Detección de nuevas mutaciones en componentes de la vía de la proteina C asociadas con un mayor riesgo trombótico.

The protein C anticoagulant pathway plays a crucial role in the control of thrombus formation. Protein C circulates in plasma as an inactive zymogen that is converted to the active enzyme, activated protein C (APC) on the surface of endothelial cells by the thrombin-thrombomodulin complex. Another receptor, the endothelial protein C receptor (EPCR) binds protein C on the endothelial cell surface and further enhances the rate of protein C activation. APC is then released from the complex, binds protein S and inhibits thrombin formation by inactivating coagulation factors Va and VIIIa. The protein C pathway also plays a significant role in inflammatory processes, and displays anti-apoptotic and neuroprotective activities. Therefore, alterations in the expression or in the assembly of these four proteins could lead to a reduction in APC levels and to an increase in the thrombotic risk. We have developed a sensitive, rapid and reproducible assay for the determination of circulating APC levels. Using this assay, we have observed that reduced APC levels constitute an independent prevalent risk for venous thrombosis, which seems to be hereditary. We have identified several mutations in the proteins that form the protein C activation complex. The C1418T (Ala455Val) polymorphism in the thrombomodulin gene is associated with increased APC levels and decreased risk of venous thromboembolism. The A4600G (Ser219Gly) polymorphism in the EPCR gene determines the levels of soluble EPCR. And the G4678C polymorphism located in the 3´ untranslated region of EPCR is associated with increased levels of circulating APC and decreased risk of venous thrombosis, as we also observed in carriers of the factor V Leiden mutation, the most common genetic risk factor for familial venous thrombosis.