Disseminated Intravascular Coagulation (DIC)

The hematologic derangements seen in DIC result from the following 4 simultaneously occurring mechanisms[19, 20] :

• Tissue factor (TF)–mediated thrombin generation

• Dysfunctional physiologic anticoagulant mechanisms (eg, depression of antithrombin and protein C system), which cannot adequately balance this thrombin generation

• Impaired fibrin removal due to depression of the fibrinolytic system – This is mainly caused by high circulating levels of plasminogen activator inhibitor type 1 (PAI-1); however, in exceptional forms of DIC, fibrinolytic activity may be increased and contribute to bleeding

• Inflammatory activation

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 TF/factor VIIa system in the initiation of thrombin generation.[21, 22, 23]

Exposure to TF in the circulation occurs via endothelial disruption, tissue damage, or inflammatory or tumor cell expression of procoagulant molecules (including TF). TF activates coagulation via the extrinsic pathway involving factor VIIa. The TF-VIIa complex activates thrombin, which cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation. The intrinsic (or contact) pathway may also be activated in DIC, though contributing more to hemodynamic instability and hypotension than to activation of clotting.[24]

Thrombin produced by the TF/factor VII pathway amplifies both clotting and inflammation through the following activities[25] :

• Platelet activation, enhancing aggregation and augmenting platelet functions in coagulation

• Activation of factors VIII, V, and XI, yielding further thrombin generation

• Enhanced activation of proinflammatory factors via protease-activated receptors (PARs)

• Activation of factor XIII to factor XIIIa, which augments production of fibrin clots from fibrinogen

• Activation of thrombin-activatable fibrinolysis inhibitor (TAFI), making clots resistant to fibrinolysis; and

• Enhanced expression of adhesion molecules (eg, L-selectin), thereby promoting the inflammatory effects of white blood cells (WBCs)

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.[26, 27]

Abrogation of the TF/factor VII(a) pathway by monoclonal antibodies specifically directed against TF or factor VIIa activity completely inhibited 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 DIC patients, TF antigen is detectable in plasma. Hence, activation of coagulation in DIC is primarily TF-driven; the intrinsic pathway of coagulation appears not to play an important role.

The actual source of the TF has not been established with certainty. TF may be expressed on mononuclear cells in vitro, and its expression on circulating monocytes of patients with severe infection has been demonstrated. In addition, it may be expressed on endothelial cells. Injured endothelial cells express TF, whereas healthy ones do not. However, the importance of endothelial cell TF expression in vivo and its role in the pathogenesis of DIC remain to be determined.

Another source of TF may be polymorphonuclear leukocytes (PMNs) and other similar cell types, though it is unlikely that these cells actually synthesize TF in substantial quantities. On the basis of the observation that TF has been transferred from leukocytes to activated platelets on a collagen surface in an ex-vivo perfusion system, it is hypothesized that this “bloodborne” TF is transferred between cells through microparticles derived from activated mononuclear cells.

Impaired coagulation inhibitor systems

Thrombin generation is usually tightly regulated by multiple hemostatic mechanisms. However, once intravascular coagulation commences, compensatory mechanisms are overwhelmed or incapacitated. Impaired functioning of various natural regulating pathways of coagulation activation may amplify further thrombin generation and contribute to fibrin formation.

Plasma levels of the most important inhibitor of thrombin, antithrombin, are usually markedly reduced in patients with DIC. This reduction is caused by the following:

• Antithrombin is continuously consumed by ongoing activation of coagulation

• Elastase produced by activated neutrophils degrades antithrombin as well as other proteins

• Further antithrombin is lost to capillary leakage

• Production of antithrombin is impaired secondary to liver damage resulting from underperfusion and microvascular coagulation[18, 28]

Low antithrombin levels in DIC are associated with increased mortality, particularly in patients with sepsis.[23] 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.[29]

In addition to the decrease in antithrombin, significant depression of the protein C system may occur. Protein C, along with protein S, also serves as a major anticoagulant compensatory mechanism. Under normal conditions, protein C is activated by thrombin when complexed on the endothelial cell surface with thrombomodulin.[18] Activated protein C combats coagulation via proteolytic cleavage of factors Va and VIIIa and proteolyzes PAR1 when bound to the endothelial cell protein C receptor (EPCR).

Impaired functioning of the protein C pathway is mainly due to down-regulation of thrombomodulin expression or its inactivation by cellular reactive oxygen species on endothelial cells by proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)–1b.[30] This downregulation has been confirmed in studies in patients with meningococcal sepsis.

In combination with low levels of zymogen protein C (due to mechanisms similar to those described for antithrombin), this process results in diminished protein C activation, which will enhance the procoagulant state. Protein C levels are further reduced via consumption, extravascular leakage, renal loss, and reduced hepatic production and by a reduction in circulating free protein S. The availability of protein S to serve as a cofactor for activated protein C is regulated by the degree it is bound to the complement protein C4B-binding protein.

Animal experiments involving severe inflammation-induced coagulation activation convincingly show that compromising the protein C system results in increased morbidity and mortality, whereas restoring adequate functioning of activated protein C improves survival and organ failure. Experiments show that mice with a 1-allele targeted deletion of the protein C gene (resulting in heterozygous protein C deficiency) have more severe 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 DIC.

TF pathway inhibitor (TFPI) is another anticoagulant mechanism that is disabled in DIC. TFPI reversibly inhibits factor Xa and thrombin (indirectly) and has the ability to inhibit the TF-VIIa 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.[31] The role of TFPI in the pathogenesis of DIC has not been fully clarified.

The experimental finding that administration of recombinant TFPI blocks inflammation-induced thrombin generation in humans, along with the observation that pharmacologic doses of TFPI are capable of preventing mortality during systemic infection and inflammation, suggests that high concentrations of TFPI are capable of modulating TF-mediated coagulation. Presumably, however, the endogenous concentration of TFPI is insufficiently capable of regulating coagulation activation and the downstream consequences during systemic inflammation.

Defective fibrinolysis

The intravascular fibrin produced by thrombin is normally eliminated via a process termed 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 rapid increase in fibrinolytic activity, most probably caused by release of plasminogen activators from endothelial cells. However, this profibrinolytic response is almost immediately followed by suppression of fibrinolytic activity due to a sustained increase in plasma levels of PAI-1[32] ; these effects are mediated by TNF-2 and IL-1.[33] High PAI-1 levels precede DIC and predict poor outcomes.[34]

Notably, strategies that can block endotoxin-induced thrombin generation completely, such as anti-TF antibodies or recombinant hirudin (r-hirudin), have no significant effect on activation and subsequent inhibition of fibrinolysis, which suggests that these 2 processes are independently regulated.

In a study of 69 DIC patients (31 with multiorgan failure), higher levels of tissue plasminogen activator (t-PA) antigen and PAI-1 with depressed levels of α2 -antiplasmin were observed in patients with DIC and multiorgan failure than in DIC patients without multiorgan failure.[35] 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). vWF 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.[36]

Rare cases of DIC are characterized by a severe hyperfibrinolytic state on top of an activated coagulation system. Examples of such situations are the DIC that occurs as a complication of acute myeloid leukemia M-3 (in the French-American-British [FAB] classification) or the DIC that may occur secondary to some forms of adenocarcinoma. 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 DIC should not be treated with antifibrinolytic agents, because this may increase the fibrinolytic deficit and may result in increased thrombosis.

Inflammatory activation

Inflammatory and coagulation pathways interact in substantial ways. It is clear that there is cross-communication between the 2 systems, whereby inflammation gives rise to activation of the clotting cascade and the resultant coagulation stimulates more vigorous inflammatory activity. There are a number of different triggers that can cause a hemostatic imbalance, giving rise to a hypercoagulable state.

Many of the activated coagulation factors produced in DIC contribute to the propagation of inflammation by stimulating endothelial cell release of proinflammatory cytokines.[37] Factor Xa, thrombin, and the TF-VIIa complex have each been demonstrated to elicit proinflammatory action. Furthermore, given the anti-inflammatory action of activated protein C and antithrombin, depression of these anticoagulants in DIC contributes to further dysregulation of inflammation.[6, 38, 39]

Several disease states may lead to the development of DIC (see Tables 1 and 2 below), generally via one of the following two pathways:

• A systemic inflammatory response, leading to activation of the cytokine network and subsequent activation of coagulation (eg, in sepsis or major trauma)

• Release or exposure of procoagulant material into the bloodstream (eg, in cancer, crush brain injury, or in obstetric cases)

In some situations (eg, major trauma or severe necrotizing pancreatitis), both pathways may be present.

Table 1. Causes of Acute (Hemorrhagic) Disseminated Intravascular Coagulation (Open Table in a new window)

Table 2. Causes of Chronic Disseminated Intravascular Coagulation (Open Table in a new window)

Bacterial infection (in particular, bloodstream infection [BSI]) is commonly associated with DIC. There is no difference in the incidence of DIC between patients with gram-negative sepsis and those with gram-positive sepsis. Systemic infections with other microorganisms, such as viruses and parasites, may lead to DIC as well.

Factors involved in the development of 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 DIC. A combination of mechanisms—including release of tissue material (eg, tissue factor [thromboplastin], fat or phospholipids) into the circulation, hemolysis, and endothelial damage—may contribute to systemic activation of coagulation. In addition, solid evidence indicates that cytokines also play a pivotal role in the occurrence of DIC in trauma patients. 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 DIC. The mechanism by which coagulation is deranged in this situation is poorly understood. Solid tumor cells can express different procoagulant molecules, including TF and a cancer procoagulant. Cancer procoagulant is found in extracts of neoplastic cells and in the plasma of patients with solid tumors. As noted, some tumors are associated with a form of DIC that is characterized by severe hyperfibrinolysis on top of an activated coagulation system.

Acute DIC occurs in obstetric calamities such as placental abruption (abruptio placentae) 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 DIC, suggesting that leakage of thromboplastinlike material from the placental system is responsible for the occurrence of DIC.

Although the coagulation system may be activated in patients with preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, clinically significant DIC occurs in only a small percentage of patients, usually in association 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 DIC, but systemic depletion of coagulation factors and platelets as a result of local consumption is a more common scenario.

DIC is a possible adverse effect of quinine administered as an antimalarial medication. A case of DIC following ingestion of large quantities of tonic water containing quinine has also been reported.[41]

DIC may occur in 30-50% of patients with sepsis,[42] and it develops in an estimated 1% of all hospitalized patients.[5] DIC occurs at all ages and in all races, and no particular sex predisposition has been noted.

The prognosis of patients with DIC depends on the severity of the coagulopathy and on the underlying condition that led to DIC. Assigning numerical figures to DIC-specific morbidity and mortality is difficult. The following are examples of mortality figures for diseases complicated by DIC:

• Idiopathic purpura fulminans associated with DIC has a mortality of 18%
• Septic abortion with clostridial infection and shock associated with severe DIC has a mortality of 50%
• In the setting of major trauma, the presence of DIC approximately doubles the mortality rate ^{[12, 13]}

A retrospective single-center Korean study of women with primary post-partum hemorrhage who presented to the emergency department found that 57 (22.4%) of the 255 patients had overt DIC. Of patients with DIC, 96.5% experienced major adverse events.[43]

DIC criteria based on the Japanese Association for Acute Medicine DIC criteria with the addition of the hemostatic endothelial molecular markers  protein C activity and plasminogen activator inhibitor 1 had a sensitivity of 84.6% and a specificity of 80.3% for predicting mortality in a study of 79 patients with severe sepsis or septic shock. Using these criteria, DIC-positive patients also had significantly higher disease severity,[44]

In general, if the underlying condition is self-limited or can be appropriately handled, DIC will disappear, and the coagulation status will normalize. A patient with acute hemorrhagic DIC that is associated with metastatic gastric carcinoma likely has a lethal condition that does not alter patient demise, regardless of treatment. On the other hand, a patient with acute DIC associated with abruptio placentae needs quick recognition and obstetric treatment; the DIC will resolve with the treatment of the obstetric catastrophe.

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.[45]

Histologic studies in patients with DIC show the presence of ischemia and necrosis due to fibrin deposition in small and medium-sized 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 DIC are acral cyanosis, hemorrhagic skin infarctions, and limb ischemia.

In addition, experimental animal studies of DIC show fibrin deposition in various organs. Amelioration of DIC by various interventions appears to improve organ failure and, in some but not all cases, mortality.

Finally, DIC has been shown to be an independent predictor of mortality in patients with sepsis and severe trauma.[46, 47, 48, 49] The presence of DIC may increase the risk of death by a factor of 1.5 to 2.0 in various studies. An increasing severity of DIC is directly related to an increased mortality.

A study utilizing the Japanese Association for Acute Medicine (JAAM) diagnostic criteria for DIC showed that septic patients with DIC had a higher mortality than trauma patients with DIC did (34.7% vs 10.5%).[50]

Complications

Complications of DIC include the following:

• Acute kidney injury
• Change in mental status
• Respiratory dysfunction
• Hepatic dysfunction
• Life-threatening thrombosis and hemorrhage (in patients with moderately severe–to–severe DIC)
• Cardiac tamponade
• Hemothorax
• Intracerebral hematoma
• Gangrene and loss of digits
• Shock
• Death

The symptoms of disseminated intravascular coagulation (DIC) are often those of the underlying inciting condition (see Etiology). Such conditions may include the following:

• Sepsis or severe infection (with any microorganism)
• Trauma (eg, polytrauma, neurotrauma, or fat embolism)
• Organ destruction (eg, severe pancreatitis)
• Malignancy – Solid tumors and myeloproliferative/ lymphoproliferative malignancies
• Obstetric calamities (eg, amniotic fluid embolism;  abruptio placentae)
• Vascular abnormalities – Kasabach-Merritt syndrome and large vascular aneurysms
• Severe hepatic failure
• Severe toxic or immunologic reactions – Snake bites, recreational drugs, transfusion reactions, and transplant rejection

In addition to the symptoms related to the underlying disease process, there is typically a history of blood loss through bleeding in areas such the gingivae and the gastrointestinal (GI) system (see Table 3 below).[50] Acutely presenting DIC often manifests as petechiae and ecchymosis, along with blood loss from intravenous (IV) lines and catheters. In postoperative DIC, bleeding can occur in the vicinity of surgical sites, drains, and tracheostomies, as well as within serous cavities.

Table 3. Main Features of Disseminated Intravascular Coagulation in Series of 118 Patients (Open Table in a new window)

Look for symptoms and signs of thrombosis in large vessels (eg, deep vein thrombosis [DVT]) and microvascular thrombosis (as in renal failure). Bleeding from at least 3 unrelated sites is particularly suggestive of DIC. As many as 25% of patients present with renal failure. Patients with pulmonary involvement can present with dyspnea, hemoptysis, and cough. Comorbid liver disease as well as rapid hemolytic bilirubin production may lead to jaundice. Neurologic changes (eg, coma, obtunded mental status, and paresthesias) are also possible.

With acute DIC, the physical findings are usually those of the underlying or inciting condition; however, patients with the acute disease (ie, the hemorrhagic variety associated with excess plasmin formation) have petechiae on the soft palate, trunk, and extremities from thrombocytopenia and ecchymosis at venipuncture sites. These patients also manifest ecchymosis in traumatized areas.

In patients with so-called chronic or subacute DIC, of which the primary manifestation is thrombosis from excess thrombin formation, the signs of venous thromboembolism may be present.

Circulatory signs include the following:

• Signs of spontaneous and life-threatening hemorrhage
• Signs of subacute bleeding
• Signs of diffuse or localized thrombosis
• Bleeding into serous cavities

Central nervous system signs include the following:

• Nonspecific altered consciousness or stupor
• Transient focal neurologic deficits

Cardiovascular signs include the following:

• Hypotension
• Tachycardia
• Circulatory collapse

Respiratory signs include the following:

• Pleural friction rub
• Signs of acute respiratory distress syndrome (ARDS)

Gastrointestinal signs include the following:

• Hematemesis
• Hematochezia

Genitourinary signs include the following:

• Signs of azotemia and renal failure
• Acidosis
• Hematuria
• Oliguria
• Metrorrhagia
• Uterine hemorrhage

Dermatologic signs include the following:

• Petechiae
• Jaundice (liver dysfunction or hemolysis)
• Purpura
• Hemorrhagic bullae
• Acral cyanosis
• Skin necrosis of lower limbs (purpura fulminans)
• Localized infarction and gangrene
• Wound bleeding and deep subcutaneous hematomas
• Thrombosis

Diagnosis of disseminated intravascular coagulation (DIC) can be difficult, especially in cases of chronic, smoldering DIC, where clinical and laboratory abnormalities may be subtle.[56] No single routinely available laboratory test is sufficiently sensitive or specific to allow a diagnosis of DIC; however, several commonly available laboratory tests often yield abnormal results in DIC. Typically, moderate-to-severe thrombocytopenia is present. Furthermore, the peripheral blood smear can demonstrate evidence of microangiopathic pathology (schistocytes). Scoring systems have been developed to facilitate diagnosis of DIC.

Imaging studies are useful only to detect an underlying cause; the diagnosis of DIC is made by combining the clinical impression with any laboratory abnormalities noted.

No specific procedures help establish a specific diagnosis of DIC. However, a number of different procedures may help to diagnose the underlying causative condition.

Patients with DIC can present with a wide range of abnormalities in their laboratory values. Typically, prolonged coagulation times, thrombocytopenia, high levels of fibrin degradation products (FDPs), elevated D-dimer levels, and microangiopathic pathology (schistocytes) on peripheral smears are suggestive findings.

Most individual laboratory tests demonstrate high sensitivity for DIC but very low specificity.[57] Furthermore, whereas acute DIC typically overwhelms compensatory anticoagulation mechanisms, resulting in depletion of factors and laboratory derangements, chronic or localized DIC may produce only minimal abnormalities in laboratory tests.[58]

It is essential to keep in mind that laboratory values may represent only a momentary glimpse into a very rapidly changing systemic process and that repeated tests may therefore be necessary in order to make a more clinically certain diagnosis.[4]

Standard tests

In clinical practice, a diagnosis of DIC can often be made by a combination of the following tests[42] :

• Platelet count
• Global clotting times (aPTT and PT)
• One or two clotting factors and inhibitors (eg, antithrombin)
• Assay for D-dimer or FDPs

Platelet count

Typically, moderate-to-severe thrombocytopenia is present in DIC. Thrombocytopenia is seen in as many as 98% of DIC patients, and the platelet count can dip below 50 × 109/L in 50%.[59] A trend toward decreasing platelet counts or a grossly reduced absolute platelet count is a sensitive (though not specific) indicator of DIC.[42] Repeated platelet counts are often necessary, as a single platelet measurement may indicate a level within the normal range, whereas trend values might show a precipitous drop from previous levels.

The peripheral blood smear can reveal schistocytes, though these are rarely seen to exceed 10% of red blood cells (RBCs). The presence of schistocytes is neither sensitive nor specific for DIC, but in certain instances, it may help confirm a chronic DIC diagnosis when the schistocytes are seen in concert with normal coagulation values and increased D-dimer levels.[59]

Clotting times and coagulation factors

Global clotting times (ie, activated partial thromboplastin time [aPTT] and prothrombin time [PT]) are typically prolonged. In as many as 50% of DIC patients, however, a normal or even an attenuated PT and aPTT may be encountered; consequently, such values cannot be used to exclude DIC.[60] This phenomenon may be attributed to certain activated clotting factors present in the circulation, such as thrombin or Xa, which may in fact enhance thrombin formation.[35]

It should be emphasized that serial coagulation tests are usually more helpful than single laboratory results in establishing the diagnosis of DIC. It is also important to note that the PT, not the international normalized ratio (INR), should be used in the DIC monitoring process; INR is recommended only for monitoring oral anticoagulant therapy.[42]

The prolongation of global clotting times may reflect the consumption and depletion of various coagulation factors, which may be further substantiated by the measurement of selected coagulation factors, such as factor V and factor VII. Measurement of coagulation factors may be helpful for detecting additional hemostatic abnormalities (eg, those caused by vitamin K deficiency).

Protein C and antithrombin are 2 natural anticoagulants that are frequently decreased in DIC. There is some evidence to suggest that they may serve roles as prognostic indicators.[61, 62] Nonetheless, the practical application of measuring these anticoagulants may be limited for most practitioners because the tests may not be generally available.[42]

DIC is associated with an unusual light transmission profile on the aPTT, known as a biphasic waveform. In one study, the degree of biphasic waveform abnormality had an increasing positive predictive value for DIC, independent of clotting time prolongation.[63] In addition, the waveform abnormalities are often evident before more conventionally used laboratory value derangements,[63] making this a quick and robust test for DIC. At present, however, the photo-optical analyzers necessary in clot formation analysis are not widely available.

Tests for fibrinogen, D-dimer, and FDPs

Because fibrin activation is a central component of DIC, it would seem logical to assume that if soluble fibrin is elevated, the diagnosis of DIC can be made with confidence.[64] However, soluble fibrin levels are not available to most clinicians within a relevant time frame. Likewise, laboratory assays aimed at differentiating between cross-linked fibrin, fibrinogen, and soluble fibrin have been developed but are not routinely available to the clinician.

The massive fibrin deposition in DIC suggests that fibrinogen levels would be decreased. Accordingly, measurement of fibrinogen has been widely advocated as a useful tool for the diagnosis of DIC; however, it is in fact not very helpful. Fibrinogen, as a positive acute-phase reactant, is increased in inflammation, and whereas values may decrease as the illness progresses, they are rarely low.[18, 65] One study demonstrated that in up to 57% of DIC patients, the levels of fibrinogen may in fact remain within normal limits.[59]

In a consecutive series of patients, the sensitivity of a low fibrinogen level for the diagnosis of DIC was only 28%, and hypofibrinogenemia was detected in a very small number of severe cases of DIC only. Sequential measurements of fibrinogen might be more useful and might be more likely to provide diagnostic clues.

Fibrinolysis is an important component of DIC; thus, there will be evidence of fibrin breakdown, such as elevated levels D-dimer and FDPs. D-dimer elevation means that thrombin has proteolyzed fibrinogen to form fibrin that has been cross-linked by thrombin-activated factor XIIIa. When fibrin becomes cross-linked insoluble, a unique D-D domain neoepitope forms. This cross-linked insoluble fibrin is then proteolyzed uniquely by plasmin to liberate the soluble D-D dimer. Thus, the D-dimer measures prior thrombin and plasmin formation. On the other hand, FDPs only inform that plasmin has been formed and it cleaved soluble fibrinogen, fibrin, or insoluble cross-linked fibrin. D-dimer is the better test for DIC.

Accordingly, testing for D-dimer or FDPs may be helpful for differentiating DIC from other conditions that may be associated with a low platelet count and prolonged clotting times, such as chronic liver disease. Most laboratories have an operational test for D-dimer. In the United States, FDPs are not used as often.

D-dimer or FDPs may be detected by means of specific enzyme-linked immunosorbent assay (ELISA) or latex agglutination assay, allowing rapid and bedside determination in emergency cases. However, some of the available assays for FDPs cross-react with fibrinogen degradation products, and this cross-reactivity may cause spuriously high results. The specificity of high levels of D-dimer and FDPs is therefore limited, and many other conditions (eg, venous thromboembolism, trauma, inflammation, and recent surgery) may be associated with elevated FDP levels.[18, 66]

Specialized tests

In a specialized setting, molecular markers for activation of coagulation or fibrin formation may be the most sensitive assays for DIC.[67] A number of clinical studies show that the presence of soluble fibrin in plasma has a 90-100% sensitivity for DIC but, unfortunately, a relatively low specificity. As noted (see above) a reliable test for quantifying soluble fibrin in plasma is not available, and one study showed a wide discordance among various assays.

The dynamics of DIC can also be judged by measuring activation markers that are released upon the conversion of the coagulation factor zymogen to an active protease, such as prothrombin activation fragment F1+2 (F1+2). Indeed, these markers are markedly elevated in patients with DIC, but again, the specificity is a problem.

In addition to the known limitations in specificity, many of the more sensitive and sophisticated tests described above are not available to general hematology laboratories. Although these tests may be very helpful in clinical trials or other research, they often cannot be used in a routine setting.

Evidence also suggests that serum levels of thrombomodulin, a marker for endothelial cell damage, correlate well with the clinical course of DIC, the development of multiple organ dysfunction syndrome (MODS), and mortality in septic patients. Thrombomodulin is elevated in DIC, and such elevation and not only correlates well with the severity of DIC but also can serve as a marker for early identification and monitoring of DIC.[68]

Regardless of the discussion above, most hospitals of all sizes in the developed world have available PT, aPTT, fibrinogen, platelet count, and D-dimer. These tests alone are sufficient to make or exclude a clinical diagnosis of DIC in the practice of medicine.

The diagnosis of DIC relies on multiple clinical and laboratory determinations. The International Society on Thrombosis and Haemostasis (ISTH) developed a simple scoring system for the diagnosis of overt DIC that makes use of laboratory tests available in almost all hospital laboratories (see the image below, and the DIC Score calculator.)[4] The presence of an underlying disorder known to be associated with DIC (see Etiology) is a sine qua non for the use of this diagnostic algorithm.

Diagnostic algorithm for the diagnosis of overt disseminated intravascular coagulation.

A score of 5 or higher indicates overt DIC, whereas a score of less than 5 does not rule out DIC but may indicate DIC that is not overt.[4] Prospective validation studies show this scoring system to be highly accurate for the diagnosis of DIC. The sensitivity of the DIC score for a diagnosis of DIC is 91-93%, and the specificity is 97-98%.[67, 69]

Other analyses show that the DIC scoring system is a strong independent predictor of a fatal outcome in intensive care unit (ICU) patients. In these studies, mortality was higher than 40% in patients with sepsis and DIC (according to the scoring system), compared with about 25% in patients without DIC. For each DIC point in the system, the odds ratio for mortality is 1.29, whereas for each Acute Physiology and Chronic Health Evaluation (APACHE) classification system point, the odds ratio for mortality is 1.07.

Despite the demonstrable utility of the ISTH scoring system for diagnosing overt DIC, concerns have been expressed about its validity for identifying nonovert DIC. In response to these concerns, the Japanese Association for Acute Medicine (JAAM) developed a diagnostic algorithm and scoring system designed for use in critically ill patients (see Table 4 below).[70]

Table 4. Japanese Association for Acute Medicine (JAAM) Scoring System for DIC (Open Table in a new window)

This system has been prospectively validated and has been found to be capable of diagnosing DIC earlier than previous methods could. Furthermore, evidence suggests that early identification of DIC using this scoring system, as well as early and aggressive treatment of DIC and the underlying disorder, can lead to improvements in patient outcome and reductions in mortality.[70]

In a study of the JAAM DIC criteria in 79 patients with severe sepsis or septic shock, Umemura et al reported that the addition of two hemostatic endothelial molecular markers—protein C activity and plasminogen activator inhibitor 1—measured within 12 hours of admission, provided greater prognostic value, predicting mortality with a sensitivity of 84.6% and a specificity of 80.3%. Protein C activity correlated best with mortality, followed by plasminogen activator inhibitor 1. Using those criteria, DIC-positive patients also had significantly higher disease severity.[44]

The Japanese Society on Thrombosis and Hemostasis (JSTH) has developed diagnostic criteria for DIC based on the underlying pathology (basic, hematopoietic, or infectious).[71] The JSTH criteria are shown in Table 5, below. 

Table 5. Japanese Society on Thrombosis and Hemostasis (JSTH) Diagnostic Criteria for DIC (Open Table in a new window)

With the JSTH system, diagnostic scoring for DIC is as follows:

• Basic: ≥6 points
• Hematopoietic (note that the platelet count is not included in the score calculation): ≥4 points
• Infectious: (note that the fibrinogen level is not included in the score calculation)  ≥5 points

Grossly, hemorrhage into all tissues (eg, brain, adrenal, lung, kidney) can develop in acute hemorrhagic DIC.

Histologic studies in patients with DIC show the presence of ischemia and necrosis due to fibrin deposition in small and medium-sized 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 DIC are acral cyanosis, hemorrhagic skin infarctions, and limb ischemia.

Treatment of disseminated intravascular coagulation (DIC) is controversial, but treatment guidelines have been published and offer broadly similar recommendations.[42, 72, 73] Treatment should primarily focus on addressing the underlying disorder. DIC can result from numerous clinical conditions, including sepsis, trauma, obstetric emergencies, and malignancy. Surgical management is limited to primary treatment of certain underlying disorders.

Management of the DIC itself has the following basic features:

• Monitor vital signs
• Assess and document the extent of hemorrhage and thrombosis
• Correct hypovolemia
• Administer basic hemostatic procedures when indicated

Platelet and factor replacement should be directed not at simply correcting laboratory abnormalities but at addressing clinically relevant bleeding or meeting procedural needs. Heparin should be provided to those patients who demonstrate extensive fibrin deposition without evidence of substantial hemorrhage; it is usually reserved for cases of chronic DIC. Heparin is appropriate to treat the thrombosis that occurs with DIC. It also has a limited use in acute hemorrhagic DIC in a patient with a self-limited condition of acral cyanosis and digital ischemia.

In general, antifibrinolytic agents (eg, tranexamic acid, ε-aminocaproic acid) should be avoided in DIC because they are known to produce thrombotic complications, such as myocardial infarction and renal artery thrombosis when there is systemic clotting. However, in patients with trauma and massive blood loss, tranexamic acid has been shown to be effective in reducing blood loss and improving survival.[74]  Similarly, in massive postpartum hemorrhage, high-dose tranexamic acid has been shown to be effective.[75]  Antifibrinolytics also may be useful in cases of DIC secondary to hyperfibrinolysis associated with acute promyelocytic leukemia and other forms of cancer when alpha-2-antiplasmin is uniquely decreased. These agents should always be administered with heparin to arrest their prothrombotic effects.[19] ​

Patients with DIC should be treated at hospitals with appropriate critical care and subspecialty expertise, such as hematology, blood bank, or surgery. Patients who present to hospitals without those capabilities and who are stable enough for transfer should be referred expeditiously to a hospital that has those resources.

The management of acute and chronic forms of disseminated intravascular coagulation (DIC) should primarily be directed at treatment of the underlying disorder.[76] Often, the DIC component will resolve on its own once the underlying disorder is addressed.

For example, if infection is the underlying etiology, the appropriate administration of antibiotics and source control is the first line of therapy. As another example, in case of an obstetric catastrophe, the primary approach is to deliver appropriate obstetric care, in which case the DIC will rapidly subside. If the underlying condition causing DIC is not known, a diagnostic workup should be initiated. Most patients with acute DIC require critical care treatment appropriate for the primary diagnosis, occasionally including emergency surgery.

A DIC scoring system has been proposed by Bick to assess the severity of the coagulopathy as well as the effectiveness of therapeutic modalities.[2] Clinical and laboratory parameters are measured with regularity (every 8 hours).

Typically, DIC results in significant reductions in platelet count and increases in coagulation times (prothrombin time [PT] and activated partial thromboplastin time [aPTT]). However, platelet and coagulation factor replacement should not be instituted on the basis of laboratory results alone; such therapy is indicated only in patients with active bleeding and in those requiring an invasive procedure or who are otherwise at risk for bleeding complications.

Platelets

Platelet transfusion may be considered in patients with DIC and severe thrombocytopenia, in particular, in patients with bleeding or in patients at risk for bleeding (eg, in the early postoperative phase or if an invasive procedure is planned).

The threshold for transfusing platelets varies. Most clinicians provide platelet replacement in nonbleeding patients if platelet counts drop below 20 × 109/L, though the exact levels at which platelets should be transfused is a clinical decision based on each patient’s clinical condition. In some instances, platelet transfusion is necessary at higher platelet counts, particularly if indicated by clinical and laboratory findings.[77] In actively bleeding patients, platelet levels from 20 × 109/L to 50 × 109/L are grounds for platelet transfusion (1 or 2 U/kg/day).

Coagulation factors

Previously, concerns have been expressed regarding the possibility that coagulation factor replacement therapy might “add fuel to the fire” of consumption; however, this has never been established in research studies.[78]

It is generally considered that cryoprecipitate and coagulation factor concentrates should not routinely be used as replacement therapy in DIC, because they lack several specific factors (eg, factor V). Additionally, worsening of the coagulopathy via the presence of small amounts of activated factors is a theoretical risk. Specific deficiencies in coagulation factors, such as fibrinogen, can be corrected by administration of cryoprecipitate or purified fibrinogen concentrate in conjuction with fresh frozen plasma (FFP) administration.

Data suggest that the consumption-induced deficiency of coagulation factors can be partially rectified by administering large quantities of FFP, particularly in patients with an international normalized ratio (INR) higher than 2.0, a 2-fold or greater prolongation of the aPTT, or a fibrinogen level below 100 mg/dL.[79] The suggested starting dose is 15 mg/kg.[42]

Repeated measurement of global clotting tests (eg, aPTT and PT) might be useful for monitoring the coagulation defect. In case of a (relative) vitamin K deficiency in the face of consumption, administration of vitamin K may be required.[18, 6, 19]

Experimental studies have suggested that heparin can at least partly inhibit the activation of coagulation in cases of sepsis and other causes of DIC.[80] However, a beneficial effect of heparin on clinically important outcome events in patients with DIC has not yet been demonstrated in controlled clinical trials. Moreover, antithrombin, the primary target of heparin activity, is markedly decreased in DIC, which means that the effectiveness of heparin therapy will be limited without concomitant replacement of antithrombin.

Furthermore, there are well-founded concerns with respect to anticoagulating DIC patients who are already at high risk for hemorrhagic complications. It is generally agreed that therapeutic doses of heparin are indicated in cases of obvious thromboembolic disease or where fibrin deposition predominates (eg, purpura fulminans or acral ischemia).[81, 82, 83] The use of heparin in chronic DIC where there is preponderance of coagulation without consumption coagulopathy is well established.[84] In other patients with acryl cyanosis and digital ischemia and DIC, heparin can be safely administered at lower doses. A dose of 4-5 U/kg constant infusion without a 80-U/kg bolus is a safe means to deliver heparin to the DIC without increasing the bleeding risk.

The use of low-molecular-weight heparin (LMWH) has been studied in DIC. Enoxaparin has been used for treatment and prophylaxis of chronic DIC in specific clinical situations. In a multicenter, cooperative, double-blinded trial from Japan that compared dalteparin with unfractionated heparin, the former was associated with a decreased bleeding tendency and reduced organ failure.[82] One randomized clinical trial showed LMWH to be superior for reducing 28-day mortality in patients with severe sepsis.[85]

Patients with DIC may benefit from prophylaxis to prevent venous thromboembolism, which will not be achieved with standard low-dose subcutaneous heparin. Theoretically, the most logical anticoagulant agent to use in DIC is directed against tissue factor activity.

Strategies for restoring anticoagulant pathways have primarily involved administration of antithrombin concentrate or recombinant human APC (drotrecogin alfa); however, drotrecogin alfa was withdrawn from the worldwide market on October 25, 2011. Tissue factor (TF) pathway inhibitor (TFPI) and recombinant thrombomodulin (rTM) have also been studied.

Antithrombin

The antithrombin pathway, an important inhibitor of coagulation in normal patients, is largely depleted and incapacitated in acute DIC. As a result, several studies have evaluated the utility of antithrombin replacement in DIC. Most have demonstrated benefit in terms of improving laboratory values and even organ function.[65, 86, 87, 88] To date, however, large-scale randomized trials have failed to demonstrate any mortality benefit in patients treated with antithrombin concentrate.

Most of the randomized controlled trials involved patients with sepsis or septic shock. In the later clinical trials, very high doses of antithrombin concentrate were used to attain supraphysiologic plasma levels. A series of relatively small trials showed a modest reduction in mortality in antithrombin-treated patients. However, in none of the trials did the effect reach statistical significance.

A large-scale multicenter, randomized controlled trial to directly address this issue showed no significant reduction in mortality of septic patients who were treated with antithrombin concentrate. In this trial, 2114 patients with severe sepsis and associated organ failure were included. Surprisingly, subgroup analyses indicated some benefit in patients who did not receive concomitant heparin, but this observation needs prospective validation.

In another study that evaluated the effects of antithrombin in 23 patients with DIC diagnosed on the basis of the Japanese Association for Acute Medicine (JAAM) criteria (a newly developed diagnostic algorithm for critical illness), patients were treated with either high-dose (60 IU/kg/day; 12 patients) or low-dose (30 IU/kg/day; 11 patients) antithrombin concentrates for 3 days.[89]

On day 0, the patients’ backgrounds and antithrombin activity were identical in the 2 groups.[89] However, on day 7, the JAAM DIC score and PT ratio were significantly improved in comparison with those on day 0. However, mortality at 28 days and interaction within the administered antithrombin doses showed no differences.[89]

There were also no differences in the time course of the platelet counts, coagulation and fibrinolytic markers, and DIC scores in the 2 groups.[89] The authors concluded that the effects of antithrombin on prognosis and coagulation and fibrinolytic parameters are independent of the doses administered in patients who have DIC associated with the systemic inflammatory response syndrome (SIRS) or sepsis.

A retrospective Japanese study in 1784 patients with severe sepsis and DIC, 715 of whom received treatment with antithrombin, found a statistically significant association between antithrombin supplementation and lower in-hospital all-cause mortality (odds ratio 0.748, P = 0.034). However, that association was not evident on quintile-stratified propensity score analysis or propensity score matching analysis.[90]

In this study, similar results were observed in DIC patients with or without concomitant heparin administration. In addition, although the number of transfusions needed was higher in the group that received antithrombin, the number of severe bleeding complications was not.[90]

A recombinant form of antithrombin, antithrombin gamma, is being developed as an alternative to antithrombin derived from human plasma. In a randomized, open-label trial in 222 patients with sepsis-induced DIC, the safety and efficacy of antithrombin gamma were comparable to that of plasms-derived antithrombin.[91]

Tissue factor pathway inhibitor

The TFPI mechanism of coagulation inhibition has received attention as a potential therapy in sepsis-associated DIC. Indeed, initial results from animal studies have been very promising in demonstrating the ability of TFPI to arrest DIC and to prevent the mortality and end-organ damage witnessed in untreated animals.[92] However, a large phase III trial of TFPI in humans with DIC did not show any mortality benefit.[93]

Recombinant thrombomodulin

In Japan, rTM is widely used for treatment of DIC. Thrombomodulin binds with thrombin, and the resulting complex allows the conversion of protein C to APC. Additionally, thrombomodulin can also bind high-mobility group B (HBGM-1), which inhibits the inflammatory process.[79]

rTM has shown beneficial effects on DIC parameters and clinical outcome in initial trials.[94] It was evaluated in a randomized controlled study involving 234 subjects and was found to yield significantly improved control of DIC in comparison with unfractionated heparin, particularly with respect to the control of persistent bleeding diathesis.[95]

However, a meta-analysis by Zhang et al found that in patients with infection complicated by DIC, treatment with rTM does not decrease short-term mortality: the risk ratio for 28- or 30-day mortality was 0.81 in randomized controlled trials and 0.96 in observational studies.[96]  In a systematic review and meta-analysis by Yamakawa et al of rTM for sepsis-induced DIC, pooled relative risk of 28-30 day mortality was 0.81 (95% CI, 0.62–1.06) in randomized controlled trials, indicating a non‐significant reduction in mortality, and 0.59 (95% CI, 0.45–0.77) in observational studies; results suggested that the probability of rTM therapy having a beneficial effect increases with increasing baseline risk.[97]

Inoue et al reported benefit with rTM treatment of DIC caused by noninfectious complications of allogeneic hematopoietic stem cell transplantation, such as acute graft-versus-host disease or thrombotic microangiopathy. In 12 episodes of DIC in 10 patients, the recovery rate was significantly higher than in historical controls.[98]

Consult a hematologist for assistance with diagnosis and management if the clinical picture is suggestive of DIC. Consult a transfusion specialist or a blood bank; determine the availability of general and specialized blood products that may be necessary for the acute management of fulminant DIC. Consult a critical care specialist if multiple organ failure is present.

Early consultation is indicated for this complicated, life-threatening condition. Obtain other subspecialty consultations as indicated by the patient’s primary diagnosis.

Outpatient medications may include antiplatelet agents for those with low-grade DIC, antibiotics appropriate to the primary diagnosis, or both. Patients who recover from acute DIC should follow up with their primary care provider or a hematologist. Patients with low-grade or chronic DIC may be treated by a hematologist on an outpatient basis after initial assessment and stabilization. Chronic DIC in patients with cancer can be managed with subcutaneous heparin or low molecular weight heparin.

The goals of pharmacotherapy in cases of disseminated intravascular coagulation (DIC) are to reduce morbidity and to prevent complications. Therapy should be based on etiology and aimed at eliminating the underlying disease. Treatment should be appropriately aggressive for the patient’s age, disease, and severity and location of hemorrhage or thrombosis. Treatment of acute DIC includes anticoagulants, blood components, and antifibrinolytics. Hemostatic and coagulation parameters should be monitored continuously during treatment.

Base therapeutic decisions on clinical and laboratory evaluation of hemostasis. In cases of low-grade DIC, therapy other than supportive care may not be warranted or may include antiplatelet agents or subcutaneous heparin; treatment decisions should be based on clinical and laboratory evaluation of hemostasis.

Class Summary

Anticoagulants are used in the treatment of clinically evident intravascular thrombosis when the patient continues to bleed or clot 4-6 hours after initiation of primary and supportive therapy. Thrombosis can present as purpura fulminans or acral ischemia. Take special precaution in obstetric emergencies or massive liver failure. The anti-inflammatory properties of antithrombin may be particularly useful in DIC secondary to sepsis.

Heparin is the only currently available antithrombotic drug that has a role in the treatment of patients with DIC. Although most experience is with standard heparin, low-molecular-weight heparins (LMWHs) are increasingly used. Moreover, although LMWHs usually do not require laboratory monitoring, it may be advisable to check anti-factor Xa levels in critically ill patients with serious renal failure.

Heparin

Heparin augments the activity of antithrombin and prevents conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis. Usage and dosing of heparin are based on the severity of DIC, the underlying cause, and the extent of thrombosis. Monitoring the results of therapy is mandatory.

Antithrombin (Atryn, Thrombate III)

Antithrombin is used for moderately severe–to–severe DIC or when levels are depressed markedly. It is an alpha2-globulin that inactivates thrombin, plasmin, and other serine proteases of coagulation, including factors IXa, Xa, XIa, XIIa, and VIIa. These effects inhibit coagulation.

Class Summary

Recombinant human APC inhibits factors Va and VIIIa of the coagulation cascade. It may also inhibit plasminogen activator inhibitor-1 (PAI-1). Drotrecogin alfa (Xigris) was withdrawn from the worldwide market on October 25, 2011.

Drotecogin alfa (Xigris)

Withdrawn from the worldwide market on October 25, 2011. Drotrecogin alfa was approved for the reduction of mortality in patients who have severe sepsis associated with acute organ dysfunction and who are at high risk for death. It is a recombinant form of human APC that exerts an antithrombotic effect by inhibiting factors Va and VIIIa.

Drotrecogin alfa exercises indirect profibrinolytic activity by inhibiting PAI-1 and limiting formation of activated thrombin-activatable fibrinolysis inhibitor. It may exert an anti-inflammatory effect by inhibiting human tumor necrosis factor (TNF) production by monocytes, blocking leukocyte adhesion to selectins, and limiting thrombin-induced inflammatory responses within the microvascular endothelium.

Class Summary

Blood components are used to correct abnormal hemostatic parameters. These products should be considered only after initial supportive and anticoagulant therapy. Washed packed red blood cells (PRBCs) and platelet concentrates are considered safe in uncontrolled DIC. Specialized blood components (eg, cryoprecipitate and fresh frozen plasma [FFP]) may interfere with or alleviate DIC.

Packed red blood cells (PRBCs; washed)

PRBCs are preferred to whole blood because they limit volume, immune, and storage complications. Obtain PRBCs after centrifugation of whole blood. Use washed or frozen PRBCs in individuals with hypersensitivity transfusion reactions.

Platelets

Platelets are considered safe for use in acute DIC.

Fresh frozen plasma (FFP)

FFP treatment entails removing blood from the body, spinning it to separate cells from plasma, and replacing cells suspended in fresh frozen plasma, albumin, or saline. FFP contains coagulation factors, as well as protein C and protein S. It can be administered either via 2 large-bore peripheral intravenous lines or via 1 multiple-lumen central line. It is recommended for patients with active bleeding and a fibrinogen level below 100 mg/dL.

Cryoprecipitate or fibrinogen concentrates

Cryoprecipitate and fibrinogen concentrates are not commonly recommended, except when fibrinogen is needed.

Class Summary

In general, antifibrinolytic agents should be avoided in DIC because they are known to produce thrombotic complications, such as myocardial infarction and renal artery thrombosis when there is systemic clotting. They may have a role in a local intravascular coagulation (LIC) as is seen in genitourinary bleeding after a transurethral resection for Kasabach-Merritt syndrome.

In addition, in patients with trauma and massive bllood loss, antifibrinolytic agents have been shown to be effective in reducing blood loss and improving survival. Similarly, in massive postpartum hemorrhage, antifibrinolytic agents have been shown to be effective. Antifibrinolytics also may be useful in cases of DIC secondary to hyperfibrinolysis associated with acute promyelocytic leukemia and other forms of cancer when alpha-2-antiplasmin is uniquely decreased.

Aminocaproic acid (Amicar)

Aminocaproic acid inhibits fibrinolysis by inhibiting plasminogen activators and, to a lesser degree, exerting antiplasmin activity. The main problem is that the thrombi that form during treatment are not lysed and that the clinical significance of reducing bleeding is uncertain.

Tranexamic acid (Cyklokapron, Lysteda)

Tranexamic acid is used as an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin.