Studies of patients after acute myocardial infarction have proved valuable in understanding the response to myocardial injury. However, such studies have not been able to provide information on thrombogenesis, since thrombus formation clearly antecedes the time of study. Evidence of procoagulant activity after myocardial infarction has occurred is unreliable as a reflection of the predisposing state since cause and effect cannot be clearly distinguished. Models have been developed, such as exercise or pacing induced angina, and while these have given insight into cardiac response to hypoxia and ischemia they have not proved useful for studies of thrombogenesis. We hypothesize that balance of thrombin and plasmin action is the major final determinant of thrombosis. Excess thrombin action produces thrombosis, excess plasmin action prevents thrombosis. Between the two extremes transient thrombi may develop and subsequently lyse, giving the syndromes of unstable angina and spontaneous ischemia. The studies we propose are aimed at obtaining data on the events preceding actual thrombosis, and their design is based on our experience of making studies in this area. We propose to make detailed serial studies of patients with unstable angina and with spontaneous ischemia. By the simultaneous Holter recording of the ECG we will relate the onset of ischemia to the plasma levels of fibrinopeptides and platelet proteins, as markers of coagulation, fibroinolysis and platelet activation. A similar approach will be taken in studies of patients post thrombolysis. This group has a high incidence of reocclusion, often with infarction, shortly after successful coronary thrombolysis. We will also study patients undergoing thrombolytic therapy to determine the origin of the thrombin activity which we have previously found. Coagulation and platelet activation in patients undergoing coronary angioplasty will be studied as a model of the plaque rupture associated with acute myocardial infarction. New assays will be developed for the activation peptides of factors IX and X, and for prothrombin fragment F1+2. These will be used to probe earlier events in the coagulation cascade. A highly sensitive and specific stable-isotope dilution assay will be developed for 11-dehydro thromboxane B2. This will allow the accurate and precise determination thromboxane A2 production, which will not be affected by ex vivo platelet activation.
NIH ExPorter
NIH ExPorter