Heparin-associated thrombocytopenia: observations on the mechanism of platelet aggregation.
We investigated the mechanism of heparin-mediated platelet aggregation in 11 patients with heparin-associated thrombocytopenia. Severe thrombocytopenia (16,000 to 66,000 platelets/microliters) developed in each patient during heparin therapy, and platelet aggregation occurred in vitro when heparin was added to mixtures of patient plasma and normal platelet-rich plasma. In 10 patients, heparin-initiated platelet aggregation was inhibited by preincubation of mixtures of normal platelet-rich plasma and heparin-associated thrombocytopenia plasma with monoclonal antiglycoprotein Ib antibodies 6D1 or LJ-Ib1. Both antibodies are directed against the von Willebrand factor binding site on glycoprotein Ib and inhibit only ristocetin-induced platelet agglutination. Purified immunoglobulin G (IgG) from patients with heparin-associated thrombocytopenia also supported heparin-induced aggregation, but equivalent amounts of antigen-binding fragments [F(ab')2] did not. We also found that F(ab')2 of LJ-Lb1 did not inhibit heparin-induced platelet aggregation but retained inhibitory activity against ristocetin-induced platelet agglutination. The monoclonal antibody 3G6, directed against the alpha-chain of glycoprotein Ib but not inhibitory of ristocetin-induced platelet agglutination, had no effect on heparin-induced platelet aggregation. Antibodies to von Willebrand factor that inhibit ristocetin-induced platelet agglutination did not inhibit heparin-mediated platelet aggregation, but antibodies to glycoprotein IIb-IIIa blocked aggregation. These data suggest that platelet aggregation in heparin-associated thrombocytopenia may be initiated by an interaction between patient IgG, heparin, and the platelet surface. Platelet activation appears to be mediated by a platelet surface crystallizable fragment (Fc) receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Adelman
B
B
Department of Medicine, Hunter Holmes McGuire Veterans Administration Hospital, Richmond, VA 23249.
Sobel
M
M
Fujimura
Y
Y
Ruggeri
Z M
ZM
Zimmerman
T S
TS
D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects*; D010980:Platelet Membrane Glycoproteins / Q000276:immunology / Q000502:physiology; D011961:Receptors, Fc / Q000502:physiology; D013921:Thrombocytopenia / Q000139:chemically induced*; D014841:von Willebrand Factor / Q000502:physiology
D007074:Immunoglobulin G; D010980:Platelet Membrane Glycoproteins; D011961:Receptors, Fc; D014841:von Willebrand Factor; D006493:Heparin