Journal of Thrombosis and Haemostasis最新文献

Background: Intravenous thrombolysis (IVT) using recombinant tissue plasminogen activator (r-tPA) prior to endovascular thrombectomy (EVT) failed to improve treatment effect in acute ischemic stroke (AIS) patients compared to EVT alone.

Objectives: We investigated whether primary and secondary hemostasis biomarkers are associated with the effect of IV thrombolytics on clinical and radiological outcomes after EVT.

Patients/methods: In MR CLEAN-NOIV study, AIS patients were randomized to receive IVT plus EVT or EVT alone. We measured hemostatic biomarkers before and 24h post-reperfusion, to determine changes in biomarkers and to determine the association of the biomarkers with short-time stroke severity (National Institutes of Health Stroke Scale (NIHSS) score), long-term functional outcome (modified Rankin scale (mRS) score), post-EVT extended thrombolysis in cerebral infarction (eTICI) score, and final infarct size.

Results: This substudy included 214 of the 539 AIS patients who underwent IVT+EVT (N=108/266) or EVT alone (N=106/273). In the EVT group, low soluble glycoprotein VI (sGPVI) and high factor (F)VIII levels before treatment were associated with severe NIHSS-score at 24h and poor mRS-score at 90-day post-treatment, respectively. Also in this group, sGPVI levels 24h after treatment were negatively associated with final infarct size. In the IVT+EVT group, high fibrinogen before treatment was associated with good eTICI-score and low ADAMTS13 activity 24h post-treatment was associated with unfavorable mRS-score at 90-day.

Conclusion: Our findings suggest that patients with high FVIII and fibrinogen and low sGPVI levels might be most suitable candidates for IVT+EVT, and that patients with low ADAMTS13 activity might be suitable for EVT alone.

Objective: Given recent concerns regarding the updated Beers Criteria, we sought to compare the effectiveness and safety of rivaroxaban with oral anticoagulants in older adults with nonvalvular atrial fibrillation (AF).

Methods: We used an administrative healthcare database and included AF patients ≥ 65 years who were new users of rivaroxaban or the comparators. We created three pairwise comparisons: rivaroxaban vs. warfarin; rivaroxaban vs. dabigatran; and rivaroxaban vs. apixaban. Study outcomes included stroke or systemic embolism (effectiveness), and gastrointestinal or intracranial bleeding (safety). In the propensity score matched sample, we used Cox proportional hazards regression to estimate hazard ratios [HRs] and 95% confidence intervals [CIs].

Results: In the matched cohorts, use of rivaroxaban (vs. warfarin) increased risk of bleeding (HR 1.13; CI 1.03 to 1.23) with no difference in ischemic stroke or systemic embolism (HR 0.90; CI 0.79 to 1.02); use of rivaroxaban (vs. dabigatran) increased risk of bleeding (HR 1.18; CI 1.03 to 1.35) with no difference in ischemic stroke and systemic embolism (HR 1.00; CI 0.83 to 1.22); and use of rivaroxaban (vs. apixaban) increased risk of stroke and systemic embolism (HR 1.23; CI 1.08 to 1.40) and bleeding (HR 1.60; CI 1.45 to 1.76).

Conclusion: In this comparative effectiveness and safety study of older patients with nonvalvular AF, use of rivaroxaban was associated with a significantly increased risk of ischemic stroke and systemic embolism compared with apixaban, and bleeding compared with warfarin, dabigatran, and apixaban. Our findings may inform anticoagulant selection in older adults with nonvalvular AF.

Background: Limited language proficiency is an established barrier to research participation among racialized populations. While prior studies have highlighted the underrepresentation of racialized populations in venous thromboembolism (VTE) research, the impact of limited language proficiency as a reason for nonconsent among eligible patients is unknown.

Objectives: To determine the impact of language barrier as the primary reason for VTE research non-participation.

Methods: We reviewed all prospective VTE studies conducted at a research-intensive academic thrombosis research program in Canada between 2014 and 2024. Studies with screening logs that systematically and consecutively captured eligibility assessment and reasons for nonconsent were included. Primary outcome was nonconsent of a screen-eligible patient due to limited language proficiency as the reported reason. We derived pooled estimates of nonconsent due to limited language proficiency as a proportion of consented participants and determined subgroup rates by phase of VTE management, associated medical conditions, and recruitment settings.

Results: Screening logs of 28 studies with 22 057 screening events, 8317 screen-eligible patients, and 3320 consented participants were included. For every 100 consented participants, 3.2 (95% CI, 2.0-5.3) screen-eligible individuals were unable to provide consent due to limited language proficiency. Rates of nonconsent were highest in studies involving cancer (5.6 per 100 participants; 95% CI, 2.9-10.4) and in studies recruiting patients from ambulatory settings outside of the thrombosis clinic (10.8 per 100 participants; 95% CI, 4.8-22.6).

Conclusion: Language proficiency is a key barrier to VTE research participation. Urgent implementation of targeted interventions aimed at mitigating linguistic barriers is essential to ensure equitable opportunities for VTE research participation for racialized patients disproportionately affected by language proficiency.

Splanchnic vein thrombosis (SpVT) is an uncommon site of venous thrombosis that is associated with complications including portal hypertension and hepatic dysfunction. The evaluation and management of this patient population has evolved in recent years, but there is limited data from clinical trials to guide management. Given the various acquired and biologic risk factors leading to the development of SpVT and the potential complications that can arise from it, input from a multidisciplinary team can be valuable in managing such patients, including thrombosis specialists or hematologists, gastroenterologists or hepatologists, interventional radiologists, and surgeons. In this manuscript, we present four cases that highlight important issues and considerations in the evaluation of SpVT including: initial diagnostic approach in a patient with a new diagnosis of SpVT, considerations for anticoagulant therapy, management of SpVT in patients with myeloproliferative neoplasms, and the role of interventional vascular procedures in the management of SpVT. By reviewing the current literature, we address clinically relevant questions that are posed to clinicians managing patients with SpVT; we also point out gaps in our current knowledge that merit future investigation.

Background: Phosphatidylserine (PS) is a procoagulant phospholipid enriched on surfaces of activated vascular cells including platelets, endothelium, monocytes, and microvesicles. As a molecular driver of thrombosis accessible to drug blockade, PS is an attractive pharmacologic target for modulating thrombogenesis, with potentially reduced bleeding risk compared to anticoagulant and antiplatelet therapies.

Objectives: Test antithrombotic capabilities of a liposomal formulation, Zn-dipicolylamine cyanine-3[22,22]/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (molar ratio, 3:97), designated as DPAL, which we previously described binds selectively to PS-enriched cell surfaces, compared with effects on bleeding, in mouse models.

Methods: PS-dependent DPAL binding to human and murine platelets was tested in vitro. Thrombosis and bleeding after DPAL intravenous administration were tested in C57Bl/6J mice following FeCl₃ carotid arterial injury and tail tip amputation, respectively. Incorporation in hemostatic clots was investigated in the cremaster muscle laser injury model. Toxicity was tested by direct exposure to human endothelial cell cultures.

Results: DPAL bound agonist-stimulated, PS-positive human and murine platelets, blocked by Annexin V or Ano6 deletion, which ablate PS exposure. DPAL prolonged prothrombin time, but did not prevent thrombin-induced fibrinogen receptor activation or aggregation, nor alter blood cell counts including platelets. Following arteriolar laser injury, DPAL bound wound surfaces and edges without destabilizing plugs. DPAL dose-dependently blocked FeCl₃-induced arterial thrombosis but did not substantially increase bleeding, or induce endothelial cell death.

Conclusion: DPAL reduces thrombogenesis with minimal effects on bleeding in mouse models via selective binding to PS. DPAL may support novel approaches to modulate pathogenic thrombin generation with improved safety profiles in multiple contexts.

Background: Although P5 (preventive, personalized, predictive, participatory, psychocognitive) medicine and patient focused healthcare are gaining ground in various healthcare areas, the diagnosis of antithrombin deficiency (ATD) is still based on crude diagnostic tests clustering patients into clinically heterogeneous subgroups whereby relevant thrombophilia phenotypes may go unnoticed. Clinical pathways and the majority of evidence are based on these tests, therefore generic treatment is still the norm.

Objectives: To unravel the heterogeneity of ATD, a mass spectrometry (LC-MRM-MS)-based test for antithrombin was developed allowing molecular characterization of the antithrombin proteoforms in patient plasma. This study provides the first insight into the tests' clinical performance.

Methods: Plasma from 91 unrelated ATD patients and 41 patients with a congenital disorder of glycosylation affecting antithrombin glycosylation were characterized functionally, genetically, and analyzed by LC-MRM-MS. An established data analysis strategy was applied for quantitation and molecular characterization of antithrombin proteoforms.

Results: The test recognized patients with a quantitative defect, discriminated between type I and type II ATD, and identified variant proteoforms. Overall, the diagnostic sensitivity for ATD was 100% for LC-MRM-MS compared to 81.1% by the functional test. Type II ATD, a subtype prone to misdiagnosis, revealed an even larger difference of 100% identification by LC-MRM-MS versus 56.8% by functional test.

Conclusions: The qualitative and quantitative MS-based AT-test can serve as a platform for investigating the molecular basis of the clinical heterogeneity of ATD. This Precision Diagnostics approach for ATD can lower diagnostic uncertainty and modernize the ATD diagnostic and clinical pathways.

Background: Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD.

Objectives: We hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime.

Methods: A cohort of stable CVD patients (N = 40) who participated in the COMPASS trial and were previously randomized to receive aspirin were prospectively recruited and assigned a revised regimen of open-label aspirin plus rivaroxaban. Blood samples were obtained at baseline (aspirin only) and 6-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis.

Results: The COMPASS regime fundamentally altered small (<200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up.

Conclusion: The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.

Background: Tumor thrombus can be associated with an increased risk of venous thromboembolism (VTE) and poor prognosis. The risks and benefits of anticoagulation remain unclear.

Objectives: To evaluate the role of anticoagulation and associated outcomes in patients with tumor thrombus.

Methods: We conducted a single-center retrospective cohort study in patients with tumor thrombus from 2019 to 2022. All patients were followed for 12 months from the diagnosis of tumor thrombus or until death if death occurred earlier. The primary outcome was the percentage of patients prescribed any dose of anticoagulation for tumor thrombus (or concurrent bland thrombus/VTE). The secondary outcomes included new thrombosis, major bleeding, clinically relevant nonmajor bleeding, and mortality. We calculated the 6- and 12-month cumulative incidence of outcomes with 95% CI and compared those given anticoagulation vs not, considering death as a competing risk.

Results: We included 211 patients, among whom 106 (50.2%; 95% CI, 47.9%-52.6%) were given anticoagulation for tumor thrombus or concurrent VTE (present in 21.8%). The most common type of cancer was hepatocellular carcinoma (28%). Splanchnic veins were the most commonly involved (49.3%). Anticoagulation was more likely used if tumor thrombus involved the inferior vena cava and/or the heart, with concurrent VTE, or if thrombosis service was consulted. The overall 12-month incidence of new VTE was 11.4% (95% CI, 7.3%-16.5%), that of major bleeding + clinically relevant nonmajor bleeding was 36.6% (95% CI, 29.6%-43.5%), and mortality of 52.5% (95% CI, 44.8%-59.6%), with no significant differences among groups given anticoagulation or not.

Conclusion: Patients with tumor thrombus carry high risks of VTE, bleeding, and mortality. The impact of anticoagulation remains unclear.

Background: Acquired hemophilia A (AHA) is a rare and severe bleeding disorder characterized by autoantibodies inhibiting coagulation factor VIII (FVIII). Current treatment of AHA involves bypassing agents, or FVIII replacement therapy, yet their efficacy is limited in cases of high inhibitor titers. Emicizumab, a humanized bispecific monoclonal antibody, has shown promising hemostatic effectiveness in congenital hemophilia A (HA) patients and AHA, but a minority of patients developed anti-drug antibodies (ADAs), compromising its efficacy.

Materials and methods: We present a comprehensive characterization of anti-emicizumab antibodies in a patient with AHA experiencing diminished emicizumab efficacy from week 10 of treatment. We developed a method for analysis of anti-emicizumab antibodies, distinguishing immunoglobulin subclasses and IgG subtype profiling. ADAs' neutralizing activity was evaluated using a modified clotting assay.

Results: The Luminex-based assay demonstrated the presence of anti-emicizumab antibodies, confirmed through competitive analysis. We detected anti-emicizumab IgG antibodies in the patient's plasma between week 16 and 29. IgG₁ and IgG₂ subclasses were identified. Longitudinal analysis showed IgG isotype antibodies against both emicizumab and FVIII. Anti-emicizumab antibodies exhibited non-inhibitory activity, confirmed by a modified Bethesda assay. Moreover, no accelerated clearance of emicizumab was observed in plasma samples from the patient.

Conclusions: This study presents the first documented case of anti-emicizumab antibodies in AHA. Our study provides insights into ADA development against emicizumab, emphasizing the need for monitoring tools. The developed method enables comprehensive evaluation of ADAs, aiding in personalized treatment strategies. These findings contribute to understanding emicizumab's immunogenicity profile in AHA, facilitating its optimized clinical use.