Improvement of Collateral Circulation after Arterial Thrombosis with Indomethacin Therapy

Summary

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).

Key words

Collateral circulation - Thrombosis - Indomethacin - Platelets

• References

• 1 Imhoff RK. Production of aortic occlusion resembling acute aortic embolism syndrome in cats. Nature (London) 1962; 192: 979-980
• 2 Butler HC. An investigation into the relationship of aortic embolus to posterior paralysis in the cat. J Sm An Prac 1968; 12: 141-158
• 3 Schaub RG, Meyers KM, Sande R, Hamilton G. Inhibition of feline collateral vessel development following thrombolic occlusion. Circ Res 1976; 39: 736-743
• 4 Schaub RG, Meyers KM, Sande R. Serotonin as a factor in depression of collateral blood flow following experimental arterial thrombosis. J Lab Clin Med 1977; 90: 645-653
• 5 Kordenat RK, Kezdi P. Serotonin blockade during experimental coronary thrombosis. Am Heart J 1979; 97: 329-338
• 6 Baumgartner HR, Born GV R. Effects of 5-hydroxytryptamine aggregation. Nature (London) 1968; 218: 137-141
• 7 Hoak JC. Structure of thrombi produced by injection of fatty acids. Brit J Exptl Path 1964; 45: 44-47
• 8 Baumgartner HR. 5-hydroxytryptamine uptake and release in relation to aggregation of rabbit platelets. J Physiol 1969; 201: 409-423
• 9 Day HJ, Ang GA T, Holmsen H. Platelet release reaction during clotting of native platelet rich plasma. Proc Soc Exptl Biol Med 1972; 139: 717-721
• 10 Page IH. The vascular action of natural serotonin, 5 and 7-hydroxytryptamine and tryptamine. J Pharm Exptl Therap 1952; 105: 58-73
• 11 Gerrard JM, White JG. Prostaglandin and Thromboxanes: »Middlemen« modulating platelet function in hemostasis and thrombosis. Prog Hemostasis Thrombosis 1978; 4: 87-125
• 12 Svenson J, Hamberg M, Samuelsson B. On the formation and effects of thromboxane A₂ in human platelets. Acta Physiol Scand 1976; 98: 285-294
• 13 Marcinkiewicz E, Grodzinska L, Gryglewski RJ. Platelet aggregation and thromboxane A₂ formation in cat platelet rich plasma. Pharmacological Res Com 1978; 10: 1-12
• 14 Meyers KM, Seachord CL, Holmson H, Smith JB, Preur DJ. A dominant role of thromboxane formation in secondary aggregation of platelets. Nature 1979; 282: 331-333
• 15 Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (London) 1971; 13: 1057-1065
• 17 Bourgain RH. The effect of indomethacin and ASA on in vivo induced white platelet arterial thrombus formation. Thromb. Res 1978; 12: 1079-1086
• 18 Bourgain RH. White platelet arterial thrombus formation is inhibited by indomethacin in vivo . Arch Int Physiol de Biochemie 1978; 86: 165-168
• 19 Cazenave JP, Kinlough-Rathbone R, Packham MA, Mustard JF. The effect of acetylsalicyclic acid and indomethacin on rabbit platelet adherence to collagen and the subendothelium in the presence of a low or high hemocrit. Thromb Res 1978; 73: 971-981
• 20 Niewiarowski S, Gurewich V. Laboratory identification of intravascular coagulation: the serial dilution protamine sulfate test for the detection of fibrin monomer and fibrin degradation products. J Lab Clin Med 1971; 77: 665-876
• 21 Moschos CB, Lahire K, Lyons M, Wasse AB, Oldervastel HA, Regan TJ. Relation of microcirculatory thrombosis to thrombus in the proximal coronary artery: Effect of aspirin, dipyridamole, and thrombolysis. Am Heart J 1973; 86: 61-68
• 22 Zahavi J. The role of platelets in myocardial infarction, ischemic heart disease, cerebrovascular disease, thromboembolic disorders and acute idiopathic pericarditis. Thromb Haemostas 1977; 38: 1073-1084
• 23 Barnett HJ M. The role of platelets in transient ischemic attacks and vascular accidents. Adv Exp Med 1978; 102: 257-263
• 24 Hoak JC, Parsons TJ, Wu KK. Platelet aggregation in freshly drawn blood. Platelet function testing 1978; HEW pub No 78-1078: 402-409
• 25 Weskler BB, Dougherty JH. Detection of platelet aggregates in cerebrovascular and coronary artery disease. 1978; HEW pub No 78-1078: 410-415
• 26 Dougherty JH, Levy DE, Weksler BB. Experimental cerebral ischemia produced by platelet aggregates. Neurology 1979; 29: 1460-1465
• 27 Hellstrom HR. Evidence in favor of the vasospastic cause of coronary artery thrombosis. Am Heart J 1979; 97: 449-452