Thrombosis Journal最新文献

Cancer-associated thrombosis (CAT), especially venous thromboembolism (VTE), is the second highest cause of mortality in cancer patients, following the cancer itself. Notably, among patients with thrombosis, cancer is the most common underlying cause of death, highlighting the strong interrelationship between these conditions. Tumour cells primarily promote a prothrombotic environment through activation of procoagulant properties of the host cells. Additionally, chemotherapy, radiotherapy and hormone treatments may amplify the thrombotic risk in cancer patients. Consequently, both arterial thromboses, including myocardial infarction (MI) and ischemic stroke (IS), and venous thrombosis, such as deep vein thrombosis (DVT) and pulmonary embolism (PE), are significantly more prevalent among patients with malignancies. This review will discuss the association between cancer and thrombosis, illustrate the most common risk factors and discuss the direct and indirect molecular mechanisms involved.

Background: Asundexian, a novel oral Factor XIa (FXIa) inhibitor, targets the intrinsic coagulation pathway to prevent thrombosis while potentially reducing bleeding risk compared to direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs). This systematic review synthesizes clinical evidence on its safety, efficacy, and pharmacological properties in managing arterial and venous thrombotic events.

Methods: Following PRISMA guidelines, we searched PubMed, Embase, Scopus, Cochrane Library, ClinicalTrials.gov, and Web of Science for clinical trials and observational studies on asundexian until January 2025. Inclusion criteria included studies reporting safety, efficacy, and pharmacokinetics/pharmacodynamics (PK/PD) outcomes. Two reviewers independently screened studies and extracted data, with quality assessed using the Cochrane Risk of Bias 2 tool.

Results: Eleven trials (n > 21,000, phases 1-3) were included. Asundexian suppressed FXIa activity, with phase 2 trials (e.g., PACIFIC-AF, PACIFIC-STROKE) showing reduced bleeding compared to apixaban. However, the phase 3 OCEANIC-AF trial was terminated early due to inferior efficacy in atrial fibrillation, with higher stroke/systemic embolism rates (2.5%) versus apixaban. PK/PD data support once-daily dosing with minimal drug interactions. Safety concerns include potential abnormal uterine bleeding, with limited data.

Conclusion: Asundexian shows promise in reducing bleeding but lacks efficacy in high-risk settings like atrial fibrillation. Ongoing trials are needed to define its role in specific thrombotic conditions.

Clinical trial number: Not applicable.

Background: Accurate coagulation parameter reference intervals are crucial for diagnosing bleeding disorders and thromboembolic diseases. However, reference intervals vary across populations due to genetic, environmental, and demographic factors. This study aimed to establish localized coagulation reference intervals for healthy adults of Debre Berhan, Northeast Ethiopia, addressing the current reliance on non-local values.

Methods: A community-based cross-sectional study was conducted in Debre Berhan, Northeast Ethiopia, from October-December 2024. We recruited 240 healthy adults (120 of each gender) using convenience sampling. Participants were interviewed face-to-face using a pre-tested questionnaire on KoBoToolbox to collect demographic data. Aseptically drawn venous blood was analyzed for coagulation parameters using Sysmex CA-104 coagulation analyzer. Stata 17 was used for data analysis, with reference intervals determined by the 2.5th and 97.5th percentiles. Gender differences were assessed using the Mann-Whitney U test (p < 0.05 significance).

Results: The established 95% coagulation reference intervals (2.5th -97.5th percentile) were: Prothrombin time (8.5-13.0 sec), international normalized ratio (0.7-1.1), and activated partial thromboplastin time (21.6-37.9 sec). Males exhibited significantly higher median PT (10.4 Vs. 9.8 sec, p = 0.0006) and INR (0.9 Vs. 0.84, p = 0.0006) values compared to females.

Conclusion: This study's findings strongly support the adoption of population-specific reference intervals to ensure accurate diagnoses and improve patient safety within the Debre Berhan adult population. The observed gender-related differences in Prothrombin time and international normalized ratio values further highlight the need for gender-specific reference intervals to improve clinical decision-making and prevent potential misinterpretations of coagulation test results.

Background: Hereditary antithrombin deficiency (HATD) is a rare disease caused by mutations in the SERPINC1 gene characterized with venous thromboembolism and/or arterial thrombotic events. We identified a proband with recurrent arterial and venous thrombosis at multiple anatomical sites and subsequently performed comprehensive thrombophilia screening and genetic analysis within the kindred.

Methods: Mutation screening of the SERPINC1 gene in the proband and family members was conducted using Sanger sequencing. Wild-type and mutant (c.473T > A; p.Leu158Gln) SERPINC1 expression plasmids were constructed and transiently transfected into HEK293T cells. Functional consequences of the variant were assessed through immunoblotting, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and computational structural analysis.

Results: Thrombophilia evaluation revealed significantly reduced antithrombin activity (46.2%) in the proband. Sanger sequencing identified an unreported heterozygous missense variant (c.473T > A; p.Leu158Gln) in SERPINC1. Cellular studies demonstrated that this mutation reduced both the quantity and functional activity of secreted antithrombin. Immunoblot analysis indicated a slightly faster migration of the mutant protein compared to wild-type, while immunofluorescence revealed abnormal cytoplasmic aggregation. Bioinformatics analysis confirmed substitution of leucine-158 by glutamine without disruption of conserved disulfide bonds (Cys40-Cys160, Cys128-Cys182, Cys247-Cys430) or N-glycosylation sites (Asn128, Asn167, Asn187, Asn224).

Conclusion: We establish the c.473T > A (p.Leu158Gln) variant in SERPINC1 as a pathogenic mutation underlying type I HATD, characterized by impaired secretion, cytoplasmic retention, and reduced functional activity of the mutant protein.

Background: Haemophilia, caused by deficiencies in factor VIII or IX, leads to deep tissue bleeding and haemophilic arthropathy. Bleeding, arthropathy, and the perioperative period of surgery for arthropathy are associated with severe pain. To avoid this pain, patients may compensate by overloading other parts of the body, potentially resulting in pain or secondary damage in areas distant from the primary site. This study investigates the use of infrared thermography (IRT) to monitor whole-body surface temperatures in people with haemophilia and to explore the potential of infrared thermography for early detection of compensatory overload.

Methods: A cross-sectional study involved 24 people with haemophilia aged 6-76 years old, experiencing pain after bleeding, post-orthopaedic surgery, or haemophilic arthropathy. Thermal images were captured with IRT and analyzed using software that utilises deep learning for whole-body temperature mapping.

Results: Increases in temperature indicative of overload were observed in areas distant from the affected site, either on the same side (vertical pattern) or on the opposite side (diagonal pattern) relative to the site of pain. These patterns were observed in 13 of 14 participants with haemophilic arthropathy, all post-orthopaedic surgery participants, and 5 of 6 after bleeding.

Conclusions: Temperature increases occurred in areas beyond the painful area, suggesting strain even in asymptomatic regions. People with haemophilia experiencing pain may require careful monitoring and treatment of surrounding areas. Our findings could aid in diagnosing haemorrhage and local inflammation while informing treatment decisions.

Clinical trial registration: Not applicable.

Background: Anticoagulant therapy is considered useful for sepsis patients with disseminated intravascular coagulation (DIC); however, the efficacy of combination therapy with anticoagulants is still under investigation.

Methods: We evaluated anticoagulant use in 1,770 patients with sepsis-induced DIC from 314 institutions by analyzing postmarketing survey data on plasma-derived antithrombin (AT) concentrates. DIC was defined as a DIC score above 4 according to the Japanese Association for Acute Medicine (JAAM). We divided patients into quartiles according to JAAM-defined DIC and Sequential Organ Failure Assessment (SOFA) scores to determine the efficacy of concomitant recombinant thrombomodulin (rTM) following AT supplementation, and we performed a propensity score-adjusted analysis.

Results: The 28-day mortality rate after AT administration was 24.1%. We categorized patients on the basis of a JAAM-defined DIC score of 6 and a SOFA score of 9, because the patients' median JAAM-defined DIC and SOFA scores were 5 and 9, respectively. Among patients with JAAM-defined DIC scores >6 and SOFA scores >9, patients treated with AT followed by rTM (concomitant rTM use) had a significantly lower mortality rate (28.5%) than did those treated without concomitant rTM (40.0%) (p = 0.031). However, among patients with JAAM-defined DIC scores of four or five, the patients treated with concomitant rTM had a significantly greater mortality rate than did those not treated with concomitant rTM, irrespective of whether their SOFA score was below or above 9 (18.5% vs. 10.1%, p = 0.036 and 37.0% vs. 24.3%, p = 0.018, respectively). The incidence of serious bleeding- related adverse events did not differ between patients with and without concomitant rTM treatment.

Conclusions: efficacy of rTM administration following AT supplementation in patients with sepsis-induced DIC is controversial, and the evidence is restricted to decreasing mortality rates in patients with JAAM-defined DIC scores >6 and SOFA scores>9. However, further studies are needed to confirm these findings.

Background: Sickle cell disease is a hemoglobinopathy characterized by alterations in the components of hemostasis. Despite efforts and individual and multiple studies carried out to understand the pathophysiology of the disease, particularly regarding abnormalities of hemostasis and coagulation, questions remain. This meta-analysis aimed to evaluate the studies linking inflammatory, coagulation, and fibrinolysis abnormalities in sickle cell patients, putting them in an intrinsic state of hypercoagulability and predisposing them to thrombotic risk.

Methods: The systematic review of databases and search engines was conducted over 24 years (2000-2024) and worldwide according to the reporting guidelines of PRISMA and the Cochrane Handbook. The research articles listed were searched in the PubMed and Web of Science databases. Only case-control articles were retained. Data were extracted from the articles and analyzed using the statistical software R version 4.3.2. The standardized mean difference (SMD) was used to assess the extent of the disease on the different parameters studied. Heterogeneity across individual studies was assessed using Higgins's inconsistency Q statistics and reported as I² and p-value. ROBINS-E was used to assess the risk of bias in the included studies.

Results: 303 studies were initially identified; after the elimination of duplicates and of works not meeting the objective of the study, 17 studies were finally included for meta-analyses. The standardized mean difference (SMD) using the common effect model is 0.79 [0.58, 1.00] for prothrombin time for 5 studies analyzed (p < 0.01), 0.26 [0.06, 0.46] for fibrinogen for 6 studies analyzed (p < 0.01), and 0.87 [0.62, 1.11] for D-dimer for 6 studies analyzed (p < 0.01); thus reflecting the strong influence of sickle cell disease on the production of Prothrombin, fibrinogen and D-dimer when compared to normal controls. For protein C, the SMD with the common effect model is -1.32 [-1.54, -1.09] for 5 studies analyzed (p < 0.01), and for protein S, it is -1.45 [-1.69, -1.22] for 5 studies analyzed (p < 0.01); thus reflecting a significant negative influence of sickle cell disease on protein C and protein S production when compared to normal controls. Finally, the SMD for antithrombin using the common effect model is 0.66 [0.35, 0.98] for 5 studies analyzed (p < 0.01), thus reflecting the strong influence of sickle cell disease on the production of antithrombin when compared to normal controls.

Conclusion: Analyses performed from these studies reported a large influence of sickle cell disease on the inflammatory, coagulation, fibrinolysis, and natural anticoagulant system when compared to normal controls, assessed by a SMD that ranged from moderate to large. These results provide more information on research related to coagulation abnormalities in sickle cell disease and will help impro

Background: Plasma coagulation factor XIII (OMIM#134570 (F13A1) and 134580(F13B), synthesized in haematopoietic cells (FXIII-A) and hepatocytes (FXIII-B); stabilizes and protects fibrin clots against fibrinolytic breakdown, ensuring haemostasis. Inherited FXIII deficiency is a rare inherited autosomal recessive bleeding disorder affecting 1-3 million people globally and demonstrating strong consanguinity contributing to high incidence of cases in Pakistan. Patients manifesting severe illness are homozygotes or compound heterozygotes.

Aims: This study aims to estimate phenotypic traits, genetic alterations, and carrier rates in families with known genetic abnormalities in individuals with Factor XIII deficiency.

Methods: This cross-sectional study was approved by Advanced Studies Research Board and Ethical Review Committee of LUMHS, Jamshoro and conducted in concordance with Declaration of Helsinki 2000 in collaboration at the Biochemistry Department of LUMHS and Haematology Department, Baqai medical university, Karachi. Written informed consent obtained from all participants included in the study. Pedigree was constructed. Direct DNA sequencing performed via big dye terminator by using selective exon as per previously identified mutations in the patients of their families. FXIII confirmed with clot solubility testing and Elisa performed for Assay antigen detection for FXIII. Pathogenicity scoring done by using different software.

Results: All the families had a history of consanguineous marriages and history of bleeding. From the six families, four families show same mutation in patient i.e. IVS11 (+ 1) G > A while two families showed c.2045G > A mutation in their homozygous patient.

Conclusion: The results of this study highlight how crucial it is to combine biochemical, clinical, and statistical approaches to increase the precision of diagnoses, improve patient treatment, and make genetic counselling easier for families who are at risk.