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 IgG3 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.
van Genderen
P J
PJ
Department of Hematology, University Hospital Dijkzigt, Rotterdam, The Netherlands.
Vink
T
T
Michiels
J J
JJ
van 't Veer
M B
MB
Sixma
J J
JJ
van Vliet
H H
HH
D000368:Aged; D000369:Aged, 80 and over; D001323:Autoantibodies / Q000097:blood* / Q000494:pharmacology; D002460:Cell Line; D003094:Collagen / Q000378:metabolism*; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood* / Q000145:classification; D007075:Immunoglobulin M / Q000097:blood; D008228:Lymphoma, Non-Hodgkin / Q000097:blood* / Q000150:complications / Q000276:immunology; D008297:Male; D010265:Paraproteinemias / Q000097:blood* / Q000150:complications / Q000276:immunology; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D014842:von Willebrand Diseases / Q000097:blood / Q000209:etiology* / Q000276:immunology; D014841:von Willebrand Factor / Q000096:biosynthesis / Q000378:metabolism*
D001323:Autoantibodies; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D003094:Collagen