The role of the fibrinolytic system in arterial and venous thrombosis

Abstract

In this thesis, we investigated the role of the fibrinolytic system in arterial and venous thrombosis. The fibrinolytic system is responsible for the dissolution of a blood clot and involves multiple proteins for activation and regulation. The primary activators of fibrinolysis are plasminogen and tissue type plasminogen activator. The primary inhibitors are plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), and alpha2-antiplasmin. Besides their function in clot dissolution, these proteins have functions in other processes, for example inflammation and insulin resistance. We measured levels of these five fibrinolytic factors in two case-control studies [Study of Myocardial Infarctions LEiden (SMILE) and Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis study] to investigate their association with myocardial infarction and venous thrombosis. We also measured fibrinolytic potential in plasma with an overall assay, measuring the time necessary to dissolve a blood clot, i.e. clot lysis time (CLT). We hypothesized that increased CLT, increased levels of inhibitors, and decreased levels of activators of fibrinolysis were associated with increased risk of myocardial infarction and venous thrombosis and that CLT in the general population was determined by the combination of plasma levels of the different fibrinolytic factors. Prolonged CLT increased the risk of a first myocardial infarction, but only in men below 50 years of age, and of a first venous thrombosis. Not all fibrinolytic factors were associated with thrombosis-risk. Elevated TAFI levels were associated with a decreased and elevated alpha2-antiplasmin levels with an increased risk of myocardial infarction. Elevated PAI-1 and TAFI levels were associated with an increased risk of venous thrombosis. PAI-1 levels were the main determinants of CLT. Plasminogen, alpha2-antiplasmin, TAFI and prothrombin levels were also associated with CLT. Our results clearly indicate a difference between the role of the fibrinolytic system in myocardial infarction and its role in venous thrombosis and emphasize the difference in etiology of the diseases. An explanation for the difference in results between venous and arterial thrombosis may be that the primary function of the fibrinolytic proteins in venous thrombosis is fibrin clot dissolution, while in arterial thrombosis other roles of fibrinolytic proteins, such as in inflammation, plaque stabilization, and insulin resistance appear more important. We also studied CLT and TAFI in relation to a recurrent venous thrombotic event. CLT and TAFI levels did not constitute risk factors for recurrent venous thrombosis. Last, we showed increased CLT to be a risk factor for a first venous thrombosis in a large kindred exhibiting type I protein C deficiency and identified regions on chromosome 11 and 13 that may point to genetic variation influencing CLT. In conclusion, prolonged CLT, as measured with an overall plasma based assay, is associated with an increased risk of myocardial infarction and first venous thrombosis. The role of the individual fibrinolytic proteins in arterial and venous thrombosis is, however, less clear possibly in part due to pleiotropic effects of these factors. Nevertheless, we have provided evidence for a role of TAFI and PAI-1 in venous thrombosis, and for TAFI and alpha2-antiplasmin in arterial disease