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.
