Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + INTRODUCTION Download Section PDF Listen +++ ++ Disseminated intravascular coagulation (DIC) is a syndrome that is characterized by systemic intravascular activation of coagulation, leading to fibrin deposition in the microvasculature and small- and mid-size vessels, thereby contributing to organ dysfunction. Simultaneously, ongoing consumption of platelets and coagulation factors leads to thrombocytopenia and impaired coagulation and may result in serious bleeding complications. DIC never occurs by itself but is always secondary to an underlying cause. Table 85–1 lists the most frequently occurring disorders know to be associated with DIC. ++Table Graphic Jump LocationTABLE 85–1CLINICAL CONDITIONS THAT MAY BE COMPLICATED BY DISSEMINATED INTRAVASCULAR COAGULATIONView Table||Download (.pdf) TABLE 85–1 CLINICAL CONDITIONS THAT MAY BE COMPLICATED BY DISSEMINATED INTRAVASCULAR COAGULATION Infectious diseases: purpura fulminans Malignancy Solid tumors Leukemias Trauma Brain injury Burns Liver diseases Heat stroke Severe allergic/toxic reactions Snake bites Vascular abnormalities/Hemangiomas Kasabach-Merritt syndrome Other vascular malformations Aortic aneurysms Severe immunologic reactions (eg, transfusion reaction) Obstetrical conditions Abruptio placentae Amniotic fluid embolism Preeclampsia/eclampsia HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome Sepsis during pregnancy Acute fatty liver Source: Williams Hematology, 9th ed, Chap. 129, Table 129–1. + PATHOGENESIS Download Section PDF Listen +++ ++ The pathogenesis of DIC is diagrammed in Figure 85–1. Exposure of blood to tissue factor appears to be the principal mechanism of activation of coagulation. Tissue factor may be expressed by mononuclear cells or by the endothelium. Other stimuli include activation of factor Xa by a cancer procoagulant, snake envenomation, and tissue/cellular debris in patients with massive trauma or pancreatitis. Activation of coagulation is insufficiently balanced by physiologic anticoagulant pathways (eg, antithrombin, protein C system) and a downregulation of endogenous fibrinolysis due to high levels of the fibrinolysis inhibitor plasminogen activator inhibitor type 1 (PAI-1). ++ FIGURE 85–1 Schematic presentation of pathogenetic pathways involved in the activation of coagulation in disseminated intravascular coagulation (DIC). In DIC, both perturbed endothelial cells and activated mononuclear cells may produce proinflammatory cytokines that mediate coagulation activation. Activation of coagulation is initiated by tissue factor expression on activated mononuclear cells and endothelial cells. In addition, downregulation of physiologic anticoagulant mechanisms and inhibition of fibrinolysis by endothelial cells further promote intravascular fibrin deposition. PAI-1, plasminogen-activator inhibitor type 1. (Source: Williams Hematology, 9th ed, Chap. 129, Fig. 129–1.) Graphic Jump LocationView Full Size||Download Slide (.ppt) + CLINICAL FEATURES Download Section PDF Listen +++ ++ Clinical features are related to the underlying disorder, to the DIC, or both. Bleeding manifestations have been observed in about 25% of cases in several series. Persistent bleeding from venipuncture sites or other skin wounds occurs frequently. Hemorrhage may be life-threatening. Extensive organ dysfunction may be induced by microvascular thrombi, or by venous and/or arterial thromboembolism. Organ dysfunction may manifest as acute renal failure (renal cortical ischemia and acute tubular necrosis occur frequently), hepatic dysfunction, and respiratory insufficiency due to acute respiratory distress syndrome. Coma, delirium, focal neurologic symptoms, and signs of meningeal irritation may occur because of thrombosis or hemorrhage in the cerebral vasculature. Mortality rates range from 30% to 85%. The presence of DIC is a strong predictor for mortality in sepsis, trauma, and other underlying conditions. + LABORATORY FEATURES Download Section PDF Listen +++ ++ The underlying disorders may influence the abnormalities expected in DIC and must be considered in interpretation of laboratory data. There is not a single laboratory test that is able to confirm or reject the diagnosis of DIC. Typically, the platelet count is low, prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged, levels of coagulation factors and coagulation inhibitors are low, and fibrin related markers (fibrin degradation products, fibrin monomers, D-dimer) are elevated. A simple scoring algorithm, utilizing the platelet count, PT, D-dimer, and fibrinogen level has been proposed by the International Society on Thrombosis and Hemostasis and has been prospectively validated (see Table 85–2). Fibrinogen levels are rarely low because fibrinogen initially acts as an acute phase protein and levels may markedly increase due to the underlying cause. Primary fibrinogenolysis may be distinguished from DIC by finding a normal platelet count, greatly elevated fibrinogen degradation products, and very low levels of α2-antiplasmin and plasminogen (see Chap. 86). ++Table Graphic Jump LocationTABLE 85–2DIAGNOSTIC ALGORITHM FOR THE DIAGNOSIS OF OVERT DISSEMINATED INTRAVASCULAR COAGULATION (DIC)*View Table||Download (.pdf) TABLE 85–2 DIAGNOSTIC ALGORITHM FOR THE DIAGNOSIS OF OVERT DISSEMINATED INTRAVASCULAR COAGULATION (DIC)* 1. Presence of an underlying disorder known to be associated with DIC (no = 0, yes = 2) 2. Score global coagulation test results Platelet count (> 100 = 0; < 100 = 1; < 50 = 2) Level of fibrin markers (soluble fibrin monomers/fibrin degradation products) (no increase: 0; moderate increase: 2; strong increase: 3) Prolonged prothrombin time (< 3 s = 0; > 3 s but < 6 s = 1; > 6 s = 2) Fibrinogen level (> 1.0 g/L = 0; < 1.0 g/L = 1) 3. Calculate score 4. If ≥ 5: compatible with overt DIC; repeat scoring daily If < 5: suggestive (not affirmative) for nonovert DIC; repeat next 1–2 days *According to the Scientific Standardization Committee of the International Society of Thrombosis and Haemostasis. Data from Taylor FBJ, Toh CH, Hoots WK, et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001 Nov;86(5):1327–1330. + TREATMENT Download Section PDF Listen +++ ++ Rapid and appropriate treatment of the underlying disorder is of utmost importance, including antibiotics and source control for infection, anticancer treatment, surgical and medical management of trauma, or evacuation of a dead fetus. Because most patients with DIC are critically ill, appropriate supportive care, including fluids, pressors, dialysis, and respiratory and ventilator management, is essential. There is no convincing evidence that transfusion of blood components “fuels the fire,” and patients with documented deficiencies who are bleeding or require surgical or invasive procedures should receive transfusion with platelets for thrombocytopenia and fresh-frozen plasma or coagulation factor concentrates for coagulation factor depletion. Critically ill patients need prophylaxis for venous thromboembolism and therefore unfractionated or low-molecular-weight heparin is recommended. The use of (therapeutic levels of) heparin to ameliorate DIC is a matter of debate. In general, in the absence of adequately controlled studies, there is no sound clinical evidence supporting the use of heparin in DIC. Heparin treatment may be beneficial in patients with purpura fulminans (overt hemorrhagic infarction of the skin and underlying tissue), overt thromboembolism, and when thrombosis is likely to cause irreversible tissue injury. In these cases, unfractionated heparin at a dose of 500 to 750 U/h via continuous infusion may be sufficient. The decision to use heparin must be individualized, and the risks and benefits considered carefully. Administration of recombinant antithrombin (1500–3000 U) or human activated protein C (drotrecogin alfa 24 μg/kg per hour by continuous infusion for 4 days) may ameliorate laboratory parameters in DIC but did not result in an improvement of clinically relevant outcome. These interventions are associated with increased risk of bleeding. Antifibrinolytic therapy is generally contraindicated in DIC because it may provoke increased thrombosis and microvascular occlusion but may be considered in patients with severe bleeding when primary fibrin(ogen)olysis, rather than DIC, is the major process (see Chap. 86). + SPECIFIC UNDERLYING DISEASES Download Section PDF Listen +++ +++ Infection ++ Neonates, asplenic patients, and pregnant patients are more prone to development of infection-related DIC. All microorganisms, including gram-positive and gram-negative bacteria, viruses, parasites, and fungal infections may cause DIC. +++ Malignancy ++ Solid tumors often produce a chronic DIC in which thrombosis is more prominent than bleeding. This syndrome may respond to heparin. Patients with acute promyelocytic leukemia (APL) frequently develop major bleeding. The pathogenesis of the hemostatic abnormalities in APL is complex and may involve both DIC and primary fibrin(ogen)olysis. With the use of modern treatment strategies, including all-trans-retinoic acid (ATRA), coagulopathy and bleeding has become a less prominent feature of APL (see Chap. 45). Acute lymphocytic leukemia has been associated with DIC, particularly with induction therapy. +++ Complications of Pregnancy ++ Abruptio placentae causes acute DIC because of rapid entry of large quantities of placental tissue factor into the maternal circulation. Amniotic fluid embolism is a rare catastrophe that occurs most often in multiparous women undergoing difficult labors with postmature, large fetuses. DIC is caused by entry into the maternal circulation of amniotic fluid that contains tissue factor. The dead fetus syndrome occurs several weeks after intrauterine death and is caused by tissue factor from the fetus slowly entering the maternal circulation. Rapid volume replacement and evacuation of the uterus are treatments of choice. Replacement therapy with fresh-frozen plasma, coagulation factor concentrates, and platelets is given if severe bleeding occurs. The DIC usually rapidly resolves when the underlying cause has been handled properly. The syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP) occurs in the third trimester or postpartum. DIC appears to have a role in the pathogenesis of the HELLP syndrome. The HELLP syndrome may be confused with other forms of thrombotic microangiopathy (eg, thrombotic thrombocytopenic purpura–hemolytic uremic syndrome [TTP-HUS]) (see Chap. 90). Patients should receive supportive care, careful monitoring, and blood component replacement therapy. +++ Trauma ++ The initial coagulation defect after severe trauma is a dilutional coagulopathy due to blood loss and replacement therapy with red cells and plasma expanders. After 24 to 48 hours, a systemic inflammatory response syndrome may occur, leading to frank DIC. In the initial phase, restoration of coagulation factors and platelets by fresh frozen plasma and platelet transfusion, respectively, should be initiated. In the later phase, supportive treatment for DIC (see above) should be considered. +++ Newborns ++ Laboratory evidence of DIC in newborns consists of progressive decline in hemostatic parameters; thrombocytopenia; and reduced levels of fibrinogen, factor V, and factor VIII. The most frequent underlying causes are sepsis, hyaline membrane disease, asphyxia, necrotizing enterocolitis, intravascular hemolysis, abruptio placentae, and eclampsia. Bleeding from multiple sites is the most frequent presentation, but in about 20%, no clinical manifestations of DIC are present. Management consists of treatment of the underlying disorder, support of vital functions, and replacement of blood components. ++ For a more detailed discussion, see Marcel Levi and Uri Seligsohn: Disseminated Intravascular Coagulation, Chap. 129 in Williams Hematology, 9th ed.