dic, inflammation, sepsis AND ACTIVATED PROTEIN C (APC)
Kimberly Schlesinger, M.D.,
Hematology Fellow, University of Pittsburgh
M.D., Director, Hemophilia Center of Western PA
New concepts are
emerging on the relationship between coagulation, inflammatory, and sepsis
pathways. These are based on studies of sepsis in humans and animal models of
intravascular coagulation (DIC), previously considered a specific disease, is
now considered part of a pathophysiologic process involving excess coagulation
such as seen in sepsis and related disorders, e.g. systemic inflammatory
response syndrome (SIRS), or multi-organ dysfunction syndrome (MODS) (1-5).
Although DIC was
previously thought to result solely from activation of the coagulation system by
endotoxin or tissue factor, new data suggest that the changes in DIC may also
reflect the activation of pro-inflammatory cytokines. These same cytokines are
part of the inflammatory response of sepsis.
The purpose of this
Update is to provide a concise summary of the relationship between
coagulation, inflammation, sepsis, and DIC. The clinical and laboratory
diagnosis of DIC, as well as new approaches to treatment will be discussed.
Sepsis: The Scope of
As many as
500,000 individuals in the U.S. develop sepsis each year, rising with the aging
population. Despite the best in antibiotic therapy and cardiopulmonary support,
and the advances in our understanding of inflammation and coagulation in sepsis,
as many as half these cases are fatal. The use of parenteral recombinant
activated protein C (APC) was recently shown in a multi-center study (3) to
significantly reduce mortality in some patients with severe sepsis. (See below).
What is the role
of APC in coagulation and in sepsis, and what is the relationship between the
coagulation and inflammatory pathways?
in Inflammation & Sepsis
Activated protein C (APC)
is a well-recognized anti-thrombotic molecule. APC inactivates activated
factors Va and VIIIa to limit and regulate clot formation. APC also promotes
clot breakdown (fibrinolysis) by inhibiting plasminogen activator inhibitor
(PAI-1). APC also acts to limit the inflammatory response to infection, by
inhibiting the continued production of “pro-inflammatory” cytokines. APC
interferes with monocyte and neutrophil migration to sites of inflammatory,
further limiting the propagation of the inflammatory response. Thus, regulation
of both the coagulation cascade, limiting excess clot formation and inflammatory
response highlight the role of APC in the septic response.
Cytokines in Sepsis and DIC
inflammatory mediators are released and activated. These so-called
“pro-inflammatory cytokines” include tumor necrosis factor (TNF-a),
interleukin-1 (IL-1), and interleukin 6 (IL-6) (1,4, 5). Anti-inflammatory
mediators, including IL-4 and IL-10, appear insufficient to regulate
pro-inflammatory cytokines in severe sepsis.
Prominent features of
the septic response include uncontrolled inflammation and coagulation. Vascular
endothelial damage is the triggering event, whether caused by endotoxin, tissue
factor, necrotic cells, or amniotic fluid, becomes the triggering event. This
endothelial damage leads to release of tissue factor, which activates the
coagulation system resulting in excess thrombin generation. Subsequent clot
formation promotes microvascular endothelial dysfunction, and, if unchecked,
hypoxemia, organ dysfunction, and organ failure ensue.
Endothelial damage and
a shift towards a prothrombotic milieu lead to decreased expression and impaired
function of endothelial receptors for thrombin, i.e. thrombomodulin, and protein
C, i.e. the endothelial protein C receptor (EPCR) (2). Both thrombomodulin and
EPCR are required for the conversion of protein C to its active form, APC. Thus,
a major system for the regulation of thrombin formation, clot propagation, and
protein C activation is lost (5).
Nearly all patients
with severe sepsis are deficient in protein C. Low protein C levels are
associated with shock and poor outcomes, including ICU stay, ventilator
dependence, and mortality (4).
Activated Protein C (APC) in
Over a decade ago, it
was shown that APC protects against organ failure and death in a baboon model of
sepsis (2). However, it was not until this year that the results of a
multicenter, randomized, double-blind trial of adults with sepsis was reported
by Bernard et al (3).
A diagnosis of severe
sepsis was strictly defined, including evidence of infection, systemic
inflammation and organ dysfunction. Activated protein C (APC, Drotrecogin alfa,
Xigris) was given as a 96-hour infusion, within 24 hours of diagnosis.
Because of its anticoagulant effects, subjects were excluded for coagulopathy,
thrombocytopenia < 30,000/ml, recent surgery, or heparin treatment.
APC treatment was
associated with a significant reduction in the pro-inflammatory cytokine IL-6
and in D-dimer, a marker of thrombin generation (3). These changes were
associated with reduced sepsis-related mortality. Bleeding was the most common
adverse event, primarily of the gastrointestinal tract.
The results of this
study of APC underscore the importance of the protein C pathway in sepsis, the
inflammatory response, and sepsis-related coagulopathy. Supplying APC
exogenously in severe sepsis helps to restore regulation of inflammatory and
coagulation responses in some patients, leading to a favorable survival benefit.
Not all patients
benefited from APC, however. It is possible, but unproven, that there is a
finite time during which the inflammatory response associated with sepsis is
reversible, and, presumably, during which treatment, if given early enough,
could favorably affect the outcome.
Hopefully, further study will help define
optimal APC use as well as lead to the development of other potent inhibitors of
the inflammation to reduce sepsis, inflammation, and DIC mortality.
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Copyright © 2002,
Institute For Transfusion Medicine