Abacavir increases platelet reactivity via competitive inhibition of soluble guanylyl cyclase.

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 μmol/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.