Monitoring of fibrin generation during thrombolytic therapy of acute myocardial infarction with recombinant tissue-type plasminogen activator.

Abstract

Fibrinopeptide A (FPA) is a very sensitive marker of fibrin generation in vivo. Because an imbalance between thrombogenic and thrombolytic forces may be responsible for the failure to recanalize and for reocclusion of coronary arteries, such a marker could be of eminent value during thrombolytic treatment of acute myocardial infarction. Thirty-four consecutive patients with acute myocardial infarction (peak creatine kinase level, 1,869±+1,543 IU/l) were treated with 100 mg recombinant tissue-type plasminogen activator (rt-PA) 3.1±1.1 hours after onset of chest pain. Angiography 12.5+±6.1 days later revealed an 81% patency rate of the infarct-related vessel. FPA plasma levels (normal, 1.9±0.5 ng/ml) were 34±46 ng/ml on admission and 93+86 ng/ml (538 ±674% with respect to each patient's admission level) after 90 minutes of rt-PA infusion (p <0.01). In patients without evidence of reocclusion (including three primary failures), FPA levels fell under continuous heparin infusion to 6.7 +9.7 ng/ml (24+33%,p<O.O1) within 30 minutes and were 3.1+2.2 ng/ml (15+1±%,p<O0.01), 1.6+1.1 ng/ ml (8±10%, p<0.01), and 2.5± 3.0 ng/ml (12±f 16%, p<0.01) 30 minutes, 9 hours, and 21 hours, respectively, after completion of rt-PA therapy. Five patients sustained intermittent or permanent coronary reocclusion after primary thrombolytic success. Their early postlytic FPA levels (13-51 ng/ml) remained high or increased again despite adequate anticoagulation. FPA allows the monitoring of fibrin generation during acute myocardial infarction and thrombolytic therapy. Despite successful recanalization, fibrin generation is increased under rt-PA administration before anticoagulation. Patients under anticoagulation with postlytic FPA levels less than 5 ng/ml or below their admission value seem to be at low risk of reocclusion for several days. FPA levels that are persistently high or that increase again despite adequate anticoagulation indicate ongoing fibrin generation. However, whether FPA can indeed be considered a useful marker of reocclusion remains to be confirmed in a larger population of patients with acute myocardial infarction. (Circulation 1989;79:980-989) F ibrin generation is initiated by the thrombininduced cleavage of fibrinopeptide A and B (FPA and FPB) from the amino termini of fibrinogen's a-and 83-chains.' FPA is thereby released at a much faster rate, whereas most of FPB is cleaved off after polymerization only.2 The possibility of specific measurements by radioimmunoassay3-7 made FPA a very sensitive marker of fibrin generation in vivo. Elevated plasma levels of FPA have been found in patients with venous

Persistent generation of thrombin after acute myocardial infarction.

“…Eisenberg et al 16 noticed that shortly after SK thrombolysis followed by heparin infusion, plasma FPA levels showed a tendency for higher values in patients in whom recanalization did not occur compared with those in whom recanalization was successful. The validity of monitoring thrombin markers for the evaluation of the success of thrombolysis was documented by Rapold et al 18 and Gulba et al 10 Our observations point to still another clinical interest in TAT and FPA assessment. In our patients, persistent thrombin generation extending beyond the acute phase of infarction was associated with heart failure, infarct extension, pulmonary emboli, and death.…”

Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase. Correlation with concomitant heparin, coronary artery patency, and recurrent ischemia. The European Cooperative Study Group.

“…These findings are compatible with the hypothesis that thrombin activity is generated during alteplase infusion, as previously implied from FPA measurements before and after heparin infusion. 22,23 In the absence of heparin, thrombin activity persists for at least 36 hours, whereas in adequately anticoagulated patients, plasma FPA levels are quickly reduced to normal levels. As expected, aspirin, given together with alteplase to all patients in this study, does not inhibit thrombin-induced platelet aggregation.…”

“…19 The present study, performed in a representative subgroup (n=334) of the ECSG trial, prospectively tests the hypothesis that plasma FPA levels depend on the intensity of anticoagulation and may be useful markers of coronary artery patency after alteplase treatment. 22 To this end, sequential FPA levels were correlated with the assignment to treatment, with the intensity of anticoagulation reflected by serial activated partial thromboplastin times (aPTIT), with subsequent angiographic coronary patency, with recurrent ischemic events, and with the echocardiographic presence of left ventricular thrombosis.…”

Increased thrombin levels during thrombolytic therapy in acute myocardial infarction. Relevance for the success of therapy.

“…When differentially analyzed for clinical course (persistent patency, nonsuccessful thrombolysis, or early reocclusion), marked differences among the three groups, however, were found. Rapid normalization occurred in patients with successful thrombolysis, and steady increases in TAT levels occurred in patients who did not undergo successful thrombolysis or who suffered reocclusion of the infarcted artery within [24][25][26][27][28][29][30][31][32][33][34][35][36] hours. To interfere with the activation process of thrombin, intravenous heparin was given to all patients enrolled in the study.…”