Overview of the Sepsis Cascade

Severe sepsis results from the body's systemic over-response to infection. This over-response disrupts homeostasis through an uncontrolled cascade of inflammation, coagulation, and impaired fibrinolysis. Here, you can learn more about this cascade with the following topics:

• Inflammation is activated in sepsis
• Coagulation is activated in sepsis
• Fibrinolysis is suppressed in sepsis
• Coagulopathy in sepsis: A driving force in acute organ dysfunction and death
• Endogenous Activated Protein C modulates inflammation coagulation and fibrinolysis in sepsis

Inflammation is activated in sepsis

Inflammation is the body's normal response to infection. The body's initial response to an infection is to induce a pro-inflammatory state. Pro-inflammatory mediators, such as tumor necrosis factor (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and platelet-activating factor (PAF) are released. These mediators have multiple overlapping effects designed to repair existing damage and limit new damage. To ensure that the effects of the pro-inflammatory mediators do not become destructive, the body then launches compensatory anti-inflammatory mediators, such as interleukin-4 (IL-4) and interleukin-10 (IL-10), which normally downregulate the initial pro-inflammatory response.

In sepsis, regulation of the early response to infection is lost, and a massive systemic reaction occurs. These excessive or inappropriate inflammatory reactions are detrimental. An excess of the inflammatory mediators, such as TNF-α and IL-1, are released, triggering an overwhelming physiological response, which causes tissue injury and results in the development of diffuse capillary injury. Finally, excessive inflammatory reactions interfere with normal tissue function, leading to tissue damage and organ dysfunction.

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Coagulation is activated in sepsis

The processes of inflammation and coagulation are intimately linked. Multiple inflammatory mediators that are released to fight infection also promote coagulation, which contributes to sepsis. In addition, the infectious agent itself can cause endothelial damage, which also promotes coagulation.

Coagulation factors are activated when blood comes into contact with sub-endothelial connective tissues or with negatively charged surfaces that are exposed as a result of tissue damage. The first step is the binding of factor XII to a sub-endothelial surface protein exposed by an injury, thereby activating factor XII. The activated factor XII activates factor XI. Eventually factor X is activated by a complex of molecules containing activated factor IX, factor VIII, calcium, and phospholipid. The end result of the clotting pathway is the production of thrombin, which converts soluble fibrinogen to fibrin. The insoluble fibrin aggregates and forms a clot, together with aggregated platelets (thrombi), blocking the damaged blood vessel and preventing further bleeding. In sepsis, multiple pro-inflammatory cytokines, such as IL-1α, IL-1β, and TNF-α, induce the expression of Tissue Factor (TF) on endothelial cells and monocytes, initiating coagulation. Tissue Factor is a key mediator between the immune system and coagulation, and is the principal activator of coagulation. Tissue Factor interacts with factor VIIa, forming the factor VIIa-TF complex, which activates factors X and IX. Amplification of coagulation via thrombin-mediated processes occurs with activated factors XI, VIII, and V. In the final stage, large amounts of thrombin are generated. Fibrin threads form a clump with activated platelets at the site of endothelial damage and a stable clot is formed.

Various clinical studies have generated data demonstrating the activation of coagulation in sepsis. For example, Levi, et al. found that marked increases in thrombin-antithrombin (TAT) complex, a parameter that correlates with the production of thrombin, occurred following both the administration of endotoxin and TNF-α in healthy volunteers.¹

Results of a D-dimer assay, which measures fibrin breakdown products, showed that D-dimer levels were significantly elevated in both survivors and nonsurvivors of sepsis compared with controls.² The presence of D-dimer in plasma indicates that activation of the clotting system has occurred in conjunction with fibrinolysis activation (during which fibrin is digested by plasmin), forming fibrin breakdown products.³

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Fibrinolysis is suppressed in sepsis

The fibrinolytic system is directly influenced by the septic process. In most patients with sepsis, fibrinolysis (the body's normal process to remove clots) is suppressed, while coagulation activation still proceeds. Plasmin, the principle effector of fibrinolysis, is formed when tissue plasminogen activating factor (t-PA) triggers the conversion of plasminogen to plasmin. Plasmin then breaks down the fibrin strands that hold a clot together and degrade fibrinogen and coagulation factors V and VIII.

A number of naturally occurring substances protect the body from excessive fibrinolysis by inhibiting activation of plasminogen and/or the fibrinolytic activity of plasmin. Two key inhibitors of fibrinolysis are plasminogen activator inhibitor-1 (PAI-1) and thrombin activatable fibrinolysis inhibitor (TAFI). PAI-1, which is produced by endothelial cells and platelets, is the major fast-acting inhibitor of t-PA. Endotoxins released by gram-negative pathogens increase the activity of PAI-1.

In patients with sepsis, the following fibrinolytic abnormalities are seen: increased PAI-1 activity; decreased t-PA activity; decreased Protein C levels; decreased plasminogen levels. Ultimately, the suppression of fibrinolysis in conjunction with activation of coagulation creates a dynamic process of coagulopathy in patients with sepsis.

Experiments in which either endotoxin or TNF-α were given to healthy volunteers demonstrated an initial fibrinolytic process followed by more profound and sustained inhibition.¹ Other data support these findings and indicate that fibrinolytic deactivation and changes in coagulation occur independently.⁴ These changes are now viewed as an important driving force in organ dysfunction and sepsis progression.^2,5

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Coagulopathy in sepsis: A driving force in acute organ dysfunction and death

As sepsis progresses, coagulopathy becomes increasingly more severe. In patients who develop septic shock, the coagulopathy accelerates markedly and includes laboratory changes consistent with profound Protein C deficiency, prolonged aPTT and PT, elevated fibrin monomers, reduced fibrinogen, and elevated D-dimer levels.

At its most extreme, the imbalance between inflammation, coagulation, and fibrinolysis results in widespread coagulopathy and microvascular thrombosis. Coagulopathy, namely disseminated intravascular coagulation (DIC), has traditionally been thought of as a late complication in sepsis. Like sepsis, DIC is a diagnosis with considerable heterogeneity that spans a spectrum of pathophysiologies from increased fibrinolysis to overactive coagulation.⁴ Importantly, multiple organ failure is now known to be a common clinical feature of coagulation-dominated DIC in sepsis and portends an extremely poor prognosis.⁴

Decreased endogenous Protein C levels are one important and widely recognized abnormality that occurs in DIC. These decreased levels also appear to occur, independent of DIC, in patients who have sepsis associated with organ dysfunction. In fact, accumulating data now indicate that coagulation abnormalities, including Protein C deficiency, develop well before the onset of defined clinical parameters of severe sepsis or septic shock.^2,3,6,7 Overall, these findings support the concept of a continuum of coagulopathy in sepsis, from initial infection or trauma through increasingly deleterious effects on the microvascular endothelium.

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Endogenous Activated Protein C modulates inflammation, coagulation, and fibrinolysis in sepsis

Under normal conditions, a number of regulatory mechanisms involving natural coagulation inhibitors, fibrinolysis activators, and anti-inflammatory mediators maintain a state of balance (homeostasis) in blood flow and the endothelial response to inflammation or trauma.⁸

These homeostatic mechanisms include the Protein C pathway, the antithrombin (AT) III-heparin sulfate system, and tissue factor pathway inhibitors. Under normal conditions these systems act in a complex interplay of negative and positive feedback loops to prevent coagulation from becoming generalized.⁵

Endogenous Activated Protein C is an important proteolytic inhibitor of coagulation cofactors Va and VIIIa, factors involved in the rate-limiting steps of coagulation.⁹ When thrombin is bound to thrombomodulin, both an endothelial cell surface protein and a soluble protein, its activity is switched from fibrin formation and platelet activation to activation of Protein C. The actions of endogenous Activated Protein C rapidly impede the clotting process. Endogenous Activated Protein C appears to play a particularly important antithrombotic role in the microvasculature.¹⁰

Natural fibrinolysis activators include tissue plasminogen activator (t-PA) and urinary plasminogen activator (u-PA). In general, the role of these enzymes is to help remove formed microthrombi from the vasculature and maintain blood fluidity.⁵ Endogenous Activated Protein C also acts to enhance fibrinolysis by neutralizing plasminogen activator inhibitor-1 (PAI-1)⁵ and by accelerating t-PA-dependent clot lysis.¹¹

Endogenous Activated Protein C may also help to interrupt the cycle of coagulation and inflammation that characterizes sepsis through anti-inflammatory activity.¹⁰ First, endogenous Activated Protein C has potent inhibitory effects on thrombin formation, which indirectly reduce the net inflammatory effect. Second, endogenous Activated Protein C has direct anti-inflammatory actions, such as decreasing cytokine production and inhibiting leukocyte attachment to the endothelium.

Endogenous Activated Protein C may therefore work to reinstate the balance in all three of the major processes driving sepsis: coagulation, suppressed fibrinolysis, and inflammation.^5,10

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