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DOI 10.1007/s11739-012-0859-9
IM - REVIEW
Received: 20 June 2012 / Accepted: 15 September 2012 / Published online: 27 September 2012
SIMI 2012
Introduction
In virtually all critically ill patients, some degree of
coagulation activation may be detected. In many cases, this
activation of coagulation will not lead to clinical complications and will not even be detected by routine laboratory
tests, but can only be measured with sensitive molecular
markers for activation of coagulation factors and pathways
[1]. However, if activation of coagulation is sufficiently
strong, the platelet count may decrease and global clotting
times may become prolonged. In its most extreme form,
systemic activation of coagulation is known as disseminated intravascular coagulation (DIC). DIC is characterized
by the simultaneous occurrence of widespread (micro)vascular thrombosis, thereby compromising blood supply to
various organs, which may contribute to organ failure [2, 3].
Because of ongoing activation of the coagulation system and
other factors, such as impaired synthesis and increased degradation of coagulation proteins and protease inhibitors,
consumption of clotting factors and platelets may occur,
resulting in bleeding from various sites.
Relevance of DIC
Activation of coagulation in concert with inflammatory
activation can result in microvascular thrombosis, which
contributes to multiple organ failure in patients with severe
systemic inflammation [4]. In support of this concept, postmortem findings in patients with coagulation abnormalities
123
24
Pathogenesis of DIC
In recent years, the molecular mechanisms of coagulation
pathways have been defined. Activation of blood coagulation requires several cofactors. For development of DIC,
the surfaces of cell remnants or intact cells, inflammatory
mediators and coagulation proteins are required. For
example, in the coagulopathy resulting from Gram-negative sepsis, endotoxin directly binds to CD 14 on monocytes, and binds to endothelial cells after forming a
complex with lipopolysaccharide binding protein (LBP)
and Toll-like receptors [8]. Through these interactions,
endotoxin induces signaling pathways that culminate in
NFjB activation and initiates the expression of
123
endothelial
cells
inflammatory cells
cytokines
Tissue factor
expression
Impairment of
physiological
anticoagulant
mechanisms
Inhibition of
fibrinolysis
due to high
levels of PAI-1
MICROVASCULAR THROMBOSIS &
MODULATION OF INFLAMMATION
Fig. 1 Pathogenesis of disseminated intravascular coagulation pathways involved in the activation of coagulation in DIC. Both perturbed
endothelial cells and activated mononuclear cells may produce
proinflammatory cytokines that induce tissue factor expression,
thereby initiating coagulation. In addition, downregulation of physiological anticoagulant mechanisms and inhibition of fibrinolysis
promote intravascular fibrin deposition. PAI-1 plasminogen activator
inhibitor, type 1
24
Pathogenesis of DIC
In recent years, the molecular mechanisms of coagulation
pathways have been defined. Activation of blood coagulation requires several cofactors. For development of DIC,
the surfaces of cell remnants or intact cells, inflammatory
mediators and coagulation proteins are required. For
example, in the coagulopathy resulting from Gram-negative sepsis, endotoxin directly binds to CD 14 on monocytes, and binds to endothelial cells after forming a
complex with lipopolysaccharide binding protein (LBP)
and Toll-like receptors [8]. Through these interactions,
endotoxin induces signaling pathways that culminate in
NFjB activation and initiates the expression of
123
endothelial
cells
inflammatory cells
cytokines
Tissue factor
expression
Impairment of
physiological
anticoagulant
mechanisms
Inhibition of
fibrinolysis
due to high
levels of PAI-1
MICROVASCULAR THROMBOSIS &
MODULATION OF INFLAMMATION
Fig. 1 Pathogenesis of disseminated intravascular coagulation pathways involved in the activation of coagulation in DIC. Both perturbed
endothelial cells and activated mononuclear cells may produce
proinflammatory cytokines that induce tissue factor expression,
thereby initiating coagulation. In addition, downregulation of physiological anticoagulant mechanisms and inhibition of fibrinolysis
promote intravascular fibrin deposition. PAI-1 plasminogen activator
inhibitor, type 1
25
123
26
Fig. 2 Schematic
representation of the link
between infection/inflammation
and coagulation. Activated
mononuclear cells and
endothelial cells induce
expression of tissue factor that
activates platelets and the
coagulation system. Activated
coagulation proteases bind to
protease-activated receptors
(PARs), that may induce
additional pro-inflammatory
stimuli by releasing cytokines
that target endothelial cells and
mononuclear cells
fibrinogen
to fibrin
conversion
PARs
thrombin
cytokines
tissue factor
p-selectin
activated
platelet
mononuclear cells
endothelial cells
Sepsis/severe infection
Trauma/burn/heatstroke
Malignancy
Solid tumors
Acute leukemia
Obstetrical conditions
Amniotic fluid embolism
Abruptio placentae
HELLP (hemolysis, elevated liver enzymes, low platelet)syndrome
Vascular abnormalities
Kasabach-Merrit syndrome
Other vascular malformations
Aortic aneurysms
Severe allergic/toxic reactions
Severe immunologic reactions (e.g., transfusion reaction)
123
DIC in malignancy
Patients with solid tumors are vulnerable to risk factors and
additional triggers of DIC that can aggravate thromboembolism and bleeding [21]. Solid tumor cells can express
different procoagulant molecules including tissue factor
and cancer procoagulant (CP), a cysteine protease with
factor X activating properties. Numerous reports on DIC
27
DIC
Prolonged aPTT and PT, increased fibrin split products, low levels of physiological anticoagulant factors
(antithrombin, protein C)
Thrombotic
microangiopathy
Heparin-induced
thrombocytopenia
Schistocytes in blood smear, Coombs-negative hemolysis, fever, neurologic symptoms, renal insufficiency,
coagulation times usually normal, ADAMTS13 levels decreased; PT and aPTT normal
Use of heparin, venous or arterial thrombosis, positive HIT test (usually ELISA for heparinplatelet factor IV
antibodies), rebound platelets after cessation of heparin; coagulation times usually normal, PT normal (aPTT
may be prolonged due to heparin)
Vitamin K deficiency
Liver insufficiency
PT and aPTT prolonged, (moderately) low platelets, liver test abnormalities, hypersplenism, jaundice
Diagnosis of DIC
A practical list of common laboratory abnormalities in
DIC is given in Table 3. Thrombocytopenia or a rapidly
Abnormality
Platelet count
Decreased
Prothrombin
time
Prolonged
APTT
Prolonged
Fibrin
degradation
products
Elevated
Protease
inhibitors*
Decreased
123
28
123
Management of DIC
Adequate management of patients with DIC depends on
vigorous treatment of the underlying disorder to alleviate
or remove the inciting injurious cause [37]. In addition,
intensive support of vital functions and supportive treatment aimed at the coagulopathy may be helpful.
Platelet and plasma transfusion
Low levels of platelets and coagulation factors may
increase the risk of bleeding. However, plasma or platelet
substitution therapy should not be instituted on the basis of
29
Fibrinogen level
([ 1.0 g/L = 0; \1.0 g/L = 1)
Calculated score
* According to the Scientific Standardization Committee of the International Society of Thrombosis and Haemostasis [29]
# Strong increase [5 9 upper limit of normal; moderate increase is [upper limit of normal, but \5 9 upper limit of normal
123
30
Details
Expectations/rationale
Treating the
underlying
disorder
Antithrombotic
agents
Transfusion
123
None.
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