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14 Lipoproteins and the haemostatic system in atherothrombotic disorders

1994; Elsevier BV; Volume: 7; Issue: 3 Linguagem: Inglês

10.1016/s0950-3536(05)80105-2

1879-2804

George J. Miller,

Lipoproteins and Cardiovascular Health

The early belief that the haemostatic system has no active role in the formation of the atheromatous plaque is no longer tenable. Rather, the association between hypercholesterolaemia and atherosclerosis appears to arise in part because of various effects of high concentrations of LDL and VLDL particles on the cellular and humoral components of the system, thereby promoting plaque growth and thrombosis. These may be summarized as follows:o1.High concentrations of native LDL have been reported to promote the adhesion of monocytes to the endothelial cell, suggesting that the latter undergoes a form of activation upon such exposure. Oxidized LDL is more potent in this respect, and persistent exposure of endothelium to such particles can eventually lead to cell injury.2.Activated endothelial cells acquire characteristics on their luminal surface conducive to thrombin generation and fibrin production. Thrombin has several actions on the endothelial cell, monocyte, smooth muscle cell and platelet which in the presence of hypercholesterolaemia will promote the formation of atheroma.3.Oxidatively modified LDL can activate circulating monocytes, when they also acquire procoagulant properties which favour thrombin production.4.Platelets show an increased tendency to aggregate when exposed to hypercholesterolaemic plasma. This effect may arise in part because the platelet of the hypercholesterolaemic patient expresses an increased number of fibrinogen binding sites on its surface following activation by agonists such as ADP. These hyperaggregable platelets adhere to activated endothelial cells which express von Willebrand factor on their surface, and to subendothelial proteins exposed in the gaps that open between injured endothelial cells. Platelets exposed to raised LDL levels also show a reduced sensitivity to prostacyclin, an antiaggregatory agent. Oxidatively modified LDL has been reported to stimulate aggregation of platelets in the absence of other agonists such as ADP or thrombin (spontaneous aggregation).5.Platelet aggregation and fibrin deposition at sites of endothelial injury will create microthrombi which become incorporated into the lesion by organization, thereby increasing the fibrous and cellular content of the atheromatous plaque.6.Lipolysis of triglyceride-rich lipoproteins at the endothelial cell surface leads to transient activation of the coagulation mechanism with activation of factor VII. Activated factor VII is a potent procoagulant when it forms a complex with tissue factor in the atheromatous lesion. Persistent hypertriglyceridaemia is accompanied by raised concentrations of factor X, factor IX, factor VII and prothrombin.7.Hypertriglyceridaemia is associated with an increased plasma concentration of PAI-1 and a reduction in plasma fibrinolytic activity.8.Upon rupture of an unstable atheromatous plaque, the thrombotic response will be dependent upon the status of the coagulant pathway at that moment. This response may be intensified at times when increased circulating concentrations of activated factor VII have been generated by a hypertriglyceridaemic state.9.Lipoprotein (a) acts on the fibrinolytic system in several ways which combine to inhibit plasminogen binding and activation, thereby impairing fibrinolytic activity and the dissolution of thrombi. High concentrations of native LDL have been reported to promote the adhesion of monocytes to the endothelial cell, suggesting that the latter undergoes a form of activation upon such exposure. Oxidized LDL is more potent in this respect, and persistent exposure of endothelium to such particles can eventually lead to cell injury. Activated endothelial cells acquire characteristics on their luminal surface conducive to thrombin generation and fibrin production. Thrombin has several actions on the endothelial cell, monocyte, smooth muscle cell and platelet which in the presence of hypercholesterolaemia will promote the formation of atheroma. Oxidatively modified LDL can activate circulating monocytes, when they also acquire procoagulant properties which favour thrombin production. Platelets show an increased tendency to aggregate when exposed to hypercholesterolaemic plasma. This effect may arise in part because the platelet of the hypercholesterolaemic patient expresses an increased number of fibrinogen binding sites on its surface following activation by agonists such as ADP. These hyperaggregable platelets adhere to activated endothelial cells which express von Willebrand factor on their surface, and to subendothelial proteins exposed in the gaps that open between injured endothelial cells. Platelets exposed to raised LDL levels also show a reduced sensitivity to prostacyclin, an antiaggregatory agent. Oxidatively modified LDL has been reported to stimulate aggregation of platelets in the absence of other agonists such as ADP or thrombin (spontaneous aggregation). Platelet aggregation and fibrin deposition at sites of endothelial injury will create microthrombi which become incorporated into the lesion by organization, thereby increasing the fibrous and cellular content of the atheromatous plaque. Lipolysis of triglyceride-rich lipoproteins at the endothelial cell surface leads to transient activation of the coagulation mechanism with activation of factor VII. Activated factor VII is a potent procoagulant when it forms a complex with tissue factor in the atheromatous lesion. Persistent hypertriglyceridaemia is accompanied by raised concentrations of factor X, factor IX, factor VII and prothrombin. Hypertriglyceridaemia is associated with an increased plasma concentration of PAI-1 and a reduction in plasma fibrinolytic activity. Upon rupture of an unstable atheromatous plaque, the thrombotic response will be dependent upon the status of the coagulant pathway at that moment. This response may be intensified at times when increased circulating concentrations of activated factor VII have been generated by a hypertriglyceridaemic state. Lipoprotein (a) acts on the fibrinolytic system in several ways which combine to inhibit plasminogen binding and activation, thereby impairing fibrinolytic activity and the dissolution of thrombi. The effects of LDL and triglyceride-rich lipoproteins on the endothelial cell, monocyte, platelet, coagulation pathway and fibrinolytic mechanism appear to be largely reversible, and may help to explain the improvement in the atherothrombotic state that follows correction of hyperlipidaemia.