Understanding hypercoagulability: determinants and impact on cardiometabolic disease

Doctoral Thesis

This thesis aims to elucidate the mechanisms underlying hypercoagulability and its role in cardiometabolic diseases. Part I investigates the genetic architecture of coagulation factor levels (FVIII, FIX, FXI, fibrinogen), thrombin generation potential, and venous thromboembolism (VTE). Using large-scale genetic analyses, it demonstrates that several VTE-associated variants affect coagulation parameters, offering mechanistic insights into VTE susceptibility. Novel genome-wide associations for FIX activity and thrombin generation potential were identified, revealing links between coagulation, metabolic traits (lipids, glucose, liver enzymes), and cardiometabolic outcomes. Mendelian randomization analyses further suggested potential causal relationships between these traits and cardiometabolic disease.
Part II explores the interplay between microvascular health, high-density lipoprotein (HDL) particle characteristics, coagulation, and type 2 diabetes risk. Endothelial glycocalyx...Show moreThis thesis aims to elucidate the mechanisms underlying hypercoagulability and its role in cardiometabolic diseases. Part I investigates the genetic architecture of coagulation factor levels (FVIII, FIX, FXI, fibrinogen), thrombin generation potential, and venous thromboembolism (VTE). Using large-scale genetic analyses, it demonstrates that several VTE-associated variants affect coagulation parameters, offering mechanistic insights into VTE susceptibility. Novel genome-wide associations for FIX activity and thrombin generation potential were identified, revealing links between coagulation, metabolic traits (lipids, glucose, liver enzymes), and cardiometabolic outcomes. Mendelian randomization analyses further suggested potential causal relationships between these traits and cardiometabolic disease.
Part II explores the interplay between microvascular health, high-density lipoprotein (HDL) particle characteristics, coagulation, and type 2 diabetes risk. Endothelial glycocalyx degradation, reflected by a larger perfused boundary region, was associated with higher coagulation factor levels, particularly in women. HDL particle composition showed size-dependent effects on coagulation factor levels: larger HDL particles were inversely associated with procoagulant activity, while smaller ones were positively associated. Finally, elevated FIX activity and thrombin generation potential were associated with higher type 2 diabetes incidence. Together, these findings deepen understanding of genetic and physiological pathways linking hypercoagulability with cardiometabolic diseases.
Show less

Coagulation factors

Thrombin generation potential

Venous thromboembolism

Genetic architecture

Mendelian randomization

Endothelial glycocalyx

High-density lipoprotein particles

Microvascular function

Type 2 diabetes

Cardiometabolic disease