Journal of Thrombosis and Haemostasis最新文献

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 (liquid chromatography coupled to multiple-reaction-monitoring 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 with 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 vs 56.8% by functional test.

Conclusion: The qualitative and quantitative mass spectrometry-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 (F)VIII. 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 persons with congenital hemophilia A (HA) and AHA, but a minority of patients developed anti-drug antibodies (ADAs), compromising its efficacy.

Objectives: This study aims to characterize the development and impact of anti-emicizumab antibodies in a patient with acquired hemophilia A (AHA) who experienced reduced efficacy of emicizumab treatment.

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 (Ig) 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 noninhibitory activity, confirmed by a modified Bethesda assay. Moreover, no accelerated clearance of emicizumab was observed in plasma samples from the patient.

Conclusion: 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.

Pregnancy is a prothrombotic state due to an estrogen-driven shift in the coagulation system, increased venous stasis, and external restriction of blood flow caused by the gravid uterus. Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in pregnancy. Preventing, recognizing, and treating thrombosis in pregnancy, as well as the postpartum period, often challenges decision making in the clinical setting. In early pregnancy, guidance with respects to thrombophilia testing and anticoagulation in increasing the likelihood of live birth among patients with recurrent miscarriages is evolving. This review explores emerging data that support clinical decision making in thrombosis care in women with common thrombotic complications in pregnancy. The first case outlines VTE diagnosis in pregnancy, initial anticoagulation management, management around delivery and postpartum, and subsequent long-term anticoagulation treatment. The second case examines testing for inherited and acquired thrombophilia in the setting of recurrent miscarriage and the management of obstetric antiphospholipid syndrome. Lastly, the third case reviews VTE risk assessment and prevention in pregnancy and the postpartum period, as well as duration and dose of postpartum thromboprophylaxis. Review of these common clinical scenarios surrounding thrombotic complications in pregnancy demonstrates recent advances in high-quality data, current gaps in knowledge, and variation in expert opinion. Ultimately, multidisciplinary discussion and teamwork remain key to optimal, safe care. Clinicians must prioritize collaborative, high-quality trials and prospective clinical management studies to better understand and define best practice in this population.

Pulmonary embolism (PE) is a common cardiovascular disease diagnosis in emergency departments that can be associated with significant morbidity and mortality. One of the first steps after diagnosing PE is to risk stratify for adverse outcomes using risk scores such as PE Severity Index and European Society of Cardiology risk scheme. While intermediate- and high-risk PE patients should be admitted to the hospital, there is increasing evidence to support early discharge and home-based anticoagulation therapy for low-risk patients. The Hestia criteria encompass many of the clinicians' considerations for who may be suitable for early discharge, considering both medical and social factors. Additionally, professional guidelines have provided algorithms on determining which low-risk patients may be suitable. Despite this, low-risk acute PE patients are still often admitted for inpatient treatment. In this review, we present a case-based approach on how to risk stratify and evaluate patients who may be good candidates for early discharge and home therapy.

Blood flow is vital to life, yet disturbed flow has been linked to atherosclerosis, thrombosis, and endothelial dysfunction. The commonly used hemodynamic descriptor "disturbed flow" found in disease and medical devices is not clearly defined in many studies. However, the specific flow regime-laminar, transitional, or turbulent-can have very different effects on hemostasis, thrombosis, and vascular health. Therefore, it remains important to clinically identify turbulence in cardiovascular flow and to have available assays that can be used to study effects of turbulence. The objective of the current communication was to 1) provide clarity and guidance for how to clinically identify turbulence, 2) define standard measures of turbulence that can allow the recreation of flow conditions in a benchtop assay, and 3) review how cells and proteins in the blood can be impacted by turbulence based on current literature.