The pathophysiology and optimal therapy of patients who develop unstable angina in spite of long-term aspirin intake ("aspirin failure") have not been well defined. As part of a prospective study of thrombolytic therapy, 19 consecutive patients were identified who were admitted with unstable angina despite long-term aspirin therapy, and they were compared with 12 patients with unstable angina without previous aspirin use. Both groups received urokinase (3.0 million units over 30 minutes intravenously), maximal antianginal therapy, and intravenous heparin. Fibrinolytic system effects were characterized with serial measurements of fibrinogen, d-dimer, and fibrinogen degradation products (FDPs) at baseline and over the 24 hours following therapy. In comparison with those without previous aspirin use, the aspirin failure patients demonstrated greater d-dimer production after treatment at all points, the values becoming highly significant at 24 hours (1337 +/- 671 versus 709 +/- 620 ng/dl, p less than 0.02), as well as significantly greater FDPs at all points in the first 24 hours after treatment. Post-treatment arteriography (at 24 to 72 hours) indicated more extensive coronary artery disease in the aspirin failure patients (2.56 +/- 8.3 versus 1.63 +/- 1.06 vessels with greater than 50% stenosis, p less than 0.01) and more severe stenoses of the culprit artery (92.7 +/- 22.9% versus 77.3 +/- 36.9% diameter reduction, p = 0.09). By 7 days, both groups had equally low rates of new ischemic events or infarction (3 of 12 for no aspirin versus 4 of 19 for aspirin failure patients). Despite more extensive underlying coronary disease, unstable angina after long-term aspirin therapy appears to respond equally well to thrombolytic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)