Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction

Abstract

Coagulation asnalysis was performed on blood samples from 386 patients with acute myocardial infarction drawn before, during, and after a continuous intravenous infusion of 150 mg recombinant tissue-type plasminogen activator (rt-PA) (Activase®). Plasma rt-PA rose to peak levels of 2.1 ± 3.1 μg/ml (mean ± SD). Fibrinogen levels measured by coagulation rate and by sulfite precipitation decreased from baseline levels of 3.0 ± 0.9 and 3.2 ± 1.0 g/l, respectively, to nadir levels of 1,4 ± 0.75 and 1.8 ± 0.92 g/l, respectively, and were associated with peak levels in serum of fibrinogen-degradation products (FDP) of 230 ± 470 μg/ml. Forty percent of patients exprienced a nadir functional-fibrinogen level of less than 1.0 g/l, whereas 20% fell below 0.5 g/l. Nadir fibrinogen levels did not correlate with patency of the infarct-related coronary artery at 90 minutes or with risk of coronary vessel reocclusion within 7-10 days. However, the risk of coronary artery reocclusion was inversely related to the baseline functional fibrinogen level (p = 0.0008), with the magnitude of its drop to nadir level (p = 0.0003) as well as to peak levels of FDP (p = 0.038). Quantitative blood loss correlated with all markers for systemic fibrinogenolysis including nadir fibrinogen level (r = -0.20, p = 0.0011), percent decrease of fibrinogen (r = 0.22, p = 0.001), and peak FDP levels (r = 0.14, p = 0.020). Both patients who experienced intracranial hemorrhage presented with high baseline fibrinogen levels and experienced extensive degradation of coagulable fibrinogen. Overall, patients at greatest risk of systemic fibrinogenolysis tended to be relatively older women with lower body weight. Peak plasma levels of t-PA antigen were weakly correlated with nadir-fibrinogen levels (r = 0.11, p = 0.041) and peak FDP levels (r = 0.12, p = 0.020), and also tended to be higher in older women of lowere body weight. Plasma levels of t-PA antigen were higher in nonoperated patients experiencing 'major' bleeding (3.4 versus 2.2 μg/ml, p = 0.002). These results indicate that changes in coagulation parameters are highly variable in the setting of thrombolytic treatment with t-PA of acute myocardial infarction, precluding their use for predictive monitoring of therapy in individual patients. Nonetheless, the overall pattern of pharmacodynamic behavior or rt-PA within a given population and its correlation with selected major clinical outcomes, particularly with risk of reocclusion and bleeding, will be most useful for the design of alternative administration schemes.