The antithrombotic effects of direct (ximelagatran and hirudin) and indirect (dalteparin) anticoagulants were compared using a deep venous thrombosis (DVT) treatment model in conscious rats. Thrombus formation was induced in the inferior caval vein by total stasis plus topically applied ferric chloride. After 1-h thrombus maturation, one group of 10 rats were sacrificed and the mean thrombus weight in this group was 27.3 +/- 2.7 mg. This thrombus weight was handled as a reference to which all other results were compared. In all other groups, the total occlusion was removed after 1 h but a partial stasis was retained, permitting some blood flow around the thrombus. Groups of animals received subcutaneous (s.c.) dalteparin (200 IU/kg), s.c. hirudin (0.75 micromol/kg), one of four oral doses of ximelagatran (2.5, 5, 10 or 20 micromol/kg) or s.c. saline (control). After the 3-h treatment, mean thrombus weight in the saline group (26.5 +/- 3.3 mg) did not differ significantly from that of the reference group (27.3 +/- 2.7 mg, see above). Ximelagatran decreased thrombus weight in a dose-dependent manner, with an estimated ID(50) of 15 micromol/kg. Mean thrombus weight with the highest ximelagatran dose (11.1 +/- 1.3 mg) was similar to that with hirudin (13.0 +/- 1.5 mg). The effect of dalteparin on thrombus regression was much less pronounced (20.2 +/- 1.2 mg), compared with ximelagatran and hirudin, even though it was administered at a dose that yielded a similar activated partial thromboplastin time (APTT) prolongation. In conclusion, the results from this DVT treatment model showed that direct thrombin inhibitors ximelagatran and hirudin exhibited superior antithrombotic properties to low molecular weight heparin (LMWH).
Copyright 2002 Elsevier Science Ltd.