To test the hypothesis that thrombus may play a role in some coronary artery disease patients without acute myocardial infarctions, Ancrod, a snake venom derivative with defibrinogenating and indirect tissue plasminogen activator properties, was given daily for 2 weeks to 10 patients with refractory angina. Coronary angiography and great cardiac vein flow studies at rest and during pacing were performed before and after Ancrod therapy to assess anatomic changes, coronary vasodilator reserve, an metabolic indices of ischemia. During coronary cineangiography, before Ancrod therapy, visible thrombi were absent in all patients. After Ancrod therapy, no instances of recannalization were seen in totally occluded bypass grafts (n=17) or native vessels (n=16). Lumen caliber changes in subtotal stenoses were also not affected by Ancrod therapy, employing quantitative coronary cineangiographic techniques. Moreover, Ancrod therapy did not improve great cardiac vein flow with pacing or metabolic indices of ischemia, including changes in arterial venous oxygen consumption and transmyocardial lactate metabolism. However, all patients increased exercise capacity greater than 50% and 3 patients had marked reduction in angina. Thus, it appears that Ancrod therapy may improve exercise capacity and reduce angina in some patients without changing objective parameters such as coronary anatomy, great cardiac vein blood flow, or metabolic indices of ischemia. This suggests that coronary thrombi were not importantly contributing to symptoms in these patients. Hence, the beneficial clinical responses to Ancrod my be relate to altered blood viscosity or as yet undetermined mechanisms.