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Unrecognized Pattern of von Willebrand Factor Abnormalities in Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura

MIRIAM GALBUSERA^*, ARIELA BENIGNI^*, SIMONA PARIS^*, PIERO RUGGENENTI^*,, CARLA ZOJA^*, CHIARA ROSSI^* and GIUSEPPE REMUZZI^*,

^* Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Division of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Italy.

Correspondence to Dr. Ariela Benigni, Mario Negri Institute for Pharmacological Research, Via Gavazzeni, 11, 24125 Bergamo, Italy. Phone: 39 (035) 319 888; Fax: 39 (035) 319 331; E-mail: abenigni{at}irfmn.mnegri.it

Abstract. Heterogeneous abnormalities in multimeric structure and fragmentation of endothelial-derived von Willebrand factor (vWF) have been reported in hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). This study was conducted to establish whether different patterns of vWF abnormalities were associated with different clinical syndromes. Plasmatic levels of vWF antigen (vWF:Ag), vWF release from endothelial cells (EC) exposed to patient sera, and vWF multimeric pattern were studied during episodes and again in remission in three groups of patients with severe forms of HUS and TTP paradigmatic of the most common clinical patterns of disease presentation: (1) plasma-responsive; (2) plasma-resistant; and (3) frequently relapsing. Plasma vWF:Ag and serum-induced vWF release from EC were increased in the acute phase of either plasma-responsive and plasma-resistant HUS and TTP, but normalized at remission only in plasma-responsive cases. Both indices were persistently normal in the relapsing forms. Enhanced vWF fragmentation as defined by disappearance of high molecular weight and increase in low molecular weight forms was a consistent finding of the acute phases, and always normalized in remission in all three groups. Unusually large vWF multimers were found exclusively in plasma of relapsing forms of HUS and TTP both during and between relapses. Enhanced levels of vWF:Ag and serum capability to induce vWF release in vitro are markers of disease activity and may reflect systemic endothelial injury and consequent activation. Their presence discriminates acute single-episode cases from relapsing forms and, when failing to normalize with plasma therapy, predicts plasma resistance. Enhanced low molecular weight multimers that closely paralleled disease activity suggest a permissive role of fragmented vWF in the formation of microvascular thrombi. Finally, finding of unusually large multimers exclusively in relapsing forms of HUS and TTP even between relapses, when no other clinical signs of disease activity could be detected, suggests that they cannot be the only factor in microvascular thrombosis.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673