Prevention of platelet-rich arterial thrombosis by selective thrombin inhibition.

Abstract

The effect of heparin and of the synthetic competitive thrombin inhibitor (2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfon yl)-L-arginyl]-2-piperidinecarboxylic acid monohydrate (argatroban) on platelet-rich arterial thrombosis was studied in a rabbit model, consisting of a 4-6-mm everted ("inside-out") femoral arterial segment. Intravenous injection of heparin (200 units/kg) failed to prevent occlusion within 60 minutes in all 10 rabbits, whereas intravenous argatroban infusion at a rate of 100 or 200 micrograms/kg/min for 60 minutes, which prolonged the thrombin time more than fourfold, prevented thrombosis in nine of 13 rabbits (p = 0.002 vs. i.v. heparin). Intra-arterial infusion of 200 units/kg heparin over 60 minutes prevented occlusion in six of nine rabbits (p = 0.003 vs. i.v. heparin), whereas intra-arterial argatroban at a rate of 100 micrograms/kg/min for 60 minutes prevented thrombosis in all 10 rabbits (p = 0.00001 vs. i.v. heparin). Patency of femoral arterial segments was maintained after the end of the intra-arterial heparin and intravenous or intra-arterial argatroban infusion for up to 3 hours despite normalization of the thrombin time and partial thromboplastin time. Pathologic examination of the graft revealed that the inverted adventitial surface was covered by layers of platelets without platelet aggregation or fibrin deposition. These findings indicate that thrombin plays an important role in platelet-rich arterial thrombosis, and that the thrombogenic stimulus is rapidly attenuated by short-term infusion of the synthetic thrombin inhibitor. Selective thrombin inhibition can constitute an alternative approach to the prevention of arterial occlusion after angioplasty or thrombolytic therapy in patients with unstable coronary syndromes.

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

“…21 Attempts to prevent thrombotic occlusion in this model with the use of aspirin or heparin, alone or in combination, have failed. 6 With a specific thrombin inhibitor, however, especially when combined with aspirin, it was possible not only to prevent platelet-mediated eversion graft thrombosis but also to maintain patency after disappearance of the inhibitor from blood. 22 This model for thrombin-initiated platelet-mediated arterial thrombosis was used in the present study because the adventitia, which is rich in tissue factor, might simulate the tissue factor-mediated thrombogenicity of an atherosclerotic plaque and allow evaluation of its contribution to the development of platelet-mediated arterial thrombosis.…”

“…6 The role of tissue factor localized in the adventitia in the activation of blood coagulation was evaluated with a tissue factor-neutralizing murine monoclonal antibody (D3).…”

“…6 Briefly, New Zealand White rabbits weighing between 2.6 and 4.1 kg were anesthetized with sodium pentobarbital. The right brachial artery was cannulated for continuous blood pressure monitoring and the right brachial vein for intravenous administration of test material.…”

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.

“…17 Adult mongrel dogs weighing 12 to 20 kg were premedicated with 0.25 mg/kg fluanisone (Hypnorm, Janssen Pharmaceutica) intramuscularly, anesthetized with 30 mg/kg intravenous sodium pentobarbital (Nembutal, CEVA) followed by 60-mg boluses when needed, intubated, and artificially ventilated. Cefazolin 1 g (Kefzol, Eli Lilly) was given intravenously.…”

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.…”