Interaction of a thrombin inhibitor and a platelet GP IIb/IIIa antagonist in vivo: evidence that thrombin mediates platelet aggregation and subsequent thromboxane A2 formation during coronary thrombolysis.
We examined the effect of a specific thrombin inhibitor, Ro 46-6240, alone and combined with an antagonist of the platelet GP IIb/IIIa, Ro44-9883, on the response to tissue-type plasminogen activator in a canine model of thrombolysis. Platelet activity was determined by measuring the excretion of 2,3-dinorthromboxane (TX)B2, an enzymatic metabolite of TXA2. Ro 46-6240 administered before tissue-type plasminogen activator induced a dose-dependent prolongation of the activated partial thromboplastin time and prothrombin time. The time to reperfusion decreased dose-dependently (P < .01) to 10 +/- 6 min vs. 52 +/- 5 min in controls. Ro 46-6240 also prevented reocclusion, which occurred in every case in control experiments. Urinary excretion of 2,3-dinor-TXB2 increased from 3 +/- 1 to 37 +/- 9 ng/mg creatinine in controls after reperfusion. This increase was reduced in a dose-dependent fashion by Ro 46-6240, such that at the highest dose, urinary 2,3-dinor-TXB2 after reperfusion was 5.6 +/- 1 ng/mg creatinine. Similar functional and biochemical effects were seen when a subthreshold dose of Ro 46-6240 was combined with Ro 44-9883. At the dose used, Ro 44-9883 alone abolished platelet aggregation ex vivo but failed to modify the response to tissue-type plasminogen activator or the excretion of 2,3-dinor-TXB2 after reperfusion (51 +/- 6 ng/mg creatinine, n = 3). However, the combination of Ro 44-9883 and Ro 46-6240 reduced the time to reperfusion (40 +/- 8 vs. 68 +/- 15 min; n = 7, P < .05), prevented reocclusion and abolished the rise in urinary 2,3-dinor-TXB2 (5 +/- 1 ng/mg creatinine, n = 4). These findings suggest that thrombin mediates platelet activation during coronary thrombolysis. The increased platelet activity results in platelet aggregation and a subsequent increase in TXA2 formation.
Pratico
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Centre for Cardiovascular Science, Dept. of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin.
Murphy
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NP
Fitzgerald
D J
DJ
D000085:Acetates / Q000494:pharmacology; D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D004347:Drug Interactions; D009281:Naphthalenes / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000096:biosynthesis*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D000085:Acetates; D000991:Antithrombins; D009281:Naphthalenes; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D014443:Tyrosine; D013928:Thromboxane A2; C084062:lamifiban; D013917:Thrombin; C087198:napsagatran