The role of platelets in the early and late vascular responses initiated by mechanical vascular injury

Abstract

Summary Endothelium is the nonthrombogenic interface separating highly-reactive elements circulating in blood from highly-thrombogenic constituents comprising subendothelial vascular and adventitial connective tissues. Mechanical vascular disruption initiates complex hemostatic interactions among platelets, coagulation, and fibrinolysis that are regulated by endothelium. Platelets attach to bared subendothelial matrix adhesive proteins via an array of receptors. Exposed membrane-bound tissue factor (TF) forms a tight complex with Factor VII/VIIa that catalytically activates Factors IX and Factor X, giving rise to the explosive production of thrombin via the assembly of the enzyme-cofactor prothrombinase complex on activated phospholipid surfaces. Thrombin activates platelets, cleaves fibrinogen and Factor XIII, producing fibrin-stabilized hemostatic plugs. Activated platelets express fibrinogen receptors by altering membrane aIIbβ3, leading to platelet cohesion via interplatelet fibrinogen linkages. Platelet recruitment is mediated by at least three independent, interrelated agonists: thrombin (physiologically the most important), adenosine phosphate (ADP), and thromboxane A2. Endothelial mechanisms limit the extension of hemostatic plug formation and inhibit thrombotic complications, including: (1) rapid binding of thrombin to thrombomodulin on intact endothelium, leading to the production of activated protein C and its subsequent inactivation of activated factor V, a critical cofactor in thrombin production; (2) thrombin-regulated endothelial generation of antiaggregatory prostacyclin and nitric oxide; (3) thrombin-enhanced endothelial secretion of tissue plasminogen activator; (4) thrombin inactivation by endothelial heparin sulfate-facilitated complexing with plasma antithrombin; (5) inactivation of platelet-secreted ADP by endothelial ecto-ADPase. Genetic and acquired abnormalities involving these protective mechanisms predispose patients to hemostatic and thrombotic disorders.