC5b9, along with depletion of Factors H and I, were significantly associated with massive transfusion within 6 hours and postinjury death. There were significant positive correlations between multiple markers of fibrinolysis and complement activation markers and significant negative correlations with Factors H and I. Significant negative correlations between fibrinolytic inhibitors and complement activation were also observed.Our findings suggest that fibrinolysis may play a direct role in complement activation in trauma through plasmin-mediated cleavage of C3 and C5.

Pulmonary embolism (PE) requires accurate risk assessment. We investigated the prognostic performance of the National Early Warning Score (NEWS) in emergency department patients with PE.We included patients ≥ 18 years from our PE registry (2017 to 2021), excluding patients after cardiac arrest or intubation before admission. The primary outcome was a composite of 30-day all-cause mortality or the need for advanced therapy (i.e., systemic or catheter-directed thrombolysis). We used logistic regression and the Cox proportional hazards models to estimate associations. The Pulmonary Embolism Severity Index (PESI) and the European Society of Cardiology (ESC) classification served as covariates. The overall score performances were quantified using receiver operating characteristic analysis.We included 524 patients. Each increase in NEWS points increased the odds of the primary outcome by 69% (odds ratio: 1.69, 95% confidence interval [CI]: 1.51-1.89, p < 0.001) and 30-day mortality by 44% (hazard ratio: 1.44, 95% CI: 1.30-1.60, p < 0.001). Within the ESC intermediate-high and high-risk group, the 30-day mortality rate was higher in patients with a NEWS ≥ 7 compared with NEWS < 7 (24 vs. 1%, p < 0.001). With a NEWS ≥ 7, 30-day mortality was lower in patients who received advanced therapy (18 vs. 39%) but not significantly. The NEWS predicted the primary outcome better than the PESI (area under the curve: 0.853 vs. 0.752, p < 0.001).The NEWS was associated with 30-day mortality and the need for advanced therapy. Incorporating the NEWS into the ESC classification could help to assess patient outcomes early and thus support timely treatment decisions.