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Distinct mechanisms account for acquired von Willebrand syndrome in plasma cell dyscrasias

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Abstract

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that may cause life-threatening hemorrhages in patients with plasma cell dyscrasias (PCDs). Early diagnosis and treatment require a thorough understanding of its underlying pathophysiology. Two patients with IgG MGUS presented with dramatically decreased plasma von Willebrand factor (VWF) and a severe type-1 pattern on multimer analysis. A prompt response to intravenous immunoglobulins (IVIG), but not to VWF/FVIII, was consistent with accelerated immunologic clearance of plasma VWF. Another IgG MGUS patient showed a type-2 pattern and a less pronounced response to IVIG, suggesting that additional mechanism(s) contributed to AVWS evolution. In a patient with Waldenström’s macroglobulinemia and severe depletion of plasma VWF, multimer analysis indicated association of the IgM paraprotein with VWF before, but not after plasmapheresis, resulting in destruction of the agarose gel and a characteristically distorted band structure of VWF multimers. A type-2 pattern with highly abnormal VWF triplets and laboratory evidence of excessive fibrinolytic activity suggested that plasmin-mediated VWF degradation contributed to AVWS in a patient with multiple myeloma (MM) and AL amyloidosis. Finally, in a patient with IgG MM, maximally prolonged PFA-100® closure times and a specific defect in ristocetin-induced platelet agglutination, both of which resolved after remission induction, indicated interference of the paraprotein with VWF binding to platelet GPIb. Importantly, in none of the six patients, circulating autoantibodies to VWF were detected by a specific in-house ELISA. In summary, when evaluating PCD patients with severe bleeding symptoms, AVWS due to various pathogenic mechanisms should be considered.

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Author contribution

CD gathered clinical data, designed and interpreted experiments, and wrote the first draft of the manuscript. SS, KH, CB, RD, and UB designed experiments, interpreted clinical and laboratory data, and critically revised the manuscript. BS conducted experiments and interpreted data. FL oversaw the study, designed and interpreted experiments, and co-wrote the manuscript.

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Correspondence to Florian Langer.

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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Conflict of interest

The authors declare that they have no conflict of interest. This case series has not been published elsewhere nor is it under consideration for publication elsewhere.

Additional information

Christina Dicke and Sonja Schneppenheim contributed equally to this work.

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Dicke, C., Schneppenheim, S., Holstein, K. et al. Distinct mechanisms account for acquired von Willebrand syndrome in plasma cell dyscrasias. Ann Hematol 95, 945–957 (2016). https://doi.org/10.1007/s00277-016-2650-x

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  • DOI: https://doi.org/10.1007/s00277-016-2650-x

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