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Importance of platelets and platelet response in acute coronary syndromes

April 1, 2009|Cleveland Clinic Journal of Medicine
Kandice Kottke-Marchant, MD, PhD
Author and Disclosure Information

Kandice Kottke-Marchant, MD, PhD
Chair, Pathology and Laboratory Medicine Institute, and Section Head, Hemostasis and Thrombosis, Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH

Correspondence: Kandice Kottke-Marchant, MD, PhD, Chair, Pathology and Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, L21, Cleveland, OH 44195; marchak@ccf.org

Dr. Kottke-Marchant reported that she has no financial interests or relationships that pose a potential conflict of interest with this article.

This article was developed from an audio transcript of Dr. Kottke-Marchant’s lecture at the CME course that formed the basis of this supplement. The transcript was edited and formatted by the Cleveland Clinic Journal of Medicine staff for clarity and conciseness, and was then reviewed, revised, and approved by Dr. Kottke-Marchant.

Dr. Kottke-Marchant received honoraria for contributing to this supplement and the CME course on which it was based. The honoraria were paid by the Cleveland Clinic Center for Continuing Education from the educational grant from Daiichi Sankyo, Inc., and Eli Lilly and Co. that supported the course and this supplement. These grantors had no input on the content of the course or this supplement.

ABSTRACT

Platelet activation is one of the essential steps in the genesis and propagation of atherothrombosis. Accumulating clinical evidence suggests that an elevated platelet count, platelet activation, and platelet hyperreactivity (defined as residual platelet activity despite antiplatelet drug therapy) may be associated with adverse cardiovascular events in patients with acute coronary syndromes. Platelet function can be analyzed using various assays and measures of platelet activation. The best assays for measuring residual platelet activity in the setting of antiplatelet therapy are still being defined, as are their predictive values. Platelet aggregation remains the gold standard, but other testing methods offer advantages for specific applications, such as detecting overall platelet hyperreactivity in the presence of antiplatelet therapy or detecting inhibition of the adenosine diphosphate receptor P2Y12. Standard testing protocols for platelet aggregation are needed to achieve consistency among studies.

KEY POINTS

  • Platelet function assays are inherently variable because they measure cell function rather than a single analyte.
  • Screening tests, or global tests for platelet function, do not identify specific causes of platelet dysfunction but combine measurement of different aspects of platelet function.
  • There appears to be a subgroup of patients with stable cardiovascular disease who have an increased risk of major cardiac events associated with platelet hyperreactivity.
  • For predicting cardiac events, receiver operating characteristic (ROC) curve analysis should be used to objectively define cutoff values for platelet hyperreactivity as opposed to reliance on arbitrary cutoff values.

Figure 1. Resting platelets stimulated by an agonist become activated; the activated platelets can trigger intravascular thrombosis and inflammatory processes and have been implicated in atherogenesis and development of acute coronary syndromes. Antiplatelet drug therapy is designed to result in a therapeutic response due to inhibited or diminished platelet activation in response to agonists. There is increasing evidence, however, that preserved platelet activity despite the presence of antiplatelet drugs, or platelet hyperreactivity, may be associated with adverse cardiovascular events.
Platelets play a substantial role in atherothrombosis, and platelet activation is implicated in the genesis of acute coronary syndromes (ACS) (Figure 1). This review describes platelet function and the mechanisms behind platelet activation, the utility of laboratory tests of platelet function for assessing cardiovascular risk, and the role of platelets in various phases of atherosclerosis. Against this backdrop, the article concludes by reviewing current evidence on the association between platelet hyperreactivity—defined as residual platelet activity despite antiplatelet drug therapy—and ACS. Here and throughout this supplement, ACS is understood to comprise unstable angina and myocardial infarction (MI) with or without ST-segment elevation.

PLATELET FUNCTION

Platelets are non-nucleated cells produced by megakaryocytes, which are very large cells (50 to 100 μm in diameter) found in bone marrow. The megakaryocyte surface membrane forms protoplatelet extensions from which platelets “bud off” and are emitted into the circulation, where they number approximately 200,000 to 400,000 per microliter of blood.

Platelet activation

Platelets play a crucial role in the vascular response to injury, and activation of platelets has long been recognized as an important step. Platelets release dense granules that contain the nucleotide adenosine diphosphate (ADP), which activates other platelets. They also possess alpha granules, which contain proteins and protein mediators (eg, platelet-derived growth factor, platelet factor 4) that are involved in inflammatory processes. The platelet surface is coated with hundreds of thousands of receptors for other cells, including activated vascular wall cells and extracellular matrix proteins. Platelets possess an affinity for adherence, especially to injured vessel walls, where they release their granule contents and then aggregate. These properties promote platelets’ involvement in many vascular processes, including ACS, as will be explored below.

Platelets exist in a nonactivated state and are drawn passively into areas of vascular injury. Initially, they adhere to proteins such as von Willebrand factor, which is a large extracellular matrix protein produced by endothelial cells. The platelet glycoprotein Ib/IX/V binds to von Willebrand factor, forming a loose association that results in platelets rolling on the surface of the vessel wall. As a multimer, von Willebrand factor exists in one subunit that is dimerized and then polymerized, making it an ideal substrate for platelets because of the multiple substrates to which platelets can adhere.

Reprinted, with permission, from Kottke-Marchant K, ed. An Algorithmic Approach to Hemostasis Testing. Northfield, IL: College of American Pathologists; 2008. © 2008 College of American Pathologists.
Figure 2. In the process of platelet activation, unactivated circulating platelets initially encounter an area of vascular injury and adhere rapidly to exposed von Willebrand factor (vWF) through the glycoprotein (GP) Ib/IX/V membrane receptor. Collagen in the extracellular matrix is also engaged through receptors α2β1 (GPIa/IIa) and GPVI, leading to platelet shape change and activation. Cell signaling results in conformational change in the fibrinogen receptor GPIIb/IIIa (αIIbβ3), with binding to fibrinogen and fibrin leading to platelet aggregation and thrombus formation.
Platelets are then engaged through receptors for collagen (ie, glycoprotein Ia/IIa or integrin α2β1) and glycoprotein VI, leading to intracellular signaling and activation of the platelets. Platelet activation is followed by firm adhesion through engagement of another integrin, the αIIbβ3 (glycoprotein IIb/IIIa) receptor, on platelet surfaces for fibrinogen. The glycoprotein IIb/IIIa receptor is involved in a homotypic platelet–platelet inter­action with an αIIbβ3 receptor on another platelet, which attracts further platelets and results in platelet–platelet adhesion, called platelet aggregation. This platelet cascade is depicted in Figure 2.

Platelet fibrinogen receptor

The platelet fibrinogen receptor (glycoprotein IIb/IIIa receptor) is an αIIbβ3 integrin that binds to arginine-glycine-aspartic acid (RGD) epitopes of proteins, such as fibrinogen. Fibrinogen has a two-dimensional symmetry, with RGD groups on both ends of the molecule, which makes it an ideal molecule for linking platelet to platelet.

von Willebrand factor has RGD groups, as do both fibronectin and glycoprotein IIb/IIIa vitronectin, and can therefore bind to many plasma and extracellular matrix proteins. The glycoprotein IIb/IIIa receptor is inactive in resting platelets. It becomes activated during the platelet activation process and binds to fibrinogen, which bridges to other platelets, causing aggregation.

ADP receptors

Various receptors on platelet surfaces are responsible for platelet activation. One is a family of receptors for ADP. As ADP is released from platelets, it can then activate other platelets by binding to the receptors. The ADP receptor P2Y12 signals through G protein pathways and is coupled to adenylate cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate to cyclic adenosine monophosphate (cAMP). High levels of cAMP inhibit platelet function; ADP binding to P2Y12 shuts down adenylate cyclase, which leads to phospho­inositide 3-kinase activation and accelerated aggregation and platelet release.

A final notable factor in the mediation of platelet activation and aggregation is phospholipase A2, which liberates arachidonic acid from the platelet membrane, metabolizing it through cyclooxygenase and thromboxane synthase to generate thromoboxane A2, which leads to release of platelet granule contents and aggregation of other platelets.

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