Peptidomimetic inhibitors for activated protein C: Implications for hemophilia management

Abstract

Background: Several clinical studies and experiments with transgenic mice have suggested that the severity of the bleeding phenotype in hemophilic patients is substantially reduced in association with impaired inactivation of factor (F) Va by activated protein C (APC) in the presence of the FV Leiden mutation. Experiments using a synthetic coagulation proteome model showed that the presence of FV Leiden significantly increased thrombin generation in the absence of FVIII or FIX. Objective: To test the effect of APC inhibition on thrombin generation in hemophilia. Methods: Prothrombinase and a synthetic coagulation proteome model of tissue factor-triggered thrombin generation were used. Results: Peptide-based APC inhibitors, which mimic the P4-P4′ residues surrounding the APC cleavage site at Arg306 of FVa, were synthesized. These compounds are specific and reversible inhibitors of APC, with Ki values as low as 1-2 μM; most have insignificant affinity for FXa or thrombin. The affinity for APC is dependent upon the location and character of the protecting groups. Representatives of this group of compounds inhibit FVa inactivation by APC and prolong FVa functional activity in the prothrombinase complex. When evaluated in a synthetic coagulation proteome model, one inhibitor partially compensated for the absence of FVIII. Conclusions: Synthetic APC inhibitors may be useful as adjuvants for hemophilia treatment. © 2006 International Society on Thrombosis and Haemostasis.