Antithrombotic effect of a novel recombinant hirudin analogue, CX-397, in a rat arterial thrombosis model.

1. The antithrombotic effect of a new specific thrombin inhibitor, CX-397, was examined in a photochemically-induced arterial thrombosis model in the rat femoral artery and compared with that of heparin. 2. Pretreatment with CX-397 (10, 20 and 40 micrograms kg-1 min-1, i.v.) from 15 min before the experiment prolonged the time required for thrombotic occlusion of the artery in a dose-dependent manner. The antithrombotic efficacy of CX-397 was associated with modest increases in activated partial thromboplastin time (APTT) and template bleeding time. 3. On the other hand, heparin at a dose of 450 micrograms kg-1 markedly prolonged APTT and the bleeding time, but did not inhibit thrombo-occlusion. 4. CX-397 selectively inhibited platelet aggregation and concurrent secretion of 5-hydroxytryptamine (5-HT) and thromboxane A2 (TXA2) production from platelets in response to thrombin, but not to collagen and ADP, in a dose-dependent manner (5-100 ng ml-1). 5. CX-397 at 10 micrograms kg-1 combined with vapiprost, a TXA2 receptor antagonist, at 0.1 mg kg-1 significantly prevented occlusion, whereas, at these doses, neither drug alone had much effect. 6. These results demonstrate that CX-397 may prove to be more efficient for preventing platelet-rich thrombosis than heparin. Thrombin may play an important role in the rat thrombosis model. 7. The additive antithrombotic effect of the combination of thrombin inhibitor and TXA2 receptor antagonist at low doses suggests that thrombin and TXA2 may work in concert to produce thrombosis.