Characterization of a myeloma patient with a life-threatening hemorrhagic diathesis: presence of a lambda dimer protein inhibiting shear-induced platelet aggregation by binding to the A1 domain of vonWillebrand factor

Summary

We have identified a patient with IgD λ-type multiple myeloma who was characterized by a severe bleeding tendency, especially after puncture of arterial vessels. Both the bleeding time (>25 min) and activated partial thromboplastin time (APTT) were prolonged. To clarify the underlying pathogenesis, we purified the APTT-prolonging activity from the patient’s serum. The purified protein was a highly negatively-charged homodimer of the λ light chain. The λ dimer protein (M-protein) inhibited ristocetin-and high shear-induced platelet aggregation, dependent on platelet glycoprotein Ibα (GPIbα), but not epinephrine-, collagen-, ADP-, thrombin-, or botrocetin-induced platelet aggregation. The λ dimer protein inhibited the binding of platelets to immobilized or ristocetin-treated von Willebrand factor (VWF). Furthermore, a 39/34 kD fragment of VWF encompassing the A1 domain specifically bound to the immobilized λ dimer protein in the presence of ristocetin, suggesting that the λ dimer protein directly binds to the A1 domain of VWF. To help elucidate the binding site within the A1 domain, binding of ristocetin-treated VWF to the immobilized λ dimer protein was assayed in the presence of various anti-A1 domain monoclonal antibodies. Based on these data, we conclude that the λ dimer protein binds to the region of the A1 domain composed of helices α3 and α4 and thus interferes with VWF-GPIbα interaction. The existence of a protein that inhibits high shear-induced platelet aggregation in acquired von Willebrand disease (VWD) has only rarely been reported. The results suggest that the hemostatic function in arteries with high shear force is profoundly disrupted if the binding of GPIbα to VWF is abrogated, supporting the relevance of shear-induced VWF interaction with GPIbα in the initiation of the hemostatic process.

Keywords

Von Willebrand disease - von Willebrand factor - platelet physiology - coagulation inhibitors

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