title: Distinct mechanisms account for acquired von Willebrand syndrome in plasma cell dyscrasias.
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.
authors.affiliation: II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum - Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Dicke
authors.affiliation: Gerinnungslabor, MEDILYS Laborgesellschaft mbH, c/o Asklepios Klinik Altona, Paul-Ehrlich-Str. 1, 22763, Hamburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Schneppenheim
authors.affiliation: II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum - Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Holstein
authors.affiliation: II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum - Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Spath
authors.affiliation: II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum - Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Gerinnungslabor, MEDILYS Laborgesellschaft mbH, c/o Asklepios Klinik Altona, Paul-Ehrlich-Str. 1, 22763, Hamburg, Germany.
authors.forename: Rita
authors.initials: R
authors.lastname: Dittmer
authors.affiliation: Gerinnungslabor, MEDILYS Laborgesellschaft mbH, c/o Asklepios Klinik Altona, Paul-Ehrlich-Str. 1, 22763, Hamburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Budde
authors.affiliation: II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum - Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Eppendorf, Martinistr. 52, 20246, Hamburg, Germany. langer@uke.uni-hamburg.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Langer
mesh_terms: D000368:Aged; D001323:Autoantibodies / Q000097:blood; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010265:Paraproteinemias / Q000097:blood* / Q000175:diagnosis* / Q000188:drug therapy; D014842:von Willebrand Diseases / Q000097:blood* / Q000175:diagnosis* / Q000188:drug therapy; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D016756:Immunoglobulins, Intravenous; D014841:von Willebrand Factor
keywords: Acquired von Willebrand syndrome; Amyloid light-chain amyloidosis; Fibrinolysis; Monoclonal gammopathy of undetermined significance; Multiple myeloma; Waldenström’s macroglobulinemia