Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa.
Acute thrombocytopenia is a recognized complication of treatment with GPIIb/IIIa inhibitors whose cause is not yet known. We studied 9 patients who developed severe thrombocytopenia (platelets less than 25 x 10(9)/L) within several hours of treatment with the GPIIb/IIIa inhibitors tirofiban (4 patients) and eptifibatide (5 patients). In each patient, acute-phase serum contained a high titer (range, 1:80-1:20 000) IgG antibody that reacted with the glycoprotein IIb/IIIa complex only in the presence of the drug used in treatment. Four patients had been previously treated with the same drug, but 5 had no known prior exposure. Pretreatment serum samples from 2 of the latter patients contained drug-dependent antibodies similar to those identified after treatment. No tirofiban- or eptifibatide-dependent antibodies were found in any of 100 randomly selected healthy blood donors, and only 2 of 23 patients receiving tirofiban or eptifibatide who did not experience significant thrombocytopenia had extremely weak (titer, 1:2) tirofiban-dependent antibodies. In preliminary studies, evidence was obtained that the 9 antibodies recognize multiple target epitopes on GPIIb/IIIa complexed with the inhibitor to which the patient was sensitive, indicating that they cannot all be specific for the drug-binding site. The findings indicate that acute thrombocytopenia after the administration of tirofiban or eptifibatide can be caused by drug-dependent antibodies that are "naturally occurring" or are induced by prior exposure to drug. These antibodies may be human analogs of mouse monoclonal antibodies that recognize ligand-induced binding sites (LIBS) induced in the GPIIb/IIIa heterodimer when it reacts with a ligand-mimetic drug.
Blood Research Institute, The Blood Center of Southeastern Wisconsin, PO Box 2178, Milwaukee, WI 53201-2178, USA. dwbougie@bcsew.edu
Daniel W
DW
Bougie
Peter R
PR
Wilker
Elizabeth D
ED
Wuitschick
Brian R
BR
Curtis
Mohammad
M
Malik
Stewart
S
Levine
Richard N
RN
Lind
Jaime
J
Pereira
Richard H
RH
Aster
D000208:Acute Disease; D000368:Aged; D001323:Autoantibodies / Q000097:blood*; D002118:Calcium / Q000494:pharmacology; D016022:Case-Control Studies; D003429:Cross Reactions; D000939:Epitopes / Q000276:immunology; D000077542:Eptifibatide; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000009:adverse effects*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000276:immunology*; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000276:immunology; D000077466:Tirofiban; D014443:Tyrosine / Q000009:adverse effects* / Q000031:analogs & derivatives*
D001323:Autoantibodies; D000939:Epitopes; D008024:Ligands; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; D000077466:Tirofiban; D000077542:Eptifibatide; D002118:Calcium