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Published on: October 26, 2018
Abacavir increases platelet reactivity via competitive inhibition of soluble guanylyl cyclase
Paul D Baum1, Paul M Sullam, Cheryl A Stoddart
1Division of Experimental Medicine, Department of Medicine bVeterans Affairs Medical Center, University of California San Francisco, San Francisco, California 94143-1234 , USA. paul.baum@ucsf.edu
Objective:
To provide a molecular mechanism that explains the association of the antiretroviral guanosine analogue, abacavir, with an increased risk of myocardial infarction.
Design:
Drug effects were studied with biochemical and cellular assays.
Methods:
Human platelets were incubated with nucleoside analogue drugs ex vivo. Platelet activation stimulated by ADP was studied by measuring surface P-selectin with flow cytometry. Inhibition of purified soluble guanylyl cyclase was quantified using an ELISA to measure cGMP production.
Results:
Pre-incubation of platelets in abacavir significantly increased activation in response to ADP in a time and dose-dependent manner. The active anabolite of abacavir, carbovir triphosphate, competitively inhibited soluble guanylyl cyclase activity with a K(i) of 55 micromol/l.
Conclusion:
Abacavir competitively inhibits guanylyl cyclase, leading to platelet hyperreactivity. This may explain the observed increased risk of myocardial infarction in HIV patients taking abacavir.
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