Introduction
In terms of incidence, prevalence, morbidity, mortality, and economic costs, heart failure represents a major and growing public health concern. Despite significant progress in the prevention and treatment of cardiovascular disease in the past two decades, the incidence and prevalence of CHF have been increasing steadily in recent years. ^{1 - 3} In the US alone, there are currently four to five million patients suffering from CHF, with approximately 400,000 new cases diagnosed, resulting in nearly one million hospitalizations, and responsible for over 250,000 deaths per year. ^{4 - 6} The number of hospitalizations of patients with a principal diagnosis of CHF has increased over the past two decades, and is expected to double as a result of progressive aging of the Western population over the next 40 years. ^2,7,8 At present, the economic impact of treating CHF is exceeding US$11 billion each year. Considering all the abovementioned facts, it is pertinent that we continue to strive to improve our understanding of the mechanisms, etiologies, and treatments of this prevalent disease.

Thromboembolism is a critical and relatively common complication of CHF. Indeed, a variety of factors associated with CHF predispose to thrombosis. For instance, the existence of CHF increases the risk of thromboembolism, whether or not concomitant atrial fibrillation (AF) is present. ⁹ Small observational studies have suggested that pulmonary thromboembolism and stroke are common in patients with dilated cardiomyopathy. ¹⁰ The annual risk of stroke is increased to 4% in patients with severe CHF.¹¹ Several studies have shown that patients with CHF have increased plasma concentrations of betathromboglobulin (ß-TG), ^{12 - 14} a marker of platelet activation. Increased plasma concentrations of fibrinopeptide A and thrombin-antithrombin III (TAT) complexes, both measures of thrombin activity, have also been demonstrated. ¹² This article summarizes the data on platelet activation in heart failure, the effects of commonly prescribed medications for CHF on platelet function, and the potential role of the platelet ADPreceptor antagonists.

CHF and Platelets
In the late 1970s, investigators noted that patients with CHF had significantly more circulating platelet aggregates when compared with healthy controls. ¹⁵ Subsequently, several markers of platelet activity have been found to be increased in CHF patients including beta thromboglobulin, platelet factor four, and cellular adhesion molecules such as P-selectin, platelet/ endothelial cell adhesion molecule, and osteonectin. The interaction between endothelial cells, leukocytes, and platelets involving various adhesion proteins may be of particular importance due to possible immunologic and inflammatory responses in the pathogenesis and natural progression of CHF. ^16,17 Although the origin of platelet activation in CHF remains to be established, and is probably multifactorial, increased platelet activity might be related to elevation of cytosolic-free calcium concentration. ¹⁸ Platelets in CHF may also be affected by enhanced sympathoadrenal activation and catecholamine release. ⁹ It seems possible that reduced kidney and liver blood flow results in decreased clearance of platelet-activating substances, which may attribute to the higher incidence of clinically manifested thrombotic events in CHF patients. Beta-thromboglobulin is an alpha-granule constituent, which is a very sensitive but not very specific marker of platelet activation. The increased level of betathromboglobulin and platelet factor four was observed in patients with ischemic and idiopathic cardiomyopathy. ²⁰ P-selectin (CD62-P), originally described as PADGEM/GMP 140, is an alpha granule membrane protein that is also expressed on the platelet surface upon activation. ²¹ Elevated soluble P-selectin levels often coincide with other abnormal markers of platelet function, deteriorated platelet morphology, and enhanced platelet aggregation in CHF patients. ^23,24 Modulation of P-selectin, von Willebrand factor (vWF), and other hemorheological indices may contribute to a hypercoagulable state in CHF, especially in female patients and in those with more severe New York Heart Association (NYHA) class. ²⁵