Influence of Cardiometabolic Risk Factors on Platelet Function

Abstract

Platelets are key players in the thrombotic processes. The alterations of platelet function due to the occurrence of metabolic disorders contribute to an increased trend to thrombus formation and arterial occlusion, thus playing a major role in the increased risk of atherothrombotic events in patients with cardiometabolic risk factors. Several lines of evidence strongly correlate metabolic disorders such as obesity, a classical condition of insulin resistance, dyslipidemia, and impaired glucose homeostasis with cardiovascular diseases. The presence of these clinical features together with hypertension and disturbed microhemorrheology are responsible for the prothrombotic tendency due, at least partially, to platelet hyperaggregability and hyperactivation. A number of clinical platelet markers are elevated in obese and type 2 diabetes (T2DM) patients, including the mean platelet volume, circulating levels of platelet microparticles, oxidation products, platelet-derived soluble P-selectin and CD40L, thus contributing to an intersection between obesity, inflammation, and thrombosis. In subjects with insulin resistance and T2DM some defects depend on a reduced sensitivity to mediators-such as nitric oxide and prostacyclin-playing a physiological role in the control of platelet aggregability. Furthermore, other alterations occur only in relation to hyperglycemia. In this review, the main cardiometabolic risk factors, all components of metabolic syndrome involved in the prothrombotic tendency, will be taken into account considering some of the mechanisms involved in the alterations of platelet function resulting in platelet hyperactivation.

Keywords: adipokines; adipose tissue; hemostasis; insulin resistance; metabolic syndrome; nitric oxide; oxidative stress; platelets; thrombosis.

Figure 1

Potential mechanisms linking cardiometabolic disorders and atherothrombotic vascular diseases.

Figure 2

Biochemical factors involved in the coagulation cascade and the atherosclerotic process released following platelet activation. AA, arachidonic acid; COX, cyclooxygenase; TXA₂, thromboxane A₂; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor β; EGF, endothelial growth factor; bFGF, fibroblast growth factor; VEGF, vascular endothelial growth factor; IGF, insulin-like growth factor; IL-1β, interleukin-1β; PAI-1, plasminogen activator inhibitor 1; vWF, von Willebrand factor; GP, glycoprotein; PECAM, platelet endothelial cell adhesion molecule; sCD40L, soluble CD40 ligand; sP-selectin, soluble P-selectin; RANTES, regulated on activation, normal T-cell expressed and secreted; MIP-1α, macrophage inflammation protein- 1α; IL-8, interleukin-8; PF4, platelet factor 4; PMPs, platelet-derived microparticles.

Figure 3

Relationships between insulin resistance, increased oxidative stress and inflammation in promoting platelet hyperactivation in obesity. AA, arachidonic acid; A-II, angiotensin-II; cAMP, 3′,5′-cyclic adenosine monophosphate; cGMP, 3′,5′-cyclic guanosine monophosphate; IR, insulin receptor; MPV, mean volume platelet; NO, nitric oxide; PAF, platelet activating factor; PAR, protease-activated receptor; PGI₂, prostaglandin I₂; PKA, cAMP-dependent protein kinase; PKG, cGMP-dependent protein kinase; ROS, reactive oxygen species; PMP, platelet-derived microparticles; TP, thromboxane receptor; TX, thromboxane.

Figure 4

Biochemical imbalance towards factors promoting endothelial dysfunction and platelet hyperactivation involved in the development of atherothrombotic diseases in the presence of multiple cardiometabolic risk factors. eNOS, endothelial nitric oxide synthase; NFκΒ, nuclear factor kappa Β; PAI-1, plasminogen activator inhibitor-1; AP-1 activator protein-1; NO, nitric oxide; PGI₂, prostaglandin I₂; EC, endothelial cell; PMPs, platelet-derived microparticles; MS, metabolic syndrome.