Thrombus formation on ruptured atherosclerotic plaques and rethrombosis on evolving thrombi.
Angiography in patients with unstable angina or myocardial infarction with subtotal coronary occlusion often reveals eccentric stenoses with irregular borders, suggesting ruptured atherosclerotic plaques and thrombosis, as documented by angioscopy and at autopsy. We have simulated and studied these processes in an ex vivo perfusion chamber and in an in vivo swine model. Our results suggest that specific local factors at the time of plaque disruption influence the degree of thrombogenicity, the stability of the growing thrombus, and, therefore, possibly also the various clinical syndromes. These factors can be divided into two groups: local vessel wall-related factors and systemic factors with local action at the area of risk. These factors include the following. 1) Exposed substrate-related effects: Plaque rupture produces a rough surface and stimulates the development of occlusive thrombus in proportion to the degree of damage. 2) Fluid dynamics-related factors: The more severe the stenotic lesion after plaque rupture, the higher the local shear rate, resulting in enhanced platelet deposition and thrombus formation. 3) Vasoconstrictive effects: Vasospasm is an important contributor to the pathogenesis of ischemic heart disease. 4) Systemic factors: There is clinical and experimental evidence to suggest that various systemic factors at the time of plaque rupture may enhance thrombogenicity (i.e., levels of epinephrine, levels of serum cholesterol, impaired fibrinolysis). We have investigated the role of residual thrombus on the process of rethrombosis and found that a residual thrombus is a very thrombogenic surface that may significantly contribute to reocclusion even in heparinized blood. Using recombinant hirudin as a pharmacological tool in our flow studies, we observed that rethrombosis is partially caused by thrombin bound to fibrin in the original thrombus, because the effect is abolished by the specific thrombin inhibitor.
Badimon
L
L
Cardiovascular Biology Research, Massachusetts General Hospital, Harvard Medical School, Boston 02114.
Chesebro
J H
JH
Badimon
J J
JJ
D000789:Angina, Unstable / Q000503:physiopathology; D001792:Blood Platelets / Q000473:pathology*; D003324:Coronary Artery Disease / Q000503:physiopathology*; D003328:Coronary Thrombosis / Q000503:physiopathology*; D005340:Fibrinogen / Q000502:physiology; D006801:Humans; D009203:Myocardial Infarction / Q000503:physiopathology; D009569:Nitric Oxide / Q000494:pharmacology; D010477:Perfusion / Q000295:instrumentation; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D012422:Rupture, Spontaneous; D013314:Stress, Mechanical; D014661:Vasoconstriction; D014841:von Willebrand Factor / Q000502:physiology
D010980:Platelet Membrane Glycoproteins; D014841:von Willebrand Factor; D009569:Nitric Oxide; D005340:Fibrinogen