Alterations in Platelet Receptors and/or Reactivity

The adverse effects of depression on cardiovascular disease also may be mediated by platelet mechanisms. Markovitz and Matthews first proposed that enhanced platelet responses to psychologic stress may trigger adverse coronary artery ischemic events. This association between platelet activation and vascular disease is supported indirectly by studies linking cerebrovascular disease and depression. The Established Populations for Epidemiologic Studies of the Elderly prospectively studied 10,294 persons age 65 and older for 6 years and determined that rates of stroke (adjusted for age, physical disability, and other medical disorders) were 2.3 to 2.7 times higher in persons designated with "high" versus "low" levels of depressive symptoms. In another prospective study, 103 consecutive stroke patients were assessed for major depression or dysthymia approximately 2 weeks after a stroke. Patients with major depression or dysthymia were 3.4 times more likely to have died during the 10-year follow-up period than were nondepressed patients (p= .007), even after controlling for confounding variables (age, medical comorbidity, type of stroke, and lesion location; p= .03).

Platelets play a central role in hemostasis, thrombosis, the development of atherosclerosis, and acute coronary syndromes through their interactions with both subendothelial components of damaged vessel walls and plasma coagulation factors, primarily thrombin. Human platelets contain adrenergic, serotonergic, and dopaminergic receptors. Through activation of platelet alpha2 adrenoceptors, increases in circulating catecholamines (>4 nmol/L) potentiate the effects of other agonists and, at higher concentrations, initiate platelet thrombotic responses, including secretion, aggregation, and activation of the arachidonate pathway. After injury to vessel endothelium, platelets and circulating leukocytes attach to the newly exposed subendothelial layer.

Platelet adhesion to exposed collagen (and other components of the subendothelial matrix) and to thrombin stimulates platelet activation. Activation converts platelet membrane GPIIb/IIIa complexes into functional receptors for fibrinogen. Activation also is accompanied by extrusion or secretion of platelet storage granule contents into the extracellular environment. Platelets activated at the site of an injury to the vessel wall accelerate the local formation of thrombin and release a variety of products from their storage granules, including chemotactic and mitogenic factors, inducing leukocyte migration from the bloodstream and vascular cell proliferation. These secreted platelet products [e.g., platelet factor 4, β-thromboglobulin (β-TG), and 5-HT] stimulate and recruit other platelets and cause irreversible platelet–platelet aggregation, ultimately leading to the formation of a fused platelet thrombus. Platelets also contribute to vascular damage by stimulating lipoprotein uptake by macrophages and mediating vasoconstriction through the production and/or release of substances such as thromboxane A, platelet-activating factor, and 5-HT. Clinical trials have confirmed the importance of platelets in vascular damage; antiaggregating medications are useful in secondary prevention, delay the progression of atherosclerotic lesions, and improve post-MI outcomes.