DEFICIENT ACTIVITY OF VON-WILLEBRAND FACTOR-CLEAVING PROTEASE IN CHRONIC RELAPSING THROMBOTIC THROMBOCYTOPENIC PURPURA

In patients with thrombotic thrombocytopenic purpura (TTP), excessive intravascular platelet aggregation has been associated with appearance in plasma of unusually large von Willebrand factor (VWF) multimers. T hese extremely adhesive vWF multimers may arise due to deficiency of a ''depolymerase'' cleaving vWF to smaller molecular forms, either by r educing the interdimeric disulfide bridges or by proteolytic degradati on, We studied the activity of a recently described vWF-cleaving prote ase in four patients with chronic relapsing TIP. Diluted plasma sample s of TTP patients were incubated with purified normal human vWF in the presence of a serine protease inhibitor, at low ionic strength, and i n the presence of urea and barium ions. The extent of vWF degradation was assayed by electrophoresis in sodium dodecyl sulfate-agarose gels and immunoblotting. Four patients, that included two brothers, with ch ronic relapsing TTP displayed either substantially reduced levels or a complete absence of vWF-cleaving protease activity, In none of these patient plasmas was an inhibitor of or an antibody against the vWF-cle aving protease established. Our data suggest that the unusually large vWF multimers found in TTP patients may be caused by deficient vWF-cle aving protease activity. Deficiency of this protease may be inherited in an autosomal recessive manner and seems to predispose to chronic re lapsing TTP. The assay of the vWF-cleaving protease activity may be us ed as a sensitive diagnostic tool for identification of subjects with a latent TTP tendency. (C) 1997 by The American Society of Hematology.