Cardiovascular disease is the number one killer not only in the United States but also worldwide. It is responsible for 30% of all deaths.1 Platelets are known to play a crucial role not only in thrombosis but also in inflammation, immunity and atherogenesis. Atherogenesis is the process of plaque formation. Plaque forms along arterial walls restricting blood flow. Clinical evidence has also demonstrated that in patients that present with an elevated platelet count, platelet activation and platelet hyper-reactivity may be associated with adverse cardiovascular events.2
Platelets are produced by megakarocytes. They do not have a nucleus but do contain dense and alpha granules. Dense granules, contain adenosine diphosphate (ADP), serotonin and calcium.2 Alpha granules are composed of fibrinogen, platelet-derived growth factor, von Willebrand factor (vWF), P-selectin, platelet factor-4.1
When vascular injury occurs, platelets adhere to exposed von Willebrand factor (vWF) through a membrane receptor glycoprotein (GP) Ib/IX/V., the exposed vWF and collagen bind to circulating platelets and activate them. Extracellular collagen is recruited through other receptors of GP Ia/IIa and GPVI.1 This contributes to platelet shape change and activation. The contents of the alpha and dense granules are released (degranulation) to recruit more platelets to the site of vessel damage and to potentiate platelet activation. The platelets also synthesize and release thromboxane, another mediator of activation. The fibrinogen receptor, GP IIb/IIIa, undergoes a conformation change binding to fibrinogen and fibrin. This in turn leads to platelet aggregation and thrombus formation.2
Platelets and Arterial Thrombosis
When atherosclerotic plaque ruptures, the arterial extracellular matrix is exposed and platelet aggregation is initiated. This is called atherothrombosis. Simultanously, the coagulation cascade is activated via tissue factor pathway. These events are responsible for clot formation and a possible clinical diagnosis of either stroke or myocardial infarction (MI).1
There are three factors that determine the extent of thrombus formation once plaque ruptures: The degree of plaque disruption, the degree of stenosis, and the physicochemical properties of the surface exposed to the circulating blood. As stenosis, or narrowing of the vessels, increases so does the deposition of platelets resulting in a larger thrombus formation. The site can be influenced by the placement of deposition in relation to blood flow. A clinical event may occur depending on the stability of the platelet aggregates and the growth of thrombosis. Plaque is heterogeneous and its thrombotic potential is related to tissue factor content and lipids. All of this plays a role in acute coronary syndromes and is a predictor of cardiac outcomes after a myocardial infarction. Arterial platelet thrombosis has been found to be prevalent in cardiac arrest or sudden death and play a role in stroke and acute peripheral ischemia.3
Mechanisms for platelet hyperreactivity are poorly understood, for example did the platelet hyperreactivity contribute to the thrombotic event or did the stress of the event cause platelet activation. Platelet hyperreactivity may still persist despite treatment with anti-platelet drugs. These patients have increased risks of recurrent ischemic events. It has been demonstrated that several clinical, genetic and cellular factors contribute to this phenomena. Gene polymorphisms can account for 15-20% variability in platelet response to treatment. It is important to determine if a patient is a responder or a non-responder to aid in the prediction of possible clinical events.4
Platelet inhibitors have been demonstrated as a benefit to patients in the prevention and treatment regimen for acute vascular events by decreasing a patients risk by about 25%.3There are three major classes of platelet inhibitors: aspirin; the theinopyridine derivatives, and GP IIb/IIIa receptor antagonists
Aspirin inhibits platelet aggregation by irreversible acetylation of platelet cyclooxygenase ( COX) enzyme. This in turn blocks the transformation of arachidonic acid into thromboxane which is a vasoconstriction and aggregating agent. This process aids in the reduction of stroke, heart attacks and death by almost 25% of cardiovascular patients.5
Thienopyridines are a class of drug that work by restricting ADP-induced platelet activation by irreversible inhibition of the P2Y12 receptor. The most common drugs are clopidogrel, ticlopidine and prasugrel which are inactive prodrugs. These are metabolized by hepatic enzymes to become active metabolites. Clopidogrel is the drug of choice due to it having a faster onset and fewer side effects.6
A third class of antiplatelet drugs are the GP IIb/IIIa receptor antagonists. These class of drugs act by blocking the binding of fibrinogen to the platelet GP IIb/IIIa receptor. The three GP IIb/IIIa receptor antagonists used are abciximab, eptifibatide, and tirofiban in patients with acute coronary syndromes. Abciximab is a long lasting a monoclonal antibody that blocks the GP IIb/IIIa receptor. Eptifibatide and tirofiban are low-molecular-weight and are rapidly acting inhibitors with half-lives of two hours.3
It is important to understand the function of platelets and their role in cardiovascular disease.
Anti-platelet drugs have played a role in the treatment of patients however, platelet hyper-reactivity is still a problem that is compounded by genetic factors.
Donna D. Castellone is clinical project manager, Siemens Healthcare Diagnostics, Tarrytown, NY, and an ADVANCE editorial advisory board member.
1. Karon, BS., Jaben, E., Platelet Function Laboratory Methods for Evaluating Effectiveness of Anti-platelet Therapy, Clinical Laboratory News, #37, 4, April 2011.
2. Marchant, K, Importance of Platelets and Platelet Response in Acute Coronary Syndromes, Cleveland Clinic Journal of Medicine, #76:1 April 2009
3. Vorchheimer, D.A., Becker, R. Platelets in Atherothrombosis, Mayo Clin Proc. 2006;81(1):59-68
4. Campo G, Parrinello G, Ferraresi P, et al. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention. J Am Coll Cardiol 2011; 57: 2474-83.
5. Lordkipanidze,M., Pharand, C., Schampaert, E., Turgeon,J., Palisaitis,D and Diodati, J., A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. European Heart Journal (2007) 28, 1702-1708
6. O'Riordan, J.M.,Margey, R.J., Blake, G., O'Connell, R., Antiplatelet Agents in the Perioperative Period ,ARCH SURG/VOL 144 (NO. 1), JAN 2009.