Role of the Endothelium in Coagulation
The endothelium serves as a dynamic regulatory interface that maintains blood fluidity under normal conditions through anticoagulant mechanisms, but transforms into a procoagulant surface when activated by injury, inflammation, or infection, thereby playing a central role in both preventing and promoting coagulation. 1
Anticoagulant Functions of Resting Endothelium
Under physiological conditions, the intact endothelium actively prevents coagulation through multiple mechanisms:
Production of platelet inhibitors: Normal endothelium produces nitric oxide and prostacyclin, which prevent platelet activation and adhesion to the vessel wall 1
Expression of anticoagulant factors: Endothelial cells release tissue factor pathway inhibitor (TFPI), which inhibits tissue factor, FVIIa, and FIXa 1
Thrombomodulin-Protein C system: Endothelial cells express thrombomodulin on their surface, which binds thrombin and activates protein C (in conjunction with protein S), leading to inhibition of factors Va and VIIIa 1
Support of antithrombin activity: The endothelial surface facilitates antithrombin function, which inhibits thrombin, FIXa, FXa, FXIa, and the FVIIa-TF complex 1
Fibrinolytic properties: Endothelial cells produce tissue plasminogen activator (tPA), which converts plasminogen to plasmin for fibrin degradation 1
Procoagulant Functions of Activated Endothelium
When endothelial cells are activated by injury, inflammation, or infection, they undergo profound transformation:
Initiation of Coagulation
Tissue factor expression: Activated endothelial cells express tissue factor (TF), the primary initiator of coagulation, which becomes accessible through damage to the vessel wall (surgery, trauma), sepsis, or cytokine stimulation during inflammation 1
TF-FVIIa complex formation: The exposed TF binds and activates factor VII, and the resulting FVIIa-TF complex activates factors IX and X, initiating the coagulation cascade 1
Support of Thrombus Formation
Platelet adhesion: Damaged endothelium exposes von Willebrand factor and collagen, which promote platelet adhesion and activation 1
Expression of adhesion molecules: Activated endothelium expresses P-selectin, E-selectin, ICAM-1, and VCAM-1, which facilitate leukocyte and platelet recruitment 1, 2
Surface for coagulation complexes: The endothelial surface provides a platform for assembly of procoagulant enzyme complexes 3
Downregulation of Anticoagulant Mechanisms
Loss of anticoagulant properties: During sepsis and inflammation, the endothelium loses its natural anticoagulant state, converting to a procoagulant phenotype 1
Reduced thrombomodulin expression: Inflammatory stimuli decrease thrombomodulin expression, impairing protein C activation 1
Increased PAI-1 production: Activated endothelium produces plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis 1
Clinical Significance in Pathological States
Sepsis-Induced Coagulopathy
Endothelial dysfunction is central: In sepsis, endothelial injury is an essential component of disseminated intravascular coagulation (DIC), though current diagnostic criteria paradoxically do not include endothelium-specific biomarkers 1
Vicious cycle formation: Inflammation induces coagulation, which in turn amplifies inflammation through complement activation, cytokine release, and further endothelial damage 1
Loss of barrier function: Activated endothelium loses tight junction integrity, leading to fluid extravasation and facilitating leukocyte transmigration 1
Biomarkers of Endothelial Involvement
Von Willebrand factor and antithrombin: These are the most clinically available markers reflecting endothelial dysfunction severity in coagulopathy 1
Thrombomodulin levels: Elevated plasma thrombomodulin (>40 μg/L) indicates endothelial injury, particularly in sepsis 4
Key Clinical Pitfalls
Important caveat: The degree of endothelial dysfunction varies substantially by underlying disease—it is most significant in sepsis-induced coagulopathy, moderate in trauma-induced coagulopathy, and variable in hematologic malignancy-associated coagulopathy 1. This heterogeneity means that therapeutic approaches targeting endothelial dysfunction must be tailored to the specific pathological context rather than applied uniformly across all coagulopathic states.