Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated.
Glycoprotein (GP) IIb/IIIa antagonists are effective therapeutic agents, but elicit thrombocytopenia with a frequency that approaches 2%. Here, we provide evidence that thrombocytopenia in humans treated with the GP IIb/IIIa antagonist roxifiban is immune mediated. Two patients underwent conversion to a highly positive drug-dependent antibody (DDAB) status temporally associated with thrombocytopenia. Despite the continued presence of DDABs, the fall in platelet count was reversed by discontinuation of drug treatment, pointing to the exquisite drug dependency of the immune response. DDABs appear to bind to neoepitopes in GP IIb/IIIa elicited on antagonist binding. This information was used to develop an enzyme-linked immunosorbent assay (ELISA) for DDAB using solid-phase GP IIb/IIIa. A high level of specificity is indicated by the observation that DDAB binding is dependent on the chemical structure of the GP IIb/IIIa antagonist and that only 2% to 5% of human blood donors and 5% of chimpanzees present with pre-existing DDABs. Furthermore, none of 108 nonthrombocytopenic patients from the phase II roxifiban study showed an increase in antibody titer. Absorption of thrombocytopenia plasma with platelets reduced the DDAB ELISA signal, indicating that the test detects physiologically relevant antibodies. Screening patients for pre-existing or increasing DDAB titer during treatment with GP IIb/IIIa antagonists may reduce the incidence of drug-induced thrombocytopenia.
Billheimer
Jeffrey T
JT
Department of Chemical Enzymology, Bristol-Myers Squibb Pharma Company, Wilmington, DE 19880-0400, USA.
Dicker
Ira B
IB
Wynn
Richard
R
Bradley
Jodi D
JD
Cromley
Debra A
DA
Godonis
Helen E
HE
Grimminger
Lisa C
LC
He
Bokang
B
Kieras
Cathy J
CJ
Pedicord
Donna L
DL
Spitz
Susan M
SM
Thomas
Beth E
BE
Zolotarjova
Nina I
NI
Gorko
Mary A
MA
Hollis
Gregory F
GF
Daly
Robert N
RN
Stern
Andrew M
AM
Seiffert
Dietmar
D
D000284:Administration, Oral; D000578:Amidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000818:Animals; D000906:Antibodies / Q000032:analysis / Q000097:blood / Q000276:immunology; D001682:Biological Availability; D017322:Clinical Trials, Phase II as Topic; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D007700:Kinetics; D002679:Pan troglodytes; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology*; D011487:Protein Conformation; D012680:Sensitivity and Specificity; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000276:immunology
D000578:Amidines; D000906:Antibodies; D000939:Epitopes; D007555:Isoxazoles; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C118235:roxifiban