clinical features of dic (gejala klinik dic)

8/12/2019 Clinical Features of DIC (Gejala Klinik DIC)

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Clinical features, diagnosis, and treatment of disseminated intravascular

coagulation

Lawrence LK Leung, MD

UpToDate performs a continuous review of over 350 journals and other resources.

Updates are added as important new information is published. The literature reviewfor version 14.1 is current through December 2005; this topic was last changed on

March 4, 2005. The next version of UpToDate (14.2) will be released in June 2006.

INTRODUCTION Disseminated intravascular coagulation (DIC, also called

consumption coagulopathy and defibrination syndrome) is a systemic processproducing 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 damageDIC is a complication of underlying illness occurring in approximately one percent ofhospital admissions [1]. Treatment is generally supportive with platelet and clotting

factor replacement therapy. In selective conditions, judicious use of heparinmay beof 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 bereviewed 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 whichthe initiating event is propagated (show figure 1).
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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 acutetriggering 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 fibrindeposition (show histology 1),
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tissue ischemic injury, and a microangiopathic hemolytic anemia (show blood smear1). (See "Extrinsic nonimmune hemolytic anemia due to mechanical damage:

Fragmentation hemolysis and hypersplenism", section on Disseminated intravascular

coagulation).
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fibrinolytic activity [4]. (See "Postischemic and postoperative acute tubular

necrosis").

Hepatic dysfunction Jaundice is common in patients with DIC and may be dueboth 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) aswell as DIC. (See "Acute respiratory distress syndrome: Definition; epidemiology;

diagnosis; and etiology"). Diffuse pulmonary microthrombosis due to DIC canaugment 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 focalneurologic symptoms. Microthrombi, hemorrhage, and hypoperfusion all may

contribute.

Malignancy Although malignancy more often causes chronic DIC, it can produceacute 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 ofcytotoxic 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 ofearly 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", sectionon Disseminated intravascular coagulation).

Chronic DIC Compensated or chronic DIC develops when blood is continuously or

intermittently exposed to small amounts of tissue factor and compensatorymechanisms in the liver and bone marrow are largely able to replenish the depleted

coagulation proteins and platelets, respectively. Under these conditions, the patientis either asymptomatic with increased levels of fibrin degradation products or has

manifestations of venous and/or arterial thrombosis. Patients with chronic DIC mayalso 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 extremitiesor superficial migratory thrombophlebitis (Trousseau's syndrome), while arterial

thromboses can produce digital ischemia, renal infarction, or stroke. Arterialischemia 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 liverdisease and differentiating DIC from thrombotic thrombocytopenic purpura-hemolytic

uremic syndrome (TTP-HUS), a clinically similar disorder with a different

pathogenesis and treatment.
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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 theperipheral blood smear (show blood smear 1and show blood smear 2).

The diagnosis is confirmed by a variety of laboratory studies which demonstrateevidence of both increased thrombin generation (eg, decreased fibrinogen) and

fibrinolysis (eg, elevated FDPs and D-dimer, show table 2);
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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 isunlikely if there is no biochemical evidence of accelerated fibrinolysis. Elevated D-

dimer levels, reflecting cross-linked fibrin degradation, are the most commonabnormal 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 reducedactivity of the components of the extrinsic and common pathways. These include

factors VII, X, V, and prothrombin, which are the most frequently decreased clottingproteins in DIC [11].

Activated partial thromboplastin time The activated partial thromboplastin

time (aPTT) measures the intrinsic and common pathways of coagulation. It issensitive 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 ofcoagulation tests").
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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 200mg/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 fibrindegradation 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 abruptioplacentae [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 procoagulantstate [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-DICwith 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 aslower rate of consumption of coagulation factors may be balanced by enhanced

synthesis of these proteins (show table 1). Thus, the platelet count may be onlymoderately 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 belargely 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 resultsin 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 associatedwith 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 thepathogenesis of another thrombotic microangiopathy, thrombotic thrombocytopenic

purpura-hemolytic uremic syndrome (TTP-HUS), which results from primary plateletactivation due in many cases to a congenital or acquired defect in von Willebrand

factor cleaving protease or primary endothelial injury. (See "Causes of thromboticthrombocytopenic 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 withTTP-HUS present with thrombocytopenia and a microangiopathic blood smear but

usually have normal levels of the coagulation components and little or noprolongation of the PT or PTT (show table 3) [17,18].
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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 themodality used to treat DIC. (See "Treatment of thrombotic thrombocytopenic

purpura-hemolytic uremic syndrome in adults"). In addition to the differentlaboratory 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 isgenerated in the absence of thrombosis. It is rare and may occur in certainconditions, 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 elevatedlevel of D-dimers. However, when fibrinolysis is prominent, elevated levels of D-

dimer and other fibrin degradation products will be present. (See "Thrombotic andhemorrhagic disorders due to abnormal fibrinolysis", section on Laboratory diagnosis

of abnormal fibrinolysis).
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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 pooroutcome in sepsis and trauma reflects the effects of DIC or the consequences of the

systemic inflammatory response. (See "Sepsis and the systemic inflammatoryresponse 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 isessential, 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 amajor risk of bleeding or thrombosis. In selected instances, the use of blood

component replacement therapy or heparinmay be of value, although there are nocontrolled studies demonstrating definitive benefit. Restoration of physiologic levels

of antithrombinmay be another therapeutic option. In contrast, the administration of

antifibrinolytic agents, such as epsilon-aminocaproic acid (EACA) or aprotinin, isgenerally 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 arenot 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), orrequire invasive procedures.

Patients with marked thrombocytopenia (less than 20,000/L) or those withmoderate 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 aless 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 asignificantly elevated prothrombin time (INR) and/or a fibrinogen concentration


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Heparin The administration of heparinor other anticoagulants to interrupt theunderlying 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 argumentsagainst 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).
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The administration of heparinis generally limited to the subset of patients with

chronic, compensated (or low-grade) DIC who have predominantly thromboticmanifestations, 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, andaortic aneurysm (prior to resection).

Low dose heparinmay 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 tosurgery, septic abortion, and mismatched transfusion [30].
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Once the clinical decision has been made to employ heparinin 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 andinactivate the serine protease procoagulants, particularly thrombin and factor Xa

(show figure 2, see below). The usual intravenous bolus heparin injection of 5,000 to10,000 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 theaPTT. Once there is evidence of heparin effect, replacement therapy with fresh

frozen plasma or cryoprecipitate is pursued. In chronic DIC, a continuous infusioncan 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 Cconcentrate [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]. Theadministration 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 anecdotalreports 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 recombinantactivated protein C could directly modulate endothelial cell gene expression patterns

[38]. It inhibits the tumor necrosis factor mediated expression of cell adhesionmolecules (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 alfaactivated: 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 patientswere 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, witha 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 inthe most acutely ill patients, as identified by APACHE II score 25 [40]. The role ofdrotrecogin alfain the treatment of pediatric sepsis, or in the treatment of adults

with less severe disease, is the subject of ongoing (phase IV) trials [41]. Drotrecoginalfa (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 inadults", section on Recombinant human activated protein Cfor a more complete

discussion of the issues surrounding the use of this agent in septic shock).
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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 ATlevels 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 decreasethe inflammatory response of mononuclear cells and cultured endothelial cells to

lipopolysaccharide by decreasing the transcription of genes for mediators such asinterleukin-6 and tumor necrosis factor alpha [42].

While some clinical studies have suggested that AT therapy is beneficial in patientswith 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 forsepsis"section on Antithrombinfor a further discussion of this issue).

RECOMMENDATION Disseminated intravascular coagulation may be acute orchronic (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 (showblood smear 1and 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 inthese 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 theseproteins. In such patients, the diagnosis may be largely based upon evidence of

microangiopathy on the peripheral blood smear and increased levels of FDPs andparticularly, D-dimer.

Treatment of the underlying disease (eg, sepsis) is of central importance in

controlling acute or chronic DIC. Hemodynamic support is essential, but manypatients 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 bleedingor thrombosis.
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clinical features of dic (gejala klinik dic)

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