Page 2322 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 139

DISSEMINATED INTRAVASCULAR COAGULATION

Marcel Levi

A variety of disorders, including infectious or inflammatory condi- and, in some cases, reduces mortality. Finally, results of clinical studies
tions and malignant disease, will lead to activation of coagulation. In also support the concept that activation of coagulation is an impor-
many cases, this activation of coagulation will not lead to clinical tant determinant of clinical outcome. DIC has been shown to be an
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complications and will not even be detected by routine laboratory independent predictor of organ failure and mortality. In a consecu-
tests, but can only be measured with sensitive molecular markers for tive series of patients with severe sepsis, 43% of the patients with
1,2
activation of coagulation factors and pathways. However, if the DIC were compared with the 27% without DIC. In that study, the
stimulus for activation of coagulation is sufficiently strong, the severity of the coagulopathy was directly related to mortality. 9
platelet count may decrease and global clotting times may become In addition to microvascular thrombosis and organ dysfunction,
prolonged. In its most extreme form, systemic activation of coagula- coagulation abnormalities may have other harmful consequences.
tion is known as disseminated intravascular coagulation (DIC). DIC Thrombocytopenia in patients with sepsis places them at risk of
is characterized by the simultaneous occurrence of widespread (micro) bleeding. For example, critically ill patients with a platelet count of
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vascular thrombosis, thereby compromising blood supply to various <50 × 10 /L have a four- to fivefold higher risk for bleeding than
3,4
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organs, which may contribute to organ failure. Because of ongoing those with higher platelet counts. Although the overall risk of
activation of the coagulation system and other factors, such as intracerebral bleeding in intensive care unit (ICU) patients is less than
impaired synthesis and increased degradation of coagulation proteins 0.5%, up to 88% of patients with this complication have platelet
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and protease inhibitors, consumption of clotting factors and platelets counts below 100 × 10 /L. The use of anticoagulants in patients with
may occur, resulting in bleeding from various sites. thrombocytopenia further increases the risk of bleeding. Regardless
In view of the multiple, often contrasting mechanisms that of the cause, multivariate analyses indicate that thrombocytopenia is
occur in patients with DIC, a consensual definition of DIC had an independent predictor of ICU mortality and increases the risk of
been a matter of debate. In 2001 the subcommittee on DIC of the death by 1.9- to 4.2-fold. In particular, thrombocytopenia that per-
International Society on Thrombosis and Hemostasis proposed a sists for more than 4 days after ICU admission, or a 50% or greater
definition that reflects the central role of the microvascular milieu, decrease in platelet count during the ICU stay, is associated with a
i.e., endothelial cells, blood cells, and the plasma protease system, in four- to sixfold increase in mortality. In fact the platelet count appears
the pathogenesis of DIC. This definition of DIC reads as follows: to be a stronger predictor of ICU mortality than composite scoring
“DIC is an acquired syndrome characterized by the intravascular systems, such as the Acute Physiology and Chronic Evaluation
activation of coagulation without a specific localization and arising (APACHE) II or Multiple Organ Dysfunction Score (MODS).
from different causes. It can originate from and cause damage to Decreased levels of coagulation factors, as reflected by prolonged
the microvasculature, which if sufficiently severe, can produce organ global coagulation times, also increase the risk of bleeding. Prolonga-
dysfunction.” 5 tion of the prothrombin time (PT) or activated partial thromboplastin
The diagnosis of DIC may be hampered by the nonspecific nature time (aPTT) to over 1.5 times the control is associated with an
of many indicators of coagulation activation, although newly devel- increased risk of bleeding and mortality in critically ill patients.
oped scoring algorithms based on readily available routine laboratory
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parameters show promising diagnostic accuracy. Owing to the
complexity of the clinical presentation, the variable and unpredictable PATHOBIOLOGY
course, and the multitude of therapies given to patients with DIC,
properly conducted clinical trials are difficult to perform and even to Traditionally, DIC was thought to be the result of activation of both
devise. Management relies on limited evidence from clinical trials in the extrinsic and intrinsic pathways of coagulation. The classical
combination with small studies employing surrogate outcome end- concept was that the extrinsic pathway was initiated by a tissue-
points and experience from case series, as well as from an understand- derived component, which activated factor VII leading to the direct
ing of the underlying pathophysiologic mechanisms. 6 conversion of prothrombin to thrombin. This process would proceed
as long as there was tissue damage from systemic infection, trauma,
circulating placental components, or malignancy. In contrast, the
EPIDEMIOLOGY intrinsic or contact pathway of coagulation was initiated by contact
activation of factor XII which, together with its cofactors, kallikrein
Activation of coagulation in concert with inflammatory activation and high molecular weight kininogen, then activated factor XI
can result in microvascular thrombosis, which contributes to multiple leading to subsequent activation of factor IX. Until recently, the
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organ failure in patients with severe sepsis. In support of this concept, initiators of contact activation were thought to include collagen and
postmortem findings in patients with coagulation abnormalities and artificial surfaces. In recent years the molecular mechanisms of coagu-
DIC on the background of severe sepsis include diffuse bleeding, lation pathway activation have been better defined (Fig. 139.1),
hemorrhagic necrosis of tissues, microthrombi in small blood vessels, thereby providing new insight into the pathogenesis of DIC. In
and thrombi in midsize and larger arteries and veins. Ischemia and general, current thinking is that thrombin and fibrin generation in
necrosis were invariably the result of fibrin deposition in small and patients with DIC is largely driven via the extrinsic pathway; the role
midsize vessels. Importantly, intravascular thrombi appear to be the of the contact system is uncertain.
driver of the organ dysfunction. Fibrin deposition in various organs
also is a characteristic finding in animal models of DIC. Thus experi-
mental bacteremia or endotoxemia causes intra- and extravascular Tissue Factor-Factor VII(a) Pathway
fibrin deposition in the kidneys, lungs, liver, brain, and other organs.
Amelioration of the hemostatic defect with various interventions The extrinsic pathway is initiated by the tissue factor (TF)–factor
reduces fibrin deposition, improves organ function in these models, VIIa complex. TF is a membrane-bound 4.5-kDa protein that is

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