Clinical features, diagnosis, and treatment of disseminated intravascular

coagulation

Lawrence LK Leung, MD
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INTRODUCTION Disseminated intravascular coagulation (DIC, also called
consumption coagulopathy and defibrination syndrome) is a systemic process
producing both thrombosis and hemorrhage. It is initiated by a number of defined
disorders and consists of the following components:
Exposure of blood to procoagulants such as tissue factor and cancer procoagulant
Formation of fibrin within the circulation
Fibrinolysis
Depletion of clotting factors
End-organ damage
DIC is a complication of underlying illness occurring in approximately one percent of
hospital admissions [1]. Treatment is generally supportive with platelet and clotting
factor replacement therapy. In selective conditions, judicious use of heparin may be
of benefit. The key to management and a favorable prognosis is effective treatment
of the underlying disease.
The clinical manifestations, diagnosis, treatment, and prognosis of DIC will be
reviewed here. The pathogenesis and etiology of this disorder are discussed
separately. (See "Pathogenesis and etiology of disseminated intravascular
coagulation").
CLINICAL MANIFESTATIONS The consequences of DIC, which include bleeding
and thrombotic manifestations, depend upon its cause and the rapidity with which
the initiating event is propagated (show figure 1).

Although there is overlap, two clinical forms have been described: acute and chronic
DIC (show table 1).

Acute DIC Acute DIC develops when blood is exposed to large amounts of tissue
factor over a brief period of time, with massive generation of thrombin. The acute
triggering of coagulation overwhelms control mechanisms, and compensatory
mechanisms do not have sufficient time to recover. The clinical consequence is a
profound systemic bleeding diathesis and, due to widespread intravascular fibrin
deposition (show histology 1),

tissue ischemic injury, and a microangiopathic hemolytic anemia (show blood smear
1). (See "Extrinsic nonimmune hemolytic anemia due to mechanical damage:
Fragmentation hemolysis and hypersplenism", section on Disseminated intravascular
coagulation).



Common manifestations of acute DIC in addition to bleeding include
thromboembolism and dysfunction of the kidney, liver, lungs, and central nervous
system. In one series of 118 patients with DIC, the main clinical manifestations were
bleeding (64 percent), renal dysfunction (25 percent), hepatic dysfunction (19
percent), respiratory dysfunction (16 percent), shock (14 percent), thromboemboli
(7 percent), and central nervous system involvement (2 percent) [2].
Bleeding Petechiae and ecchymoses are common in conjunction with blood
oozing from wound sites, intravenous lines, catheters, and, in some cases, mucosal
surfaces. The bleeding can be life-threatening if it involves the gastrointestinal tract,
lungs, or central nervous system. In patients who develop DIC after surgical
procedures, hemorrhage may develop around indwelling lines, catheters, drains, and
tracheostomies, and blood may accumulate in serous cavities.
Acute renal failure Acute renal failure occurs in 25 to 40 percent of patients with
acute DIC. Two major mechanisms are involved: microthrombosis of afferent
arterioles may produce cortical ischemia or necrosis, and hypotension and/or sepsis
can lead to acute tubular necrosis. Endotoxin-induced endothelial injury may
predispose to intrarenal thrombus formation by directly promoting platelet
aggregation, by diminishing the release of nitric oxide (endothelium-derived relaxing
factor), which normally inhibits platelet aggregation [3], and by increasing the
synthesis of plasminogen activator inhibitor type 1, leading to a reduction in
fibrinolytic activity [4]. (See "Postischemic and postoperative acute tubular
necrosis").
Hepatic dysfunction Jaundice is common in patients with DIC and may be due
both to liver disease and increased bilirubin production secondary to hemolysis. In
addition, hepatocellular injury may be produced by sepsis and hypotension.
Pulmonary disease Pulmonary hemorrhage with hemoptysis and dyspnea may
result from damage to the vascular endothelium. In addition, sepsis, trauma, and
amniotic fluid embolism are causes of acute respiratory distress syndrome (ARDS) as
well as DIC. (See "Acute respiratory distress syndrome: Definition; epidemiology;
diagnosis; and etiology"). Diffuse pulmonary microthrombosis due to DIC can
augment the lung injury associated with ARDS.
Central nervous system dysfunction A number of neurologic abnormalities can
occur in patients with DIC. These include coma, delirium, and transient focal
neurologic symptoms. Microthrombi, hemorrhage, and hypoperfusion all may
contribute.
Malignancy Although malignancy more often causes chronic DIC, it can produce
acute DIC, particularly in acute promyelocytic leukemia. Among patients with this
disorder, DIC is often present at the time of diagnosis or soon after the initiation of
cytotoxic chemotherapy. It can cause pulmonary or cerebrovascular hemorrhage in
up to 40 percent of patients and some studies report a 10 to 20 percent incidence of
early hemorrhagic deaths [5]. The induction of tumor cell differentiation with all-
trans-retinoic acid can lead to rapid improvement in the coagulopathy [5]. (See
"Clinical features and treatment of acute promyelocytic leukemia in adults", section
on Disseminated intravascular coagulation).
Chronic DIC Compensated or chronic DIC develops when blood is continuously or
intermittently exposed to small amounts of tissue factor and compensatory
mechanisms in the liver and bone marrow are largely able to replenish the depleted
coagulation proteins and platelets, respectively. Under these conditions, the patient
is either asymptomatic with increased levels of fibrin degradation products or has
manifestations of venous and/or arterial thrombosis. Patients with chronic DIC may
also have minor skin and mucosal bleeding.
Malignancy, particularly solid tumors, is the most common cause of chronic DIC.
Venous thromboses commonly present as deep venous thrombosis in the extremities
or superficial migratory thrombophlebitis (Trousseau's syndrome), while arterial
thromboses can produce digital ischemia, renal infarction, or stroke. Arterial
ischemia can also be due to embolization from nonbacterial thrombotic (marantic)
endocarditis. (See "Hypercoagulable disorders associated with malignancy").
DIAGNOSIS The laboratory findings that are used to confirm the diagnosis of DIC
are somewhat different in acute and chronic disease (show table 1). Other issues
that must be addressed are establishing the presence of DIC in patients with liver
disease and differentiating DIC from thrombotic thrombocytopenic purpura-hemolytic
uremic syndrome (TTP-HUS), a clinically similar disorder with a different
pathogenesis and treatment.
Acute DIC The diagnosis of acute DIC is suggested by the history (sepsis,
trauma, malignancy), clinical presentation, moderate to severe thrombocytopenia
(less than 100,000/L) and the presence of microangiopathic changes on the
peripheral blood smear (show blood smear 1 and show blood smear 2).

The diagnosis is confirmed by a variety of laboratory studies which demonstrate
evidence of both increased thrombin generation (eg, decreased fibrinogen) and
fibrinolysis (eg, elevated FDPs and D-dimer, show table 2);

the degree of abnormality in these findings may correlate with the extensiveness of
organ involvement (show table 1) [2,6-9]. (See "Approach to the patient with a
bleeding diathesis").
Fibrin degradation product or D-dimer levels Clinically significant DIC is
unlikely if there is no biochemical evidence of accelerated fibrinolysis. Elevated D-
dimer levels, reflecting cross-linked fibrin degradation, are the most common
abnormal parameter in patients with DIC [10,11]. Measurement of D-dimer is more
specific although somewhat less sensitive than a latex agglutination test for fibrin
degradation products [10]. The method of choice is the enzyme-linked
immunosorbent assay (ELISA).
Prothrombin time Prolongation of the prothrombin time (PT) reflects reduced
activity of the components of the extrinsic and common pathways. These include
factors VII, X, V, and prothrombin, which are the most frequently decreased clotting
proteins in DIC [11].
Activated partial thromboplastin time The activated partial thromboplastin
time (aPTT) measures the intrinsic and common pathways of coagulation. It is
sensitive to deficiencies of factors XII, XI, IX and VIII, and less sensitive than the PT
to deficiencies of components of the common pathway. (See "Clinical use of
coagulation tests").
Plasma fibrinogen concentration The plasma fibrinogen concentration is
usually low in acute decompensated DIC, but may be elevated as an acute phase
reactant in certain conditions, including pregnancy. Thus, a plasma fibrinogen of 200
mg/dL, although within the normal range, may represent a significant decrease in a
patient whose baseline level, because of underlying malignancy, sepsis, or
inflammation, should be 800 mg/dL.
Other studies which may be useful include the thrombin time and reptilase time,
which are usually prolonged due to hypofibrinogenemia and the presence of fibrin
degradation products. (See "Clinical use of coagulation tests", section on Thrombin
time). Specific assays can also be used to monitor various coagulation factors.
Factors V and VIII, in addition to fibrinogen, are usually significantly depressed.
Prothrombin levels may be normal in some patients, particularly those with abruptio
placentae [12]. (See "Abruptio placentae").
Acute DIC is also characterized by reduced levels of endogenous coagulation
inhibitors such as antithrombin (AT), protein C, and protein S [13]. A marked
reduction in AT levels at the onset of septic shock may be a sensitive marker of
unfavorable prognosis, presumably by permitting persistence of the procoagulant
state [13,14]. Another potentially useful marker is measurement of soluble fibrin
monomers. One study has shown that levels are elevated in both DIC and pre-DIC
with a high degree of sensitivity and specificity [15]. However, specific assays for
soluble fibrin monomers are not generally available.
Chronic DIC The above laboratory studies are variable in chronic DIC because a
slower rate of consumption of coagulation factors may be balanced by enhanced
synthesis of these proteins (show table 1). Thus, the platelet count may be only
moderately reduced, plasma fibrinogen is often normal or slightly elevated, and the
PT and PTT may be within normal limits. In such patients, the diagnosis may be
largely based upon evidence of microangiopathy on the peripheral blood smear and
increased levels of FDPs and particularly, D-dimer.
Acute DIC in the presence of severe liver disease Severe liver disease results
in decreased synthesis of coagulation factors and inhibitors [16], and
thrombocytopenia may be induced by hypersplenism. (See "Approach to the adult
patient with thrombocytopenia"). In addition, liver disease alone may be associated
with chronic or intermittent fibrinolysis, fibrinogenolysis, and elevated levels of FDPs.
DIC versus TTP-HUS The pathogenesis of DIC, a thrombotic microangiopathy
resulting from activation of the coagulation system, is different from the
pathogenesis of another thrombotic microangiopathy, thrombotic thrombocytopenic
purpura-hemolytic uremic syndrome (TTP-HUS), which results from primary platelet
activation due in many cases to a congenital or acquired defect in von Willebrand
factor cleaving protease or primary endothelial injury. (See "Causes of thrombotic
thrombocytopenic purpura-hemolytic uremic syndrome in adults").
Differences in pathogenesis between TTP-HUS and DIC result in coagulation
abnormalities that usually permit these disorders to be distinguished. Patients with
TTP-HUS present with thrombocytopenia and a microangiopathic blood smear but
usually have normal levels of the coagulation components and little or no
prolongation of the PT or PTT (show table 3) [17,18].

Establishing the correct diagnosis is important clinically, because TTP-HUS in adults
is usually treated with plasma exchange, which may be life-saving; this is not the
modality used to treat DIC. (See "Treatment of thrombotic thrombocytopenic
purpura-hemolytic uremic syndrome in adults"). In addition to the different
laboratory findings, TTP-HUS is usually not seen in the typical clinical settings that
are associated with DIC (eg, sepsis, trauma, malignancy, and obstetrical
complications).
DIC versus fibrinolysis Primary fibrinogenolysis occurs when plasmin is
generated in the absence of thrombosis. It is rare and may occur in certain
conditions, such as direct infusion of thrombolytic agents and in patients with
prostate cancer [19-21]. It can be distinguished from DIC by the absence of elevated
level of D-dimers. However, when fibrinolysis is prominent, elevated levels of D-
dimer and other fibrin degradation products will be present. (See "Thrombotic and
hemorrhagic disorders due to abnormal fibrinolysis", section on Laboratory diagnosis
of abnormal fibrinolysis).
TREATMENT Acute DIC is a serious complication that is associated with a high
mortality rate, determined in part by the underlying disease. The reported mortality
rate ranges from 40 to 80 percent in patients with severe sepsis, trauma, or burns
[2,22-27]. Risk factors for death include increasing age and the severity of the organ
dysfunction and hemostatic abnormalities [2]. It is not clear, however, if the poor
outcome in sepsis and trauma reflects the effects of DIC or the consequences of the
systemic inflammatory response. (See "Sepsis and the systemic inflammatory
response syndrome: Definitions and prognosis").
The last observation illustrates the central importance of correction of the underlying
disease and initiating factors in any patient with DIC. Hemodynamic support is
essential, but many patients do not require specific therapy for the coagulopathy,
either because it is of short duration or because it is not severe enough to present a
major risk of bleeding or thrombosis. In selected instances, the use of blood
component replacement therapy or heparin may be of value, although there are no
controlled studies demonstrating definitive benefit. Restoration of physiologic levels
of antithrombin may be another therapeutic option. In contrast, the administration of
antifibrinolytic agents, such as epsilon-aminocaproic acid (EACA) or aprotinin, is
generally contraindicated, since blockade of the fibrinolytic system may increase the
risk of thrombotic complications [28].
Platelet transfusion and fresh frozen plasma Patients with DIC bleed because
of thrombocytopenia and coagulation factor deficiency. There is no evidence to
support the administration of platelets and coagulation factors in patients who are
not bleeding or at high risk of bleeding. However, treatment is justified in patients
who have serious bleeding, are at high risk for bleeding (eg, after surgery), or
require invasive procedures.
Patients with marked thrombocytopenia (less than 20,000/L) or those with
moderate thrombocytopenia (less than 50,000/L) and serious bleeding should be
given platelet transfusions (1 to 2 units per 10 kg per day). (See "Clinical and
laboratory aspects of platelet transfusion therapy"). Such patients typically show a
less than expected rise in platelet count, due to the ongoing consumption. (See
"Refractoriness to platelet transfusion therapy", section on Other clinical situations).
With respect to replacement therapy, patients who are actively bleeding with a
significantly elevated prothrombin time (INR) and/or a fibrinogen concentration <50
mg/dL, should receive fresh frozen plasma or cryoprecipitate, the latter for
fibrinogen replacement. It is preferable to keep the fibrinogen level above 100 mg/dL
(show table 4). (See "Transfusion of plasma components").

Heparin The administration of heparin or other anticoagulants to interrupt the
underlying coagulopathy in DIC would appear to be a logical therapeutic approach.
However, there are no controlled trials indicating benefit and there is little evidence
that the use of heparin improves organ dysfunction [29-31]. Additional arguments
against the routine use of heparin include potential aggravation of bleeding and the
likelihood that it will have reduced effect due to the low levels of AT (show figure 2).
(See "Clinical use of heparin and low molecular weight heparin", section on Heparin).

The administration of heparin is generally limited to the subset of patients with
chronic, compensated (or low-grade) DIC who have predominantly thrombotic
manifestations, such as migratory thrombophlebitis and acral ischemia. Heparin may
be useful in patients with retained dead fetus and hypofibrinogenemia prior to the
induction of labor, excessive bleeding associated with a giant hemangioma, and
aortic aneurysm (prior to resection).
Low dose heparin may be a useful adjunct in the DIC associated with acute
promyelocytic leukemia. However, since the DIC in that situation generally responds
to treatment with all-trans retinoic acid, heparin is now rarely indicated. (See
"Clinical features and treatment of acute promyelocytic leukemia in adults"). Other
settings in which heparin might be used include malignancy and chronic DIC prior to
surgery, septic abortion, and mismatched transfusion [30].
Once the clinical decision has been made to employ heparin in acute DIC, it is
important to be sure that the patient's antithrombin (AT) level is near normal (ie, 80
to 100 percent), so that the biologically important heparin-AT complex can form and
inactivate the serine protease procoagulants, particularly thrombin and factor Xa
(show figure 2, see below). The usual intravenous bolus heparin injection of 5,000 to
10,000 units should be avoided. One may start with an IV dose of 500 units per
hour, aiming for an aPTT of about 45 sec. If the patient's baseline aPTT is prolonged,
the situation is more difficult, and one aims for further slight prolongation of the
aPTT. Once there is evidence of heparin effect, replacement therapy with fresh
frozen plasma or cryoprecipitate is pursued. In chronic DIC, a continuous infusion
can be used, beginning at 500 units/hour. Low molecular weight heparins are also
efficacious.
Protein C concentrate Patients with homozygous protein C deficiency or
acquired protein C deficiency (eg, due to meningococcemia) may develop purpura
fulminans. Such patients appear to benefit from the administration of protein C
concentrate [32-34]. In one series of 12 patients with purpura fulminans so treated,
none died despite a predicted mortality rate of 60 to 80 percent [33]. The
administration of FFP as a source of protein C is more difficult because of the short
half-life of protein C in the plasma. (See "Protein C deficiency"). There are anecdotal
reports that repeated plasma exchange has been helpful in maintaining normal levels
of protein C when protein C concentrate is not available [35,36].
Activated protein C Activated protein C (aPC) has both anticoagulant and anti-
inflammatory activities [37]. The anti-inflammatory effect of aPC may be due, in
part, to its direct action on endothelial cells. Studies have shown that recombinant
activated protein C could directly modulate endothelial cell gene expression patterns
[38]. It inhibits the tumor necrosis factor mediated expression of cell adhesion
molecules (eg, ICAM-1, VCAM-1, and E-selectin) on endothelial cell surface by down-
regulation of the transcription factor NF-kB. At the same time, it enhances the
expression of several anti-apoptotic genes, such as the Bcl-2 homologue protein.
(See "Plasma derivatives and recombinant DNA-produced coagulation factors",
section on Activated protein C).
In a randomized, double-blind, placebo-controlled trial, patients with severe sepsis
were randomly assigned to receive an intravenous infusion of either recombinant aPC
(drotrecogin alfa activated: 24 g/kg per hour) or placebo for 96 hours [39]. The
primary endpoint was death from any cause at 28 days. A total of 1690 patients
were treated; the trial was terminated early because a statistically significant
favorable result was observed in the recombinant aPC-treated group. The mortality
rate was 30.8 percent in the placebo group and 24.7 percent in the aPC group, with
a reduction in the relative risk of death of 19.4 percent.
Based upon post-hoc analysis of the study data, treatment was of greater benefit in
the most acutely ill patients, as identified by APACHE II score 25 [40]. The role of
drotrecogin alfa in the treatment of pediatric sepsis, or in the treatment of adults
with less severe disease, is the subject of ongoing (phase IV) trials [41]. Drotrecogin
alfa (Xigris) was narrowly approved by the FDA in November, 2001 as a treatment
for adults with septic shock. (See "Management of severe sepsis and septic shock in
adults", section on Recombinant human activated protein C for a more complete
discussion of the issues surrounding the use of this agent in septic shock).
Antithrombin As mentioned above, acute DIC is also characterized by reduced
levels of endogenous coagulation inhibitors such as antithrombin (AT, formerly
known as antithrombin III), protein C, and protein S [13]. A marked reduction in AT
levels at the onset of septic shock may be a sensitive marker of unfavorable
prognosis, presumably by permitting persistence of the procoagulant state [13,14].
In vitro data suggest that, in addition to anticoagulant properties, AT may decrease
the inflammatory response of mononuclear cells and cultured endothelial cells to
lipopolysaccharide by decreasing the transcription of genes for mediators such as
interleukin-6 and tumor necrosis factor alpha [42].
While some clinical studies have suggested that AT therapy is beneficial in patients
with severe sepsis or septic shock [43,44] a subsequent randomized placebo
controlled trial in 2314 patients with sepsis found no benefit, in terms of mortality,
from AT administration, and there was an increased risk of bleeding in those who
received both AT and heparin [45]. (See "Investigational and ineffective therapies for
sepsis" section on Antithrombin for a further discussion of this issue).
RECOMMENDATION Disseminated intravascular coagulation may be acute or
chronic (show table 1).
The diagnosis of acute DIC is suggested by the history (sepsis, trauma, malignancy),
clinical presentation, moderate to severe thrombocytopenia (less than 100,000/L)
and the presence of microangiopathic changes on the peripheral blood smear (show
blood smear 1 and show blood smear 2). The diagnosis is confirmed by
demonstrating increased thrombin generation (eg, decreased fibrinogen) and
increased fibrinolysis (eg, elevated FDPs and D-dimer; the degree of abnormality in
these findings may correlate with the extensiveness of organ involvement.
The above laboratory studies are variable in chronic DIC because a slower rate of
consumption of coagulation factors may be balanced by enhanced synthesis of these
proteins. In such patients, the diagnosis may be largely based upon evidence of
microangiopathy on the peripheral blood smear and increased levels of FDPs and
particularly, D-dimer.
Treatment of the underlying disease (eg, sepsis) is of central importance in
controlling acute or chronic DIC. Hemodynamic support is essential, but many
patients do not require specific therapy for the coagulopathy, either because it is of
short duration or because it is not severe enough to present a major risk of bleeding
or thrombosis.