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

作者：Brummel Ziedins K E; Whelihan M F; Rivard G E; Butenas S

来源：Journal of Thrombosis and Haemostasis, 2011, 9(11): 2262-2267.

DOI：10.1111/j.1538-7836.2011.04504.x

• activated protein C
• blood coagulation
• hemophilia A
• inhibitors
• thrombin generation
• tissue factor

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 factor VIII-deficient plasma (FVIII: C < 1%). The addition of PNASN-1 to tissue factor-triggered (5 pM) 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 162 nM, which approached that observed in blood from a healthy individual (201 nM). 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.

• 出版日期2011-11