Disseminated Intravascular Coagulation ?>

Disseminated Intravascular Coagulation

Disseminated Intravascular Coagulation

Introduction
Background

Disseminated intravascular coagulation (DIC) is not a specific diagnosis, and its presence always indicates another underlying disease. There are many diseases that may lead to the occurrence of disseminated intravascular coagulation (DIC) (see Causes).

Disseminated intravascular coagulation (DIC) is characterized by a systemic activation of the blood coagulation system, which results in the generation and deposition of fibrin, leading to microvascular thrombi in various organs and contributing to the development of multiorgan failure.1 Consumption and subsequent exhaustion of coagulation proteins and platelets, due to the ongoing activation of the coagulation system, may induce severe bleeding complications, although microclot formation may occur in the absence of severe clotting factor depletion and bleeding.2

Derangement of the fibrinolytic system further contributes to intravascular clot formation, but in some cases, accelerated fibrinolysis (eg, due to consumption of alpha2-antiplasmin) may cause severe bleeding. Hence, a patient with disseminated intravascular coagulation (DIC) can present with a simultaneously occurring thrombotic and bleeding problem, which obviously complicates the proper treatment.

For excellent patient education resources, visit eMedicine’s Cuts, Scrapes, Bruises, and Blisters Center. Also, see eMedicine’s patient education articles Bruises and Wilderness: Bleeding.

Related eMedicine topics:
Consumption Coagulopathy
Disseminated Intravascular Coagulation [in the Emergency Medicine section]
Hemolytic Anemia
Hemostatic Disorders, Nonplatelet

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Pathophysiology

Several simultaneously occurring mechanisms play a role in the pathogenesis of disseminated intravascular coagulation (DIC). The main pathways leading to fibrin deposition are (1) tissue factor-mediated thrombin generation and (2) dysfunctional physiologic anticoagulant mechanisms, such as the antithrombin system and the protein C system, which insufficiently balance this thrombin generation.

A third pathway in addition to enhanced fibrin formation is impaired fibrin removal due to depression of the fibrinolytic system. This impairment of endogenous thrombolysis is mainly caused by high circulating levels of the fibrinolytic inhibitor PAI-1. As mentioned earlier, in exceptional forms of disseminated intravascular coagulation (DIC), fibrinolytic activity may be increased and contribute to bleeding. These mechanisms are outlined in more detailed as follows:

Thrombin generation and tissue factor

Thrombin generation is detectable at 3-5 hours after the occurrence of bacteremia or endotoxemia. Ample evidence exists for a pivotal role of the tissue factor/factor VIIa system in the initiation of thrombin generation.3

Abrogation of the tissue factor/factor VII(a) pathway by monoclonal antibodies specifically directed against tissue factor or factor VIIa activity resulted in a complete inhibition of thrombin generation in endotoxin-challenged chimpanzees and prevented the occurrence of DIC and mortality in baboons that were infused with Escherichia coli. Indeed, in most patients with disseminated intravascular coagulation (DIC), tissue factor antigen is detectable in plasma. Hence, activation of coagulation in disseminated intravascular coagulation (DIC) is tissue factor–driven, whereas the intrinsic pathway of coagulation was shown not to play an important role.

An unresolved issue concerns the actual source of the tissue factor: Tissue factor may be expressed on mononuclear cells in vitro, and tissue factor expression on circulating monocytes of patients with severe infection has indeed been demonstrated. In addition, tissue factor may be expressed on endothelial cells, although the importance of endothelial cell tissue factor expression in vivo and its role in the pathogenesis of disseminated intravascular coagulation (DIC) is disputed.

Another source of tissue factor may be its localization on polymorphonuclear cells and other cell types, although it is unlikely that these cells actually synthesize tissue factor in substantial quantities. Based on the observation of transfer of tissue factor from leukocytes to activated platelets on a collagen surface in an ex vivo perfusion system, it is hypothesized that this “blood borne” tissue factor is transferred between cells through microparticles derived from activated mononuclear cells.

Impaired coagulation inhibitor systems

An impaired function of various natural regulating pathways of coagulation activation may amplify the further thrombin generation and contribute to fibrin formation. Plasma levels of the most important inhibitor of thrombin, antithrombin III, are usually markedly reduced in patients with disseminated intravascular coagulation (DIC). This reduction is caused by a combination of consumption, due to ongoing thrombin generation; degradation by elastase, that is released from activated neutrophils; and impaired synthesis.

Low antithrombin III levels in disseminated intravascular coagulation (DIC) are associated with increased mortality. The fact that low levels of antithrombin precede the clinical manifestation of sepsis in prospective studies suggests that antithrombin is indeed involved in the pathogenesis of this disease and associated organ dysfunction.4

In addition to the decrease in antithrombin III, a significant depression of the protein C system may occur. This impaired function of the protein C pathway is mainly due to downregulation of thrombomodulin expression on endothelial cells by proinflammatory cytokines, like tumor necrosis factor-alpha (TNF-alpha) and interleukin 1b (IL-1b). The downregulation of thrombomodulin has been confirmed in studies in patients with meningococcal sepsis. This, in combination with low levels of zymogen protein C (due to similar mechanisms as described for antithrombin), results in diminished protein C activation, which will enhance the procoagulant state.

Animal experiments of severe inflammation-induced coagulation activation convincingly show that compromising the protein C system results in increased morbidity and mortality, whereas restoring an adequate function of activated protein C improves survival and organ failure. Interestingly, experiments in mice with a 1-allele targeted deletion of the protein C gene (resulting in heterozygous protein C deficiency) have more severe disseminated intravascular coagulation (DIC) and organ dysfunction and a higher mortality than wild-type littermates. Besides being implicated in the physiologic regulation of thrombin formation, activated protein C probably also has important inflammation-modulating effects, which may be of relevance in the pathogenesis of disseminated intravascular coagulation (DIC).

The third significant inhibitor of coagulation is tissue factor pathway inhibitor (TFPI). The role of TFPI in the pathogenesis of disseminated intravascular coagulation (DIC) is not completely clear. Experiments that show administration of recombinant TFPI (and thereby achieving higher than physiologic plasma concentrations of TFPI) blocks inflammation-induced thrombin generation in humans and the observation that pharmacologic doses of TFPI are capable of preventing mortality during systemic infection and inflammation suggest that high concentrations of TFPI are capable of modulating tissue factor–mediated coagulation. However, the endogenous concentration of TFPI is presumably insufficiently capable of regulating coagulation activation and the downstream consequences during systemic inflammation.

Defective fibrinolysis

Experimental models indicate that at the time of maximal activation of coagulation, the fibrinolytic system is largely shut off. Experimental bacteremia and endotoxemia result in a rapidly occurring increase in fibrinolytic activity, most probably due to the release of plasminogen activators from endothelial cells. However, this profibrinolytic response is almost immediately followed by a suppression of fibrinolytic activity due to a sustained increase in plasma levels of plasminogen activator inhibitor, type 1 (PAI-1).

Of note, strategies that are able to completely block the endotoxin-induced thrombin generation, such as anti-tissue factor antibodies or recombinant hirudin (r-hirudin), were without any effect on the activation and subsequent inhibition of fibrinolysis, suggesting an independent regulation of these 2 processes.

Rare cases of disseminated intravascular coagulation (DIC) are characterized by a severe hyperfibrinolytic state on top of an activated coagulation system. Examples of such situations are the disseminated intravascular coagulation (DIC) that occurs as a complication ofacute myeloid leukemiaM-3, according to the French-American-British [FAB] classification) or the disseminated intravascular coagulation (DIC) that may occur secondary to some forms of adenocarcinoma (eg, prostatic cancer). Although hyperfibrinolysis predominates in this situation, disseminated thrombosis is still found in a considerable number of patients at autopsy. Clinically, however, these patients suffer from severe bleeding.

In general, patients with disseminated intravascular coagulation (DIC) should not be treated with antifibrinolytic agents, because this may increase the fibrinolytic deficit and may result in increased thrombosis.
Mortality/Morbidity

Obviously, the clinical importance of a severe depletion of platelets and coagulation factors in patients with diffuse, widespread bleeding or in patients who need to undergo an invasive procedure is clear. In addition, the intravascular deposition of fibrin, as a result of the systemic activation of coagulation, contributes to organ failure and mortality.

Histologic studies in patients with disseminated intravascular coagulation (DIC) show the presence of ischemia and necrosis due to fibrin deposition in small- and mid-size vessels of various organs. The presence of these intravascular thrombi appears to be clearly and specifically related to the clinical dysfunction of the organ. Specific thrombotic complications that are sometimes seen in the framework of disseminated intravascular coagulation (DIC) are acral cyanosis, hemorrhagic skin infarctions, and limb ischemia.

Secondly, experimental animal studies of disseminated intravascular coagulation (DIC) show fibrin deposition in various organs. Amelioration of disseminated intravascular coagulation (DIC) by various interventions appears to improve organ failure and, in some but not all cases, mortality.

Lastly, disseminated intravascular coagulation (DIC) has been shown to be an independent predictor of mortality in patients with sepsis and severe trauma. The presence of disseminated intravascular coagulation (DIC) may increase the risk of death by 1.5 to 2.0 in various studies. An increasing severity of disseminated intravascular coagulation (DIC) is directly related to an increased mortality.

Race

Disseminated intravascular coagulation (DIC) occurs in all races.
Sex

No particular sex predisposition exists for disseminated intravascular coagulation (DIC).
Age

Disseminated intravascular coagulation (DIC) affects individuals of all ages.
Clinical
History

The symptoms of disseminated intravascular coagulation (DIC) are often those of the underlying inciting condition (see Causes). In addition, symptoms of thrombosis, embolism, organ dysfunction, or bleeding may be present.

Sepsis/severe infection (any microorganism)
Trauma (eg, polytrauma, neurotrauma, fat embolism)
Organ destruction (eg, severe pancreatitis)
Malignancy
Solid tumors
Myeloproliferative/lymphoproliferative malignancies
Obstetric calamities
Amniotic fluid embolism
Abruptio placentae
Vascular abnormalities
Kasabach-Merritt syndrome
Large vascular aneurysms
Severe hepatic failure
Severe toxic or immunologic reactions
Snake bites
Recreational drugs
Transfusion reactions
Transplant rejection
Physical
Acute disseminated intravascular coagulation (DIC): The physical findings associated with disseminated intravascular coagulation (DIC) are usually those of the underlying or inciting etiology; however, patients with the acute disease (ie, hemorrhagic variety associated with excess plasmin formation) have petechiae on the soft palate and legs from thrombocytopenia and ecchymosis at the venepuncture sites. These patients also manifest with ecchymosis in traumatized areas.
Chronic or subacute disseminated intravascular coagulation (DIC): In patients with so-called chronic or subacute disseminated intravascular coagulation (DIC) whose manifestation is thrombosis from excess thrombin formation, the symptoms and signs of venous thromboembolism may be present.
Causes

Several disease states may lead to the development of disseminated intravascular coagulation (DIC). In general, 2 major pathways may cause disseminated intravascular coagulation (DIC): (1) a systemic inflammatory response, leading to activation of the cytokine network and subsequent activation of coagulation (eg, in sepsis or major trauma); and/or (2) release or exposure of procoagulant material into the bloodstream (eg, in cancer or in obstetric cases). In some situations, both pathways may be present (eg, major trauma or severe necrotizing pancreatitis). Some of the most frequently occurring conditions are outlined below.

Bacterial infection, in particular septicemia, is commonly associated with disseminated intravascular coagulation (DIC). No difference exists in the incidence of disseminated intravascular coagulation (DIC) in patients with gram-negative sepsis or gram-positive sepsis. In addition, systemic infections with other microorganisms, such as viruses and parasites, may lead to disseminated intravascular coagulation (DIC) as well.Factors involved in the development of disseminated intravascular coagulation (DIC) in patients with infections may be specific cell membrane components of the microorganism (lipopolysaccharide or endotoxin) or bacterial exotoxins (eg, staphylococcal alpha toxin). These components cause a generalized inflammatory response, characterized by the systemic occurrence of proinflammatory cytokines.
Severe trauma is another clinical condition frequently associated with disseminated intravascular coagulation (DIC). A combination of mechanisms—including release of tissue material (fat, phospholipids) into the circulation, hemolysis, and endothelial damage—may contribute to the systemic activation of coagulation. In addition, solid evidence indicates that cytokines play a pivotal role in the occurrence of disseminated intravascular coagulation (DIC) in trauma patients as well. In fact, systemic cytokine patterns have been shown to be virtually identical in trauma patients and septic patients.
Both solid tumors and hematologic malignancies may be complicated by disseminated intravascular coagulation (DIC). The mechanism of the derangement of the coagulation system in this situation is poorly understood. Solid tumor cells can express different procoagulant molecules, including tissue factor and a cancer procoagulant, a cysteine protease with factor X–activating properties. Cancer procoagulant is found in extracts of neoplastic cells and in the plasma of patients with solid tumors.Some tumors are associated with a form of disseminated intravascular coagulation (DIC) that is characterized by severe hyperfibrinolysis on top of an activated coagulation system. For example, this is the case in acute promyelocytic leukemia and some forms of prostatic cancer. Although clinically bleeding predominates in this situation, disseminated thrombosis is found in a considerable number of patients at autopsy.
Acute disseminated intravascular coagulation (DIC) occurs in obstetric calamities such as placental abruption and amniotic fluid emboli. Amniotic fluid has been shown to be able to activate coagulation in vitro, and the degree of placental separation correlates with the extent of the disseminated intravascular coagulation (DIC), suggesting that leakage of thromboplastinlike material from the placental system is responsible for the occurrence of disseminated intravascular coagulation (DIC).Although the coagulation system may be activated in patients with preeclampsia, and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, clinically significant disseminated intravascular coagulation (DIC) only occurs in a small percentage of patients, usually with secondary complications.
Vascular disorders, such as large aortic aneurysms or giant hemangiomas (Kasabach-Merritt syndrome), may result in local activation of coagulation. Activated coagulation factors can ultimately “overflow” to the systemic circulation and cause disseminated intravascular coagulation (DIC) but more common is the systemic depletion of coagulation factors and platelets as a result of local consumption.
Other causes of disseminated intravascular coagulation (DIC) include severe toxic or immunologic reactions (eg, transfusion reactions) or severe inflammation (eg, acute pancreatitis).

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