von Willebrand factor-cleaving protease activity in congenital thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopat hic haemolytic anaemia (MAHA), thrombocytopenia, fluctuating neurological i mpairment, renal dysfunction and fever. Both acquired and congenital forms are recognized. Recurrent episodes, which may be predictable (occurring eve ry 21-28 d), are seen in congenital disease and may be treated by infusion with Fresh-frozen plasma (FFP). Congenital TTP has recently been associated with deficiency of a novel von Willebrand factor (VWF)-cleaving protease. To investigate whether residual protease activity dictates clinical manifes tations, we determined protease activity in three patients with congenital TTP of varying severity. Intrinsic VWF-cleaving protease activity of a rang e of plasma-derived products was also assessed as one patient had been succ essfully maintained for many years, initially using an Intermediate-purity factor VIII concentrate (Kryobulin) and then cryoprecipitate. All three pat ients had a severe absolute deficiency of VWF-cleaving protease activity (< 3%) up to 5 months after clinical symptoms. Three relatives were also foun d to have a mild reduction in protease activity (25-50%). Nevertheless, the intrinsic VWF-cleaving protease activity of plasma-derived products correl ated with their clinical efficacy: significant (100%) protease activity was found in FFP, cryosupernatant, solvent-detergent-treated plasma, cryopreci pitate and Kryobulin. Two clinically ineffective factor VIII products (Fahn di and Haemate P) possessed only low protease activity (6.25% and 12.5% res pectively). Although this suggests that VWF-cleaving protease activity is c entral to the pathogenesis of congenital TTP, either small differences in p rotease activity below 3% or hitherto unknown factors have a profound influ ence on clinical phenotype. The possible use of factor VIII concentrates in the treatment of this condition also warrants further investigation.