Site hosted by Build your free website today!












           By: Bryce Younger
  • Introduction        

              "When infection is the underlying cause of systemic inflammatory response syndrome the condition is called sepsis.  Recent evidence indicates that the tendency to develop severe sepsis and septic shock is not a function of the organism involved but rather is determined by the host response to infection". The patients own defenses towards infection may result in tissue damage, organ dysfunction, organ failure, and death. In general the pathogenesis of sepsis can be thought of a dysfunction of the opposing mechanisms that normally maintain homeostasis. Bacterial toxins formed by the infectious organism trigger immunologic reactions.  These toxins produce proteins that stimulate the host inflammatory response. Gram-negative organisms prodce endotoxins.  These endotoxins are prodcued by the bacterial cell walls and are called lipopolysaccharides (LPS).  Endotoxin is a potent stimulus for macrophage and neutrophil production of proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin-1 (IL-1).  Gram-positive organisms produce exotoxins and are also produced by the cell wall including peptidoglycan and teichoic acid.  Fungi also release cellular products into the host body.  It is important to understand that homeostasis is lost by the uncontrollable cascade of inflammation, coagulation, and Fibrinolysis .  We will discuss each of them shortly to identify there role in sepsis.

  • Homeostasis

               As the patient's body is introduced to the intial insult to the vascular endothelium a cascade of destruction has started. On one side of the endothelial injury is increased inflammation and coagulation such as pro-inflammatory mediators, tissue factor expression, and thrombin production.  On the other side is suppressed fibrinolysis, which counteracts pro-coagulant forces,  increased levels of plasminogen activator inhibitor 1 (PAI-1), and decreased levels of Protein C and endogenous Activated Protein C that is an inhibitor of PAI-1.  Endogenous Activated Protein C is activated by the thrombin/thrombomodulin complex.  Activated Protein C, an important homeostatic mediator of inflammation, coagulation, and fibrinolysis, and t-PA augment the fibrinolytic cascade. Inhibition of endogenous Activated Protein C causes a significant increase in coagulation and a decrease in fibrinolysis.

             Endogenous modulators of homeostasis, such as Protein C and antithrombin III (AT III), are consumed and as the levels decrease, the body attempts to return to a normal functional state.  Under normal conditions endothelial surface proteins, thrombomodulin and endothelial Protein C receptor (EPCR), activate Protein C which inhibits PAI-1. In sepsis, the endothelial damage inhibits the function of thrombomodulin and EPCR, and the cascade keeps growing.  Unopposed, endothelial damage continues the uncontrollable cascade of inflammation and coagulation fuels the progression of sepsis, resulting in hypoxia, widespread ischemia, organ dysfunction, and lastly death.

  • Inflammation 

             Inflammation is the body's normal response to infection. It is intended to be a local process and may be caused by bacterial or non bacterial factors.  The initial response is the pro-inflammatory state. Mediators such as Tumor necrosis factor (TNF-a), Interleukin-1 (IL-1), Interleukin-6 (IL-6), and platelet-activating factor (PAF) repair existing damage and limit new damage to endothelial. To compensate for the intial response, anti-inflammatory mediators such as interleukin-4 (IL-4) interleukin-10 (IL-10), down regulate the initial pro-inflammatory response.

              In sepsis, the regulation of the early response to infection is lost.  A tremendous amount of  inflammatory mediators are released, which causes tissue injury and results in the development of diffuse capillary injury that interferes with normal tissue function,  and consequently, organ dysfunction  The endothelial damage causes neutrophil activation, neutrophil-endothelial cell adhesion, and further elaboration of inflammatory cytokines. As a result of microvasucalr dysfunction due to the cytokines, decreased tissue perfusion, hypoxemia, and possible organ failure can occur.

              Chemokines  that attract neutrophils  to the site of infection stimulate cells to release proteolytic enzymes, free radicals, and arachidonic acid metabolism products, causing local vascular endothelium damage. Then procoagulant proteins are released and vessel permeability increases, leading to loss of water from the circulatory system into the surrounding tissues. This loss of volume causes many of the circulatory and cardiac abnormalities seen in sepsis.


  • Coagulation

              Coagulation is an  important step in the progression of sepsis.  It is promoted in two very different ways.  First the infectious insult can cause endothelial damage which intern promotes coagulation.  Secondly the cytokines released in the pro inflammatory stage cause coagulation.  Both of these steps help the progression and spread of sepsis.  

             Coagulation factors are primarily activated when blood comes into direct 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 and activation of factor XII to a sub-endothelial surface exposed by an injury. Activated factor XII starts a complex pathway including factor XI factor X factor IX, factor VIII, calcium, and phospholipids. The end result of the clotting pathway is the production of thrombin, which converts fibrinogen to fibrin. The fibrin aggregates and forms a clot effectively blocking the damaged blood vessel and preventing further bleeding.

              Pro-inflammatory cytokines, such as the interlukins (IL), IL-1a, IL-1b, and also Tumor Necrosis Factor A  (TNF-a), cause the expression of Tissue Factor (TF) on endothelial cells and monocytes which initiate coagulation. TF is the primary activator of coagulation. There is an intereaction between TF and factors: V, VIIa, VIIa-TF, VIII,  IX,  X,  resulting in the creation of thrombin and the fibrin threads form a clot with activated platelets at the site of endothelial damage

             As a result of the clots, blood flow to the capillary exchange vessels is subsequently hindered.  The delivery of vital substances like O2, and the removal of CO2 and waste products is decreased.  This decreased perfusion also affects important organs like the kidneys and brain and subsequently causes the failure of one or more of the visceral organs.


  • Fibrinolysis

              Fibrinolysis is the process that breaks down fibrin clots. In sepsis Fibrinolysis is suppressed and coagulation still proceeds. Plasmin, the primary 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.

              Many substances protect the body from excessive fibrinolysis by inhibiting activation of plasminogen and/or the fibrinolytic activity of plasmin. Two of these many key inhibitors of fibrinolysis are plasminogen activator inhibitor 1 (PAI-1) and thrombin activatable fibrinolysis inhibitor (TAFI). PAI-1  is produced by endothelial cells at the site of injury.  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 and decreased plasminogen levels. 

  • Summary

              In conclusion, sepsis is a systemic inflammatory response cause by the patients immunologic response to a microbial insult.  This insult triggers the release of cytokines that can do more harm to the patient than good. All major systems of the body can be affected and the resulting damage is dependent on the level of host response to invasion.










Picture taken from