Thrombin inhibition and endogenous prostacyclin prevent reocclusion in carotid artery thrombosis after alfimeprase‐induced thrombolysis

Thrombolytic (TL) therapy is compromised by bleeding, reocclusion, and plasminogen conversion to plasmin, which mediates rethrombosis via platelet activation. Alfimeprase (Alf), a non‐plasmin dependent TL agent, is inactivated by α2‐macroglobulin, minimizing bleeding, but leads to reocclusion due to vessel injury. We hypothesized that hirudin (thrombin inhibitor) plus the thromboxane A2 receptor antagonist S18886 (S18) would prevent reocclusion after Alf. Methods In anesthetized beagles, carotid artery thrombosis was induced by electrolytic endothelial injury. After occlusion, animals were randomized to six groups (see table). Carotid blood flow was monitored for 90 minutes after the infusion of Alf or tissue plasminogen activator (tPA). Results Groups 3 and 4 had a greater number of reperfused vessels compared to the control group; however, only Group 4 showed an increase in carotid blood flow. Using a TIMI grading scale, quality of flow was improved in Groups 3 and 4. Sustained TL did not occur in the presence of RO3244794 (RO, PGI2 receptor antagonist), indicating the role of PGI2 in maintaining vessel patency. Treatment with tPA had decreased carotid blood flow, a longer time to reperfusion, and a lower TIMI score compared to Group 4. Conclusions Endogenous PGI2 and thrombin inhibition enhance the TL activity of Alf and sustains vessel patency without a systemic lytic effect. Support: CV Research Fund