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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 610-620
Increased Fragmentation of von Willebrand Factor, Due to Abnormal
Cleavage of the Subunit, Parallels Disease Activity in Recurrent
Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura and
Discloses Predisposition in Families
Miriam Galbusera,
Marina Noris,
Chiara Rossi,
Silvia Orisio,
Jessica Caprioli,
Zaverio M. Ruggeri,
Barbara Amadei,
Piero Ruggenenti,
Beatrice Vasile,
Giorgio Casari, and
Giuseppe Remuzzi on
behalf of the Italian Registry of Familial and Recurrent HUS/TTP
From the Clinical Research Center for Rare Diseases "Aldo and Cele
Daccò," Mario Negri Institute, Villa Camozzi-Ranica, Italy;
The Scripps Research Institute, La Jolla, CA; TIGEM-S. Raffaele Science
Park, Milan, Italy; and the Unit of Nephrology and Dialysis, Azienda
Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy.
We investigated here the changes in von Willebrand factor (vWF)
multimers in 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 the subunit. Unusually large vWF
multimers were found in blood of 8 of 10 patients with recurrent
HUS/TTP, both in the acute phase and in remission, but never in
familial and sporadic cases. Instead, all of the groups showed evidence
of enhanced fragmentation of vWF multimers during the acute phase.
Increased fragmentation was also shown by decrease in native 225-kD vWF
subunit. In recurrent and sporadic HUS/TTP, enhanced fragmentation
normalized at remission, but the abnormality persisted in familial
HUS/TTP patients. The latter findings suggest that patients with
familial HUS/TTP may have a congenital abnormality in vWF processing.
Analysis with specific monoclonal antibodies showed the presence of the
normal vWF fragments with apparent molecular mass of 189, 176, and 140 kD in all patients; however, in 6 recurrent and in 5 familial cases,
novel fragments that differed in size from normal 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.
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