Thrombosis: A common arrival point of different pathways

Abstract

The cause and cure of thrombosis remain unknown. The majority of arterial thrombotic events occur in patients without obvious risk factors. The sensitivity and specificity of the known risk factors is poor, although several investigators have devised risk calculators in which the cumulative effect of risk factors is summated. Arterial thrombi usually occur in arteries previously affected by atherosclerosis. As staled by Virchow ( 1856) important determinants of thrombosis are the nature of the vessel, the type of flow within it, and the nature of the plasma components. The importance of rupture of the atherosclerotic plaque, causing haemorrhage within the plaque and thrombus formation on it has been emphasised. For instance, there is angioscopic evidence that myocardial infarction is caused by complete occlusive thrombus, whereas unstable angina is secondary to non-occlusive thrombus. The localisation of thrombosis is determined by the anatomical shape of the vessels, being greatest at areas of blood flow disturbance at curves or collaterals in the vessel. Partial thrombotic occlusion leads to further blood flow disturbance, precipitating thrombosis. The clinical importance of the platelet in thrombus formation has come, paradoxically, from the undoubted beneficial effect of aspirin in thrombosis which lowers clinical arterial events by about 20%. Although there is a wealth of biochemical evidence suggesting that platelets may become activated in patients with arterial disease, tests of platelet function to identify individuals al risk of thrombosis have been disappointing. At present they lack the sensitivity and specificity lo provide useful clinical information lo predict the course of arterial disease in a single individual. The plasma components contributing to thrombosis consist of the coagulation and fibrinolytic proteins. Coagulation occurs in a series of complex steps leading to the formation of thrombin, which both clots fibrin and stimulates platelet aggregation. The intrinsic coagulation pathway is triggered by factor XII, whereas the extrinsic pathway is initiated by tissue factor from damaged endolhelial cells or tissues. Finally, the fibrinolytic enzyme is responsible for removal of fibrin in the thrombus. The two main plasminogen activators are tissue type plasminogen activator ((PA) which is derived from intact endolhelium and urokinase type activator (uPA) which is excreted in urine and secreted by kidney and other cells. Their action is promoted by the presence of fibrin and inhibited by plasminogen activators (PAI). The present concept that thrombosis can be promoted by reduction of plasminogen activator activity and increased PAI activity needs further support from clinical studies. In summary, abnormalities in all four major pathways to thrombosis, the vessel wall, the platelets, coagulation and fibrinolysis may all contribute to thrombus formation.