Beta-lactam antibiotics exert inhibitory effects on platelets, in part, by binding to the platelet surface and thereby preventing interaction of platelet agonists with their receptors. We have investigated the effect of penicillin G on the membrane receptor glycoproteins lb, lb/IX complex, llb/llla complex and PADGEM (platelet activation dependent granule-external membrane protein). Aggregation measurements, immunoblotting and flow cytometric techniques were used to assess the surface receptor functions. Aggregation studies showed inhibition of thrombin-induced aggregation after exposure of platelet concentrates for 24-48 hours to 2-10 mM penicillin G. Inhibition of aggregation was also observed after exposure of washed platelets to the antibiotic for 15 minutes. Plasma membranes were isolated for platelets after incubation with or without penicillin G for 24 hours. SDS-page and immunoblotting with antibodies to glycoproteins lb and llb showed no effect of penicillin G on glycoprotein migration or concentration. Dose-dependent effects of penicillin G on activation-induced changes in the glycoprotein receptors have been observed by flow cytometry. Thrombin- mediated expression of PADGEM, down-regulation of GPlb and GPlb/IX complex, and up-regulation of GPllb/llla complex were all inhibited by millimolar concentrations of penicillin. These results suggest that penicillin G induces platelet dysfunction by impairing the activation- linked regulation of surface receptors. Further studies will be aimed at elucidation of the mechanisms of induction of surface receptors. Further studies will be aimed at elucidation of the mechanisms of induction of the acquired abnormalities of platelet function using immunological and flow cytometric techniques. One manuscript describing a portion of this work has been submitted to Blood and is in revision. A second manuscript is in preparation.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Intramural Research (Z01)
Project #
1Z01BH001012-02
Application #
3804877
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Center Biologics Evaluation Research Hematology
Department
Type
DUNS #
City
State
Country
United States
Zip Code