Journal of Thrombosis and Haemostasis : JTH

In response to growing recognition that non-adherence prevents children, adolescents, and young adults from achieving the therapeutic benefits of anticoagulant medication, the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis convened a working party on medication adherence. The primary aim of this manuscript was to synthesize recommendations from the larger adherence science literature to provide guidance regarding the classification, collection, and interpretation of anticoagulation adherence data...

Bleeding is a well-recognized side effect of anticoagulant therapy, which is used to treat venous thromboembolism (VTE) in individuals of all ages, including those of female sex, who commonly experience VTE as a complication of hormonal therapies and/or pregnancy. Heavy menstrual bleeding (HMB) is also extremely common in reproductive aged individuals of female sex. Despite these overlapping situations, relatively little attention has been paid to the impact of anticoagulant-associated HMB on treatment strategies and the patient experience...

BACKGROUND: Thus far, all the clinical models developed to predict major bleeding in patients on extended anticoagulation therapy use the baseline predictors to stratify patients into different risk groups. Therefore, these models do not account for the clinical changes and events that occur after the baseline visit, which can modify risk of bleeding. However, it is difficult to develop predictive models from the routine follow-up clinical interviews which are irregular sequences of multivariate time series data...

This invited review follows the oral presentation "To Sequence or Not to Sequence, That Is Not the Question; But "When, Who, Which and What For?" Is " given during the State Of the Art session Translational Genomics in Thrombosis: From OMICs to Clinics" of the ISTH 2023 congress. Emphasizing the power of next-generation sequencing technologies and the diverse strategies associated with DNA variant analysis, this review highlights the unresolved questions and challenges in their implementation both for the clinical diagnosis of venous thromboembolism and in translational research...

BACKGROUND: Valoctocogene roxaparvovec transfers a human factor VIII (FVIII) coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection. OBJECTIVE: Present 3-year efficacy and safety in the multicenter, open-label, single-arm, phase 3 GENEr8-1 trial. METHODS: GENEr8-1 enrolled 134 adult males with severe hemophilia A who were receiving FVIII prophylaxis. Efficacy endpoints included annualized bleeding rate (ABR), annualized FVIII utilization (AFU), FVIII activity (chromogenic substrate assay; imputed as 1 IU/dL at baseline and 0 IU/dL after discontinuation), and the Haemophilia-Specific Quality of Life Questionnaire for Adults (Haemo-QOL-A)...

BACKGROUND: Carfilzomib (CFZ) is a second-generation proteasome inhibitor used to treat multiple myeloma. Potent inhibition of the proteasome results in chronic proteotoxic endoplasmic reticulum (ER) stress, leading to apoptosis. While CFZ has improved survival rates in multiple myeloma, it is associated with an increased risk of cardiovascular adverse effects. While this has been putatively linked to cardiotoxicity, CFZ could potentially also exhibit adverse effects on the endothelium...

BACKGROUND: Emicizumab has been approved for the prophylaxis of patients with hemophilia A with or without inhibitors. However, spontaneous and trauma-induced breakthrough bleeds have been reported in patients on emicizumab prophylaxis and no laboratory assay is validated to evaluate the hemostatic activity of emicizumab . OBJECTIVES: The thrombin generation assay (TGA) could be a surrogate marker of the hemostatic efficacy of emicizumab. The correlation between TGA and the methods used to measure emicizumab blood concentration was evaluated in this study...

BACKGROUND: Venous thromboembolism (VTE) is a major preventable cause of morbidity, disability, and mortality in subjects with cancer. A global appraisal of cancer-associated VTE education and awareness is not available. OBJECTIVES: To evaluate VTE-related education, awareness, and unmet needs from the perspective of people living with cancer using a quantitative and qualitative approach. PATIENTS/METHODS: This cross-sectional study used data from an online-based survey covering multidimensional domains of cancer-associated VTE...

BACKGROUND: The effect of the vitamin K antagonist (VKA) acenocoumarol on coagulation needs to be reversed when patients undergo an invasive procedure with considerable bleeding risk. A strategy to achieve this is administering oral vitamin K before a procedure while continuing acenocoumarol. OBJECTIVES: To assess the effect on periprocedural International Normalized Ratio (INR)-values and safety using oral vitamin K as anticoagulant reversal method. METHODS: In this prospective cohort study, consecutive patients using acenocoumarol undergoing elective procedures between 2019 and 2022 were included...

BACKGROUND: Chimeric antigen receptor T cell (CAR T-cell) therapy is increasingly utilized for treatment of hematologic malignancies. Hematologic toxicities including thrombosis and bleeding complications have been reported. Accurate estimates for thrombotic and bleeding outcomes are lacking. METHODS: We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to February 2022 for studies reporting thrombotic or bleeding outcomes in patients receiving CAR T-cell therapy...

BACKGROUND: Coagulopathy and associated bleeding and deep vein thrombosis (DVT) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated. OBJECTIVES: To evaluate the associations between biomarker levels and bleeding and DVT in acute leukemia patients. PATIENTS/METHOD: We examined plasma levels of activators, inhibitors and biomarkers of the coagulation and fibrinolytic pathways in patients ≥18 years with newly diagnosed acute leukemia compared to normal controls...

BACKGROUND: Endothelial colony forming cells (ECFCs) derived from patients can be used to investigate pathogenic mechanisms of vascular diseases like Von Willebrand Disease. Considerable phenotypic heterogeneity has been observed between ECFC clones derived from healthy donors. This heterogeneity needs to be well understood in order to use ECFCs as endothelial models for disease. Therefore, we aim to determine phenotypic and gene expression differences between control ECFCs. METHODS: A total of 34 ECFC clones derived from 16 healthy controls were analyzed...

BACKGROUND: Patients with cancer are at an increased risk of developing a hypercoagulative phenotype and venous thromboembolism. However, no clinical trial has yet confirmed that anticoagulant therapy improves cancer prognosis, and the mechanism underlying hypercoagulation in patients with bladder cancer is not well understood. OBJECTIVES: We hypothesized that the prognostic genes affect tumor progression via tumor-mediated coagulation. METHODS: We detected the most significant prognostic genes of bladder cancer with The Cancer Genome Atlas dataset, and validated them in two Gene Expression Omnibus and one ArrayExpress datasets...

BACKGROUND: Laboratory diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains challenging when ADAMTS13 activity ranges between 10-20%. To prevent misdiagnosis, open ADAMTS13 conformation gained clinical attention as a novel biomarker especially to diagnose acute iTTP in patient with diagnostic undecisive ADAMTS13 activity. Plasma ADAMTS13 conformation analysis corrects for ADAMTS13 antigen with both parameters being characterized in enzyme-linked immunosorbent assay (ELISA)-based reference assays requiring expert technicians...

BACKGROUND: Interventional therapies (ITs) are an emerging treatment modality for pulmonary embolism (PE); however, the degree of racial, sex-based, and sociodemographic disparities in access and timing is unknown. OBJECTIVES: To investigate barriers to access and timing of ITs for PE across the United States. METHODS: A retrospective cohort study utilizing the Nationwide Inpatient Sample from 2016-2020 included adult patients with PE. The use of ITs (mechanical thrombectomy and catheter-directed thrombolysis) was identified via International Classification of Diseases 10th revision codes...

BACKGROUND: Extensive evidence is available on hormonal contraceptive (HC) use and the risk of a first venous thromboembolism (VTE) event. Despite recommendations to discontinue combined hormonal contraceptive (CHC) use, some women continue or start after a first VTE. We aimed to evaluate the VTE recurrence risk of HC use in premenopausal women. METHODS: Premenopausal women with a first VTE, included in the MEGA study between 1999 and 2004, were followed for a recurrence until 2010...

BACKGROUND: Megakaryocytes (MKs) are polyploid cells responsible for producing ∼1011 platelets daily in humans. Unraveling the mechanisms regulating megakaryopoiesis holds the promise for the production of clinical-grade platelets from stem cells, overcoming significant current limitations in platelet transfusion medicine. Previous work identified that loss of the epigenetic regulator SETD2 was associated with an increased platelet count in mice. However, the role of SETD2 in megakaryopoiesis remains unknown...

PURPOSE: Cancer-associated venous thromboembolism (VTE) management guideline recommendations include continued therapeutic anticoagulation while active cancer persists. The Federal Drug Administration label for apixaban for secondary VTE prevention includes a dose reduction to 2.5 mg twice daily after 6 months of treatment. The study purpose was to determine whether this dose reduction is advisable for cancer-associated VTE. PATIENTS AND METHODS: A randomized, double-blind trial compared apixaban 2...

BACKGROUND: Mathematical models of coagulation have been developed to mirror thrombin generation in plasma, with the aim of investigating how variation in coagulation factor levels regulate haemostasis. However, current models vary in the reactions they capture, in reaction rates used, and their validation is restricted by a lack of large coherent datasets, resulting in questioning of their utility. OBJECTIVES AND METHODS: To address this debate, we systematically assessed current models against a large dataset, using plasma coagulation factor levels from 348 individuals with normal haemostasis as inputs, and compared model predictions with measured thrombin generation...

There have been substantial advances in vascular protein disulfide isomerases (PDIs) in platelet function and thrombosis in recent years. There are 4 known prothrombotic thiol isomerases; PDI, endoplasmic reticulum protein (ERp)57, ERp72, and ERp46, and 1 antithrombotic PDI; transmembrane protein 1. A sixth PDI, ERp5, may exhibit either prothrombotic or antithrombotic properties in platelets. Studies on ERp46 in platelet function and thrombosis provide insight into the mechanisms by which these enzymes function...