TIX-5 Novel insights into the physiology of the FXa-mediated activation of FV with the aid of a tick protein

Within the coagulation system, coagulation factor V (FV) plays a central role with its procoagulant and anticoagulant functions. Our group showed recently that, while FV can become activated by thrombin, activation by factor Xa (FXa) plays a bigger role than originally thought. This was investigated with the aid of the tick salivary protein TIX-5, which functions as an anticoagulant by specifically inhibiting the FXa-mediated activation of FV. This thesis focuses on the development and characterization of a thrombin generation test in plasma that determines the contribution of the FV activation by FXa to thrombin generation using TIX-5. This to gain insight in the inter-individual differences of this pathway in healthy individuals and with the aim to determine whether FXa-mediated activation of FV is involved in patients that suffered from major bleeding or thrombotic events. We show the importance of the activation of FV activation by FXa in healthy person and in patients on anticoagulant treatment. Additionally, we found that the dependence on activation of FV by FXa is also increased during acute thrombosis. Since we discovered the importance of FXa-mediated FV activation for thrombin generation only a few years ago, we now show by employing TIX-5 sensitivity of thrombin generation that this pathway correlates with major cardiovascular complications.