Improvement of Collateral Circulation after Arterial Thrombosis with Indomethacin Therapy

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Abstract
We compared development of feline hindlimb collateral circulation and coagulation changes 3 hours following aortic thrombosis in five non-treated and five indomethacin treated (20 mg/kg) cats. Coagulation changes were monitored with the one stage prothrombin time (OSPT), partial thromboplastin time (PTT), protamine sulfate dilution test for fibrin monomer (PSD), and platelet counts. Collateral circulation was assessed with aortograms. Significant changes in coagulation parameters with the exception of platelet counts were not observed in either group. Platelet counts of non-treated cats were reduced to 63 ± 5% of control while platelet counts of treated cats were 96 ± 3% of control. Aortograms of non-treated cats indicated poor hindlimb perfusion around the thrombus, while aortograms of indomethacin treated animals indicated significant blood flow to the hindlimbs through collateral channels. These results support a role for the platelet in post thrombosis vasospasms and suggest that anti-platelet therapy could have positive effects in reducing the extent of ischemic damage which follows arterial thrombosis. Several studies, using cat and dog models, have demonstrated a significant reduction of collateral blood flow can occur following formation of an occlusive arterial thrombus (1–5). The collateral flow which developed after thrombosis was significantly less than when occlusion was accomplished with mechanical methods such as ligation (1, 3, 4). This suggested the presence of a thrombus produced effects on blood vessels more complex than simple mechanical obstruction. Imhoff originally suggested that the inhibition of collateral flow which followed thrombosis was related to the release or formation of a vasoactive substance which would induce constriction of collateral source or re-entry vessels (1). Butler, in later studies, suggested that it was serotonin which was responsible for the post thrombosis inhibition of collateral blood flow (2). The involvement of serotonin would seem logical, since the majority of blood serotonin is found in the platelet (6), is released upon platelet activation (7-9), and is a potent vasoconstrictor (10). A mechanism for serotonin involvement has proposed that the platelets in the flowing blood come into contact with the thrombus, are activated and release serotonin (2–4). Consideration of the biochemistry of platelet activation makes it apparent that serotonin is neither the only nor the most powerful vasoactive substance released by the platelet. Thromboxane A2 (TxA) is a critical substance in the activation, release, and aggregation of platelets (11, 12, 13). Thromboxane A2 is a particularly powerful vasoconstrictor which would be a more likely candidate to produce the type of long lasting vasospasm necessary to reduce collateral flow in the post thrombosis state (11, 12, 13). The relationship between thromboxane A2 and serotonin is suggested by recent studies which demonstrate that serotonin can initiate thromboxane A2 release from canine and feline platelets (14). Therefore, serotonin could be an intermediate mechanism in the process of collateral inhibition. If this hypothesis is correct, then inhibition of TxA synthesis should prove as beneficial in improving collateral flow after thrombosis as serotonin antagonists. To test this hypothesis we examined the effect of indomethacin treatment on development of collateral circulation following aortic thrombosis. Indomethacin is a non-steroidal, anti-inflammatory drug which inhibits cyclooxygenase, the major enzyme in the PG and TxA synthetic pathway (15–19).