What is the role of coagulation and fibrinolysis abnormalities in the pathophysiology of sepsis/septic shock?

Updated: Oct 07, 2020
  • Author: Andre Kalil, MD, MPH; Chief Editor: Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM  more...
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Answer

An imbalance of homeostatic mechanisms leads to disseminated intravascular coagulopathy (DIC) and microvascular thrombosis, causing organ dysfunction and death. [21] Inflammatory mediators instigate direct injury to the vascular endothelium; the endothelial cells release tissue factor (TF), triggering the extrinsic coagulation cascade and accelerating thrombin production. Plasma levels of endothelial activation biomarkers are higher in patients with sepsis-induced hypotension than in patients with hypotension from other causes. [22]

The coagulation factors are activated as a result of endothelial damage. The process is initiated through binding of factor XII to the subendothelial surface, which activates factor XII. Subsequently, factor XI and, eventually, factor X are activated by a complex of factor IX, factor VIII, calcium, and phospholipid. The final product of the coagulation pathway is the production of thrombin, which converts soluble fibrinogen to fibrin. The insoluble fibrin, along with aggregated platelets, forms intravascular clots.

Inflammatory cytokines, such as IL-1α, IL-1β, and TNF-α, initiate coagulation by activating TF. TF interacts with factor VIIa to form factor VIIa-TF complex, which activates factors X and IX. Activation of coagulation in sepsis has been confirmed by marked increases in thrombin-antithrombin complexes and the presence of D-dimer in plasma, indicating activation of the clotting system and fibrinolysis. [23, 24] Tissue plasminogen activator (t-PA) facilitates conversion of plasminogen to plasmin, a natural fibrinolytic.

Endotoxins increase the activity of inhibitors of fibrinolysis—namely, plasminogen activator inhibitor (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI). levels of protein C and endogenous activated protein C (APC) are also decreased in sepsis. Endogenous APC is an important inhibitor of coagulation cofactors Va and VIIa. Thrombin, via thrombomodulin, activates protein C, which then acts as an antithrombotic in the microvasculature. Endogenous APC also enhances fibrinolysis by neutralizing PAI-1 and accelerating t-PA–dependent clot lysis.

The imbalance among inflammation, coagulation, and fibrinolysis results in widespread coagulopathy and microvascular thrombosis and suppressed fibrinolysis, ultimately leading to multiple organ dysfunction and death. The insidious nature of sepsis is such that microcirculatory dysfunction can occur while global hemodynamic parameters such as blood pressure may remain normal. [25]


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