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 oxide mediated 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 proteaseactivated receptors (PARs); (4) it activates factor XIII to factor 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 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 under-opposed 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 2-antiplasmin 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

History

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 gingiva and gastrointestinal system. Acutely presenting DIC often manifests as petechiae and ecchymosis, along with blood loss from intravenous lines and catheters. In postsurgical DIC, bleeding can occur in the vicinity of surgical sites, drains, tracheostomies, and within serous cavities. Look for symptoms and signs of thrombosis in large vessels, such as deep venous thrombosis (DVT), and of microvascular thrombosis, such as renal failure. Bleeding from at least 3 unrelated sites is particularly suggestive of disseminated intravascular coagulation (DIC). Up to 25% percent of patients can present with renal failure. Patients with pulmonary involvement can present with dyspnea, hemoptysis, and cough. Jaundice can be seen because of comorbid liver disease as well as rapid hemolytic bilirubin production. Neurological changes are also possible, including coma, obtunded mental status, and parasthesias.

Epistaxis Gingival bleeding Mucosal bleeding Cough Dyspnea Hemoptysis Confusion, disorientation Jaundice Fever Bruising, petechiae Changes in mental status

Table 1. Main Features of DIC in a Series of 118 Patients[31] (Open Table in a new window) Affected Patients, % Bleeding 64% Renal dysfunction 25% Hepatic dysfunction 19% Respiratory dysfunction 16% Shock 14% Central nervous system dysfunction 2% Features

Physical
Circulation

Signs of spontaneous and life-threatening hemorrhage

Signs of subacute bleeding Signs of diffuse or localized thrombosis Bleeding into serous cavities

Central nervous system

Nonspecific altered consciousness/stupor Transient focal/neurologic deficits

Cardiovascular system

Hypotension Tachycardia Circulatory collapse

Respiratory system

Pleural friction rub Signs of adult respiratory distress syndrome (ARDS)

Gastrointestinal system

Hematemesis Hematochezia

Genitourinary system

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

Dermatologic system

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

Causes
Causes of DIC can be classified as acute or chronic, systemic or localized. DIC may be the result of a single or multiple conditions.

Acute DIC
Infectious

Bacterial (eg, gram-negative sepsis, gram-positive infections, rickettsial) Viral (eg, HIV, cytomegalovirus [CMV], varicella, hepatitis) Fungal (eg, Histoplasma) Parasitic (eg, malaria)

Malignancy

Hematologic (eg, acute myelocytic leukemias) Metastatic (eg, mucin-secreting adenocarcinomas)

Obstetric

Placental abruption Amniotic fluid embolism Acute fatty liver of pregnancy Eclampsia

Trauma

Burns Motor vehicle accidents (MVAs) Snake envenomation

Transfusion

Hemolytic reactions Massive transfusion

Other

Liver disease - Acute hepatic failure Prosthetic devices Shunts (Denver, LeVeen)

Ventricular assist devices

Chronic DIC
Malignancies

Solid tumors Leukemia

Obstetric

Retained dead fetus syndrome Retained products of conception

Hematologic

Myeloproliferative syndromes Paroxysmal nocturnal hemoglobinuria

Vascular

Rheumatoid arthritis Raynaud disease

Cardiovascular - Myocardial infarction Inflammatory

Ulcerative colitis Crohn disease Sarcoidosis

Localized DIC

Aortic aneurysms Giant hemangiomas (Kasabach-Merritt syndrome) Acute renal allograft rejection Hemolytic uremic syndrome

Differentials

Acute or chronic liver failure

Hemolytic Uremic Syndrome Heparin-induced thrombocytopenia Other consumptive coagulopathy Thrombocytopenic Purpura

Laboratory Studies
Patients with DIC present can present with a wide range of abnormalities in their laboratory values. Typically, elongated coagulation times, thrombocytopenia, high levels of fibrin split products, and microangiopathic pathology (schistocytes) on peripheral smears are suggestive findings. No one test is sensitive and specific enough to diagnose disseminated intravascular coagulation (DIC). Rather, the diagnosis is made based on the clinical picture in combination with laboratory studies, best evaluated serially. Most individual laboratory tests demonstrate high sensitivity but very low specificity for DIC.[33] Furthermore, while 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.[34] Furthermore, it is important to note that laboratory values may represent only a momentary glimpse into a very rapidly changing systemic process, and therefore repeated tests may be necessary in order to make a more clinically certain diagnosis.[35] Given that acute DIC entails massive thrombin activation and fibrin deposition with consumption of coagulation factors, many laboratory abnormalities are manifest. Because fibrin activation is a central component of DIC, evidence suggests that if soluble fibrin is elevated, the diagnosis of DIC can be made with confidence.[36] However, soluble fibrin levels are not available to most clinicians in 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. However, other commonly available laboratory tests often are frequently deranged in DIC. Typically, moderate-to-severe thrombocytopenia is present in DIC. Furthermore, the peripheral blood smear can demonstrate evidence of microangiopathic pathology (schistocytes). Fibrinolysis is an important component of DIC. As such, there is evidence of fibrin breakdown such as elevated D-dimer and fibrin degradation products (FDPs).However, both of these assays may be elevated in other conditions such as venous thromboembolism, trauma, or recent surgery, limiting the specificity of these tests.[11, 37] Given the massive fibrin deposition in DIC, fibrinogen levels would seem to be decreased. However, this is not the case. Fibrinogen, as a positive acutephase reactant is increased in inflammation, and while values may decrease as the illness progresses, they are rarely low.[11, 38] Given ongoing consumption of coagulation factors and

impaired hepatic synthesis secondary to hypoperfusion or organ damage, typically global clotting times (aPTT and PT) are elevated. Additionally, it is important to note the role played by the loss of coagulation factors via hemorrhage and decreased production due to liver pathology.[39] Conversely, a normal or even attenuated PT and aPTT may be encountered in up to 50% of DIC patients, and therefore such values cannot be used to exclude DIC.[40] 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.[41] It is also important to note that only PT, and not INR should be used in the DIC monitoring process, as INR has only been proscribed for monitoring oral anticoagulants.[30] Antithrombin levels as well as other individual factors (V and VII) may also be diminished in acute DIC. Typically, moderate-to-severe thrombocytopenia is present in DIC. Thrombocytopenia is seen in up to 98% of DIC patients, and, in 50% of the patients, the platelet count can dip below 50 X 109.[42] A decreasing trend in platelet counts or a grossly reduced absolute platelet count is a sensitive (although not specific) indicator of DIC.[30] 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 demonstrate evidence of schistocytes, although these are rarely seen in excess of 10% of RBCs. The presence of schistocytes is neither sensitive nor specific for DIC, but in certain instances, they may help confirm a chronic DIC diagnosis when they are seen in concert with normal coagulation values and increased D-Dimers.[42] One study demonstrated that in up to 57% of DIC patients, the levels of fibrinogen may in fact remain within normal limit.[42] Protein C and antithrombin are 2 natural anticoagulants that are frequently decreased in DIC. These are also significant because some studies have shown that they may serve roles as prognostic indicators.[43, 44] Nonetheless, the practical application of measuring these anticoagulants may be limited for most practitioners, because of generalized limitations in their availability.[30] DIC has been shown to have association with an unusual light transmission profile on the aPTT, known as a biphasic waveform. The degree of biphasic waveform abnormality on has been shown in an 1187-patient ICU study to have an increasing positive predictive value for DIC, and it occurs independently of clotting time prolongation. Additionally, the waveform abnormalities are often evident prior to more conventionally used laboratory value derangements,[45] making it a quick and robust test for DIC. The limitations of this approach lie in the current lack of widespread availability of the photo-optical analyzers necessary in clot formation analysis. The diagnosis of DIC relies on multiple clinical and laboratory determinations. The International Society on Thrombosis and Haemostasis developed a simple scoring system for the diagnosis of

overt DIC (see Table 2). A score of 5 or greater indicates overt DIC, whereas a score of less than 5 does not rule out DIC but may indicate non-overt DIC.[1] Studies have demonstrated the DIC score to be 93% sensitive and 98% specific for DIC.[46] Table 2. DIC Score[1] (Open Table in a new window)
Risk assessment Does the patient have an underlying disorder (eg, sepsis, trauma, obstetric emergency) compatible with DIC?

Laboratory coagulation Platelet count tests

D-dimer and FDPs

Fibrinogen

PT and aPTT

Scoring

Platelet count: >100 = 0 points, < 100 = 1 point, < 50 = 2 points

Elevated fibrin marker: No elevation = 0 points, moderate increase = 2 points, strong increase = 3 points

Prolonged PT: < 3 sec = 0 points, >3 < 6 = 1 point, >6 = 2 points

Fibrinogen level: >1 g/L = 0 points, < 1 = 1 point

Calculate score

Greater than or equal to 5 = compatible with overt DIC, repeat scoring daily

Less than 5 suggestive of non-overt DIC

Despite the utility of this scoring regimen for the diagnosis of DIC, there has been concern regarding the validity of this tool in identifying non-overt DIC. In response to these concerns, the Japanese Association for Acute Medicine (JAAM) developed the following diagnostic criteria for critically ill patients. This system has been prospectively validated and found to be able to diagnose DIC earlier than previous methods. Furthermore, evidence suggests that early identification of patients with DIC using this scoring system and as well early and aggressive treatment of DIC and the underlying disorder can lead to improvements in patient outcome and reduced mortality.[47] Table 3: Scoring System for DIC (Japanese Association for Acute Medicine)[47] (Open Table in a new window)
Clinical conditions that should be ruled out Thrombocytopenia

Dilution and abnormal distribution

Massive blood loss, massive infusion

Idiopathic thrombocytopenic purpura (ITP), TTP/HUS, HIT, HELLP

Disorders of hematopoiesis

Liver disease

Hypothermia

Spurious laboratory results

Diagnostic algorithm for systemic inflammatory response syndrome Temperature >38C or < 36C

Heart rate >90 beats per minute

Respiratory rate >20 breaths/min or PaCO2 < 32 torr (< 4.3 kPa)

White blood cell >12,000 cells/mm3, < 4000 cells/mm3, or 10% immature (band) forms

Diagnostic algorithm

Score

Systemic inflammatory response system criteria

>3 0-2

1 0

Platelet count (109/L) < 80 or >50 % decrease within 24 hours >80 and < 120 or >30% decrease within 24 hours >120 Prothrombin time (value of patient/normal value) >1.2 < 1.2 Fibrin/fibrinogen degradation products (mg/L) >25 >10 and < 25 < 10 Diagnosis 3 1 0 DIC 1 0 3 1 0

4 points or more

Recent evidence also suggests that serum thrombomodulin levels correlate well with the clinical course of DIC, multiorgan system dysfunction, and mortality in septic patients. Thrombomodulin, a marker for endothelial cell damage, is elevated in DIC and correlates well with not only the severity of DIC but can also serve as a marker for the early identification as well as monitoring of DIC.[48]

Imaging Studies

Base diagnostic imaging on the underlying pathologic process as well as on areas suggestive of thrombosis and hemorrhage. Perform a bilateral perihilar soft-density chest radiograph if pulmonary injury is present.

Prehospital Care
Monitor vital signs, assess and document extent of hemorrhage and thrombosis, correct hypovolemia, and administer basic hemostatic procedures when indicated.

Emergency Department Care

The management of acute and chronic forms of disseminated intravascular coagulation (DIC) should primarily be directed at treatment of the underlying disorder. Often, the DIC component will resolve on its own with treatment. Typically, DIC results in significant reductions in platelet count and increases in coagulation times (PT and aPTT). Despite these abnormalities, routine platelet and coagulation factor replacement is not indicated in acute DIC unless ongoing bleeding is present or invasive procedures are planned. Most clinicians will provide platelet replacement in nonbleeding patients if platelet counts drop below 20 X 106/mL, though the exact levels at which platelets should be transfused is a clinical decision based on each individual patient. In some instances, platelet transfusion is necessary at higher platelet counts, particularly if indicated as per clinical and laboratory findings.[49] In actively bleeding patients, platelet levels from 20 X 106/mL to 50 X 106/mL are grounds for platelet transfusion (1 or 2 units per kg, daily). Previously, concern has been raised regarding "fueling the fire" of consumption by providing coagulation factor replacement therapy; however, this has never been established in research studies.[50] Current literature suggests that the consumption-induced deficiency of coagulation factors can be partially rectified by the administration of large quantities of FFP, particularly in those patients with elevated INR (>2.0), a 2-times prolongation of aPTT, and/or fibrinogen levels below 100 mg/dL.[51] The suggested starting dose is 15 mg/kg of FFPs.[30] Cryoprecipitates should not routinely be used as replacement therapy in DIC as they lack several specific factors (factor V). Additionally, worsening of the coagulopathy via the presence of small amounts of activated factors is a theoretical risk. Provision of vitamin K to correct relative deficiencies in the face of consumption may be required.[11, 7, 13] Anticoagulation in DIC has recently received much attention. Some past experimental studies have suggested that heparin shows some effect in the inhibition of coagulation pathways in DIC.[52] However, the beneficial effect of high- or low-dose heparin therapy in patients with acute DIC has never been convincingly established. Moreover, antithrombin (AT), the primary target of heparin activity is markedly decreased in DIC, limiting the effectiveness of heparin therapy without concomitant replacement of AT.

Furthermore, well-founded concern exists in anticoagulating patients already at high risk for hemorrhagic complications. It is generally agreed that heparin is indicated in cases with obvious thromboembolic disease or where fibrin deposition predominates.[53, 54, 55] The use of heparin in chronic DIC where there is preponderance of coagulation without consumption coagulopathy is well established.[56] Lovenox (Enoxaparin) has also seen use in the treatment and prophylaxis of chronic DIC in specific clinical situations. In a multicenter, cooperative, double-blinded trial in Japan that compared the low molecular weight Fragmin (Dalteparin) with unfractionated heparin, there was a decreased bleeding tendency and reduced organ failure (P < .05).[57] As stated above, the AT pathway is an important inhibitor of coagulation in normal patients. This system is largely depleted and incapacitated in acute DIC. As a result, several studies have evaluated the utility of AT replacement in DIC. Most have demonstrated benefit in terms of improving laboratory values and even organ function.[38, 58, 59, 60] However, large-scale randomized trials have failed to demonstrate any mortality benefit in patients treated with AT concentrate. The tissue factor pathway inhibitor (TFPI) mechanism of coagulation inhibition has likewise 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.[61] However, a large, phase III human trial of TFPI in DIC did not show any mortality benefit.[62] As with TFPI and AT, activated protein C (APC) is an important regulator of coagulation. It deactivates factor VIIIa and factor Va and additionally has a role in activating protease-activated receptor 1 (PAR-1), which has an inhibitory effect on inflammation and apoptosis.[51] In studies of patients with sepsis who had associated organ failure, APC has been shown to reduce mortality and improve organ function. The PROWESS study (Human Recombinant Activated Protein C Worldwide Evaluation in Sepsis) documented reductions in 28-day mortality and improved organ function in APC-treated patients, despite an increase in the overall number of bleeding complications.[63, 64] These results were confirmed by the ENHANCE trial, which also suggested that APC might be more effective when administered earlier.[65] A retrospective, subgroup analysis of the PROWESS study demonstrated a lower mortality rate among patients treated with APC who met criteria for DIC with a modified DIC scoring system.[66] Other studies of APC in patients with a low risk of death from sepsis have failed to show an effect, suggesting that APC may be most useful in severely ill patients.[67] Recombinant thrombomodulin (rTM) can be used for treatment of DIC in cases of severe sepsis and hematopoietic malignancy. Thrombomodulin binds with thrombin, and the resulting complex allows the conversion of protein C to activated protein C. Additionally, thrombomodulin can also bind high-mobility group B (HBGM-1), which inhibits the inflammatory process.[51] The effect of recombinant thrombomodulin was examined in a randomized controlled study with 234 subjects. A significant improvement in controlling DIC was noted versus unfractionated heparin, particularly in regard to the control of persistent bleeding diathesis.[68]

Future directions
As understanding of the inflammatory and coagulation derangements in DIC has improved in recent years, the range of therapeutic considerations has broadened. Treatment modalities focused on the TF-VIIa complex include inactivated factor VII and NAPc2, a member of the nematode family of anticoagulant proteins (NAPs) and an inhibitor of the complex between TF, factor VIIa, and factor Xa. NAPc2 has been observed to inhibit coagulation activation in a primate model of sepsis.[7, 13] Other research has used antibodies against tissue factor/factor VIIa in animal trials, with promising results.[13] Hirudin, a direct inhibitor of thrombin has also been shown to be effective in treating DIC in animal studies.[13] A small pilot study (5 patients) analyzed the effects of recombinant hirudin (r-hirudin) in relation to thrombin-antithrombin III complex and thrombin-hirudin complex (THC) in patients with DIC. The subsequent results and statistical analysis indicated that r-hirudin was more efficacious in the inhibition of thrombin rather than ATIII without heparin; this suggests that r-hirudin potentially may have a clinical use as a DIC treatment modality.[69] Recombinant factor VIIa has also been demonstrated to be useful in cases of severe bleeding as can be seen in DIC.[13] However, given the procoagulant effect of rVIIa, a careful consideration of the risks and benefits in patients with DIC should be undertaken before administration. Further, antifibrinolytic agents, such as epsilon-aminocaproic acid or tranexamic acid, can also be considered in patients with DIC in which bleeding predominates. These agents should always be administered with heparin to arrest their prothrombotic effects.[13, 70] Recognition of the importance of inflammation in both sepsis and DIC has led to further investigation of inhibitors of inflammation. In a murine model, researchers have shown antiselectin antibodies and heparin to block leukocyte and platelet adhesion.[71] Similarly, focus has been placed on interleukin 10 (IL-10), an anti-inflammatory cytokine that may have effects on coagulation activation. Initial studies of IL-10 have shown promise in preventing coagulation activation associated with endotoxemia.[72] Other researchers have targeted p38 mitogen activated protein kinase (MAPK), an important element in intracellular signaling responsible for inflammatory responses. Inhibition of MAPK has been shown to reduce coagulation activation, fibrinolysis, and endothelial activation in endotoxemia.[73]

Medication Summary
Therapy should be based on etiology and aimed at eliminating the underlying disease. Therapy should be appropriately aggressive for the patient's age, disease, and severity and location of hemorrhage/thrombosis. Treatment for acute disseminated intravascular coagulation (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 lowgrade 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. Activated human protein C has been shown to reduce the rate of mortality in the setting of severe sepsis for patients at high risk for death; this should be used cautiously and appropriately, following guidelines for administration.

Anticoagulant agents
Class Summary
These agents are used in the treatment of clinically evident intravascular thrombosis when the patient continues to bleed or clot 4-6 h 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 III may be particularly useful in DIC secondary to sepsis.

Heparin
Use and dose of heparin is based on severity of DIC, underlying cause, and extent of thrombosis. Monitoring results of therapy is mandatory. Heparin augments antithrombin III activity and prevents conversion of fibrinogen to fibrin. Does not actively lyse but inhibits further thrombogenesis. Prevents reaccumulation of a clot after spontaneous fibrinolysis.

Antithrombin III (ATnativ, Thrombate III)

Used for moderately severeto severe DIC or when levels are depressed markedly. Alpha 2-globulin that inactivates thrombin, plasmin, and other serine proteases of coagulation, including factors IXa, Xa, XIa, XIIa, and VIIa. These effects inhibit coagulation.

Recombinant human activated protein C

Class Summary
These agents inhibit factors Va and VIIIa of the coagulation cascade. They may also inhibit plasminogen activator inhibitor-1 (PAI-1).

Drotrecogin alfa-activated (Xigris)

Indicated for reduction of mortality in patients with severe sepsis associated with acute organ dysfunction and at high risk of death. Recombinant form of human activated protein C that exerts antithrombotic effect by inhibiting factors Va and VIIIa. Has indirect profibrinolytic activity by inhibiting PAI-1 and limiting formation of activated thrombin-activatable-fibrinolysis-inhibitor. May exert antiinflammatory effect by inhibiting human tumor necrosis factor (TNF) production by monocytes, blocking leukocyte adhesion to selectins, and limiting thrombin-induced inflammatory responses within microvascular endothelium.

Blood components
Class Summary
Blood components are used to correct abnormal hemostatic parameters. These products should be considered only after initial supportive and anticoagulant therapy. Washed PRBCs and platelet concentrates are considered safe in uncontrolled DIC. Specialized blood components (cryoprecipitate, FFP) may interfere with or improve DIC.

Packed red blood cells (PRBCs; washed)

Preferred to whole blood since 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
Considered safe for use in acute DIC.

Fresh frozen plasma (FFP)

This treatment entails removing blood from body, spinning it to separate cells from plasma, and replacing cells suspended in fresh frozen plasma, albumin, or saline. Contains coagulation factors as well as protein C and protein S. Can be performed by using either 2 large-bore peripheral IV sites or multiple lumen central line. Recommended with active bleeding and fibrinogen < 100 mg/dL.

Cryoprecipitate or fibrinogen concentrates

Not commonly recommended except when fibrinogen is needed.

Antifibrinolytic agents
Class Summary
These agents are used only after all other therapeutic modalities have been tried and deemed unsuccessful. Increase in circulating plasmin and laboratory evidence of decreased plasminogen should be documented. Antifibrinolytics may be useful in cases of DIC secondary to hyperfibrinolysis associated with acute promyelocytic leukemia and other forms of cancer. Related to the use of activated protein C is the recent utilization of protein C concentrate to treat coagulation abnormalities in adult patients with sepsis. Protein C concentrate was found to be safe and useful in restoring coagulation and hematologic parameters. Further study is required and prospective evaluation of its safety and efficacy are indicated.[74]

Aminocaproic acid (Amicar)

Inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. Main problem is that thrombi that form during treatment are not lysed, and clinical significance of reducing bleeding is uncertain.

Tranexamic acid (Cyklokapron)

Used as alternative to aminocaproic acid. Inhibits fibrinolysis by displacing plasminogen from fibrin.

Further Inpatient Care

Most patients with acute disseminated intravascular coagulation (DIC) require critical care treatment appropriate for the primary diagnosis, occasionally including emergent 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.[75] Clinical and laboratory parameters are measured with regularity (every 8 h).

Further Outpatient Care

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.

Inpatient & Outpatient Medications

Outpatient medications may include antiplatelet agents for those with low-grade DIC and/or antibiotics appropriate to the primary diagnosis. DIC can result from several clinical conditions including sepsis, trauma, obstetric emergencies, and malignancy. DIC results in intravascular coagulation mediated largely by exposure of blood to tissue factor via damage to the endothelium or by the expression of procoagulants by endothelial, malignant, and inflammatory cells. Ongoing coagulation in acute DIC quickly consumes coagulation factors and platelets producing a microangiopathic picture with simultaneous intravascular coagulation and hemorrhage. Diagnosis can be difficult, especially in cases of chronic, smoldering DIC, where clinical and laboratory abnormalities may be subtle. Treatment should primarily focus on addressing the underlying disorder. Platelet and factor replacement should be directed not at correcting laboratory abnormalities but to clinically relevant bleeding or procedural needs. Heparin should be provided to those patients who demonstrate extensive fibrin deposition without evidence of substantial hemorrhage and is usually reserved for cases of chronic DIC. Subgroups of patients with sepsis who have DIC may benefit from activated protein C (APC), with consideration given to its anticoagulant effects. Recognition of the importance of inflammation in sepsis, coagulation, and DIC is vitally important in directing the development of novel therapeutic strategies.

Complications

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