We have identified a patient with
IgD lambda-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 lambda light chain. The lambda dimer
protein (M-
protein) inhibited ristocetinand high shear-induced platelet aggregation, dependent on
platelet glycoprotein Ibalpha (GPIbalpha), but not
epinephrine-,
collagen-,
ADP-,
thrombin-, or
botrocetin-induced platelet aggregation. The lambda 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 lambda dimer
protein in the presence of
ristocetin, suggesting that the lambda 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 lambda dimer
protein was assayed in the presence of various anti-A1 domain
monoclonal antibodies. Based on these data, we conclude that the lambda dimer
protein binds to the region of the A1 domain composed of helices alpha3 and alpha4 and thus interferes with VWF-GPIbalpha 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 GPIbalpha to VWF is abrogated, supporting the relevance of shear-induced VWF interaction with GPIbalpha in the initiation of the
hemostatic process.