Integrin Polymorphisms as Risk Factors for Thrombosis
Authors: Bray Paul 
Published: March 2018

Introduction

By the year 2020, ischemic heart disease will become the number one public health problem on the planet, surpassing lower respiratory infections, diarrheal disease, perinatal problems, and unipolar major depression.1 Acute myocardial infarction, the most feared complication of coronary artery disease, results from the formation of an occlusive thrombus at the site of a ruptured atherosclerotic plaque. The 1990s have seen an increased awareness of the contribution of inherited disorders of hemostasis as risks for coronary thrombosis. Consideration for potential hypercoagulable states in patients with these disorders would seem justified, since, for example, the risk for an acute coronary event is considerably greater with an abnormally elevated fibrinogen level than with an elevated total cholesterol level.2,3 The clinical benefit of thrombolytic therapy in acute myocardial infarction provides further support for the importance of fibrin formation or dissolution in this setting.4,5 An appropriate hypercoagulable evaluation of an unusual arterial thrombosis, particularly in a young patient, would include assays for hyperhomocysteinemia, the lupus anticoagulant, anticardiolipin antibodies, as well as assays for fibrinogen and plasminogen activator inhibitor-1. Currently, less evidence exists to support measurements of tissue plasminogen activator, von Willebrand factor (vWF), factors VII or XIII, or those factors associated with venous thrombosis, such as activated protein C resistance/factor V Leiden or deficiencies of antithrombin III, protein C, or protein S.

There is also abundant evidence that platelet thrombi play a crucial role in the development of acute myocardial infarction. In 1974, Chandler et al summarized a series of pathologic studies examining coronary arteries of patients with acute myocardial infarction and reaffirmed the basic understanding that coronary artery thrombi can cause acute ischemia and myocardial infarction.6 DeWood et al provided in vivo evidence to corroborate pathologic data,7 and Trip et al correlated platelet hyperreactivity with coronary events and mortality in patients with established coronary artery disease.8 The clinical arena has also provided additional support for the central role of platelets in the acute ischemic coronary syndromes, myocardial infarction, and unstable angina. Antiplatelet therapy with aspirin, ticlopidine, clopidogrel, and inhibitors of integrin αIIbβ3 (e.g., abciximab and integrilin) has demonstrated beneficial effects in a number of coronary artery disease settings.9-11

Platelet physiology is arbitrarily divided into phases of adhesion, activation, secretion, and aggregation. When arterial subendothelium is exposed, vWF molecules are rapidly localized to these areas, and the initial platelet contact with the wound is a tethering to this insoluble form of vWF via glycoprotein (GP) Ibα.12,13 Stable adhesion and platelet activation is then mediated through integrin α2β1 binding to exposed collagen and integrin αIIbβ3 binding to vWF and fibrinogen.14 Fibrinogen has multiple αIIbβ3 binding sites, and an expanding thrombus ensues when platelets aggregate via the intercellular bridging of fibrinogen and vWF binding to the activated conformation of αIIbβ3. Three platelet membrane glycoprotein receptors, αIIbβ3, α2β1, and GP Ib-IX, have highly interactive and additive adhesive effects, ultimately resulting in stable thrombus formation.

Attempts to educate both physicians and the lay public about the so-called “traditional” risk factors for coronary artery disease and acute ischemic coronary syndromes have been successful,15 and there are now established preventive therapies, such as blood pressure control, cessation of cigarette smoking, and cholesterol lowering. Genetic variations confer a potent risk for coronary artery disease in many families, and, although these risks fall outside the domain of preventive medicine, an emerging concept in the field is that targeted genetic testing may be used to direct therapeutic decisions. Although inherited alterations of hemostatic factors are believed to be important in the development of acute ischemic coronary syndromes, until recently, inherited platelet risk factors had not been considered. This review will focus on the potential link between the genetic and platelet components of arterial thrombosis, in particular, coronary artery disease.