Recombinant Human FVIIa Reduces Heparin and Low Molecular Weight Heparin (LMWH)-Induced Bleeding in Rats.

Recombinant human FVIIa (rFVIIa, NovoSeven, Novo Nordisk A/S) is approved for treatment of bleeding in hemophilia patients with inhibitors. Recent data indicate that rFVIIa is useful in other bleeding conditions. Heparin and low molecular weight heparin (LMWH) are widely used for anticoagulant management of venous thromboembolic events. Both agents can however cause uncontrollable bleeding. While protamine can reverse the anticoagulant effect of heparin no effective antidote for LMWH is currently available. We have tested if rFVIIa was capable of reducing the bleeding caused by either heparin or LMWH in a rat tail bleeding model. We pre-treated rats with a single dose of either heparin (Heparin, Leo; 200 IU/kg; i.v.) or LMWH (tinzaparin; Innohep, Leo; 500 IU/kg; i.v.), which significantly prolonged total bleeding time following tail transection (table 1). Similarly, blood loss increased significantly by pre-treatment with heparin and tinzaparin (table 2). rFVIIa, intravenously injected 5 minutes after induction of tail bleeding in doses of 5, 10 and 20 mg/kg (n=8), dose-dependently reduced bleeding time of the heparin-induced bleeding, reaching statistical significance at 20 mg/kg (table 1). In accordance, blood loss decreased significantly by treatment with 10 and 20 mg/kg rFVIIa (table 2). A similar response was seen in the tinzaparin pre-treated animals with a dose-dependent decrease in bleeding time (table 1), and a significant decrease in blood loss at 10 and 20 mg/kg rFVIIa (table 2).

This study illustrates the pharmacological effect of rFVIIa in the presence of heparin and LMWH and the results indicate that rFVIIa may be an effective way to treat heparin and LMWH induced bleeding, however the dose requirements are specific for the rat and cannot be extrapolated to other species. Future studies will investigate the hemostatic effect of rFVIIa in bleedings induced by coumarin analogues, thrombin inhibitors, factor Xa inhibitors, and platelet inhibitors.