Endothelial cells and coagulation

Abstract

Endothelial cells form a monolayer, which lines blood vessels. They are crucially involved in maintaining blood fluidity and providing controlled vascular hemostasis at sites of injury. Thereby endothelial cells facilitate multiple mechanisms, including both procoagulant and anticoagulant, which must be kept in balance. Under physiological conditions, endothelial cells constitute a nonadhesive surface preventing activation of platelets and the coagulation cascade. Multiple fibrinolytic and antithrombotic properties act on their cell surface contributing to the maintenance of blood fluidity. These include platelet inhibition, the heparin-antithrombin III system, tissue factor pathway inhibition, thrombomodulin/protein C system, and fibrinolytic qualities. At sites of vascular damage, platelets react immediately by adhering to the exposed extracellular matrix, followed by platelet-platelet interactions to form a clot that effectively seals the injured vessel wall to prevent excessive blood loss. For solid thrombus formation, functional platelets are essential. In this process, endothelial cells serve as a support surface for formation of procoagulant complexes and clotting. This review gives an overview about the central role of the endothelium as a dynamic lining which controls the complex interplay of the coagulation system with the surrounding cells.

Keywords: Endothelial injury; Hemostasis; Platelets; Thrombosis; Von Willebrand factor.

Fig. 1

Inhibitory properties of endothelial cells. Inhibition of platelet function and coagulation by several endothelial molecules and factors and the targeted coagulation factors are shown. Endothelial cells (ECs) express nitric oxide (NO), prostacyclin (PGI₂), and ectonucleoside triphosphate diphosphohydrolase-1 (E-NTPDase1), which inhibit platelet adhesion and aggregation. Heparin-like molekules (Hep) expressed on endothelial surface serve as a cofactor for antithrombin III (ATIII) inactivating several coagulation factors. ECs express tissue factor pathway inhibitor (TFPI), which limits the action of tissue factor (TF) and inhibits excessive TF-mediated activation of coagulation factors VII and X. Thrombomodulin (TM) binds thrombin activating protein C and degrades factor Va and VIIIa. Activation of fibrinolysis by endothelial tissue plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and their inhibition by plasminogen activator inhibitor (PAI-1) is depicted. PLG plasminogen

Fig. 2

Procoagulation properties of endothelial cells. At sites of vascular injury, Von Willebrand factor (VWF) binds to the exposed subendothelial collagen. VWF then captures platelets from the circulation via the interaction of the VWF with GPIb on the platelet. The binding of GPVI with collagen leads to further platelet activation. This results in the integrin-mediated adhesion of platelets and cellular activation releasing mediators. Selected platelet agonists and their receptors are indicated. Thrombin binds to GPIb and activates protease-activated receptor 1 and 4 (PAR1 and PAR4, respectively), ADP activates P2Y₁ and P2Y₁₂ receptor, and thromboxane A₂ (TxA₂) activates the thromboxane receptor (TP). Agonist stimulation results in integrin α_IIbβ₃ activation and the transition to an active conformation, which binds fibrinogen and mediates platelet aggregate formation. SMC smooth muscle cell