Bacterial infections are among the most common causes of DIC.5,149 Certain patients are particularly vulnerable to infection-induced DIC, such as immune-compromised hosts, asplenic patients whose ability to clear bacteria, particularly pneumococci and meningococci, is impaired, and newborns whose coagulation inhibitory systems are immature. Infections are frequently superimposed on trauma and malignancies, which themselves are potential triggers of DIC. In addition, infections can aggravate bleeding and thrombosis by directly inducing thrombocytopenia, hepatic dysfunction, and shock associated with diminished blood flow in the microcirculation.150 Clinically overt DIC may occur in 30 to 50 percent of patients with Gram-negative sepsis.151,152 DIC is similarly common in patients with Gram-positive sepsis.153,154 Extreme examples of sepsis-related DIC are (1) group A streptococcus toxic shock syndrome, characterized by deep tissue infection, vascular collapse, vascular leakage, and multiorgan dysfunction; a streptococcal M protein forms complexes with fibrinogen, and these complexes bind to β2 integrins of neutrophils leading to their activation155; and (2) meningococcemia, a fulminant Gram-negative infection characterized by extensive hemorrhagic necrosis, DIC, and shock. The extent of hemostatic derangement in patients with meningococcemia correlates with prognosis.156,157 More frequent Gram-negative infections associated with DIC are caused by Pseudomonas aeruginosa, E. coli, and Proteus vulgaris. Patients affected by such bacteremias may have only laboratory signs of activated coagulation or may present with severe DIC, especially when shock develops.158,159
Severe secondary deficiency of a disintegrin-like metalloprotease with thrombospondin type 1 repeats (ADAMTS13), the von Willebrand cleaving protease, occurs in patients with sepsis-induced DIC and is associated with a high incidence of acute renal failure.160
Among the Gram-positive infections, Staphylococcus aureus bacteremia can cause DIC accompanied by renal cortical and dermal necrosis. The mechanism by which DIC is elicited may be related to an α-toxin that activates platelets and induces IL-1 secretion by macrophages.161 Streptococcus pneumoniae infection is associated with the Waterhouse-Friderichsen syndrome,162 particularly in asplenic patients. Initiation of DIC in these conditions is ascribed to the capsular antigen of the bacterium and to antigen–antibody complex formation.163 Other Gram-positive bacteria that can cause DIC are the anaerobic clostridia. Clostridial bacteremia is a highly lethal disease characterized by septic shock, DIC, renal failure, and hemolytic anemia.164
Activation of the coagulation system has also been documented for nonbacterial pathogens, that is, viruses (causing hemorrhagic fevers),164,165 protozoa (Malaria),166,167 and fungi.168 Common viral infections, such as influenza, varicella, rubella, and rubeola, rarely are associated with DIC.169 However, purpura fulminans associated with DIC has been reported in patients with infections and either hereditary thrombophilias,170,171 or acquired antibodies to protein S.172 Other viral infections can cause “hemorrhagic fevers” characterized by fever, hypotension, bleeding, and renal failure. Laboratory evidence of DIC can accompany Korean, rift valley, and dengue-related hemorrhagic fevers.173,174,175 Release of TF from cells in which viruses replicate28 and increased levels of proinflammatory cytokines have been suggested as mechanisms for initiation of the TF pathway in these conditions.163
Purpura fulminans is a severe, often lethal form of DIC in which extensive areas of the skin over the extremities and buttocks undergo hemorrhagic necrosis.176 The disease affects infants and children predominantly, and occasionally adults.177,178 Diffuse microthrombi in small blood vessels, necrosis, and occasionally vasculitis are present in biopsies of skin lesions. Onset can be within 2 to 4 weeks of a mild infection such as scarlet fever, varicella, or rubella, or can occur during an acute viral or bacterial infection in patients with acquired or hereditary thrombophilias affecting the protein C inhibitory pathway.156,177 Homozygous protein C deficiency presents in neonates soon after birth as purpura fulminans, with or without extensive thrombosis.179,180 Patients affected by purpura fulminans are acutely ill with fever, hypotension, and hemorrhage from multiple sites; they frequently have typical laboratory signs of DIC.177 Excision of necrotic skin areas and grafting are indispensable at a later stage.
Trousseau was the first to describe the propensity to thrombosis of patients with cancer and cachexia, and evidence for malignancy-related primary fibrinolysis and/or DIC was provided 75 years ago.9,181,182
In 182 patients with malignant disorders, excessive bleeding was recorded in 75 cases, venous thrombosis in 123, migratory thrombophlebitis in 96, arterial thrombosis in 45, and arterial embolism resulting from nonbacterial thrombotic endocarditis in 31.183 Multifocal hemorrhagic infarctions of the brain, caused by fibrin microemboli and manifested as disorders of consciousness, have been described. Patients with solid tumors and DIC are more prone to thrombosis than to bleeding, whereas patients with leukemia and DIC are more prone to hemorrhage. The incidence of DIC in consecutive patients with solid tumors was 7 percent.184
Solid-tumor cells can express different procoagulant molecules including TF, which forms a complex with factor VII(a) to activate factors IX and X, and a cancer procoagulant, a cysteine protease with factor X activating properties.185,186 In breast cancer, TF is expressed by vascular endothelial cells as well as the tumor cells.187,188 TF also appears to be involved in tumor metastasis and angiogenesis.189,190,191 Cancer procoagulant is an endopeptidase that can be found in extracts of neoplastic cells but also in the plasma of patients with solid tumors.192,193 The exact role of cancer procoagulant in the pathogenesis of cancer-related DIC is unclear.
Interactions of P- and L-selectins with mucin from mucinous adenocarcinoma can induce formation of platelet microthrombi and probably constitute a third mechanism of cancer-related thrombosis.194 Depending on the rate and quantity of exposure or influx of shed vesicles from tumors containing TF, a nonovert or overt DIC develops.39,195,196 For instance, a patient may be asymptomatic or present with venous thromboembolism if the tumor cells expose or release TF slowly or intermittently and the ensuing utilization of fibrinogen and platelets is compensated by increased production of these components. Conversely, massive thrombosis or severe bleeding may supervene in a patient whose circulation is deluged by TF.184,186
Another mechanism by which tumor cells may contribute to the pathogenesis of DIC is by expressing fibrinolytic proteins.197,198 Despite the ability of many malignant cells to express urokinase-type plasminogen activator and t-PA, most tumors induce a hypofibrinolytic state. Because DIC is commonly characterized by a shutdown of the fibrinolytic system, mostly because of high levels of PAI-1, this may represent an alternative mechanism for the development of DIC in cancer.
Virtually all pathways that contribute to the occurrence of DIC are driven by cytokines. IL-6 has been identified as one of the most important proinflammatory cytokines that is able to induce TF expression on cells.21,199 Indeed, inhibition of IL-6 results in an inhibition of endotoxin-stimulated activation of coagulation. In contrast, changes in fibrinolysis and microvascular physiologic anticoagulant pathways are mostly dependent on TNF-α.200,201,202 Other cytokines that participate in the systemic activation of coagulation are IL-1β and IL-8, whereas antiinflammatory cytokines, such as IL-10, are able to inhibit DIC.203,204,205 Because many types of tumors have the ability to synthesize and release cytokines or to stimulate other cells to activate the cytokine network, it is likely that cytokine-dependent modulation of coagulation and fibrinolysis plays a role in cancer-related DIC.
Patients with solid tumors are vulnerable to risk factors and additional triggers of DIC that can aggravate thromboembolism and bleeding.182 Risk factors include advanced age, stage of the disease, and use of chemotherapy or antiestrogen therapy.197 Triggers include septicemia, immobilization, and involvement of the liver by metastases that impede the function of the liver in controlling DIC. Microangiopathic hemolytic anemia frequently is induced by DIC in patients with malignancies and is particularly severe in patients with widespread intravascular metastases of mucin-secreting adenocarcinomas.206
Numerous reports on DIC and fibrinolysis complicating the course of acute leukemias have been published. In 161 consecutive patients who presented with acute myeloid leukemia, DIC was diagnosed in 52 (32 percent).207 In acute lymphoblastic leukemia, DIC was diagnosed in 15 to 20 percent.208 Some reports indicate that the incidence of DIC in acute leukemia patients might further increase during remission induction with chemotherapy.209 In patients with acute promyelocytic leukemia (APL), DIC is present in more than 90 percent of patients at the time of diagnosis or after initiation of remission induction.210,211
The pathogenesis of hemostatic disturbance in APL is related to properties of the malignant cells and their interaction with the host’s endothelial cells.192,208 APL cells express TF and the cancer procoagulant that can initiate coagulation, and they release IL-1β and TNF-α, which downregulate endothelial thrombomodulin, thereby compromising the protein C anticoagulant pathway. APL cells also express increased amounts of annexin II, which mediates augmented conversion of plasminogen to plasmin (Chap. 135). The overall results of these processes are DIC and hyperfibrinolysis, followed by major bleeding that can lead to death.212 All-trans-retinoic acid, used for induction and maintenance therapy of APL, inhibits in vitro and in vivo the deleterious effect of APL cells and has led to a reduced frequency of early hemorrhagic death; however, all-trans-retinoic acid may induce thrombotic complications.192,213
When DIC complicates trauma, it usually occurs in severely injured patients. Extensive exposure of TF to the blood circulation and hemorrhagic shock probably are the most immediate triggers of DIC in such instances, although direct proof of this mechanism is lacking. An alternative hypothesis is that cytokines play a pivotal role in the occurrence of DIC in trauma patients. In fact, the changes in cytokine levels are virtually identical in trauma patients and septic patients.214 The levels of TNF-α, IL-1β, PAI-1, circulating TF, plasma elastase derived from neutrophils, and soluble thrombomodulin all can be elevated in patients with signs of DIC, predicting multiorgan dysfunction (ARDS included) and death.215,216 Careful monitoring of laboratory signs of DIC, reduced fibrinolytic activity, and perhaps low AT levels also are useful for predicting the outcome of such patients.217
DIC can be aggravated in patients with severe trauma who require massive blood replacement because stored blood components are diluted and do not contain sufficient amounts of viable platelets and factors V and VIII. Moreover, in such patients, there is an activation of fibrinolysis that further aggravate bleeding in combination with acidosis, and hypotension.218,219,220,221 Infection commonly occurs in such patients and may contribute to the DIC.
The time interval between trauma and medical intervention correlates with the development and magnitude of DIC. Experience during wars proved that fast evacuation and prompt medical care reduce the risk of DIC.222,223,224
Brain injury can be associated with DIC, most likely because the injury exposes the abundant TF of brain to blood. Specimens of contused brain, obtained during surgery in patients with head injury and of liver, lungs, kidneys, and pancreas obtained during autopsy, revealed microthrombi in arterioles and venules.225,226 In adults and children with head injuries, a high rate of mortality occurred when DIC was present.227 A laboratory DIC score has predictive value for prognosis in patients with head injuries, thereby supplementing the Glasgow coma score.228 Bleeding in patients with DIC that is related to brain injury can be managed by replacement therapy.
TF exposed to blood at sites of burned tissue, the systemic inflammatory response syndrome induced by the burn, and the common presence of superimposed infections, all can trigger DIC.229 Bleeding, laboratory tests indicative of DIC, and vascular microthrombi in biopsies of undamaged skin have been described in patients with extensive burns.230 Kinetic studies with labeled fibrinogen and labeled platelets disclosed that, in addition to systemic consumption of hemostatic factors, significant local consumption occurs in burned areas.231 Laboratory signs of DIC are associated with organ failure; the extent of protein C and AT deficiencies correlates with a poor outcome.230 A clinicopathologic study of 139 patients who died during treatment for a severe burn disclosed that 18 percent had cerebral infarctions caused by septic arterial occlusions or DIC and approximately 4 percent had intracranial hemorrhage.232
Very complicated derangements of hemostasis occur in patients with severe liver disease and during liver transplantation (Chap. 129). Synthesis of most coagulation factors and natural anticoagulants (protein C, protein S, and AT) and of the main components of the fibrinolytic system (plasminogen, TAFI, and α2-antiplasmin) is reduced. The capacity of the liver to clear the circulation of activated factors IX, X, and XI, and of t-PA is decreased. Moreover, thrombocytopenia is common as a result of hypersplenism and decreased production of thrombopoietin by the liver. The similarities between the hemostatic defects observed in patients with liver disease and in patients with DIC are striking and have evoked an ongoing controversy as to whether or not DIC contributes to hemostatic derangements associated with liver disease.233
Several laboratory and clinical observations support the hypothesis that DIC accompanies hepatic disorders. They include a shortened half-life of radiolabeled fibrinogen and prolongation of fibrinogen half-life by administration of heparin234,235; failure of replacement therapy to significantly increase the levels of hemostatic factors (suggesting continuous consumption); and increased blood levels of D-dimer, thrombin–AT (TAT) complexes, and fibrinopeptide A, all consistent with ongoing thrombin generation.236,237,238
Other observations and considerations argue against the hypothesis that DIC accompanies liver diseases. They include (1) a very low incidence (2.2 percent) of microthrombosis in the tissues of patients who die of liver disease and (2) causes other than, or inconsistent with, DIC for the deranged findings in liver disease.237 Examples of alternative explanations include the following: (1) a prolonged thrombin time may result from acquired dysfibrinogenemia239; (2) low levels of coagulation factors and inhibitors may result from reduced synthesis240; (3) increased FDP levels may be a consequence of primary fibrinogenolysis induced by reduced synthesis of α2-antiplasmin and PAI-1 and by decreased clearance of t-PA; (4) factor VIII levels are commonly increased rather than decreased241; (5) the kinetic data show that the apparently excessive consumption of fibrinogen can be explained by loss of fibrinogen into extravascular spaces242; and (6) fibrinogen and plasminogen do not appear to be removed rapidly when labeled endogenously by 75Se-selenomethionine.243
A third hypothesis maintains that patients with liver disease usually do not present with DIC but are extremely sensitive to the various triggers of DIC because of their impeded capacity to clear procoagulants and to synthesize essential components of the coagulation, inhibitory, and fibrinolytic systems. Patients with primary or metastatic liver disease who undergo a peritoneovenous shunt operation for severe ascites are more likely to develop DIC than are patients with ascites who undergo the same procedure because of other causes.244
What, then, should be the approach to patients with liver disease and bleeding without an apparent local cause? First, possible underlying causes of DIC should be considered and identified, and then a hemostatic profile should be examined at frequent intervals so as to detect any dynamic changes that may be helpful in recognizing DIC. The sensitive assays that reflect thrombin generation (TAT complex and prothrombin fragments 1.2) or concomitant thrombin and plasmin generation (D-dimer), as well as finding a normal or decreased level of factor VIII may help establish the diagnosis of DIC in a patient with liver disease.245
In 1841, James Wellstead published his book Travels to the City of the Caliphs (currently known as Baghdad) and vividly described that on an extremely hot day in the Persian Gulf the decks of the ship Liverpool resembled a slaughterhouse, so numerous were the bleeding patients.246 This is probably one of the first written reports on the occurrence of DIC in humans who suffer from heatstroke.229 Heat stroke is a syndrome characterized by a rise in body temperature to higher than 42°C, which follows collapse of the thermoregulatory mechanism. The following predisposing factors have been identified: high environmental temperature, strenuous physical activity, infection, dehydration, and lack of acclimatization.247,248 Extensive hemorrhage, unclottable blood, and venous engorgement were found as early as 1838 in postmortem examinations of patients who died of heat stroke.246 Investigations confirm that a severe hemorrhagic diathesis and multiple organ failure often accompany heat stroke.229,249,250,251 Diffuse fibrin deposition and hemorrhagic infarctions are found in fatal human cases. DIC associated with profound fibrin(ogen)olysis is evident in patients with heat stroke. The possible triggers of DIC in patients with heat stroke include endothelial cell damage and TF released from heat-damaged tissues.249
In a series of 18 critically ill patients from Paris with heat stroke during the 2003 heat wave in Western Europe that caused numerous deaths in France alone,251 patients had very high levels of IL-6 and IL-8. In addition, there was a striking activation of white blood cells, as demonstrated by β2-integrin upregulation and increased production of reactive oxygen species. All patients also had evidence of a significant systemic activation of coagulation and DIC was present in approximately 35 percent of patients. There was a marked correlation between the extent of inflammation and coagulation activation and the clinical severity of the heat stroke.
The severity of the syndrome and the stage of its development affect the type and magnitude of hemostatic alterations. Thus, in a study of 56 patients, three groups were discernible: nonbleeders, bleeders without DIC but with slight consumption of hemostatic factors, and bleeders with typical signs of DIC.252 Prompt cooling and support of vital functions have substantially reduced the high mortality that was commonly observed in early studies.
Several species of snakes belonging to the Viperidae family produce venoms that have a wide range of activities affecting hemostasis. Prominent among these species are the Vipera, Echis (E. carinatus or E. coloratus), Aspis, Crotalus, Bothrops, and Agkistrodon. Venoms of these snakes contain enzymes or peptides that exert the following activities253,254,255: (1) thrombin-like activity, cleaving fibrinopeptide A from the Aα chain of fibrinogen (Agkistrodon rhodostoma); (2) activation of prothrombin even in the absence of calcium ions (E. carinatus); (3) activation of factors X and V (Russell viper venom); (4) fibrinogenolytic activity (Agkistrodon acutus); (5) induction of thrombocytopenia by platelet aggregation; (6) inhibition of platelet aggregation by the low-molecular-weight arginine-glycine-aspartic acid–containing peptides from a variety of snake species; (7) activation of protein C; and (8) activities causing damage to endothelial cells, leading to bleeding, tissue ischemia, and edema. Interestingly, victims of snake bites rarely experience excessive bleeding or thromboembolism, in spite of the serious derangements in hemostatic tests and findings that are sometimes consistent with DIC.256,257,258
The major symptoms and signs related to envenomation are vomiting, diarrhea, apprehension, hypotension, local swelling, ischemia, and necrosis. Consequently, treatment for victims of snake bites consists of immediate immobilization, administration of antivenom and fluids, and other general measures to preserve vital functions. Local incisions, cooling, and application of tourniquet should be avoided.253
In 1940, Kasabach and Merritt described the association between giant hemangioma and a bleeding tendency occurring mainly in infants. The pathogenesis and management of this syndrome have been reviewed.259 Studies using radiolabeled fibrinogen and platelets provided evidence that within the hemangioma, consumption of platelets and fibrinogen occurs because of localized intravascular clotting and excessive fibrinogenolysis.260,261 Conceivably, concomitant local activation of the coagulation pathway and release of large amounts of t-PA by the abnormal endothelium lining the tumor vessels occur. Microangiopathic hemolytic anemia and laboratory signs of DIC and fibrinolysis have been demonstrated in patients with giant hemangiomas.262 Accelerated growth of these hemangiomas in infants is associated with augmented consumption of hemostatic factors, and can be effectively treated with glucocorticoids. Radiotherapy and interferon-α are also effective, but should only be used in life-threatening circumstances after failure of glucocorticoid therapy because of severe adverse events.263 Spontaneous mild to moderate bleeding manifestations have been observed, but severe bleeding generally occurs only after surgery or trauma.
Extensive vascular malformation may persist and cause pain, probably resulting from thrombosis, and bleeding following trauma, which is related to the localized or generalized consumption of clotting factors and platelets and hyperfibrinolysis.264 Graded permanent elastic compression, when possible, and low-molecular-weight heparin constitute the only effective treatment in such cases.
An association between aortic aneurysm and DIC is well documented.265,266 In a series of patients with aortic aneurysm, 40 percent had elevated levels of FDPs, but only 4 percent had significant bleeding and laboratory evidence of DIC.265 Several factors predispose patients with aortic aneurysms to the development of DIC: a large surface area, dissection, and expansion of the aneurysm.267 Clinical and laboratory signs of DIC should be carefully sought in patients with an aortic aneurysm because bleeding may seriously complicate surgical repair of the aneurysm.267,268 The initiation of localized and generalized intravascular coagulation can be ascribed to activation of the TF pathway by the abundant amounts of TF present in atherosclerotic plaques.269 When patients present with significant bleeding or when surgery is planned, hemostatic defects should be sought and ongoing coagulation activation may be corrected by (low-molecular-weight) heparin.270 Stent-grafting, which is a common procedure for repair of aortic aneurysms, was complicated by DIC and death in two patients, of whom one had cirrhosis and the other underwent a lengthy procedure.271 However, a study of 31 such patients failed to detect DIC following stent-grafting of thoracic aneurysms.272
DIC accompanies incompatible blood transfusion, in which massive hemolysis is commonly associated with excessive bleeding with widespread thrombosis in fatal cases (Chap. 138). The trigger of DIC in these cases cannot be simply ascribed to the release of red cell stroma, as patients with massive oxidative hemolysis because of glucose-6-phosphate dehydrogenase deficiency do not develop DIC.273 Rather, extensive antigen–antibody reaction appears to cause DIC as a result of release of elastase and TNF-α from neutrophils, and activation of monocytes that release TNF-α express TF and complement, with assembly of the membrane attack complex inflicting damage to endothelial cells.274,275
DISSEMINATED INTRAVASCULAR COAGULATION DURING PREGNANCY
Pregnancy predisposes patients to DIC for at least four reasons: (1) pregnancy itself produces a hypercoagulable state, manifested by evidence of low-grade thrombin generation, with elevated levels of fibrin monomer complexes and fibrinopeptide A; (2) during labor, leakage of TF from placental tissue into the maternal circulation causes a hypercoagulable state; (3) pregnancy is associated with reduced fibrinolytic activity because of increased plasma levels of PAI-1; and (4) pregnancy is associated with a decline in the plasma level of protein S. DIC may be difficult to diagnose during pregnancy because of the high initial levels of coagulation factors such as fibrinogen, factor VIII, and factor VII.276,277 Progressive reductions in these factors, however, can confirm or exclude the diagnosis of DIC in suspected cases. Thrombocytopenia may be particularly helpful in determining whether DIC is present, provided other causes of thrombocytopenia are excluded.278
The dramatic clinical presentation of abruptio placentae was first reported by DeLee in 1901,279 but the immediate cause of sudden rupture of uterine spiral arteries and detachment of the placenta is still unknown. Placental abruption is a leading cause of perinatal death.280 Older multiparous women or patients with one of the hypertensive disorders of pregnancy are thought to be at highest risk. The severe hemostatic failure accompanying abruptio placentae is the result of acute DIC emanating from the introduction of large amounts of TF into the blood circulation from the damaged placenta and uterus.281 Amniotic fluid is able to activate coagulation in vitro, and the degree of placental separation correlates with the extent of DIC, suggesting that leakage of thromboplastin-like material from the placental system is responsible for the occurrence of DIC. Abruptio placentae occurs in 0.2 to 0.4 percent of pregnancies,282 but only 10 percent of these cases are associated with DIC.278 Different grades of severity are found among those who develop DIC, with only the more severe forms resulting in shock and fetal death. Rapid volume replenishment and evacuation of the uterus is the treatment of choice.280 Transfusion of cryoprecipitate, fresh-frozen plasma, and platelets should be given when profuse bleeding occurs. However, in the absence of severe bleeding, administration of blood components may not be necessary because depleted coagulation factors increase rapidly following delivery. Heparin or antifibrinolytic agents are not indicated.
This rare catastrophic disorder, described by Steiner and Lushbaugh in 1941, occurs only in one in 8000 to one in 80,000 deliveries.283 A maternal mortality rate of 86 percent was reported in a 1979 review of 272 cases, but in a later population-based study, the maternal mortality (26.4 percent) was significantly lower.284,285 Patients predisposed to amniotic fluid embolism are multiparous women whose pregnancies are postmature with large fetuses and women undergoing a tumultuous labor after pharmacologic or surgical induction. Apparently, amniotic fluid is introduced into the maternal circulation through tears in the chorioamniotic membranes, rupture of the uterus, and injury of uterine veins.284 The trigger of DIC probably is TF present in amniotic fluid.286,287 The mechanical obstruction of pulmonary blood vessels by fetal debris, meconium, and other particulate matter in the amniotic fluid enhances local fibrin–platelet thrombus formation and fibrinolysis. The extensive occlusion of the pulmonary arteries and an acute anaphylactoid response reminiscent of severe systemic inflammatory response syndrome provoke sudden dyspnea, cyanosis, acute cor pulmonale, left ventricular dysfunction, shock, and convulsions. These symptoms are followed within minutes to several hours by severe bleeding in 37 percent of patients.284 Hemorrhage is particularly severe from the atonic uterus, puncture sites, gastrointestinal tract, and other organs. The best prospect for decreasing mortality lies in early termination of parturition in patients at high risk and prevention of hypertonic and tetanic uterine contractions during labor. When the syndrome is recognized, immediate termination of pregnancy under pulmonary and cardiovascular support is essential.
Preeclampsia and Eclampsia
Thrombocytopenia described in early reports of eclampsia and widespread deposition of fibrin in blood vessels observed in fatal cases were interpreted as evidence of DIC triggered by placental TF exposure to the circulation.1 A critical analysis of the literature concluded that the thrombocytopenia in these patients stems from endothelial injury rather than DIC.288 However, other investigators provided evidence for significant DIC in preeclampsia and eclampsia.289,290 Moreover, in a large series of patients, a good correlation was noted between the clinical severity and abnormalities in platelet counts and FDPs.291 Also consistent with DIC were results of assays of sensitive parameters of thrombin generation and activation of fibrinolysis, such as TAT complexes, D-dimer, and fibrinopeptide Bβ1–42. Despite these observations, administration of heparin to patients with preeclampsia and eclampsia has not resulted in convincing benefits.292
The syndrome of hemolysis (H), elevated liver enzymes (EL), low platelet count (LP), and severe epigastric pain is a complication of pregnancy-induced hypertension.293 Seventy percent of the cases occur during the third trimester of pregnancy and 30 percent occur during the postpartum period.294 HELLP syndrome occurs more often in whites, multipara, and women older than 35 years.292 Liver biopsy findings of fibrin deposition in hepatic blood vessels and laboratory tests consistent with DIC in a significant proportion of patients imply that DIC plays a role in the pathogenesis of the syndrome.294,295,296 Hepatic imaging in 33 patients revealed subcapsular hematomas in 13 and intraparenchymal hemorrhage in 6.297 What actually triggers DIC in these cases is not known but has been related to endothelial dysfunction.292 Multiple organ dysfunctions manifested by acute renal failure, ascites, pulmonary edema, and severe hemorrhage resulting from DIC may develop, leading to significant maternal and perinatal mortality rates. Management of patients with HELLP syndrome consists of supportive care, careful monitoring, and blood component replacement therapy. With few exceptions, immediate delivery, not necessarily by cesarian section, is indicated. HELLP syndrome tends to recur in subsequent gestations.298
Gram-negative bacteria, group A streptococci, and Clostridium perfringens are among the more common causes of sepsis during pregnancy. These infections are frequently associated with fulminant DIC. The pathogens gain entry into the circulation during abortion, via amnionitis that may follow invasive procedures or rupture of membranes, by endometritis developing during labor, and by way of the urinary tract. Approximately 40 percent of bacteremic patients experience shock, which is associated with significant mortality.299 In addition, a high rate of bleeding and organ dysfunction affects the kidneys, lungs, and central nervous system.
Treatment of all cases of sepsis-related DIC should include antibiotics, support of vital functions, and surgical intervention to remove any local nidus of infection. Abortion or hysterectomy may be considered.
Several weeks after intrauterine fetal death, approximately one-third of patients may exhibit laboratory signs of DIC, occasionally accompanied by bleeding.278,300 Apparently, TF from the retained dead fetus or placenta slowly enters the maternal circulation and initiates DIC, which sometimes is accompanied by significant fibrinolysis.13 This complication currently is rarely observed because labor is induced promptly after the diagnosis of fetal death is made. However, if labor induction is unavoidably delayed, serial blood coagulation tests should be performed.
The entity of fetal death and DIC can occur following the demise of one of multiple gestations. If it occurs at term, therapy is started as discussed. If it occurs prior to fetal maturity, prolonged administration of heparin can be useful. Interestingly, when selective termination of the life of an anomalous fetus is performed in women with multiple pregnancies, hemostatic abnormalities develop in only approximately 3 percent of cases.301
Acute fatty liver of pregnancy is a rare disorder that occurs during the third trimester of pregnancy.302 It can lead to hepatic failure, encephalopathy, and death of the mother and fetus.303,304,305,306 In 15 to 20 percent of cases, acute fatty liver of pregnancy is associated with fetal homozygosity or compound heterozygosity for long-chain acyl-coenzyme A dehydrogenase (LCAD) deficiency.307 Infants born with LCAD deficiency fail to thrive and are prone to liver failure and death. LCAD is one of four enzymes taking part in β-oxidation of fatty acids in mitochondria. When it is deficient, accumulation of medium- and long-chain fatty acid occurs. One predominant mutation (G1528C) accounts for 65 to 90 percent of cases with the deficiency. The precise mechanism by which LCAD deficiency in the fetus causes the severe liver disease in the heterozygous mother is unclear. The acute fatty liver disease of pregnancy is characterized by severe liver dysfunction, renal failure, hypertension, and signs of DIC.304,308 The typical histologic feature is microvesicular fatty infiltration of the liver. Exceedingly low levels of AT and other laboratory signs of DIC were observed in a series of 28 patients, but no definite clinical benefit from AT concentrate infusion was achieved.308 The primary therapy for these patients is early delivery and supportive care, which yield a maternal survival of 90 percent and perinatal survival of more than 85 percent.304,309 Pancreatitis is a potentially lethal complication of acute fatty liver of pregnancy.310
Newborns have a limited capacity to cope with triggers of DIC for several reasons: (1) their ability to clear soluble fibrin and activated factors is reduced; (2) their fibrinolytic potential is decreased because of a low plasminogen level; and (3) their capacity to synthesize coagulation factors and inhibitors is limited.311,312 Criteria for diagnosis of DIC in newborns are different from those for diagnosis in adults.313 Important to consider are the physiologic hemostatic findings common at this age, which include low levels of the vitamin K–dependent factors, reduced AT and protein C levels, and prolonged thrombin time. The laboratory evidence of DIC in the newborn is based on the progressive decline of hemostatic parameters, thrombocytopenia, and reduced levels of fibrinogen, factor V, and factor VIII.311,314,315
DIC occurs in sick neonates and particularly in those who are premature. More than one underlying cause usually can be identified in newborns with DIC. The most frequent underlying conditions are sepsis, hyaline membrane disease (respiratory distress syndrome), asphyxia, necrotizing enterocolitis, intravascular hemolysis, abruptio placentae, and eclampsia.312,316
Bleeding from multiple sites is the most common manifestation of DIC in newborns, with intracranial hemorrhage being the most life-threatening condition. No clinical manifestations of DIC are apparent in approximately 20 percent of neonates,314 so a high index of suspicion in patients at risk is essential.