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CHAPTER 129 DEFINITION AND HISTORY

DISSEMINATED Disseminated intravascular coagulation (DIC) is a clinicopathologic
syndrome in which widespread intravascular coagulation occurs as a
INTRAVASCULAR result of exposure or production of procoagulants insufficiently bal-
anced by natural anticoagulant mechanisms and endogenous fibrinoly-
sis. Perturbation of the endothelium in the microcirculation along with
COAGULATION stimulated inflammatory cells and release of inflammatory mediators
play a key role in this mechanism. DIC may cause tissue ischemia from
occlusive microthrombi, and bleeding from the consumption of plate-
lets and coagulation factors and, in some cases, an excessive fibrinolytic
Marcel Levi and Uri Seligsohn response. DIC complicates a variety of disorders, and the complexity of
its pathophysiology has made it the subject of a voluminous literature. 1–7
In 1834, Dupuy reported that injection of brain material into
animals caused widespread clots in blood vessels, thus providing the
SUMMARY first description of DIC. In 1865, Trousseau described the tendency
8
to thrombosis, sometimes disseminated, in cachectic patients with
When procoagulants are produced or introduced into the blood and overcome malignancies. In 1873, Naunyn showed that disseminated thrombo-
9
the anticoagulant mechanisms of coagulation, intravascular thrombin is gen- sis could be evoked by intravenous injection of dissolved red cells, and
erated systemically, which can lead to disseminated intravascular coagulation Wooldridge demonstrated that the procoagulant involved was a sub-
(DIC). The clinical manifestations of intravascular coagulation include (1) mul- stance contained in the stroma of the red cells. 10–12
tiorgan dysfunction caused by microthrombi; (2) bleeding caused by consump- In 1955, Ratnoff and associates described the hemostatic abnor-
tion of platelets, fibrinogen, and other coagulation factors; and (3) secondary malities, which we would currently classify as DIC, that occur in women
fibrinolysis. Exposure of blood to tissue factor is the most common trigger. This with fetal death or amniotic fluid embolism. The mechanism by which
13
event can occur when mononuclear cells and endothelial cells are induced to DIC can lead to bleeding was clarified only in 1961, when Lasch and
generate and express tissue factor during the systemic inflammatory response coworkers introduced the concept of consumption coagulopathy, and
syndrome (e.g., Gram-negative and Gram-positive infections, fungemia, burns, McKay established that DIC is a pathogenetic feature of a variety of dis-
1,14
severe trauma), or when contact is established between blood and tissue factor eases. Sizable series of cases were first described in the late 1960s,
following the introduction of defined laboratory criteria for DIC. Yet
15
constitutively present on membranes of cells foreign to blood (e.g., malignant, despite the vast experience that has been accumulated, DIC still consti-
placental, brain, adventitial cells, or traumatized tissues). Laboratory features tutes a major clinicopathologic and therapeutic challenge.
include thrombocytopenia, reduced levels of fibrinogen and other coagula-
tion factors (leading to prolonged partial thromboplastin, prothrombin, and
thrombin times), and elevated levels of D-dimer and fibrin(ogen) degradation PATHOLOGY
products. Several underlying disorders affect these hemostatic parameters and
can lead to a false-positive diagnosis of DIC (e.g., liver disease–related coag- Diffuse multiorgan bleeding, hemorrhagic necrosis, microthrombi in
ulation abnormalities and thrombocytopenia) or to a false-negative diagnosis small blood vessels, and thrombi in medium and large blood vessels
(e.g., pregnancy-related high fibrinogen levels). Reexamining these variables are common findings at autopsy, although patients who had unequiv-
every 6 to 8 hours may permit a specific diagnosis. Early detection, vigorous ocal clinical and laboratory signs of DIC may not have had confirming
treatment of the underlying disorder, and support of vital functions are essen- postmortem findings. 16,17 Conversely, some patients in whom clinical
tial for survival of affected patients. Blood component therapy is effective in and laboratory signs were not consistent with DIC had typical autopsy
18,19
patients who bleed excessively, whereas heparin administration is indicated in a findings. This occasional lack of correlation among clinical, labora-
tory, and pathologic findings is partly a result of extensive postmortem
limited number of circumstances. Intravascular coagulation and the underlying changes in the blood, for example, excessive fibrinolysis, but remains
disorders causing it contribute to a high rate of mortality. The severity of the unexplained in most instances. Organs most frequently involved by
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organ dysfunction and extent of hemostatic failure, as well as increasing patient diffuse microthrombi are the lungs and kidneys, followed by the brain,
age, have been associated with a grave prognosis. heart, liver, spleen, adrenal glands, pancreas, and gut. Specific immu-
nohistologic techniques and ultrastructural analysis have revealed that
most thrombi consist of fibrin monomers or polymers in combination
with platelets. In addition, involvement of activated mononuclear cells
Acronyms and Abbreviations: APACHE, acute physiology and chronic health and other signs of inflammatory activation are frequently present. In
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evaluation; APC, activated protein C; APL, acute promyelocytic leukemia; aPTT, cases of long-lasting DIC, organization and endothelialization of the
activated partial thromboplastin time; ARDS, adult respiratory distress syndrome; microthrombi are often observed. Acute tubular necrosis is more fre-
AT, antithrombin; DIC, disseminated intravascular coagulation; EPCR, endothelial quent than renal cortical necrosis. 16
protein C receptor; FDP, fibrinogen degradation product; HELLP, hemolysis, elevated A significant proportion of patients with chronic DIC have non-
liver enzymes, low platelet count; IL, interleukin; LCAD, long-chain acyl-coenzyme A bacterial thrombotic endocarditis involving mainly the mitral and
dehydrogenase; LPS, lipopolysaccharide; PAI, plasminogen-activator inhibitor; PAR, aortic valves. Moreover, in a retrospective pathologic study, approxi-
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protease-activated receptor; TAFI, thrombin-activatable fibrinolysis inhibitor; TAT, mately 50 percent of patients with nonbacterial thrombotic endocarditis
thrombin–antithrombin; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TNF, had DIC. These heart lesions can be a source of arterial embolization,
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tumor necrosis factor; t-PA, tissue-type plasminogen activator. leading to infarction of the brain, kidneys, and myocardium.

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