Na+/H+ exchanger in the regulation of platelet activation and paradoxical effects of cariporide

• Overview of the current research of platelet biology and regulation
• Summary of the roles of Na+/H+ exchanger 1 in the regulation of platelet function
• Insight for NHE1 as a therapeutic target for ischemia–reperfusion injury
• Paradoxical effects of cariporide on platelet activation and ischemic stroke
• A need to better understand NHE1 in platelet function and procoagulant regulation

Platelets are anucleated cell fragments derived from mature megakaryocytes and function in hemostasis when the endothelium is injured. Hemostasis involving platelets can be divided into four phases: adhesion, activation, secretion, and aggregation. Platelet activation requires a rise in intracellular Ca2 + concentrations and results in both a morphological change and the secretion of platelet granule contents. Na+/H+ exchanger isoform 1 (NHE1) regulates the intracellular pH (pHi) and the volume of platelets. In addition, NHE1 plays a large role in platelet activation. Thrombus generation involves NHE1 activation and an increase in [Ca2 +]i, which results from NHE1-mediated Na+ overload and the reversal of the Na+/Ca2 + exchanger. Cariporide (HOE-642), a potent NHE1 inhibitor, has inhibitory effects on the degranulation of human platelets, the formation of platelet–leukocyte-aggregates, and the activation of the GPIIb/IIIa receptor (PAC-1). However, despite the demonstrated protection against myocardial infarction as mediated by cariporide in patients undergoing coronary artery bypass graft surgery, the EXPEDITION clinical trial revealed that cariporide treatment increased mortality due to thromboembolic stroke. These findings suggest that a better understanding of NHE1 and its effect on platelet function and procoagulant factor regulation is warranted in order to develop therapies using NHE inhibitors.