Eptifibatide-induced thrombocytopenia and thrombosis in humans require FcgammaRIIa and the integrin beta3 cytoplasmic domain.
Thrombocytopenia and thrombosis following treatment with the integrin alphaIIbbeta3 antagonist eptifibatide are rare complications caused by patient antibodies specific for ligand-occupied alphaIIbbeta3. Whether such antibodies induce platelet clearance by simple opsonization, by inducing mild platelet activation, or both is poorly understood. To gain insight into the mechanism by which eptifibatide-dependent antibodies initiate platelet clearance, we incubated normal human platelets with patient serum containing an alphaIIbbeta3-specific, eptifibatide-dependent antibody. We observed that in the presence of eptifibatide, patient IgG induced platelet secretion and aggregation as well as tyrosine phosphorylation of the integrin beta3 cytoplasmic domain, the platelet FcgammaRIIa Fc receptor, the protein-tyrosine kinase Syk, and phospholipase Cgamma2. Each activation event was inhibited by preincubation of the platelets with Fab fragments of the FcgammaRIIa-specific mAb IV.3 or with the Src family kinase inhibitor PP2. Patient serum plus eptifibatide did not, however, activate platelets from a patient with a variant form of Glanzmann thrombasthenia that expressed normal levels of FcgammaRIIa and the alphaIIbbeta3 complex but lacked most of the beta3 cytoplasmic domain. Taken together, these data suggest a novel mechanism whereby eptifibatide-dependent antibodies engage the integrin beta3 subunit such that FcgammaRIIa and its downstream signaling components become activated, resulting in thrombocytopenia and a predisposition to thrombosis.
Gao
Cunji
C
Blood Research Institute, Blood Center of Wisconsin, 638 N. 18th Street, Milwaukee, WI 53201, USA.
Boylan
Brian
B
Bougie
Dan
D
Gill
Joan C
JC
Birenbaum
Jessica
J
Newman
Debra K
DK
Aster
Richard H
RH
Newman
Peter J
PJ
D000368:Aged; D000906:Antibodies / Q000276:immunology; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology; D023921:Coronary Stenosis / Q000097:blood / Q000601:surgery; D000077542:Eptifibatide; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D039661:Integrin beta3 / Q000276:immunology*; D008297:Male; D010455:Peptides / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D015539:Platelet Activation / Q000276:immunology / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010976:Platelet Count; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015607:Stents; D013915:Thrombasthenia / Q000097:blood / Q000235:genetics / Q000276:immunology; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000276:immunology*; D013927:Thrombosis / Q000139:chemically induced* / Q000276:immunology*
D000906:Antibodies; C080568:Fc gamma receptor IIA; D007074:Immunoglobulin G; D039661:Integrin beta3; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D017452:Receptors, IgG; D006493:Heparin; D000077542:Eptifibatide