A perspective on the potential problems with aspirin as an antithrombotic agent: a comparison of studies in an animal model with clinical trials.
Aspirin is the most widely prescribed agent to reduce the platelet-mediated contributions to atherosclerosis, coronary thrombosis and restenosis after angioplasty. While aspirin treatment has led to significant reductions in morbidity and mortality in many clinical trials, there are several scenarios in which aspirin may fail to provide a full antithrombotic benefit. The cyclic flow model of experimental coronary thrombosis suggests that elevations of plasma catecholamines, high shear forces acting on the platelets in the stenosed lumen and the presence of multiple, input stimuli can activate platelets through different mechanisms that may lead to thrombosis despite aspirin therapy. Aspirin therapy is limited because it only blocks some of the input stimuli, leaving aspirin-independent pathways through which coronary thrombosis can be precipitated. These include thrombin and thrombogenic arterial wall substrates such as tissue factor. New agents that block the adenosine diphosphate (ADP) receptor, or regulate platelet free cytosolic calcium, such as direct nitric oxide donors, may be more potent overall than aspirin. Agents that block the platelet integrin GPIIb-IIIa receptor inhibit the binding of fibrinogen to platelets regardless of which input stimuli activate the platelet and, thus, as demonstrated in the cyclic flow model, would be much more potent than aspirin as an antithrombotic agent. The cyclic flow model has been useful in predicting which agents are likely to be of benefit in clinical trials.
Folts
J D
JD
Coronary Thrombosis Research Laboratory, University of Wisconsin Medical School, Madison 53792-3248, USA. JdF@medicine.wisc.edu
Schafer
A I
AI
Loscalzo
J
J
Willerson
J T
JT
Muller
J E
JE
D000818:Animals; D001241:Aspirin / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003327:Coronary Disease / Q000188:drug therapy*; D004195:Disease Models, Animal; D004285:Dogs; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D015539:Platelet Activation; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism