Role of thrombin and thromboxane A2 in reocclusion following coronary thrombolysis with tissue-type plasminogen activator.

Abstract

Reocclusion of the coronary artery occurs after thrombolytic therapy of acute myocardlal infarction despite routine use of the anticoagulant heparin. However, heparin is inhibited by platelet activation, which is greatly enhanced in this setting. Consequently, it is unclear whether thrombin induces acute reocclusion. To address this possibility, we examined the effect of argatroban {MCI9038, (2R,4R)--2-piperidinecarboxylic acid}, a specific thrombin inhibitor, on the response to tissue-type plasminogen activator in a dosed-chest canine model of coronary thrombosis. MCI9038 prolonged the thrombin time and shortened the time to reperfusion (28 + 2 min vs. 59 ± 7 min in controls; mean ± SEM, n = 5, P < 0.01). At the highest dose, 2.5 mg/kg per hr, complete reocclusion was prevented in four of the five experimental animals, whereas reocclusion occurred in all five controls. However, reperfusion was complicated by cycles of decreased flow, which were abolished by the thromboxane A2 antagonist, GR32191. GR32191 at 1 mg/kg combined with MCI9038 at 0.5 mg/kg per hr prevented reocclusion, whereas, at these doses, either drug alone was without effect. In addition, thromboxane A2 biosynthesis, determined as excretion of its metabolite 2,3-dinor-thromboxane B2, was increased after reperfusion at all doses of MC19038. These data demonstrate that thrombin impairs thrombolysis induced by tissue-type plasminogen activator in vivo and induces acute reocclusion. Furthermore, the response to thrombin inhibition may be impaired by continued formation of thromboxane A2.

Time course of the effects of a single bolus injection of F(ab')2 fragments of the antiplatelet GPIIb/IIIa antibody 7E3 on arterial eversion graft occlusion, platelet aggregation, and bleeding time in dogs.

“…Patency status during the initial 2-hour observation period and at 24 hours was not significantly different (P=. 16 and P=.48, respectively) between the groups given 7E3-F(ab') 2 10 minutes before vessel clamp release (groups Ha and lib) or 48 hours before grafting (group He).…”

Antithrombotic effect of a monoclonal antibody against tissue factor in a rabbit model of platelet-mediated arterial thrombosis.

“…910 The mechanism of thrombus formation on ruptured plaques is probably complex, comprising activation of platelets as well as of the blood coagulation system 9 ' 13 and resulting in a thrombus that is variably composed of PR and ER zones. 9 Low-molecular-weight thrombin inhibitors but not heparin have a potent inhibitory effect on platelet-mediated arterial thrombosis, 6 -14 - 16 which is indicative of a pivotal role of thrombin in the pathogenesis of arterial occlusion. Thrombin formation may be initiated via either contact activation of the intrinsic blood coagulation system by subendothelial structures or activation by thromboplastin of the extrinsic coagulation system 13 and may be amplified by assembly of blood coagulation complexes, such as the prothrombinase complex on phospholipid membranes of activated platelets.…”

Characterization of a functional thrombin receptor. Issues and opportunities.

“…The surprising inhibitory effects of thrombin on neurite outgrowth (13,14) and the apparent expression ofprothrombin mRNA in brain (15) (16)(17)(18)(19)(20). In general, the importance ofthrombin in mediating nonthrombotic responses in vivo remains to be defined.…”