Drug-induced
Immune thrombocytopenia (DIT) is a common complication of several medications, including commonly used
antibiotics. The most widely studied DIT is caused by
quinine. In DIT,
antibodies predominantly bind to the
platelet membrane glycoprotein (GP) IX in a drug-dependent fashion resulting in increased platelet clearance. Binding of the sensitizing drug, such as
quinine, to GPIX has been proposed but is yet to be established. This work demonstrates that
quinine is retained specifically by human GPIX.
Quinine binding was first analyzed in wild-type mouse platelets and in transgenic mouse platelet expressing human GPIX using high performance liquid chromatography. Binding of
quinine to GPIX was then measured in Chinese hamster ovary (CHO) cells expressing a combination of wild type, human or mouse, three human/mouse chimeric constructs and six mutant GPIX
proteins.
Quinine was retained by human GPIX. No detectable absorption was observed with mouse GPIX or human GPIbα. The
quinine binding site was mapped to residues 110-115 of human GPIX suggesting that
quinine interacts with specific residues of the GP. These findings provide further insights into the molecular mechanisms of DIT.