A myeloma paraprotein with specificity for platelet glycoprotein IIIa in a patient with a fatal bleeding disorder.

Abstract

Impaired platelet aggregation, normal shape change, and agglutination and normal ATP secretion and thromboxane synthesis in response to high concentrations of thrombin or arachidonic acid were found in a patient with multiple myeloma and hemorrhagic tendency. The purified IgG1 kappa or its F(ab'}2 fragments induced similar changes when added in vitro to plateletrich plasma from normal subjects. In addition, the paraprotein inhibited adhesion to glass microbeads, fibrin clot retraction, and binding of radiolabeled fibrinogen or von Willebrand factor to platelets exposed to thrombin or arachidonic acid without affecting intraplatelet levels of cAMP. The radiolabeled paraprotein bound to an average of 35,000 sites on normal platelets but it bound to <2,000 sites on the platelets from a patient with Glanzmann's thrombasthenia. Immunoprecipitation studies showed that the platelet antigen identified by the paraprotein was the glycoprotein IlIa. Furthermore, binding of radiolabeled prostaglandin El (PGEI) to resting platelets as well as binding of von Willebrand factor to platelets stimulated with ristocetin were entirely normal in the presence of patient's inhibitor. These studies indicate that bleeding occurring in dysproteinemia may be the result of a specific interaction of monoclonal paraproteins with platelets. In addition, our data support the concept that the interaction of fibrinogen and/or von Willebrand factor with the platelet glycoprotein Ilb-IIla complex is essential for effective hemostasis.

Platelet-associated anti–GPIIb-IIIa autoantibodies in chronic immune thrombocytopenic purpura recognizing epitopes close to the ligand-binding site of glycoprotein (GP) IIb

“…51,52 On the other hand, GT-like functional defects caused by anti-GPIIb-IIIa autoantibodies without thrombocytopenia have been reported in some patients with bleeding tendency. [53][54][55][56][57][58] Although analysis of platelet function in chronic ITP has been limited by concomitant thrombocytopenia, our sensitive ELISA suggested that in most patients, PA anti-GPIIbIIIa autoantibodies have the potential to inhibit fibrinogen binding and may contribute to functional defects in this disorder. In addition, it has recently been suggested that antibodies directed against conformational epitopes on GPIIb-IIIa are more pathogenic than other platelet antibodies and act through an Fc-dependent mechanism in an animal model.…”

Abnormally high thromboxane biosynthesis in homozygous homocystinuria. Evidence for platelet involvement and probucol-sensitive mechanism.

“…Aggregation of platelets in platelet-rich plasma, TXB2 synthesis, and ATP secretion in response to 1 or 5 U/ml thrombin, preparation of suspensions ofwashed platelets, purification and labeling of human fibrinogen, thrombin-dependent fibrinogen binding, and analysis ofthe binding data were performed as previously described (23). For studies on the sensitivity of platelets to aggregating agents, the AC50 was calculated.…”

Bleeding and Thrombosis Risks in Plasma Cell Dyscrasias

“…Rarely, in vitro investigations have confirmed that bleeding and abnormal platelet aggregation studies were due to a paraprotein-specific qualitative platelet defect such as binding to GPIIIa. 10 Over 450 cases of acquired von Willebrand factor (VWF) deficiency, representing multiple underlying disorders and probable mechanisms, have been published or summarized in an international registry of acquired von Willebrand syndrome (AVWS). 11 Although an accurate estimate of the incidence of AVWS is not available, clinically apparent cases are uncommon.…”