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 of 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.
Future longitudinal studies are needed to test whether inflammatory markers mediate the relationships between smoking, clinical risk factors, and suicidal behavior; and to examine whether smoking cessation could reduce the risk for suicidal behavior in at-risk patients.
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