Background

Disseminated intravascular coagulation (DIC) is a complex systemic thrombohemorrhagic disorder involving the generation of intravascular fibrin and the consumption of procoagulants and platelets. The resultant 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 of coagulation with loss of localization arising from different causes. It can originate from and cause damage to 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 and is 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 consistent components including activation of intravascular coagulation, depletion of clotting factors, and end-organ damage (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] Although bacteremia, including both gram-positive and gram-negative organisms, is most commonly associated with DIC, other organisms including viruses, fungi, and parasites may cause DIC. Trauma, especially neurotrauma, is also frequently associated with DIC. DIC is more frequently observed in those patients with trauma who develop the systemic inflammatory response syndrome. [5] Evidence indicates that inflammatory cytokines play a central role in DIC in both trauma patients and septic patients. In fact, systemic cytokine profiles in both septic patients and trauma patients are nearly identical.[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 liver enzymes, 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 to procoagulants occurs, including tissue factor (tissue thromboplastin), generating intravascular coagulation. Compensatory hemostatic mechanisms are quickly overwhelmed, and, as a consequence, a severe consumptive coagulopathy leading to hemorrhage develops. Abnormalities of blood coagulation parameters 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 or intermittently exposed to small amounts of tissue factor. Compensatory mechanisms in the liver and bone marrow are not overwhelmed, and there may be little obvious clinical or laboratory indication of the

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

Pathophysiology
DIC is caused by widespread and ongoing activation of coagulation, leading to vascular or microvascular fibrin 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 a hypercoagulable state. Inflammatory cytokines are the most important mediators responsible for this imbalance.[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 coagulation stimulates 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, and inflammatory activation.[13]Activation of intravascular coagulation is mediated almost entirely by the intrinsic clotting pathway. The pathogenesis of DIC starts at the level of the endothelium of the capillary bed, where the main interaction 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. In sepsis, the cytokines produce a state of intense inflammatory activity that causes the down-regulation of endothelial glycosaminoglycans present in the glycocalyx, thereby impairing the functions of antithrombin (AT), tissue factor pathway inhibitor (TFPI), leukocyte adhesion, and leukocyte transmigration. The integrity 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 with platelet adhesion within a matter of minutes. These events make the endothelium become a procoagulant surface, 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, or inflammatory or tumor cell expression of procoagulant molecules, including tissue factor. Tissue factor activates coagulation by the extrinsic pathway involving factor VIIa. Factor VIIa has been implicated as the central mediator of intravascular coagulation in sepsis. Blocking the factor VIIa pathway in sepsis has been shown to prevent the development of DIC, whereas interrupting alternative pathways did not demonstrate 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. Evidence suggests that the intrinsic (or contact) pathway is also activated in DIC, while contributing more to hemodynamic instability and hypotension than to activation of clotting. [17] Thrombin produced by the tissue factor pathway amplifies both clotting and inflammation through the following activities: (1) platelet activation, enhancing aggregation and augmenting platelet functions in coagulation; (2) it activates factors VIII, V, and XI, yielding further thrombin generation; (3) it enhances the activation of proinflammatory factors via protease-activated receptors (PARs); (4) it activates factor XIII to factor XIIIa, which augments the production of fibrin clots from fibrinogen; (5) it activates thrombinactivatable 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 of white blood cells.[18] Thrombin generation is usually tightly regulated by multiple hemostatic mechanisms. However, once intravascular coagulation commences, compensatory mechanisms are overwhelmed or incapacitated. Antithrombin is one such mechanism responsible for regulating thrombin levels. However, due to multiple factors, antithrombin activity is reduced in patients with sepsis. First, antithrombin is continuously consumed by ongoing activation of coagulation. Moreover, elastase produced by activated neutrophils degrades 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

microvascular coagulation.[11, 19] Decreased levels of antithrombin correlate well with elevated mortality in patients with sepsis.[4] Protein C, along with protein S, serves as an important anticoagulant compensatory mechanism. Under normal conditions, protein C is activated by thrombin and is complexed on the endothelial cell surface with thrombomodulin.[11]Activated protein C combats coagulation via proteolytic cleavage of factors Va and 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 cell surface.[20] Protein C levels are further reduced via consumption, extravascular leakage, and reduced hepatic production and by a reduction in freely circulating protein S. Tissue factor pathway inhibitor (TFPI) is another anticoagulant mechanism that is disabled in DIC. TFPI reversibly inhibits factor Xa and thrombin, and has the ability to inhibit the factor VIIa-tissue factor complex. Although levels of TFPI are normal in patients with sepsis, a relative insufficiency in DIC is evident. TFPI depletion in animal models predisposes to DIC, and TFPI blocks the procoagulant effect of endotoxin in humans.[21] The intravascular fibrin produced by thrombin is normally eliminated via a process termed 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) of fibrinolysis 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 underopposed fibrin deposition in the vasculature. In experimental models of DIC, initially fibrinolysis is activated but subsequently inhibited, because of an increased release of plasminogen activator inhibitor-I (PAI-1) produced by endothelial cells.[24] These effects 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 2antiplasmin were observed in patients with DIC and multiorgan failure compared with DIC patients without multiorgan failure.[26] This finding supports the conclusion that fibrinolysis is a mechanism vital to the prevention of multiorgan failure. Playing a key role in the process of coagulation and hemostasis is the vascular endothelium, which is responsible for the production of Von-Willebrand factor (vWF). Von Willebrand factor mediates the adhesion 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 thrombomodulin expression may result in facilitated thrombin generation, which subsequently results in increased platelet activation and the conversion of fibrinogen to fibrin.[27] Inflammatory and coagulation pathways interact in substantial ways. Many of the activated coagulation factors produced in DIC contribute to the propagation of inflammation by stimulating endothelial cell release of proinflammatory cytokines. Factor Xa, thrombin, and the tissue factor-VIIa complex have each been demonstrated to elicit proinflammatory action. Furthermore, given the anti-inflammatory action of activated 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