Activated protein C inhibitor for correction of thrombin generation in hemophilia A blood and plasma

Abstract

Background:Replacement therapy for hemophilic patient treatment is costly, because of the high price of pharmacologic products, and is not affordable for the majority of patients in developing countries. Objective:To generate and evaluate low molecular weight agents that could be useful for hemophilia treatment. Methods:Potential agents were generated by synthesizing specific inhibitors [6-(Lys-Lys-Thr-[homo]Arg)amino-2-(Lys[carbobenzoxy]-Lys[carbobenzoxy]-O-benzyl)naphthalenesulfonamide] (PNASN-1)] for activated protein C (APC) and tested in plasma and fresh blood from hemophilia A patients. Results:In the activated partial thromboplastin time-based APC resistance assay, PNASN-1 partially neutralized the effect of APC. In calibrated automated thrombography, PNASN-1 neutralized the effect of APC on thrombin generation in normal and congenital factorVIII-deficient plasma (FVIII:C<1%). The addition of PNASN-1 to tissue factor-triggered (5pm) contact pathway-inhibited fresh blood from 15 hemophilia A patients with various degrees of FVIII deficiency (FVIII:C<1-51%) increased the maximum level of thrombin generated from 78 to 162nm, which approached that observed in blood from a healthy individual (201nm). PNASN-1 also caused a 47% increase in clot weight in hemophilia A blood. Conclusions: Specific APC inhibitors compensate to a significant extent for FVIII deficiency, and could be used for hemophilia treatment. © 2011 International Society on Thrombosis and Haemostasis.