Disseminated

Disseminated Intravascular Coagulation

1

Intravascular
Coagulation Roger S. Riley, M.D., Ph.D.
April, 2005

Feature Disease Facts

Synonyms DIC, consumption coagulopathy, consumptive thrombo-hemorrhagic disease, defibrina-
tion syndrome.

Epidemiology DIC is one of the most common and clinically important acquired disorders of hemosta-
sis. The true incidence of DIC is unknown because the disease is difficult to diagnosis.
DIC occurs in acute and chronic forms of DIC.

Pathogenesis DIC is widespread intravascular activation of the coagulation system ("runaway hemo-
stasis") caused by a disruption in the intricate control mechanisms of hemostasis. DIC is
not a specific disease, but the sequelae of many pathologic conditions with various ef-
fects on the hemostatic system (See Table). These conditions lead to release of pro-
inflammatory cytokines, uncontrolled thrombin generation, widespread microvascular
thrombosis, impairment of anticoagulant pathways, activation or impairment of the fi-
brinolytic system, and other effects. Tissue damage and the deposition of fibrin also re-
sult in the release and activation of plasminogen activators and the generation of plas-
min in amounts that overwhelm its inhibitor, (
2-antiplasmin). Plasmin degrades factors
VIII, V, and I and produces fibrin/fibrinogen degradation products. These substances, as
well as the products of incompletely polymerized fibrin, impair platelet function and
normal fibrin polymerization. Microvascular thrombosis leads to tissue ischemia, necro-
sis, and organ dysfunction, and the release of tissue factor, which further accelerates
the process. In acute DIC, the consumption of platelets and clotting factors occurs more
rapidly than they can be replenished and bleeding results. The bleeding can be severe
or even fatal. Chronic DIC (compensated DIC, nonovert DIC) occurs when time or
intensity of the trigger mechanism is such that the the regulatory mechanisms of co-
agulation are able to control systemic activation of coagulation, and the liver and bone
marrow are able replace the missing coagulation factors and platelets. The following ta-
ble lists the pathogenic mechanism of DIC in different diseases.

Disease DIC Pathogenic Factors

Tissue damage, Release of thromboplastic substances with activation of extrinsic coagu-

trauma lation pathway. Increased proinflammatory cytokines with TF-mediated
coagulation activation, suppression of anticoagulation, and PAI-1-
mediated inhibition of fibrinolysis.

Shock Decreased blood flow with loss of hemodilution. Ischemia and multiple
organ failure.

Gram-negative Release of endotoxin with induction of inflammatory cytokines. Tissue

septicemia factor expression and suppression of thrombomodulin. Downregulation of
protein C-protein S system. Hypotension and septic shock.

Acute leukemia Tumor cell-related factors with procoagulant and fibrinolytic properties,
cytokine release by leukemia cells, effect of chemotherapy, infectious
complications
Disseminated Intravascular Coagulation

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Feature Disease Facts

Pathogenesis Disease DIC Pathogenic Factors

Advanced Various mechanisms including release of procoagulant substances by

malignancy tumor cells

Microangiopathic Decreased blood flow with loss of hemodilution. Ischemia and multiple
hemolytic anemias organ failure.
(TTP, HUS, malig-
nant hypertension,
chemotherapy-
induced, HEELP)

Obstetric complica- Various mechanisms, especially release of placental tissue factor

tions (pre-
eclampsia, amniotic
fluid embolism,
HELLP)

Vascular disorders Chronic local coagulation activation with consumption of platelets and
(aortic aneurysms, coagulation factors, release of plasminogen activators by abnormal
hemangiomas) endothelium

Liver disease Impaired ability to clear procoagulants from the circulation and
synthesize clotting factors

Hyperthermia Endothelial injury and tissue damage

Snakebite Endothelial damage, direct activation of coagulation by venom

Clinical The clinical presentation and consequences of DIC depend on the etiology and the ra-
Presentation pidity of the initiating event. Acute events lead to intravascular coagulation, with de-
pletion of platelets and procoagulant factors, the production of fibrin degradation
products, and bleeding. Slow or chronic activation of coagulation (compensated DIC,
chronic DIC) leads to an excess of activated coagulation products, predisposing to
thrombosis, vascular infarction, and venous thrombosis. DIC is more common in in-
jured or seriously ill hospitalized than in outpatients. The usual signs include bleeding
into deep tissues, as well as hemorrhage into wound sites, intravenous lines, and
catheters. The intravascular fibrin strands produce microangiopathic hemolytic ane-
mia. Fever, hypotension, acidosis, proteinuria, and hypoxia may also occur. Acute DIC
may be fatal unless the condition is promptly diagnosed and appropriate treatment
undertaken (DIC = Death is Coming).

Laboratory No single laboratory assay is pathognomonic of DIC. Instead, the diagnosis

Features must be made through consideration of both laboratory and clinical findings. Serial
laboratory studies may be needed in early DIC. Thrombocytopenia is the usual labora-
tory finding leading to the consideration of DIC. Peripheral blood smear examination is
essential, and shows a characteristic combination of thrombocytopenia, schistocytes,
leukocytosis with a left shift, mild polychromatophilia, and large young platelets in
fulminant cases. Unfortunately, schistocytes may be absent in chronic DIC. The bone
marrow examination is contraindicated in DIC, but will show adequate megakaryo-
cytes in spite of thrombocytopenia. Coagulation evaluation reveals a prolonged
prothrombin time (PT) and activated thromboplastin time (aPTT), decreased fibrino-
gen and plasmin levels, and enhanced fibrinolysis, with elevated levels of fibrinogen
degradation products (FDPs) and D-dimers.
Disseminated Intravascular Coagulation

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Laboratory Of these laboratory tests, the D-dimer level is the most useful, since an elevated
Features (Contd) values indicate the formation and breakdown of fibrin thrombi. Unfortunately,
elevated D-dimers levels are normally found after trauma, surgery, malignancy,
and other conditions where DIC is common. A number of laboratory assays un-
der evaluation focus on therombin generation (i.e., prothrombin fragment 1+2),
thrombin activation of the protein C and fibrinolytic pathways (i.e., activated pro-
tein C inhibitor and plasmin-antiplasmin complexes), and the end products of
thrombin activity (i.e., fibrinopeptide A, soluble fibrin).

Treatment The only definitive therapy for DIC is control of the initiating disease
process. In the meantime, replacement of the deficient platelets and clotting
factors is required, and the cautious use of heparin may reverse the cycle of
consumption and clot formation. Otherwise, an uncontrollable, self-propagating
clinical disaster of simultaneous bleeding and clotting can rapidly lead to the
death of the patient. Until recently, FFP and/or cryoprecipitate were used to re-
place the missing clotting factors. However, clinical trials with antithrombin III,
activated protein C, and tissue factor pathway inhibitor (TFPI) appear promising.

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