Journal of Thrombosis and Haemostasis最新文献

Background: Hemophilic arthropathy (HA) is a joint disease characterized by local iron overload stemming from erythrocyte rupture and closely linked to synovial lesions. However, the precise molecular characteristics of clinical HA synovial samples remain to be defined.

Objectives: To gain insight into HA synovial tissue lesions, we utilized a metalloprotein strategy to compare the metal and protein spectra of HA with those of osteoarthritis and rheumatoid arthritis.

Methods: We collected synovial samples from patients with HA, osteoarthritis, and rheumatoid arthritis. Tissue metal and protein profiles were obtained by metallomics and proteomics, respectively. Finally, metalloproteomics strategies compared metal content, proteins, metalloproteins, and the life processes involved.

Results: Our metallomics analysis revealed an explicit increase in heavy metal content, particularly arsenic and mercury, in HA synovial samples. Through proteomics, we delineated specific metalloproteins and identified correlations between metals and pathways.

Conclusion: These findings yield valuable insights into the pathogenesis of HA and offer potential therapeutic targets for conditions characterized by iron overload.

Background: Reliable diagnostic coding schemas are essential for accurately assessing bleeding risks in patients on oral anticoagulants, particularly in observational studies.

Objectives: This study evaluated how different published diagnostic coding schemas impact the assessment of major bleeding risks associated with direct oral anticoagulants (DOACs) and warfarin.

Methods: This retrospective cohort study included patients with atrial fibrillation who initiated DOACs or warfarin between 2012 and 2019 using Taiwan's national claims database. Major bleeding events, including gastrointestinal bleeding, intracranial hemorrhage (ICH), and other major bleeding events, were identified using coding schemas from Cunningham et al., the Mini-Sentinel protocol, and Yao et al. Propensity score matching was performed to ensure covariate balance. Incidence rates and hazard ratios (HRs) were estimated to evaluate the bleeding risks.

Results: After matching, each cohort comprised 20 704 patients. The number of reported major bleeding events was influenced by the strictness of the coding schema, with Cunningham yielding the most events, followed by the Mini-Sentinel and Yao schemas. DOACs were associated with a consistently lower risk of composite major bleeding (HR range across different coding schemas, 0.73-0.76; all P < .05) and ICH (HR range, 0.43-0.63; all P < .05) but not gastrointestinal bleeding (HR range, 0.87-0.90; all P > .05), regardless of the coding schema applied. Restricting ICH definitions to primary diagnosis or spontaneous cases revealed a more pronounced reduction in ICH risk associated with DOACs.

Conclusion: While the choice of coding schemas has a negligible impact on overall bleeding risk comparisons between DOACs and warfarin, it significantly affects ICH risk assessment. This underscores the importance of careful coding schema selection in observational studies evaluating major bleeding risks.

Background: Although rare, vaccine-induced thrombotic thrombocytopenia (VITT) following adenoviral vector COVID-19 vaccination is a concerning and often severe adverse effect of vaccination. The generation of high anti-platelet factor 4 (PF4) antibody titers, promotes the formation of immune complexes capable of activating platelets and neutrophils through FcγRIIa.

Objective: Given that Platelet-leukocyte aggregate (PLA) formation and inflammasome activation are common features of thromboinflammatory diseases, we aimed to evaluate if these are also features of VITT.

Methods: Samples from a cohort of 57 postvaccination thrombosis patients and 28 age- and sex-matched unvaccinated individuals were used for ex-vivo investigation of PLA formation and inflammasome activation.

Results: Patients with clinical features of VITT presented elevated levels of activated caspase-1, IL-18 and IL-1β in the plasma. We also found that soluble factors in the plasma of VITT patients induce the formation of platelet-neutrophil aggregates but not platelet-monocyte or platelet-T-cell aggregates, which are associated with increased caspase-1 activation in neutrophils ex-vivo. Platelet-neutrophil aggregate formation was prevented through blockage of FcγRIIa with the neutralizing antibody IV.3, and through blockage of P-selectin or integrin αIIbβ3, also inhibiting caspase-1 activation. Additionally, MCC950, an NLRP3 inflammasome inhibitor, blocked caspase-1 activation.

Conclusions: Taken together, these data show that VITT plasma induces platelet-neutrophil aggregate formation in an FcγRIIa-dependent manner and that platelet-neutrophil interactions may contribute to thromboinflammation in VITT patients by supporting NLRP3 inflammasome activation. These data shed light on novel immunopathological events associated with inflammation and thrombosis in VITT patients.

Background: Growing evidence suggests that myocardial infarction (MI) may be a marker of cancer risk, but many aspects of this relation are poorly understood.

Objectives: To examine the short- and long-term risk of incident cancer in patients presenting with MI.

Methods: Using nationwide population-based Danish health registries, we identified all patients with a first-time diagnosis of MI (1995-2021) and followed them for up to 28 years for any subsequent diagnosis of cancer. We computed risks and standardized incidence ratios with 95% CIs as the observed number of cancers relative to the expected number based on national cancer incidence rates by sex, age, and calendar year.

Results: Among 185 065 patients diagnosed with MI, we observed 25 315 subsequent cancers. The risk of any cancer was 2.4% after 1 year of follow-up, increasing to 25.8% after 28 years, taking the competing risks of death into account. During the first year of follow-up, the standardized incidence ratio of any cancer was 1.67 (95% CI, 1.62-1.73). The standardized incidence ratio remained moderately elevated during 2 to 5 years (1.03; 95% CI, 1.01-1.05) and beyond 5 years (1.07; 95% CI, 1.05-1.09). The strongest associations were found for hematological as well as obesity- and smoking-related cancers during the first year of follow-up, whereas primarily, the risk of smoking-related cancers remained elevated throughout the entire follow-up period.

Conclusion: MI was associated with subsequent risk of cancer, driven by hematologic, obesity-, and smoking-related cancers in the short term and smoking-related cancers in the long term.

Background: Venous thromboembolism (VTE) is a frequent complication of childhood acute lymphoblastic leukemia (ALL).

Objectives: We aimed to identify molecular markers and signatures of leukemia microenvironment associated with VTE in childhood ALL, by dual-omics approach of gene expression (GEP) and DNA-methylation profiling.

Patients/methods: Eligible children were aged 1-21 years old with newly diagnosed ALL enrolled on the Dana Farber Cancer Institute 16-001 trial with available RNA sequencing data from bone marrow at diagnosis. Primary outcome was VTE requiring medical intervention, divided between early events (ET), within 6 weeks from ALL diagnosis, or late (LT) otherwise. We compared differential gene expression and DNA-methylation in children with and without VTE and in the subgroup of children with ETs. The DNA-methylation cis-regulation was explored by dual-omics integration. Functional gene set enrichment analyses were performed to assess dysregulated pathways associated with thrombosis. GEP-based signature for thrombosis-free interval was determined using Kaplan-Meier estimator and log-rank tests.

Results: We included 248 patients (median age: 7.5 years, 78% precursor B-cell ALL), of whom 56 (23%) developed VTE. Genes and metabolic pathways involved in coagulation, platelet activation and neutrophil extracellular trap formation (NETosis) were associated with ETs. Dual-omics analysis indicated that methylation reprogramming might be responsible for the over-expression of genes involved in NETosis and coagulation in patients with ETs. A prothrombotic gene signature, based on VWF, PF4 and CXCL8 expression, predicted thrombosis-free interval.

Conclusions: This suggests that gene markers and epigenetic regulation of the leukemic microenvironment are drivers of VTE, notably early events, in childhood ALL.

Arterial and venous thromboses are the leading causes of morbidity and mortality worldwide. Numerous antithrombotic agents are currently available with antiplatelet, thrombolytic/fibrinolytic, and anticoagulant activity. However, all the currently available antithrombotic agents carry a risk of bleeding that often prevents their use. This unfavorable risk-benefit profile is particularly challenging for patients with cancer-associated venous thromboembolism, patients with atrial fibrillation at a high risk of bleeding, and patients with end-stage renal disease. Patients with ischemic stroke and acute coronary syndromes have not yet found a favorable risk-benefit profile with anticoagulant therapy to help reduce the residual thromboembolic risk that remains after antiplatelet and lipid therapy. Two emerging classes of antithrombotic agents, factor (F)XI or activated factor Ⅺ (FⅪa) inhibitors and glycoprotein VI inhibitors, have shown promise in their ability to prevent pathologic thrombosis without increasing the risk of hemostatic-related bleeding in phase 2 studies. Among the FⅪ/FXIa inhibitors of coagulation, a parenterally administered monoclonal antibody (abelacimab) and 2 orally administered small molecule inhibitors (asundexian, milvexian) are collectively being studied in patients with atrial fibrillation, cancer-associated venous thromboembolism, acute coronary syndrome, and ischemic stroke. One parenterally administered glycoprotein VI antiplatelet agent (glenzocimab) is currently being studied in patients with ischemic stroke. If shown to be efficacious and safe in ongoing phase 3 studies, both classes of emerging antithrombotic agents have the potential to greatly improve outcomes for patients with challenging thrombotic conditions.

Bleeding is a leading cause of trauma deaths and surgical complications. Excessive bleeding has traditionally been treated with the transfusion of donated blood. However, the complicated logistics of sourcing and storing donated blood increases the cost and reduces the accessibility of treatment, particularly as rates of blood donation decline. Advances in biomaterials for targeted drug delivery have presented the opportunity for alternative synthetic injectable hemostats. Among these leading technologies are lipid and polymeric particles and polymer platforms that bind to ligands present at wound sites and amplify hemostatic pathways. As leading hemostatic biomaterials advance toward clinical application, we review current preclinical research models and findings as well as future research directions for next-generation biomaterial injectable hemostatic technologies.

The history of hemophilia is well-documented, yet reports focus heavily on the male-perspective and severe forms of the disease. Although hemophilia was initially believed to only affect men with women seen as silent carriers, it is now universally acknowledged that women and girls can also be affected. In this narrative review, we track the progression of beliefs about women and hemophilia as documented in the literature from pre-1800's to the present time. We present a timeline of evolving beliefs and testing practices and identify nine distinct time periods when key shifts occurred related to various scientific discoveries. Our review highlights how women affected by hemophilia experienced complete dismissal of their health issues despite evidence of bleeding symptoms as early as the 1900's. We identify 1990 as a major timepoint for shifting beliefs when large scale acknowledgement that hemophilia also affects women is documented and systematic testing for bleeding risk is first suggested. Women evolve from being seen as unaffected genetic transmitters only to being recognized as a population affected by hemophilia in unique ways requiring timely testing and effective treatment. Yet despite documented progress, recent publications document many persistent issues such as delayed diagnosis, untreated symptoms, and barriers to care. Ongoing research and advocacy efforts are required to improve knowledge translation until real-world outcomes are seen in screening, diagnosis, treatment and prevention of bleeding.

Background: Although routine monitoring is not needed for direct oral anticoagulants (DOACs), knowing if a clinically relevant DOAC level is present can be critical, especially in cases of severe bleeding or urgent surgery. Rapid assays to exclude these levels are necessary but not widely available.

Objectives: To determine the test performance of MRX PT DOAC for excluding clinically relevant DOAC drug levels.

Methods: The MRX PT DOAC (Nordic Biomarker, Umeå, Sweden) assay measures the functional effect of DOACs using the clot-time ratio, a ratio between DOAC-sensitive prothrombin time (PT) and DOAC-insensitive PT. We conducted a multicenter retrospective study of 152 samples from 151 patients with known DOAC levels to assess whether the MRX PT DOAC assay could exclude clinically relevant drug levels >50 ng/mL and whether test performance differed across coagulation analyzers. To assess generalizability, the assay was run on 4 coagulation analyzers: Werfen ACLTOP 750, Diagnostica Stago STACompact MAX, Sysmex CS2500, and Sysmex CN-6000.

Results: The MRX PT DOAC assay had a sensitivity of 100% with a CI of 70% to 100% and negative predictive value (NPV) of 100% (CI: 57%-100%) for edoxaban drug levels >50 ng/mL. For rivaroxaban, sensitivity was 100% (CI: 61%-100%) and NPV was 100% (CI: 5%-100%). For apixaban, sensitivity ranged from 59% to 83% (CI: 41%-93%) and NPV ranged from 0% to 50% (CI: 0%-69%). The specificity of the assay ranged from 61% to 86% (CI: 36%-97%) for apixaban, 36% to 50% (CI: 2%-97%) for edoxaban, and 75% to 100% (CI: 5%-100%) for rivaroxaban.

Conclusion: The MRX PT DOAC assay reliably excludes clinically relevant levels of edoxaban and rivaroxaban, but not apixaban, across multiple analyzers.