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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.
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Picture taken from www.sepsis.com
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