Autoantibody inhibits binding of von Willebrand factor to glycoprotein Ib and collagen in multiple myeloma: recognition sites present on the A1 loop and A3 domains of von Willebrand factor.

Abstract

A 49-year-old man with multiple myeloma (IgG-lambda Bence-Jones protein positive) presented a bleeding tendency: characterized intramuscular hemorrhage. Coagulation studies showed a von Willebrand factor (vWF) defect (Duke bleeding time > 20 min; ristocetin cofactor activity [vWF:RC] < 6%; significant reduction of large multimers of vWF. Mixing study suggested the presence of inhibitor directed against vWF:RC activity and collagen binding activity of vWF. The inhibitor was identified as an antibody of the IgG class. The inhibitor blocked the interaction of vWF with glycoprotein Ib in the presence of ristocetin, as did the pepsin-digested fragment of the inhibitor [F(ab)2'], but neither blocked botrocetin-mediated interaction of vWF with glycoprotein Ib. They also inhibited the binding of vWF to immobilized collagen type I. The inhibitor and the F(ab)2' reacted strongly with native vWF and fragment I (amino acids 911-1365) and with the 39/34 kDa fragment (amino acids 480/481-718), but not with fragment II (amino acids 1366-2050) and fragment III-T2 (heavy chains, amino acids 273-511; light chains, amino acids 674-728). We conclude that the IgG antibody inhibits both vWF:RC activity and the binding of vWF to collagen by reacting with the epitopes present on the A1 loop and A3 domains of vWF.