Nicole Barrella, DVM
The cell-based model of coagulation describes the three distinct, overlapping phases leading to clot formation as a result of platelet interaction with tissue factor (TF). The first phase, initiation, occurs when a TF-bearing cell, such as a sub-endothelial cell, is exposed to flowing blood. Circulating factor VIIa (FVIIa) binds to TF and initiates the coagulation cascade resulting in thrombin formation. The thrombin binds to receptors on the surface of the platelet leading to platelet shape change, creation of a procoagulant membrane surface, and platelet granule release. The granules contain agonists, such as thromboxane, von Willebrand’s factor (vWF) and ADP to amplify platelet activation and cause aggregation of platelets. Fibrinogen is also released and binds to integrin receptor αIIbβ3 which mediates platelet-platelet interactions. This is the amplification phase. The final phase is propagation, which results in the recruitment of additional platelets to the site of injury, and continued thrombin formation via cleavage of prothrombin to thrombin by factors Va and Xa. As the concentration of thrombin increases, there is increased cleavage of fibrin from fibrinogen. The soluble fibrin molecules will polymerize into fibrin strands and become an insoluble fibrin matrix.
Fibrinolysis begins when clot formation is complete to limit the extent of the clot and to breakdown the clot. In the presence of fibrin, plasminogen is converted to plasmin by tissue plasminogen activator (t-PA). Plasmin degrades fibrinogen and soluble fibrin into fibrinogen/fibrin degradation products (FDPs) and degrades cross-linked fibrin into D-dimers.
Virchow’s triad describes three factors involved in thrombus formation – blood stasis, endothelial disturbances, and hypercoagulability – with an alteration in any of the three resulting in a blood clot.
Endothelial dysfunction leads to numerous changes that ultimately alter the coagulability of blood. Damage to the endothelium disrupts the anti-coagulant, anti-platelet and fibrinolytic effects that serve to prevent pathological clot formation. The endothelium consists of vascular endothelial cells and the glycocalyx layer. The glycocalyx contains anticoagulant elements and acts as a mechanoreceptor leading to release of nitric oxide in conditions of increased shear stress. The glycocalyx also acts as a shield preventing binding of inflammatory mediators onto the cell surface.
An endothelial disturbance can occur secondary to injury from high shear conditions, such as in cases of hypertension or turbulent blood flow, or due to activation by inflammatory mediators such as tumor necrosis factor-α, bradykinin, and histamine.
Upon activation or injury, endothelial cells release ultra large multimers of vWF, which can initiate platelet activation and adhesion. In healthy patients, these multimers are broken down into smaller components by the enzyme ADAMTS13. Lower concentrations of ADAMTS13 can lead to systemic platelet aggregation and thrombosis.
Decreased Endogenous Anticoagulant Elements
The three main endogenous anticoagulants are antithrombin (AT), protein C, and tissue factor pathway inhibitor (TFPI). Antithrombin inhibits thrombin and factor Xa, and is most effective when bound to endogenous or exogenous heparins. Antithrombin can be decreased secondary to decreased production, consumption, or degradation by neutrophils. Antithrombin is a small protein and can be lost into urine in cases of glomerulonephritis or, less frequently, into the intestines in cases of protein-losing enteropathy. Protein C inhibits factors Va and VIIIa, decreasing the breakdown of prothrombin to thrombin. Activated protein C also enhances fibrinolysis by suppressing plasminogen activator inhibitor-1 activity and thrombin activatable fibrinolytic inhibitor activity, resulting in increased conversion of plasminogen to plasmin. In patients with systemic inflammation, there is decreased Protein C production. Additionally, activation of Protein C is decreased by the effects of inflammatory cytokines on the endothelium.