Editors' ChoiceCardiovascular Disease

Getting the Yin Without the Yang with Antiplatelet Therapy

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Science Translational Medicine  04 Jul 2012:
Vol. 4, Issue 141, pp. 141ec118
DOI: 10.1126/scitranslmed.3004531

When platelet function is inhibited, we are no longer able to form clots to stop bleeding or prevent a heart attack. Nevertheless, the goal of antiplatelet therapies is to prevent blood clots in the arteries during acute coronary syndromes and percutaneous coronary interventions (PCIs). However, these therapies also run the risk of increased bleeding. Zhang et al. have now identified an inhibitor, PZ-128, which may be able to decrease arterial blood clots without affecting bleeding—in essence, decreasing the "yin" without affecting the "yang" in the delicate balance of hemostasis and thrombosis.

The authors identified PZ-128—a cell-penetrating pepducin inhibitor against the PAR1 receptor in platelets—by screening 57 pepducins derived from the intracellular loops of PAR1. Using guinea pigs, which is the only other animal species besides humans and other primates to have PAR1 on their platelets, they showed that PZ-128 can specifically inhibit ex vivo platelet aggregation that had been induced by a PAR1 agonist but not when aggregation had been induced by other types of platelet agonists. They also used a carotid artery chemical injury model in guinea pigs to show that PZ-128 inhibits arterial thrombosis in a dose-dependent manner when used alone, and has synergistic effects with another clinically used antiplatelet agent, clopidogrel. In addition, the authors found that PAR1 inhibition by PZ-128 was reversible and has a rapid onset of action (maximal activity at 30 minutes) and elimination (24 to 48 hours), which reduces the risk of excessive bleeding in patients undergoing PCIs. Most importantly, PZ-128 was found to inhibit platelet-dependent clot formation under conditions of high arterial blood flow without affecting hemostasis parameters, such as bleeding time, activated clotting time, or platelet counts, making it a better alternative to existing therapies.

Zhang and colleagues obtained similar results in baboons, suggesting that this antiplatelet approach may work in humans. Specific PAR1 inhibition represents a novel therapeutic strategy for inhibiting arterial thrombosis in patients at risk for blood clots. The numerous positive attributes of PZ-128—which include rapid onset of action, reversibility, potency, specificity, and rapid elimination—puts it above other small-molecule inhibitors of PAR1.

P. Zhang et al., Suppression of arterial thrombosis without affecting hemostatic parameters with a cell-penetrating PAR1 pepducin. Circulation 15 June 2012 (10.1161/CIRCULATIONAHA.112.091918). [Abstract]

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