Bioscience

Biography

Biography: Rinku Majumder

Abstract

Background: Current treatment of hemophilia-B consists of infusion of factor IX (FIX) concentrates to substitute for deficient FIX, i.e., replacement therapy. Yet, replacement is only temporary, as infused FIX is cleared rapidly from a patient’s plasma. We found that Protein S (PS) inhibits FIX and importantly, anti-PS antibody increased FIX activity in hemophilia-B plasma, implying that blocking PS activity may achieve longer lasting replacement therapy.

Aims: To assess the effectiveness of anti-PS antibody in reducing clotting time.

Method & Results: We used a modified aPTT assay (clotting initiated with FIX) with FIX-deficient plasma and varied the concentrations of added FIX and anti-PS antibody. The aPTT clotting times in the presence and absence of anti-PS antibody were measured for 2.5 (51 sec+Ab; 69 sec+Ab), 5 (43 sec+Ab; 59 seconds+Ab), 10 (38 sec+Ab; 51 sec+Ab), and 20 nM FIXa (33 sec+Ab; 40 sec+Ab). Results showed that in FIX-deficient plasma, an anti-PS antibody would make added FIXa ~3 fold more active. We also performed a thrombin generation assay with the same FIX-deficient plasma in the presence of 1, 2.5 and 5 nM FIXa and measured peak thrombin formation in the presence of anti-PS antibody. Both the thrombin generation assay and the clotting assay gave similar results, i.e., addition of neutralizing anti-PS antibody made FIX ~3 fold more active. In wild type mice we have found that PS inhibited thrombin generation. Work is underway to assess hemostasis in hemophilia-B mice receiving a low dose of FIX and PS antibodies. Improved hemostasis in this mouse model would move anti-PS antibody to the forefront as a possible adjunct in hemophilia therapy.

Conclusion: Our findings suggest that administration of anti-PS antibodies to hemophilia-B patients may achieve the goal of longer lasting replacement therapy. Antibody blocking PS activity towards FIXa is the most straightforward approach and one most likely to succeed.