Molecular Determinants of Thrombosis Recurrence Risk Across Venous Thromboembolism Subtypes.

Venous thromboembolism (VTE) is a frequent (annual incidence of 1-2 per 1,000) and potentially life-threatening (case-fatality rate up to 10%) disease. VTE is associated with serious short-term and long-term complications, including a recurrence rate approaching 20% within five years. Anticoagulant therapy, the mainstay of VTE treatment, drastically reduces the risk of early VTE recurrence, but it exposes patients to a substantial risk of bleeding.

Multi-population GWAS for venous thromboembolism identifies novel loci followed by experimental validation in zebrafish.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality. Although many genetic risk factors have been identified, a substantial portion of the heritability remains unexplained. Here we employ genome wide association study (GWAS) VTE across 9 international cohorts of the Global Biobank Meta-analysis Initiative (GBMI) to address this question, along with in vivo functional validation.

Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of von Willebrand disease and bleeding.

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (≤ 50 IU/dL) in the general population is underexplored.

Objectives: To identify genetic variants influencing VWF:Ag levels ≤ 50 IU/dL.

A multiomics approach reveals novel regulators of plasma factor V levels, highlighting CLEC4M as a clearance receptor.

Coagulation factor V (FV) is a key protein in maintaining the hemostatic balance, with abnormal plasma levels associated with both thrombotic and hemorrhagic conditions. We propose a comprehensive bioinformatic analysis integrating large-scale proteogenomics and transcriptomic data from original and public data sets. We identify a biological fingerprint of 26 new proteins and loci involved in the regulation of plasma FV levels.

Genome-wide meta-analysis of heavy menstrual bleeding reveals 36 risk loci.

Heavy menstrual bleeding (HMB) is a widespread occurrence among women of reproductive age and inflicts a substantial impact on their well-being and on health care expenses. To better characterize the genetic architecture of HMB, we conducted a meta-analysis of the summary statistics of genome-wide association studies (GWAS) from 5 biobanks that included up to 84 633 HMB cases and 598 195 controls from several ancestries. Of the 21 signals significantly associated with HMB in a discovery GWAS meta-analysis that combined 4 biobanks, 20 had a concordant direction of effect in the remaining cohort, including 10 that were significantly replicated.

General Kernel Machine Methods for Multi-Omics Integration and Genome-Wide Association Testing With Related Individuals.

Integrating multi-omics data may help researchers understand the genetic underpinnings of complex traits and diseases. However, the best ways to integrate multi-omics data and use them to address pressing scientific questions remain a challenge. One important and topical problem is how to assess the aggregate effect of multiple genomic data types (e.

Genomic Landscape of Thrombosis Recurrence Risk Across Venous Thromboembolism Subtypes.

Venous thromboembolism (VT) is a frequent (annual incidence of 1 to 2 per 1,000) and potentially life-threatening (case-fatality rate up to 10%) disease. VT is associated with serious short-term and long-term complications including a recurrence rate of approximately 20% within five years. Anticoagulant therapy, the mainstay of VT treatment, drastically reduces the risk of early VT recurrence, but it exposes patients to a substantial risk of bleeding.

G protein-coupled receptor kinase 5 regulates thrombin signaling in platelets.

Background: Our prior genome-wide association study of thrombin-induced platelet aggregation identified a G protein-coupled receptor kinase 5 (GRK5) noncoding variant (rs10886430-G) that is strongly associated with increased platelet reactivity to thrombin. This variant predisposes to increased risk of stroke, pulmonary embolism, and venous thromboembolism.

Objectives: To determine role of platelet specific GRK5 in platelet responses to agonists and injury.

Cardiorespiratory Fitness Is Associated with Decreased Platelet Reactivity.

Purpose: Platelets are key mediators in cardiovascular disease (CVD). Low cardiorespiratory fitness (CRF) is a risk factor for CVD. The purpose of our study was to assess if CRF associates with platelet function.

Factors that modulate platelet reactivity as measured by 5 assay platforms in 3429 individuals.

Background: Assessment of platelet function is key in diagnosing bleeding disorders and evaluating antiplatelet drug efficacy. However, there is a prevailing "one-size-fits-all" approach in the interpretation of measures of platelet reactivity, with arbitrary cutoffs often derived from healthy volunteer responses.

Objectives: Our aim was to compare well-used platelet reactivity assays.

Genetic and nongenetic drivers of platelet reactivity in healthy Tanzanian individuals.

Background: Platelets play a key role in hemostasis, inflammation, and cardiovascular diseases. Platelet reactivity is highly variable between individuals. The drivers of this variability in populations from Sub-Saharan Africa remain largely unknown.

Alcohol intake including wine drinking is associated with decreased platelet reactivity in a large population sample.

Background: Alcohol consumption is linked to decreased platelet function. Whether this link is dependent on sex or type of beverage remains unclear.

Methods: Cross-sectional data were obtained from the Framingham Heart Study (N = 3427).

Sources of variability in the human platelet transcriptome.

Platelets are anucleated cells produced by megakaryocytes, from which they inherit all the components necessary to carry their functions. They circulate in blood vessels where they play essential roles in coagulation, wound repair or inflammation, and have been implicated in various pathological conditions such as thrombosis, viral infection or cancer progression. The importance of these cells has been established over a century ago, and effective anti-platelet medications with different mechanisms of action have since been developed.

Causal relationships between risk of venous thromboembolism and 18 cancers: a bidirectional Mendelian randomisation analysis.

Background: People with cancer experience high rates of venous thromboembolism (VTE). Additionally, risk of subsequent cancer is increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer.

Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism.

Venous thromboembolism (VTE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. Here we show, using proteomics profiling to screen plasma from patients with suspected acute VTE, and several case-control studies for VTE, how Complement Factor H Related 5 protein (CFHR5), a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker.

The association between platelet reactivity and lipoprotein levels in Framingham Heart Study participants.

Background: Hypertriglyceridemia is an independent risk factor for major adverse cardiovascular events, though the mechanisms linking triglycerides and platelet function with thrombosis, remain elusive. The aim of this study was to assess the association between platelet function and triglyceride levels.

Methods: We included participants from the Framingham Heart Study Third Generation cohort, OMNI, and New Offspring Spouse cohort who attended the third examination cycle (2016-2019).