INTERACTION OF A THROMBIN INHIBITOR AND A PLATELET GP IIB IIIA ANTAGONIST IN-VIVO - EVIDENCE THAT THROMBIN MEDIATES PLATELET-AGGREGATION AND SUBSEQUENT THROMBOXANE A(2) FORMATION DURING CORONARY THROMBOLYSIS/

Citation
D. Pratico et al., INTERACTION OF A THROMBIN INHIBITOR AND A PLATELET GP IIB IIIA ANTAGONIST IN-VIVO - EVIDENCE THAT THROMBIN MEDIATES PLATELET-AGGREGATION AND SUBSEQUENT THROMBOXANE A(2) FORMATION DURING CORONARY THROMBOLYSIS/, The Journal of pharmacology and experimental therapeutics, 281(3), 1997, pp. 1178-1185
Citations number
29
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
00223565
Volume
281
Issue
3
Year of publication
1997
Pages
1178 - 1185
Database
ISI
SICI code
0022-3565(1997)281:3<1178:IOATIA>2.0.ZU;2-Y
Abstract
We examined the effect of a specific thrombin inhibitor, Ro 46-6240, a lone and combined with an antagonist of the platelet GP IIb/IIIa, Ro44 -9883, on the response to tissue-type plasminogen activator in a canin e model of thrombolysis. Platelet activity was determined by measuring the excretion of 2,3-dinor-thromboxane (TX)B-2, an enzymatic metaboli te of TXA(2). Ro 46-6240 administered before tissue-type plasminogen a ctivator induced a dose-dependent prolongation of the activated partia l thromboplastin time and prothrombin time. The time to reperfusion de creased dose-dependently (P < .01) to 10 +/- 6 min vs. 52 +/- 5 min in controls. Ro 46-6240 also prevented reocclusion, which occurred in ev ery case in control experiments. Urinary excretion of 2,3-dinor-TXB2 i ncreased from 3 +/- 1 to 37 +/- 9 ng/mg creatinine in controls after r eperfusion. This increase was reduced in a dose-dependent fashion by R o 46-6240, such that: at the highest dose, urinary 2,3-dinor-TXB2 afte r reperfusion was 5.6 +/- 1 ng/mg creatinine. Similar functional and b iochemical effects were seen when a subthreshold dose of Ro 46-6240 wa s combined with Ro 44-9883. At the dose used, Ro 44-9883 alone abolish ed platelet aggregation ex vivo but failed to modify the response to t issue-type plasminogen activator or the excretion of 2,3-dinor-TXB2 af ter reperfusion (51 +/- 6 ng/mg creatinine, n = 3). However, the combi nation of Ro 44-9883 and Ro 46-6240 reduced the time to reperfusion (4 0 +/- 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 activ ation during coronary thrombolysis. The increased platelet activity re sults in platelet aggregation and a subsequent increase in TXA(2) form ation.