Increased fragmentation of von Willebrand factor, due to abnormal cleavageof the subunit, parallels disease activity in recurrent hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and discloses predisposition in families

We investigated here the changes in von Willebrand factor (VWF) multimers i n recurrent, sporadic and familial forms of hemolytic uremic syndrome (HUS) /thrombotic thrombocytopenic purpura (TTP) to see whether they are actually proteolyzed in vivo in these patients. Molecular determinants of fragments in vWF were also characterized to identify possible sites of cleavage of t he subunit. Unusually large vWF multimers were found in blood of 8 of 10 pa tients with recurrent HUS/TTP, both in the acute phase and in remission, bu t never in familial and sporadic cases. Instead, all of the groups showed e vidence of enhanced fragmentation of VWF multimers during the acute phase. Increased fragmentation was also shown by decrease in native 225-kD vWF sub unit, In recurrent and sporadic HUS/TTP, enhanced fragmentation normalized at remission, but the abnormality persisted in familial HUS/TTP patients. T he latter findings suggest that patients with familial HUS/TTP may have a c ongenital abnormality in vWF processing. Analysis with specific monoclonal antibodies showed the presence of the normal vWF fragments with apparent mo lecular mass of 189, 176, and 140 kD in all patients; however, in 6 recurre nt and in 5 familial cases, novel fragments that differed in size from norm al ones were found. The size of these abnormal fragments differed from one patient to another and none of them was ever found in normal plasma. These results documented, for the first time in HUS/TTP, an abnormal cleavage of the vWF subunit that might account for the increased fragmentation observed in these patients. (C) 1999 by The American Society of Hematology.