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BackgroundDisseminated intravascular coagulation (DIC) is a complex systemic thrombohemorrhagic disorderinvolving the generation of intravascular fibrin and the consumption of procoagulants and platelets. Theresultant clinical condition is characterized by intravascular coagulation and hemorrhage.

The subcommittee on DIC of the International Society on Thrombosis and Haemostasis has suggested

the following definition for DIC: "An acquired syndrome characterized by the intravascular activation ofcoagulation with loss of localization arising from different causes. It can originate from and cause damageto the microvasculature, which if sufficiently severe, can produce organ dysfunction."[1]

DIC is not an illness on its own but rather a complication or an effect of progression of other illnesses andis estimated to be present in up to 1% of hospitalized patients.[2]

DIC is always secondary to an underlying disorder and is associated with a number of clinical conditions(see List below), generally involving activation of systemic inflammation. DIC has several consistentcomponents including activation of intravascular coagulation, depletion of clotting factors, and end-organdamage (see Components of DIC). DIC is most commonly observed in severe sepsis and septic shock.Indeed the development and severity of DIC correlates with mortality in severe sepsis.[3, 4]Althoughbacteremia, including both gram-positive and gram-negative organisms, is most commonly associatedwith DIC, other organisms including viruses, fungi, and parasites may cause DIC.

Trauma, especially neurotrauma, is also frequently associated with DIC. DIC is more frequently observedin those patients with trauma who develop the systemic inflammatory response syndrome.[5] Evidenceindicates that inflammatory cytokines play a central role in DIC in both trauma patients and septicpatients. In fact, systemic cytokine profiles in both septic patients and trauma patients are nearlyidentical.[6]

Conditions associated with disseminated intravascular coagulation include the following [7] :

Sepsis/severe infection

Trauma (neurotrauma)

Organ destruction

Malignancy (solid and myeloproliferative malignancies)

Severe transfusion reactions Rheumatologic illness - Adult Stills disease, lupus

Obstetric complications -Amniotic fluid embolism;abruptio placentae; hemolysis, elevated liverenzymes, low platelets (HELLP) syndrome/eclampsia

Retained dead fetus syndrome

Vascular abnormalities -Kasabach-Merritt syndrome, large vascular aneurysms

Severe hepatic failure

Severe toxic reactions - Envenomations,transfusion reactions, transplant rejection

Heat stroke/hyperthermia

Hemorrhagic skin necrosis (purpura fulminans)[8, 9]

Catastrophic antiphospholipid syndrome (rare)[10]

Acute DIC versus chronic DIC

DIC exists in both acute and chronic forms. DIC develops acutely when sudden exposure of blood toprocoagulants occurs, including tissue factor (tissue thromboplastin), generating intravascularcoagulation. Compensatory hemostatic mechanisms are quickly overwhelmed, and, as a consequence, asevere consumptive coagulopathy leading to hemorrhage develops. Abnormalities of blood coagulationparameters are readily identified, and organ failure frequently occurs in acute DIC.

In contrast, chronic DIC reflects a compensated state that develops when blood is continuously orintermittently exposed to small amounts of tissue factor. Compensatory mechanisms in the liver and bonemarrow are not overwhelmed, and there may be little obvious clinical or laboratory indication of the

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presence of DIC. Chronic DIC is more frequently observed in solid tumors and in large aorticaneurysms.[11]

PathophysiologyDIC is caused by widespread and ongoing activation of coagulation, leading to vascular or microvascularfibrin deposition, thereby compromising an adequate blood supply to various organs.

There are a number of different triggers that can cause a hemostatic imbalance, giving rise to ahypercoagulable state. Inflammatory cytokines are the most important mediators responsible for thisimbalance.[12] It is clear that there is cross-communication between coagulation and inflammatory systems,whereby inflammation gives rise to activation of the clotting cascade, and the resultant coagulationstimulates more vigorous inflammatory activity.

Four different mechanisms are primarily responsible for the hematologic derangements seen in DIC:increased thrombin generation, a suppression of anticoagulant pathways, impaired fibrinolysis, andinflammatory activation.[13]Activation of intravascular coagulation is mediated almost entirely by theintrinsic clotting pathway.

The pathogenesis of DIC starts at the level of the endothelium of the capillary bed, where the maininteraction between inflammation and coagulation takes place. Endothelial cell damage results in the

release of tissue factor into the circulation, and that initiates the activation of the clotting cascade. Insepsis, the cytokines produce a state of intense inflammatory activity that causes the down-regulation ofendothelial glycosaminoglycans present in the glycocalyx, thereby impairing the functions of antithrombin(AT), tissue factor pathway inhibitor (TFPI), leukocyte adhesion, and leukocyte transmigration. Theintegrity of the vascular barrier and nitric oxidemediated vasodilation can also be impaired in DIC.[14]

Moreover, the specific disruption of the endothelial glycocalyx causes thrombin generation together withplatelet adhesion within a matter of minutes. These events make the endothelium become a procoagulantsurface, which leads to microvascular thrombosis with subsequent multiorgan dysfunction and then,ultimately, failure.

Exposure to tissue factor in the circulation occurs via endothelial disruption, tissue damage, orinflammatory or tumor cell expression of procoagulant molecules, including tissue factor. Tissue factoractivates coagulation by the extrinsic pathway involving factor VIIa. Factor VIIa has been implicated asthe central mediator of intravascular coagulation in sepsis. Blocking the factor VIIa pathway in sepsis hasbeen shown to prevent the development of DIC, whereas interrupting alternative pathways did notdemonstrate any effect on clotting.[15, 16] The tissue factor-VIIa complex then serves to activate thrombin,which, in turn, cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation. Evidencesuggests that the intrinsic (or contact) pathway is also activated in DIC, while contributing more tohemodynamic instability and hypotension than to activation of clotting.[17]

Thrombin produced by the tissue factor pathway amplifies both clotting and inflammation through thefollowing activities: (1) platelet activation, enhancing aggregation and augmenting platelet functions incoagulation; (2) it activates factors VIII, V, and XI, yielding further thrombin generation; (3) it enhances theactivation of proinflammatory factors via protease-activated receptors (PARs); (4) it activates factor XIII tofactor XIIIa, which augments the production of fibrin clots from fibrinogen; (5) it activates thrombin-activatable fibrinolysis inhibitor (TAFI), making clots resistant to fibrinolysis; and (6) it increases

expression of adhesion molecules, such as L-selectin, thereby promoting the inflammatory effects ofwhite blood cells.[18]

Thrombin generation is usually tightly regulated by multiple hemostatic mechanisms. However, onceintravascular coagulation commences, compensatory mechanisms are overwhelmed or incapacitated.Antithrombin is one such mechanism responsible for regulating thrombin levels. However, due to multiplefactors, antithrombin activity is reduced in patients with sepsis. First, antithrombin is continuouslyconsumed by ongoing activation of coagulation. Moreover, elastase produced by activated neutrophilsdegrades antithrombin as well as other proteins. Further antithrombin is lost to capillary leakage. Lastly,production of antithrombin is impaired secondary to liver damage resulting from under-perfusion and

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microvascular coagulation.[11, 19] Decreased levels of antithrombin correlate well with elevated mortality inpatients with sepsis.[4]

Protein C, along with protein S, serves as an important anticoagulant compensatory mechanism. Undernormal conditions, protein C is activated by thrombin and is complexed on the endothelial cell surfacewith thrombomodulin.[11]Activated protein C combats coagulation via proteolytic cleavage of factors Vaand VIIIa. However, the cytokines (tumor necrosis factor [TNF-], interleukin 1 [IL-1]) produced in

sepsis and other generalized inflammatory states largely incapacitate the protein C pathway.Inflammatory cytokines down-regulate the expression of thrombomodulin on the endothelial cellsurface.[20] Protein C levels are further reduced via consumption, extravascular leakage, and reducedhepatic production and by a reduction in freely circulating protein S.

Tissue factor pathway inhibitor (TFPI) is another anticoagulant mechanism that is disabled in DIC. TFPIreversibly inhibits factor Xa and thrombin, and has the ability to inhibit the factor VIIa-tissue factorcomplex. Although levels of TFPI are normal in patients with sepsis, a relative insufficiency in DIC isevident. TFPI depletion in animal models predisposes to DIC, and TFPI blocks the procoagulant effect ofendotoxin in humans.[21] The intravascular fibrin produced by thrombin is normally eliminated via a processtermed fibrinolysis. The initial response to inflammation appears to be augmentation of fibrinolytic action;however, this response soon reverses as inhibitors (plasminogen activator inhibitor-1 [PAI-1], TAFI) offibrinolysis are released.[22] Indeed, high levels of PAI-1 precede DIC and predict poor

outcomes.[23]

Fibrinolysis cannot keep pace with increased fibrin formation, eventually resulting in under-opposed fibrin deposition in the vasculature.

In experimental models of DIC, initially fibrinolysis is activated but subsequently inhibited, because of anincreased release of plasminogen activator inhibitor-I (PAI-1) produced by endothelial cells.[24] Theseeffects are mediated by TNF-2 and IL-1.[25] In a study of 69 DIC patients (31 with multiorgan failure),higher levels of tissue-type plasminogen activator (t-PA) antigen and PAI-1 with depressed levels of 2-antiplasmin were observed in patients with DIC and multiorgan failure compared with DIC patients withoutmultiorgan failure.[26] This finding supports the conclusion that fibrinolysis is a mechanism vital to theprevention of multiorgan failure.

Playing a key role in the process of coagulation and hemostasis is the vascular endothelium, which isresponsible for the production of Von-Willebrand factor (vWF). Von Willebrand factor mediates theadhesion between the platelet surface receptors and the vessel wall and is increased in cases of

thrombotic microangiopathy related to DIC. Impaired control of endothelial cell thrombomodulinexpression may result in facilitated thrombin generation, which subsequently results in increased plateletactivation and the conversion of fibrinogen to fibrin.[27]

Inflammatory and coagulation pathways interact in substantial ways. Many of the activated coagulationfactors produced in DIC contribute to the propagation of inflammation by stimulating endothelial cellrelease of proinflammatory cytokines. Factor Xa, thrombin, and the tissue factor-VIIa complex have eachbeen demonstrated to elicit proinflammatory action. Furthermore, given the anti-inflammatory action ofactivated protein C and AT, their impairment in DIC contributes to further dysregulation of inflammation.[7,28, 29]

Components of DIC include the following[13] :

Exposure of blood to procoagulant substances

Fibrin deposition in the microvasculature Impaired fibrinolysis

Depletion of coagulation factors and platelets (consumptive coagulopathy)

Organ damage and failure