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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:555.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

Individual Heterogeneity in Platelet Response to Lysophosphatidic Acid

Evidence for a Novel Inhibitory Pathway

Zehra Pamuklar; Jin Sun Lee; Hsin-Yuan Cheng; Manikandan Panchatcharam; Steve Steinhubl; Andrew J. Morris; Richard Charnigo; Susan S. Smyth

From the Division of Cardiovascular Medicine (Z.P., H.-Y.C., M.P., S.S., A.J.M., R.C., S.S.), The Gill Heart Institute, University of Kentucky, Lexington; the School of Medicine (J.S.L.), The University of North Carolina at Chapel Hill; and the Department of Biostatistics (R.C.), College of Public Health, University of Kentucky, Lexington and the Department of Veterans Affairs Medical Center, Lexington, KY (S.S.S.).

Correspondence to Susan S. Smyth, MD PhD, The Gill Heart Institute, 326 Charles T Wethington Building, 900 S. Limestone Street, Lexington, KY 40536. E-mail susansmyth{at}uky.edu

Abstract

Objective— The bioactive lipid lysophosphatidic acid (LPA) stimulates platelet actin reorganization, adhesion, shape change, and aggregation. LPA is present in blood and exposure or release of LPA after atherosclerotic plaque rupture has been proposed to trigger platelet thrombus formation.

Methods and Results— In this report, we characterize heterogeneity in LPA responses among individuals. Platelets isolated from approximately 20% of healthy donors consistently failed to aggregate in response to LPA. Our studies indicate that, rather than lacking stimulatory pathways, platelets from "nonresponsive" donors respond to LPA by triggering inhibitory pathway(s) to block platelet aggregation. Consistent with this observation, LPA-induced aggregation could be partially restored to "nonresponsive" platelets by pharmacological inhibition of cAMP generation. LPA "nonresponsiveness" may be related to heightened platelet expression of LPA receptor 4 and PPAR. Among 70 patients with stable coronary artery disease (CAD), only 1 (1.4%) was identified as an LPA nonresponder. Moreover, in 33 patients presenting for diagnostic catheterization, CAD was identified as having a bivariate association with platelet LPA responder/nonresponder status.

Conclusions— Platelet LPA signaling may involve stimulatory and inhibitory pathways, with the inhibitory pathway predominating in 20% of individuals. Diseases such as CAD that affect platelet reactivity may attenuate this inhibitory pathway in platelets.

The bioactive lipid mediator lysophosphatidic acid stimulates actin reorganization and aggregation of human platelets. We report that LPA may trigger an inhibitory response in platelets from 20% of healthy individuals. Furthermore, we provide evidence that the presence of coronary artery disease may attenuate this inhibitory pathway.

Key Words: platelet aggregation • platelet activation • lysophosphatidic acid • coronary artery disease