Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis

Abstract

Summary. Background: Thrombin plays a major role in thrombus formation through activation of platelets and conversion of fibrinogen to fibrin. Objectives: To investigate the antithrombotic effects of the oral direct thrombin inhibitor (DTI) ximelagatran and the parenteral DTI r-hirudin in humans. Subjects and methods: Healthy male volunteers randomized into four parallel groups each with 15 subjects received either ximelagatran (20, 40 or 80 mg orally) or r-hirudin (0.4 mg kg À1 intravenous bolus þinfusion of 0.15 mg kg À1 h À1 for 2 h and 0.075 mg kg À1 h À1 for 3 h). Antithrombotic effects were assessed as changes in total thrombus area (TTA) and total fibrin area (TFA) from baseline, using the Badimon perfusion chamber model at baseline and 2 h and 5 h after drug administration. Results: Two hours postdosing, ximelagatran showed antithrombotic effects at both high and low shear rates (TTA% of mean baseline value AESEM was 76 AE 13% and 71 AE 17% [both P < 0.05] for the 20-mg dose, 85 AE 11% [P > 0.05] and 62 AE 15% [P < 0.05] for the 40-mg dose and 60 AE 11% and 26 AE 7% [both P < 0.05] for the 80-mg dose, respectively). r-Hirudin also showed a significant antithrombotic effect at high and low shear rates (76 AE 11% [P ¼ 0.05] and 57 AE 17% [P < 0.05] of baseline values, 2 h postdosing, respectively). The inhibitory effects on TFA were similar to those on TTA. Conclusions: The oral DTI ximelagatran shows antithrombotic effects under both high and low shear conditions. The antithrombotic effect of 40-80 mg ximelagatran appeared comparable to that of parenterally administered rhirudin, which has been previously demonstrated to be clinically effective in acute coronary syndromes.

Blood Thrombogenicity Is Independently Associated With Serum TSH Levels in Post–Non-ST Elevation Acute Coronary Syndrome

“…The Badimon perfusion chamber system is a validated ex vivo model of vessel injury and thrombosis and has previously been used to evaluate the effects of novel antithrombotic agents in human subjects in different disease states (18,19). We have used this perfusion system to evaluate the effects of antiplatelet therapy on thrombus formation in various high-risk population groups, such as patients with established CAD and type 2 diabetes mellitus.…”

Emerging Anticoagulants

“…Administration of ximelagatran results in increases in PT, APTT and TT [139]. In a human ex vivo model of arterial thrombosis, melagatran was effective in the inhibition of thrombus formation under both high and low shear conditions [140].…”

Prevention and Treatment of Venous Thromboembolism and Pulmonary Embolism: The Role of Novel Oral Anticoagulants

“…Ximelagatran was also tested against diagnosed VTE, as it was found to be an effective agent against acute thrombus formation [54]. The effort to evaluate ximelagatran as a secondary prevention of VTE resulted in the THRIVE (Thrombin Inhibitor in Venous Thromboembolism) study program [55][56][57].…”