FACTOR-VIII AND DDAVP REVERSE THE EFFECT OF RECOMBINANT DESULFATOHIRUDIN (CGP-39393) ON BLEEDING IN THE RAT

The infusion of a high dose of recombinant desulphatohirudin HVI (CGP 39393) for 40 min at 30 mug/kg/min, resulted in a prolongation of bleeding time in the rat when evaluated using transection of the tail. The prolonged bleeding was evident both immediately, and 30 min after cessation of the infusion of hirudin (CGP 39393). Bleeding time returned to normal after 60 min. The effect of several agents, reported to be successful in reducing bleeding tendencies in man, were evaluated in this rat model. The agents were administered immediately following cessation of the CGP 39393 infusion and their ability to normalize the prolonged bleeding-time, observed at 30 min after cessation of the CGP 39393 infusion, determined. Desmopressin (DDAVP), recombinant factor VIII and Vueffe reduced the bleeding time to the control range but did not exert any significant effects on the bleeding time in rats which did not receive CGP 39393. Epsilon-aminocaproic acid (EACA) and recombinant factor VII were ineffective, at the doses used. In conclusion, DDAVP, factor VIII and Vueffe are effective in reversing the effect of direct thrombin inhibition on bleeding in the rat.