TH open : companion journal to thrombosis and haemostasis最新文献

Background: Ischemic stroke occurs when a thrombus blocks a cerebral artery, and an important component is the fibrin clot. Different plasma fibrinogen variants have been associated with stroke risk in type 2 diabetes (T2D). We hypothesized that in vitro fibrin clot characteristics are associated with stroke risk and correlate with fibrinogen variants.

Objective: To investigate the association of fibrin clot characteristics with risk of ischemic stroke in T2D and the correlation of fibrinogen variants with clot characteristics.

Methods: In a nested case-control study with a median follow-up of 4.1 years, we included 144 T2D patients with ischemic stroke (cases) and 144 matched T2D patients without ischemic stroke (controls). Clot formation (velocity [ V _max ], maximum absorbance [MA], overall hemostasis potential [OHP]), lysis, and structure (fiber density, diameter) were analyzed by turbidimetry. Clot characteristics were compared between cases and controls using a Mann-Whitney test and associated with stroke risk using conditional logistic regression to determine associations with stroke risk. Spearman's rank correlation was used to determine correlations between clot characteristics and fibrinogen variants (fibrinogen α _E , fibrinogen γ ', and sialylated fibrinogen).

Results: Fibrin fiber density at baseline was significantly lower in future stroke cases (4.2 [3.7-4.7] ×10 ²² Da/cm ³ ) than in controls (4.5 [4.0-4.9] ×10 ²² Da/cm ³ ), p : 0.01. Moreover, patients in the highest versus lowest tertile of fiber density had an adjusted OR for ischemic stroke of 0.7 (95% CI: 0.3-1.5). Patients with higher V _max , MA, OHP, and fiber diameter all had ischemic stroke ORs around 1.5, yet the limited statistical precision of the estimates hampered firm conclusions. Absolute, but not relative, levels of fibrinogen variants correlated with clot characteristics.

Conclusion: In our study, turbidimetric fibrin clot characteristics were not convincingly associated with ischemic stroke in T2D. Absolute levels of fibrinogen variants correlated consistently with clot characteristics.

Introduction: Reduced-dose direct oral anticoagulants (DOACs) may provide similar efficacy with less bleeding than standard dose for extended venous thromboembolism (VTE) treatment. It is unclear whether standard doses are preferable in certain subgroups.

Methods: We systematically searched MEDLINE, EMBASE, EMCARE, and Cochrane Central Register of Controlled Trials (CENTRAL) for randomized trials comparing reduced- with standard-dose DOACs for extended VTE treatment (registration number: INPLASY202550061). Outcomes included recurrent VTE, major bleeding, clinically relevant non-major bleeding (CRNMB), and mortality.

Results: Five trials (8,781 patients) were included. Reduced-dose DOACs (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily, n  = 4,395), compared to standard dose (apixaban 5 mg twice daily or rivaroxaban 20 mg once daily, n  = 4,386), resulted in similar rates of recurrent VTE (1.66% vs. 1.78%; risk ratio [RR] 0.94, 95% confidence interval [CI] 0.68-1.29). Major bleeding was less frequent with reduced dose (1.16% vs. 1.96%; RR 0.62, 95% CI 0.42-0.92), as was CRNMB (5.16% vs. 7.00%; RR 0.75, 95% CI 0.63-0.88). Mortality rates were comparable (4.91% vs. 5.81%; RR 0.86, 95% CI 0.63-1.17). These results held for high-risk subgroups, including patients with recurrent VTE or active cancer, except that reduced-dose DOACs appeared to lower recurrent VTE risk in males but increase risk in females ( p  = 0.04). Risk of bias was rated "low" in four studies and "some concerns" in one study. Certainty of evidence was moderate for three outcomes and low for one outcome.

Conclusion: For extended VTE treatment, reduced-dose DOACs have a similar risk of recurrent VTE and a lower risk of major and CRNMB compared to standard dose, including high-risk patients. A potential interaction with sex warrants further investigation.

Diabetes mellitus (DM), particularly type 1 (T1D) and type 2 (T2D), is a growing global health burden with complex pathophysiology extending beyond glucose dysregulation. Both forms of diabetes involve cellular stress, chronic inflammation, and β-cell dysfunction. Heat shock proteins (HSPs), key mediators of protein homeostasis and immune modulation, are emerging as critical players in the progression and complications of diabetes. In T1D, HSPs act at the crossroads of β-cell stress and autoimmunity, while in T2D, their dysregulation contributes to insulin resistance and mitochondrial dysfunction. Misfolded proteins, particularly amylin aggregates, further drive β-cell apoptosis in T2D and may influence immune activation in T1D. Hyperthermia (HT) and passive heat therapy (hT) activate protective stress responses through HSP induction, mimicking some benefits of exercise and improving glycemic control, insulin sensitivity, and vascular health. Preclinical and early clinical studies suggest that thermal interventions could complement standard care, especially in patients unable to engage in regular physical activity. This review consolidates current evidence on the roles of HSPs, amylin misfolding, and hT in the pathogenesis of diabetes, with a particular emphasis on vascular and thrombotic complications and their therapeutic implications. Targeting these converging molecular pathways may offer new avenues for preserving β-cell function, mitigating metabolic complications, and enhancing diabetes management.

Introduction: Limited data are available on the relationship between bleeding outcomes and physical activity, and the quality of daily life (QoL), in children with haemophilia A (HA) receiving emicizumab prophylaxis.

Aim: TSUBASA evaluated physical activity, bleeding events, safety, and QoL in Japanese people with HA initiating emicizumab prophylaxis. This paper reports the results from the final analysis, focusing on children and adolescents with HA without factor VIII inhibitors, and their caregivers.

Methods: TSUBASA was a prospective, multicentre, observational study conducted across 50 medical institutions in Japan. Participants received emicizumab for 97 weeks. Bleeding events and physical activity data were obtained using an electronic patient-reported outcomes application; activity intensity was collected by wearable activity trackers worn over five 8-day monitoring periods. Adverse events (AEs) were documented on the electronic case report form and QoL was assessed using questionnaires.

Results: A total of 46 participants aged <18 years were enrolled; most (84.8%) had severe HA. Over a median observation period of 674 days (quartile 1-quartile 3: 665-690), the mean annualized bleed rate was 0.86 (standard deviation: 1.26). In all Twenty-six participants experienced 66 AEs, of which 2 were injection-site reactions deemed related to emicizumab. J-KIDSCREEN-52 questionnaire scores were maintained from baseline onwards. Of the completed caregiver questionnaires ( n  = 32), 43.8% reported increased activity and 56.3% reported unchanged activity. Additionally, 56.3% reported decreased anxiety about bleeding and 37.5% reported unchanged anxiety about bleeding. A total of 172 events of physical activity were recorded by 19 participants; 44 were high risk, 70 were moderate risk, and 42 were low risk. One activity-related traumatic bleed resulting from the impact of a basketball occurred, and more than 25 different types of physical activity were performed without bleeding.

Conclusion: Children and adolescents with HA who receive prophylaxis with emicizumab may be able to engage in consistent physical activity, with a low risk of experiencing bleeds. Additionally, the questionnaire responses from caregivers on physical activity and caregiver experience provide rare insights into the real-world impact of emicizumab prophylaxis. These findings present a more comprehensive view of the benefits of emicizumab. No new safety signals were observed and QoL was maintained for 2 years after emicizumab initiation.

Abstract:

Background: Fibrinolysis is the process of blood clot breakdown by the enzyme plasmin. Despite increased usage of large animals such as pigs to study fibrinolysis in human disease models, a comprehensive study comparing the human and porcine fibrinolytic factors has not been reported.

Objective: To directly compare and characterize structural and functional differences between human and porcine fibrinolytic factors.

Methods: Using human or porcine source of plasminogen, tissue-type plasminogen activator (tPA), and fibrinogen, we investigated how various permutations of the three fibrinolytic factors affect overall plasmin generation. Human or porcine plasmin breakdown of fibrin generated from human or porcine fibrinogen was also investigated using turbidity-based lysis assay and visualized using SDS-PAGE. Primary structures of the various proteins were also compared.

Results: All-human components had a 24-fold higher plasmin generation than all-porcine components. Species dependence on plasmin generation was the most dependent on fibrin source, where human fibrin presence led to a 2- to 34-fold higher plasmin generation than porcine fibrin. Porcine plasmin was the better enzyme for human or porcine fibrin breakdown due to a 2.7-fold and 6.7-fold higher k _cat , respectively. Peptide sequence analyses show the greatest differences lie in Kringle domain 1 for plasminogen and Kringle domain 2 for tPA, both of which bind fibrin. Fibrinogen chains also show the greatest difference within the αC domain, which has known plasminogen and tPA binding sites.

Conclusion: Although similar, there are notable and specific differences between the human and porcine fibrinolytic systems, particularly toward plasmin generation and fibrin breakdown.

Neonatal acute peritonitis is a leading cause of morbidity and mortality and poses challenges that demand prompt diagnosis and treatment, particularly in infants with disseminated intravascular coagulation. Here, we report a case series of four infants with acute peritonitis caused by necrotizing enterocolitis, gastrointestinal perforation, and meconium peritonitis. Laboratory tests for thrombin-antithrombin III complex (TAT), plasmin-α2-plasmin inhibitor complex (PIC), soluble thrombomodulin (sTM), and tissue plasminogen activator-inhibitor complex (t-PAIC) suggested the activation of the coagulation system followed by treatment with anticoagulant therapy in these infants. Overall, TAT, PIC, t-PAIC, and sTM may guide anticoagulant therapy, offering prospects for improving the outcomes in neonates with acute peritonitis.

Background: Central venous catheter (CVC) insertion is a cornerstone procedure in hospitalized and critically ill adults. However, many patients requiring CVCs have coagulopathy, thrombocytopenia, liver disease, or hematologic malignancies, raising concerns about bleeding risk. The true incidence of hemorrhagic complications and the value of preventive measures in these populations remain uncertain.

Objective: The objective of this study is to systematically evaluate the incidence of bleeding related to CVC placement in adults at increased hemorrhagic risk and to assess the effectiveness of periprocedural preventive strategies.

Methods: PubMed, Embase, Cochrane Library, and Web of Science were searched from January 2000 to March 2025. Randomized trials and observational studies involving adults with elevated bleeding risk undergoing CVC placement were included. Data extraction and risk of bias assessment (RoB 2 and Newcastle-Ottawa Scale) were performed independently by two reviewers. Certainty of evidence was rated using GRADE (Grading of Recommendations Assessment, Development, and Evaluation), and random-effects meta-analyses were conducted when appropriate.

Results: Forty-one studies encompassing 7,603 patients and 8,796 CVC insertions were analyzed. Major bleeding occurred in 0.57% of procedures and minor bleeding in 8.1%. The pooled incidence of any bleeding across 22 studies was 6.8% (95% confidence interval, 3.7-10.7%). Bleeding was more frequent among patients with hematologic malignancies, severe thrombocytopenia, or critical illness. Ultrasound guidance markedly reduced complications compared with landmark technique. Platelet transfusion was effective only below 30 × 10 ⁹ /L, whereas fresh-frozen plasma showed no clear benefit.

Conclusions: CVC placement in adults with coagulopathy or thrombocytopenia is generally safe. Ultrasound guidance, restrictive transfusion thresholds, and thromboelastography-guided assessment enhance procedural safety and reduce unnecessary transfusions.

A rare prothrombin variant (c.1787G > A, p.Arg596Gln), also known as the prothrombin Belgrade variant, has been associated with an increased predisposition to thrombosis through resistance to antithrombin. This variant has been previously reported in individuals from Serbia, Japan, China, and India. In this case report, we described the first reported case of heterozygosity for the prothrombin Belgrade variant in a Mexican-American family. Affected individuals had negative results on standard hypercoagulable studies; however, they exhibited a history of early-onset and recurrent venous thromboembolism (VTE). Although rare, the prothrombin Belgrade variant-and other prothrombin variants associated with antithrombin resistance-may be underrecognized in patients with recurrent thrombotic events, particularly among individuals from ethnic backgrounds not previously associated with this variant. These findings support the consideration of comprehensive genetic thrombophilia testing, including full sequencing of the prothrombin gene, in patients with negative standard hypercoagulable studies but a strong personal and/or family history of VTE.