Research Program of Kathleen P. Pratt, PhD
My laboratory is investigating the structure, function and pathologies due to defects in the blood coagulation cofactor known as factor VIII (FVIII). This large protein circulates in the plasma as a heterodimer, forming a noncovalent complex with von Willebrand factor (VWF), which protects it from degradation and delivers it to wound sites. VWF becomes anchored to collagen that is exposed upon injury, and it releases proteolytically activated FVIII (FVIIIa) as platelets aggregate to form a “platelet plug” to staunch blood loss. FVIIIa then associates with activated membrane surfaces, where it associates with the serine protease factor IXa (FIXa). The substrate for FIXa is the zymogen form of the next serine protease in the coagulation cascade, factor X (FX), which is activated by cleavage of its propeptide. FVIIIa is not a protease; rather, it serves a cofactor function. By associating with FIXa at a negatively charged membrane surface, in the presence of calcium, it increases the catalytic efficiency of FIXa by approximately four orders of magnitude. This acceleratory activity constitutes a critical control point in hemostasis. The importance of FVIII function is underscored by the fact that a severe deficiency in FVIII, which can be caused by gene rearrangements, deletions, or point mutations, results in the bleeding disorder hemophilia A.

Hemophilia A is treated by infusing patients with FVIII. Unfortunately, approximately one quarter of the patients who receive these infusions develop antibodies that bind to FVIII and interfere with its pro-coagulant function. Current projects in my laboratory are focused on characterizing these immune responses and designing less immunogenic versions of FVIII. We are also collaborating with Dr. Tom E. Howard, of the Greater Los Angeles VA, to investigate the reasons that hemophilia A patients with black African ancestry are more likely to develop these immune responses.