Increased thromboxane biosynthesis during coronary thrombolysis. Evidence that platelet activation and thromboxane A2 modulate the response to tissue-type plasminogen activator in vivo.
Platelet activation is markedly increased during coronary thrombolysis and limits the response to thrombolytic therapy. A possible mediator of platelet activation in this setting is thromboxane (TX) A2, a potent platelet agonist formed in greatly increased amounts during coronary thrombolysis in man. To address this hypothesis, we examined the role of TXA2 in modulating the response to intravenous tissue-type plasminogen activator (t-PA) in a chronic canine model of coronary thrombosis. Reperfusion occurred in 60 +/- 5 minutes and was complicated by spontaneous reocclusion. The times to reperfusion and reocclusion were platelet-dependent. Consistent with a role for TXA2 in this process, TXA2 biosynthesis, determined a excretion of its enzymatic metabolite, 2,3-dinor-TXB2, was markedly increased during coronary thrombolysis. Furthermore, inhibition of TXA2 by aspirin, given alone or in combination with a TXA2/prostaglandin endoperoxide receptor antagonist, accelerated reperfusion and partly inhibited cyclic flow variations during reperfusion. The delay in reperfusion and reocclusion induced by TXA2 appeared to be mediated by platelet aggregation since the F(ab')2 fragment of 7E3, a monoclonal antibody to the platelet GPIIb/IIIa, also accelerated reperfusion and prevented reocclusion without altering TXA2 biosynthesis. These finding suggest that platelet aggregation limits the response to coronary thrombolysis and that platelet activation in this setting is partly TXA2-dependent.
Fitzgerald
D J
DJ
Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.
Wright
F
F
FitzGerald
G A
GA
D000792:Angiography; D000818:Animals; D000911:Antibodies, Monoclonal; D001777:Blood Coagulation; D001792:Blood Platelets / Q000502:physiology*; D003327:Coronary Disease / Q000188:drug therapy*; D003328:Coronary Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004285:Dogs; D011464:Epoprostenol / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D010974:Platelet Aggregation; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D013929:Thromboxane B2 / Q000096:biosynthesis* / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D007140:Immunoglobulin Fab Fragments; D013929:Thromboxane B2; D013928:Thromboxane A2; D011464:Epoprostenol; D010959:Tissue Plasminogen Activator