ACQUIRED VON-WILLEBRAND DISEASE CAUSED BY AN AUTOANTIBODY SELECTIVELY INHIBITING THE BINDING OF VON-WILLEBRAND-FACTOR TO COLLAGEN

An 82-year-old man with a low-grade malignant non-Hodgkin lymphoma and an IgG(3) lambda monoclonal gammopathy presented a recently acquired bleeding tendency, characterized by recurrent epistaxis, easy bruising, and episodes of melena, requiring packed red blood cell transfusions. Coagulation studies showed a von Willebrand factor (VWF) defect (Ivy bleeding time, > 15 minutes; vWF antigen [VWF:Ag], 0.08 U/mL; ristocetin cofactor activity [VWF:RCoF], <0.05 U/mL; collagen binding activity [vWF:CBA], 0.01 U/mL; absence of the high molecular weight multimers of vWF on multimeric analysis). Mixing experiments suggested the presence of an inhibitor directed against the vWF:CBA activity of vWF without significantly inhibiting the FVIII:C, vWF:Ag, and vWF:RCoF activities. The inhibitor was identified as an antibody of the IgM class by immunoabsorption of VWF and inhibitor-vWf complexes from the plasma of the patient. Subsequent immunoprecipitation experiments using recombinant fragments of vWF showed that the inhibitor reacted with both the glycoprotein Ib binding domain (amino acids [aa] 422-826) and the A3 (aa 909-1112) domain of vWF, but not with the A2 (aa 716-908) or D4 (aa 1183-1535) domains. We conclude that the IgM autoantibody inhibits the vWF:CBA activity by reacting with an epitope present on both the glycoprotein Ib and A3 domains of vWF. (C) 1994 by The American Society of Hematology.