The Role of the Coagulation System in Peripheral Arterial Disease: Interactions with the Arterial Wall and Its Vascular Microenvironment and Implications for Rational Therapies

Abstract

Peripheral artery disease (PAD) is a clinical manifestation of atherosclerotic disease with a large-scale impact on the economy and global health. Despite the role played by platelets in the process of atherogenesis being well recognized, evidence has been increasing on the contribution of the coagulation system to the atherosclerosis formation and PAD development, with important repercussions for the therapeutic approach. Histopathological analysis and some clinical studies conducted on atherosclerotic plaques testify to the existence of different types of plaques. Likely, the role of coagulation in each specific type of plaque can be an important determinant in the histopathological composition of atherosclerosis and in its future stability. In this review, we analyze the molecular contribution of inflammation and the coagulation system on PAD pathogenesis, focusing on molecular similarities and differences between atherogenesis in PAD and coronary artery disease (CAD) and discussing the possible implications for current therapeutic strategies and future perspectives accounting for molecular inflammatory and coagulation targets. Understanding the role of cross-talking between coagulation and inflammation in atherosclerosis genesis and progression could help in choosing the right patients for future dual pathway inhibition strategies, where an antiplatelet agent is combined with an anticoagulant, whose role, despite pathophysiological premises and trials’ results, is still under debate.

Molecular Pathways of Vulnerability Carotid Plaques at Risk for Ischemic Stroke: A Narrative Review

“…When the endothelium is damaged, platelets adhere to the vascular wall, inducing the formation of a platelet-rich thrombus through the binding of the platelet glycoprotein (GP) Iba receptor and the von Willebrand factor (vWF), expressed from the damaged endothelium. GPIba receptor also recruits circulating leucocytes binding integrins and P-selectin, perpetuating the inflammatory process [67,68]. Two platelet collagen receptors mediate platelet adhesion and activation [GPIa/IIa (integrin a2b1) and GPVI (immunoglobulin)] favoring the growth of the thrombus .…”

Endothelial dysfunction, platelet hyperactivity, hypertension, and the metabolic syndrome: molecular insights and combating strategies

“…It is generally recommended that individuals with CVD take these medications, unless otherwise specified. Although clinical trials have not demonstrated the effectiveness of these drugs in individuals with type-2 diabetes who do not have CVD, they are still widely recommended ( 52 ). Furthermore, aspirin prophylaxis is a viable treatment option for individuals diagnosed with MetS who are at a relatively high risk of experiencing CVD-related events ( 53 ).…”

Sex, Endothelial Cell Functions, and Peripheral Artery Disease

“…Coagulation factors such as tissue factor can also promote inflammatory responses by activating protease-activated receptors [55]; however, sex-dependent effects are unclear. The crosstalk between inflammation and coagulation factors contributing to PAD pathogenesis, recently reviewed elsewhere [56], highlights the complexity of this system. More studies are needed to fully appreciate the impact of sex-dependent EC thrombo-inflammatory processes in PAD.…”