Activated Protein C Inhibitor Effective in Hemophilia A

Specific APC inhibitor PNASN-1 increases thrombin generation to near normal in FVIII deficiency

FRIDAY, Sept. 30 (HealthDay News) -- Specific activated protein C (APC) inhibitor PNASN-1 significantly increases thrombin generation in the blood and plasma of individuals with congenital hemophilia A, with and without factor VIII (FVIII) deficiency, according to a study published online Sept. 15 in the Journal of Thrombosis and Haemostasis.

Kathleen E. Brummel-Ziedins, Ph.D., from the University of Vermont in Burlington, and colleagues generated and evaluated low molecular weight agents for hemophilia treatment. Specific inhibitors were synthesized for APC and tested in fresh blood and plasma of 15 young male adults with hemophilia A and a healthy donor. Replacement therapy was not withheld, and the participants did not self-infuse with factor VIII prior to the blood draw. An activated partial thromboplastin time (APTT)-based APC-resistance assay, and calibrated automated thrombography were performed.

The investigators found that inhibitor PNASN-1 partially neutralized the effect of APC in the APTT-based APC-resistance assay. Automated thrombography in normal and congenital FVIII-deficient plasma revealed that PNASN-1 neutralized the effect of APC on thrombin generation. The maximum level of thrombin generated increased from 78 to 162 nM, and approached that of healthy individuals (201 nM) on adding PNASN-1 to tissue factor-triggered contact pathway-inhibited fresh hemophilia A blood. The clot weight increased by 47 percent on addition of PNASN-1 to hemophilia A blood.

"Specific APC inhibitors compensate to a significant extent for FVIII deficiency and could be used for hemophilia treatment," the authors write.

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