Association of FXI activity with thrombo-inflammation, extracellular matrix, lipid metabolism and apoptosis in venous thrombosis

Abstract

Animal experiments and early phase human trials suggest that inhibition of factor XIa (FXIa) safely prevents venous thromboembolism (VTE), and specific murine models of sepsis have shown potential efficacy in alleviating cytokine storm. These latter findings support the role of FXI beyond coagulation. Here, we combine targeted proteomics, machine learning and bioinformatics, to discover associations between FXI activity (FXI:C) and the plasma protein profile of patients with VTE. FXI:C was measured with a modified activated partial prothrombin time (APTT) clotting time assay. Proximity extension assay-based protein profiling was performed on plasma collected from subjects from the Genotyping and Molecular Phenotyping of Venous Thromboembolism (GMP-VTE) Project, collected during an acute VTE event (n = 549) and 12-months after (n = 187). Among 444 proteins investigated, N = 21 and N = 66 were associated with FXI:C during the acute VTE event and at 12 months follow-up, respectively. Seven proteins were identified as FXI:C-associated at both time points. These FXI-related proteins were enriched in immune pathways related to causes of thrombo-inflammation, extracellular matrix interaction, lipid metabolism, and apoptosis. The results of this study offer important new avenues for future research into the multiple properties of FXI, which are of high clinical interest given the current development of FXI inhibitors.

Sex‐specific aspects of venous thromboembolism: What is new and what is next?

“…Higher levels of leptin were associated with higher levels of fibrinogen and plasminogen activator inhibitor‐1 in persons with an unhealthy metabolic profile 70 . In a similar scope, the close relation between coagulation and inflammation was further evaluated by Pallares Robles et al, who showed an interesting interaction between FXI activity and thrombo‐inflammation and lipid metabolism 71 …”

Substrates, Cofactors, and Cellular Targets of Coagulation Factor XIa

“…107 This clinical observation is echoed by recent proteomics analyses of plasma from patients presenting with a venous thromboembolism (VTE). 108 These analyses show that more than 80 proteins were associated with FXI coagulation activity (FXI:C) both during the acute VTE event and in the 12 months following the event. The FXI-related proteins identified were involved in immune pathways, extracellular matrix interaction, lipid metabolism, and apoptosis.…”

Association between venous thromboembolism‐associated genetic variants, coagulation factor levels, and thrombin generation potential

“…Elevated total and LDL cholesterol levels were associated with increased FXI activity [38] whereas the use of lipid-lowering drugs resulted in decreased levels of FXI [39][40][41]. Proteomics analysis indicated associations between proteins involved in lipid metabolism and FXI activity in patients with VTE at 12 months follow-up [42]. Lowering FXI activity was associated with improved fibrin clot permeability, which indicated increased susceptibility to clot lysis in coronary artery disease [41].…”