C4BPA, a new player in venous thromboembolism and complement system interactions – ComplementVTE

Venous thromboembolism (VTE), which encompasses deep venous thrombosis (DVT) and pulmonary embolism (PE), is the third leading cause of cardiovascular death after myocardial infarction and stroke. VTE is a frequent disease, 1 to 2 per 1000 per year, associated with long term complications affecting life expectancy and quality of life of patients. Major complications include recurrent VTE and conditions associated with incomplete thrombus resolution after DVT (post-thrombotic syndrome) or after PE (chronic thromboembolic disease and chronic thromboembolic pulmonary hypertension). The cellular and molecular mechanisms involved in VTE recurrence and/or long-term complications are still unknown. For this reason, all patients with unprovoked VTE are treated with anti-coagulants indefinitely to prevent the risk of VTE-associated sequelae. Although this strategy has proven efficacy as long as the treatment is maintained, it exposes these patients to higher risk of hemorrhage. To better identified patients at high risk of VTE recurrence and complications, we have developed the hypothesis that unprovoked VTE is likely due to unknown thrombophilia. We recently identified a new variant located in the exon6 of the complement inhibitor C4BPA. It has been long known that the complement system and the coagulation cascade are intimately intricate. However, how these systems interact in VTE is still unclear. Variants of C4BPA have been identified by our partner and confirmed in GWAS data from 18 studies to be associated with increased risk of VTE. Thus, we hypothesize that C4BPA may be involved in venous thromboembolism. We will use state-of-art models and techniques to uncover new targets or regulatory pathways involved in the early phase of VTE and correlated with the risk of long-term complications. This would help the field to identify reliable biomarkers to better stratify patients and adapt therapies according to their individual risk of presenting long-term sequelae.