There is increasing evidence that platelets play a crucial role in all stages of the pathogenesis of vascular disease – particularly atherosclerosis. Research over the last 10–15 years has demonstrated that atherosclerosis involves an active inflammatory process rather than the benign accumulation of intra-luminal lipids.31 Platelets play key roles in the development and progression of atherosclerotic plaques, by the action of released mediators and facilitating interactions with other inflammatory cells. For the subset of atherosclerotic plaques that are unstable or prone to rupture, localized platelet activation and aggregation result in an occlusive platelet thrombus interrupting blood flow and causing distal ischemic injury. This mechanism underpins myocardial infarction and acute coronary syndromes, and explains to some degree the effectiveness of anti-platelet agents in the treatment and prevention of such conditions.
Role of platelets in the initiation of atherosclerosis
Platelets are the first cell to arrive at the developing atherosclerotic lesion. Studies demonstrate that platelets adhere to carotid endothelium of ApoE deficient mice.33 P-selectin (CD62P) and E-selectin are expressed on the surface of activated endothelial cells (and platelets) which interact with GP1βα, PSGL-1 and the von Willebrand receptor complex receptors on the platelet surface in a loose manner which is insufficient for stable adherence, but instead facilitates the rolling process34 (Figure 11.1). In addition, soluble von Willebrand factor is secreted by endothelium in response to inflammatory stimuli. Mice deficient in von Willebrand factor demonstrate a reduced propensity towards atherosclerosis.35 As platelets roll along the surface of activated endothelium, they become activated, and firm adhesion can occur via the interaction between β3 integrins present on endothelial cells and the fibrinogen bound GPIIb/IIIa receptor on platelets (Figure 11.1). Once activated, platelets become firmly adherent and are able to recruit other platelets to the area of endothelial injury.36 Inhibition of platelet activation, such as suppression of COX-1 dependant thromboxane A2 production or activity, has been demonstrated to slow the formation of atherosclerosis in murine models.
Role of platelets in the progression of atherosclerosis
Activated platelets also express P-selectin on their surface, which not only mediates plateletendothelial interactions, but also stimulates neighboring monocytes and macrophages to release pro-inflammatory mediators. For example, P-selectin mediated signaling between aggregated platelet and monocytes promotes up regulation of COX-2 mRNA and the production of interleukin-1β, which promotes inflammation and further platelet activation.38 Firmly attached platelets have also been shown to recruit monocytes from the blood stream to the site of vascular injury in a process described as ‘tethering’. Such platelets interact with circulating monocytes via PSGL-1 (P-selectin glycoprotein ligand-1 – on monocytes) and P-selectin expressed by platelets, multiple platelet receptors including the fibrinogen bound activated GPIIb/IIIa receptor and MAC-1 (on monocytes) and the lymphocyte function associate antigen (LFA-1), which binds to ICAM-2 on platelets. These interactions result in monocyte recruitment to the injured endothelium.39 These platelets release an array of pro-inflammatory mediators such as interleukin-1β, platelet factor 4, RANTES (regulated upon activation, normal T cell expressed and secreted) and CD40 ligand.25 These mediators promote localized inflammation and atherosclerotic development by activating the vascular endothelium to facilitate the chemoattraction, chemotaxis and transmigration of monocytes.
Role of platelets in vulnerable plaques and plaque rupture
Platelets have a well-established role in the development of a thrombus after the rupture of the thin fibrous cap present in vulnerable plaques. Disruption of the thin fibrous cap, usually in the adjoining shoulder region, exposes the highly thrombogenic lipid core to the bloodstream, triggering a cascade of platelet activation and thrombosis. However, the extent to which platelets interact with an established vulnerable plaque before it undergoes a clinically significant rupture is uncertain. It is circumstantially suggested by the success of antiplatelet therapies in reducing ischemic events.40 Subclinical plaque rupture is a frequent event with 9% of autopsies on patients not dying from myocardial infarction demonstrating ruptured fibrous caps (22% in patients with cardiovascular risk factors). This suggests that rather than every plaque rupture precipitating an ischemic event, it is likely that the thrombotic response to plaque disruption is dynamic with thrombosis and thrombolysis occurring simultaneously in patients with acute coronary syndrome.41,42 Consequently, a rupture prone plaque may suffer periodic disruptions in its fibrous cap resulting in ongoing interactions with activated platelets.43 Thus, in addition to their role in acute plaque rupture, at any given time, activated platelets may be associated with unstable plaques presumably in a number and frequency proportional to the degree of plaque instability. The detection of such activated platelets potentially may allow identification of unstable plaques prior to rupture.
