1 Comment


Williams Hematology



Definition and History
Etiology and Pathogenesis


Clinical Features


Thrombosis and Thromboembolism


Renal Dysfunction

Liver Dysfunction

Central Nervous System Dysfunction

Pulmonary Dysfunction

Laboratory Features

Acute DIC

Chronic DIC

DIC Accompanied by Primary Fibrino(geno)lysis

Primary Fibrinogenolysis

Management of Underlying Disorders

Blood Component Therapy

Heparin Administration

Antithrombin-III Concentrate

Inhibitors of Fibrinolysis

Other Treatment Modalities
Specific Underlying Disorders

Infectious Diseases

Purpura Fulminans

Solid Tumors



Brain Injury


Liver Diseases

Heat Stroke

Snake Bites

Infusion of Factor IX and Factor XI Concentrates


Aortic Aneurysm

Hemolytic Anemias

DIC During Pregnancy

Chapter References

When procoagulants are introduced or produced in the blood circulation and manage to overcome the control mechanisms of blood coagulation, widespread thrombin is generated which can lead to disseminated intravascular coagulation (DIC). The clinical manifestations of DIC include multiorgan dysfunction caused by microthrombi and bleeding caused by consumption of platelets, fibrinogen, factor V, and factor VIII, as well as secondary fibrinolysis. Tissue factor exposure to blood is the most common trigger of DIC. This can occur when monocytes and endothelial cells are induced to generate and express tissue factor during the systemic inflammatory response syndrome (e.g., gram-negative and gram-positive infections, fungemia, burns, severe trauma) or when contact is established between blood and tissue factor constitutively present on membranes of cells foreign to blood (e.g., malignant cells, placenta, brain cells, adventitia, traumatized tissues). Both DIC and the underlying disorders causing DIC contribute to a high rate of mortality. The severity of the organ dysfunction and extent of hemostatic failure, as well as increasing age, have been associated with a grave prognosis. Laboratory features include thrombocytopenia, reduced fibrinogen level, elevated levels of D-dimer and fibrin(ogen) degradation products, and prolonged partial thromboplastin, prothrombin, and thrombin times. Several underlying disorders affect these hemostatic parameters and can lead to a false positive diagnosis of DIC (e.g., liver-disease–related coagulation abnormalities and thrombocytopenia) or to a false negative diagnosis (e.g., pregnancy-related high fibrinogen levels). Repeating the tests every 6 to 8 h can overcome these limitations. Early detection of DIC, vigorous treatment of the underlying disorder, and support of vital functions are essential for survival of affected patients. Blood component therapy is pertinent in patients who bleed excessively, whereas heparin administration is indicated in a limited number of circumstances.

Acronyms and abbreviations that appear in this chapter include: APL, acute promyelocytic leukemia; aPTT, activated partial thromboplastin time; ARDS, adult respiratory distress syndrome; AT, antithrombin; ATRA, all-trans-retinoic acid; DIC, disseminated intravascular coagulation; FDP, fibrinogen degradation products; HELLP, hemolysis, elevated liver enzymes, low platelet count; IL, interleukin; PAI, plasminogen activator inhibitor; PAP, plasmin-antiplasmin; PS, protein S; SIRS, systemic inflammatory response syndrome; TAFI, thrombin activatable fibrinolysis inhibitor; TAT, thrombin-AT; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TNF, tissue necrosis factor; t-PA, tissue plasminogen activator; TT, thrombin time.

Disseminated intravascular coagulation (DIC) is a clinicopathologic syndrome in which widespread intravascular coagulation is induced by procoagulants that are introduced or produced in the blood circulation and overcome the natural anticoagulant mechanisms. DIC may cause tissue ischemia from occlusive microthrombi as well as bleeding from both the consumption of platelets and coagulation factors and the anticoagulant effect of products of secondary fibrinolysis. DIC complicates a variety of disorders, and the complexity of its pathophysiology has made it the subject of a voluminous literature, including books,1,2,3,4,5,6 and 7 book chapters, review articles, and case studies.4,7,8,9,10,11,12,13,14,15,16,17 and 18
In 1834, Dupuy reported that injection of brain material into animals caused widespread clots in blood vessels, thus providing the first description of DIC.19 Trousseau, in 1865,20 described the tendency to thrombosis, sometimes disseminated, in cachectic patients with malignancies. Naunyn, in 1873,21 showed that disseminated thrombosis could be evoked by intravenous injection of dissolved red cells, and Wooldridge22,23 then demonstrated that the procoagulant involved was a substance contained in the stroma of the red cells.
The mechanism by which DIC can lead to bleeding was clarified only in 1961, when Lasch and coworkers introduced the concept of consumption coagulopathy,24 and McKay established that DIC is a pathogenetic feature of a variety of diseases.1 Sizable series of cases were first described in 1967, following the introduction of defined laboratory criteria for DIC.8 Yet in spite of the vast experience that has been accumulated, DIC still constitutes a major clinicopathologic and therapeutic challenge.
Extensive data on autopsy findings in cases with DIC are available.1,7,9,15,25,26,27,28,29,30,31,32,33,34 and 35 Common findings include diffuse multiorgan bleeding, hemorrhagic necrosis, microthrombi in small blood vessels, and thrombi in medium and large blood vessels. Not all patients who had unequivocal clinical and laboratory signs of DIC had all these postmortem findings,15,25,27,30 and conversely, some patients in whom clinical and laboratory signs were not consistent with DIC did have the typical autopsy findings.15,26,27 and 28 This occasional lack of correlation between the clinical, laboratory, and pathologic findings still remains unexplained.
Organs most frequently involved by diffuse microthrombi are the lungs and kidneys, followed by the brain, heart, liver, spleen, adrenals, pancreas, and gut. Acute tubular necrosis is more frequent than renal cortical necrosis in patients with DIC.25,27,31 A significant proportion of cases with chronic DIC have nonbacterial thrombotic endocarditis involving mainly the mitral and aortic valves.15,27,28,33,34 Moreover, in a retrospective pathologic study, about 50 percent of patients with nonbacterial thrombotic endocarditis had DIC.32 These heart lesions can be a source of arterial embolization, leading to infarction of the brain, kidneys, and myocardium.32,34
The intravascular generation of substantial amounts of thrombin via the tissue factor pathway, combined with the failure of the natural blood coagulation inhibitory mechanisms, initiates DIC in most instances. The major clinical conditions causing DIC and the presumptive initiating pathways are shown in Fig. 126-1. Tissue factor is constitutively present in cell membranes of most tissues, including the media and adventitia of blood vessels. Under normal circumstances blood is not exposed to tissue factor. When, however, blood becomes exposed to tissues (e.g., with trauma, burns, or abruptio placentae) or cells foreign to blood enter the circulation (e.g., metastasis, leukemic cells, amniotic fluid embolism), the coagulation system is ignited. Tissue factor can also be generated and expressed on membranes of monocytes and endothelial cells during the systemic inflammatory response syndrome (SIRS). SIRS designates a series of inflammatory events arising from a variety of infections or other insults like burns, trauma, or autoimmune disorders.36,37 When bacteria are the cause of SIRS the severity of the syndrome can be graded as sepsis, severe sepsis, and septic shock,36 with stepwise increases in the rates of DIC, multiorgan dysfunction, and mortality.38,39 and 40

FIGURE 126-1 Initiation and consequences of DIC. TF, tissue factor; FDP, fibrinogen and fibrin degradation products.

The complex events that occur during SIRS involve monocytes, endothelial cells, neutrophils, and platelets; interactions among these cells; cytokines and other mediators; and activation of the complement system.37 During these events, tissue factor can be generated and expressed by monocytes and by endothelial cells throughout the vasculature. In vitro studies and investigations of primates injected with live Escherichia coli and of humans injected with low doses of endotoxin have provided evidence that endotoxin can cause tissue factor exposure to blood by acting directly on monocytes and endothelial cells or by acting indirectly through monocyte secretion of tissue necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6.41,42 Platelets can also be activated by endotoxin,43 and activated platelets exhibiting P-selectin enhance tissue factor generation by monocytes.44 Additional effects of endotoxin and the cytokines released in response to endotoxin include (1) down-regulation of the two major physiological inhibitory mechanisms of coagulation, endothelial cell thrombomodulin,45 and glycosaminoglycans46; (2) brief enhancement of fibrinolysis by tissue plasminogen activator (t-PA) secretion from endothelial cells; and (3) longer-term profound inhibition of fibrinolysis caused by increased plasma concentrations of plasminogen activator inhibitor (PAI)-1.42
Initiation of DIC by activation of the contact system of coagulation during SIRS is probably unimportant. Thus, blockade of the contact system by a monoclonal antibody against factor XII does not prevent endotoxin-induced DIC,47 and only a modest increase in factor XIIaa is observed in patients with septic shock.48 In contrast, neutrophils become activated during SIRS and release elastase, which both injures the vessel wall49 and inactivates antithrombin.50
Less common initiators of DIC are: a cancer procoagulant that activates factor X, snake venoms that activate factor X or factor II, and activated coagulation factors that are variably contained in concentrates of coagulation factor IX and factor XI (see Infusion of Factor IX and Factor XI Concentrates, below).
The widespread generation of thrombin induces deposition of fibrin, which leads to vessel obstruction and consumption of substantial amounts of hemostatic factors, i.e., platelets; fibrinogen; factors V, VIII, and others; protein C (PC); and antithrombin-III (AT-III). These events result in tissue ischemia, mild microangiopathic hemolytic anemia, bleeding, and further impairment of the control mechanism of coagulation.
The intravascular thrombi and thrombin itself51 trigger secretion of t-PA from endothelial cells, which sets off compensatory thrombolysis; this, if successful, leads to reopening of the occluded blood vessels. The by-products of thrombolysis, fibrin/fibrinogen degradation products, may, however, further enhance bleeding by interfering with platelet aggregation, fibrin polymerization, and thrombin activity (see Fig. 126-1).
Several protective mechanisms either neutralize components that initiate DIC or correct its deleterious consequences. Thrombin generated in DIC can be effectively removed by the enormous endothelial cell surface area of the microcirculation by means of forming a complex with AT-III, which is bound to endothelial heparan sulfate,52 and by binding to thrombomodulin on the endothelial surface. The latter interaction abolishes thrombin’s procoagulant effects on fibrinogen, factor XIII, and platelets, while enhancing activation of the anticoagulant protein PC. Activated PC, in turn, inactivates factors Va and VIIIa in the presence of protein S (PS) and exerts a profibrinolytic effect by inhibiting activation of thrombin activatable fibrinolysis inhibitor (TAFI).53 Tissue factor pathway inhibitor (TFPI) is another line of defense at the vessel wall, although its effect is only exerted when relatively small amounts of tissue factor gain access to the circulation.54 Thrombin binding to endothelial cells also stimulates the release of t-PA, thereby enhancing fibrinolysis.51 Thus, as long as blood flow through the microcirculation is maintained, there is effective neutralization of procoagulant material, unless overwhelming amounts have entered the circulation.
The mononuclear phagocyte system also plays a role in protection from DIC. It can remove soluble tissue factor55 and the soluble complexes of fibrin monomers.56 Liver parenchymal cells also take part in the control of DIC by clearing activated factors IX, X, and XI from the circulation57,58 and by replenishing depleted coagulation factors, plasminogen, a2-antiplasmin, AT-III, and PC. The bone marrow is another tissue that plays an important role in the control of DIC by increasing the production of platelets by megakaryocytes.
The control mechanisms may be seriously compromised by the underlying disease that initiated the DIC. For example, leukemias may deplete or suppress the megakaryocyte pool, hepatic disease may impair both the synthetic and clearance functions of the liver, or shock may decrease neutralization of thrombin by decreasing blood flow through the microcirculation.
The manifestations of DIC depend on the magnitude and rate of exposure of blood to the DIC trigger. For example, the dramatic cases of “acute” DIC, characterized by severe bleeding due to excessive consumption of hemostatic components, may develop when blood is exposed to large amounts of tissue factor over a brief period of time. Such a trigger overwhelms the control mechanisms before any compensatory mechanisms have had enough time to respond. Alternatively, “chronic” DIC develops when blood is continuously or intermittently exposed to small amounts of tissue factor. In such instances, the control mechanisms have time to partially contain the DIC trigger and replenish the depleted coagulation, fibrinolytic, and inhibitory proteins by augmented production. Under these circumstances, clinical signs may be minimal or altogether absent, and most coagulation tests will be only slightly impaired. More sensitive assays such as increased turnover of platelets and fibrinogen, increased levels of D-dimer (see Laboratory Features, below), and increased levels of fibrin/fibrinogen degradation products will, however, indicate that compensated chronic DIC is occurring.
Numerous disorders can provoke DIC (see Fig. 126-1), but only a few constitute major causes, as can be inferred from retrospective clinical studies.4,7,10,12,14,15 and 16 Infectious diseases and malignant disorders together account for about two-thirds of the DIC cases in the major series, except for one study7 that included a disproportionately large number of obstetric cases (Table 126-1). Trauma was a major cause of DIC in two series,10,12 probably reflecting the specialized nature of the clinical material in the two centers. Two Japanese series14,15 had a relatively high proportion of cases with malignant diseases and a relatively low number of obstetric cases.


Clinical manifestations are attributable to the disseminated intravascular coagulation, to the underlying disease, or to both. Bleeding manifestations were common in all series of DIC cases, but considerable variation existed in the relative frequency of shock and of dysfunction of the liver, kidney, lungs, and central nervous system (Table 126-2). These variations probably reflect the different nature of the underlying disorders in the respective series.


Acute DIC is frequently heralded by hemorrhage into the skin at multiple sites.4,10 Petechiae, ecchymoses, and oozing from venipunctures, arterial lines, catheters, and injured tissues are common. Bleeding may also occur on mucosal surfaces. Hemorrhage may be life threatening, with massive bleeding into the gastrointestinal tract,10 lungs,4 central nervous system, or orbit.7 Patients with chronic DIC usually exhibit only minor skin and mucosal bleeding.
Extensive organ dysfunction can result from microvascular thrombi or from venous and/or arterial thromboembolism. For example, involvement of the skin can cause hemorrhagic bullae, acral necrosis, and gangrene.4,7 Thrombosis of major veins and arteries and pulmonary embolism occur but are rare4,10; cerebral embolism can complicate nonbacterial thrombotic endocarditis in patients with chronic DIC.32
Both the diseases underlying DIC and DIC itself can cause shock. For example, septicemia or excessive blood loss due to trauma or to obstetric complications can by themselves cause shock. Whatever may be the cause of shock, its advent in cases with DIC is of great concern.
Renal cortical ischemia induced by microthrombosis of afferent glomerular arterioles and acute tubular necrosis related to hypotension are the major causes of renal dysfunction in DIC. Oliguria, anuria, azotemia, and hematuria were observed in 25 to 67 percent of the cases in all series (see Table 126-2).
Hepatocellular dysfunction sufficient to cause jaundice has been reported in 22 percent10 and 57 percent7 of patients with DIC. Infectious diseases and prolonged hypotension contribute to hepatic dysfunction.
Microthrombi, macrothrombi, emboli, and hemorrhage in the cerebral vasculature have all been held responsible for the nonspecific neurologic symptoms and signs displayed by patients with DIC.4,9 These include coma, delirium, transient focal neurologic symptoms, and signs of meningeal irritation. Careful exclusion of causes other than DIC is essential.
Symptoms and signs of respiratory dysfunction in DIC range from transient hypoxemia in mild cases to pulmonary hemorrhage and adult respiratory distress syndrome (ARDS) in severe cases. While pulmonary hemorrhage is specific for DIC,4,35 ARDS is not.59,60 and 61 Pulmonary hemorrhage is heralded by hemoptysis, dyspnea, and chest pain, and physical examination reveals rales, wheezing, and occasionally a pleural friction rub. Chest X-rays show diffuse infiltration due to excessive intra-alveolar hemorrhage. ARDS is characterized by tachypnea, auscultatory silence, hypoxemia, low lung compliance, normal wedge pressure, and “white lungs” on chest X-rays.60 It stems from severe damage to the pulmonary vascular endothelium, which permits egress of blood components into the pulmonary interstitium and alveoli. This leads to intra-alveolar hyaline membrane formation and severe respiratory insufficiency. ARDS can be caused by septic shock, severe trauma, fat embolism, amniotic fluid embolism, and heat stroke—all of which can also incite DIC. Yet, only a fraction of patients with ARDS exhibit signs of DIC.59 When DIC and ARDS are simultaneously triggered, each will aggravate the other. Regardless of the mechanism, ARDS is a serious complication in patients with DIC.
Both DIC and its underlying disorders contribute to the high rate of mortality. Mortality is correlated independently with the extent of organ dysfunction,10 the degree of hemostatic failure,10,17 and increasing age.10 Mortality rates in major series of patients with DIC ranged from 31 to 86 percent,10,11 and 12,18,39,62 whether or not heparin was administrated.
Knowledge of the potential underlying disorders can lead to early detection of acute and chronic DIC. Laboratory tests confirm or exclude a presumptive diagnosis of DIC, discriminate acute from chronic DIC, and distinguish between DIC associated with secondary fibrinolysis and primary fibrinogenolysis. They may also provide guidelines for treatment, help monitor therapy, and provide predictive information with regard to mortality.10,18 The underlying diseases themselves, however, may affect the laboratory findings. For example, impairment of hemostasis, and/or thrombocytopenia unrelated to DIC, can arise from hepatic disease and from marrow involvement by leukemia; impaired hemostasis may also occur normally in the neonatal period. Conversely, the elevated levels of some hemostatic components that are normally observed during pregnancy may obscure the presence of DIC. These limitations in laboratory diagnosis of DIC can be overcome by repeating the tests every 6 to 8 h and observing the dynamics of the process.
Patients with acute DIC are critically ill, and therefore rapid diagnosis is essential. The following tests are adequate: platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, thrombin time (TT), fibrinogen level, fibrinogen degradation products (FDP), and a blood film to check for fragmented red cells. These parameters will reflect the extent of consumption of hemostatic components, the presence of by-products of in vivo thrombin generation, and the extent of secondary fibrinolysis. In most instances, changes in three or more parameters in addition to a decreased platelet count are consistent with DIC, and no further tests are necessary. A normal fibrinogen level may, however, be present relatively early in DIC since many of the underlying disorders are associated with increased fibrinogen levels, and thus the increased fibrinogen consumption may not have had sufficient time to decrease the fibrinogen below normal levels. Since the normal fibrinogen half-life time is approximately 4 days, a 50 percent or greater decrease in fibrinogen level over a 1-day period is compelling evidence supporting DIC or fibrinolysis, regardless of whether the final value is within the normal range.
Several DIC scoring systems based on laboratory data10 or a combination of laboratory data and clinical manifestations16 have been proposed to assess the severity of DIC. These scores have prognostic value, since good correlations have been found between the degree of abnormality of the laboratory results and the extent of organ involvement, as well as between the severity of hemostatic impairment and subsequent mortality.10,18
Assay of plasma D-dimer is very useful for evaluation of patients with acute DIC.63,64 Increased levels indicate that cross-linked fibrin generated by thrombin has been digested by plasmin.
The presence of thrombin-AT-III (TAT) complexes65 and of plasmin-antiplasmin (PAP) complexes66 reflect the extent of activation of the coagulation and fibrinolytic systems, respectively.67 Patients with sepsis-induced DIC usually have high levels of TAT and low levels of PAP, indicating that the balance is tipped to thrombosis rather than fibrinolysis, resulting in multiorgan dysfunction, whereas patients with acute promyelocytic leukemia may have high PAP levels associated with bleeding due to excessive fibrino(geno)lysis67 (see Leukemia, below).
A continuous or intermittent slow rate of initiation of intravascular coagulation occurs in distinct clinical entities including metastatic carcinoma, giant hemangioma, or the dead fetus syndrome. In these conditions the control mechanisms may effectively prevent severe clinical manifestations by neutralizing active enzymes and by augmenting the synthesis of the consumed hemostatic components. Consequently, laboratory tests reveal variable values. For example, the platelet count may be only mildly reduced, fibrinogen levels can be normal or high, and the PT and aPTT may be within normal limits. However, there usually are increases in fibrin(ogen) degradation products and D-dimer levels. Fragmented red cells are commonly, but not universally, found in DIC, but the degree of fragmentation is almost always less than that usually observed in thrombotic thrombocytopenic purpura.
When DIC is accompanied by primary fibrino(geno)lysis, both the coagulation and the fibrinolytic systems are triggered concomitantly, that is, thrombin and plasmin are generated independently. The typical laboratory findings are a decreased platelet count, increased levels of D-dimer, shortened whole blood clot lysis, shortened euglobulin lysis time, and very high levels of fibrin(ogen) degradation products. However, these crude parameters can also be abnormal when there is DIC and secondary fibrinolysis, and therefore the distinction between DIC with secondary fibrinolysis from DIC accompanied by primary fibrino(geno)lysis is not clear. Notwithstanding these difficult ambiguities in pathophysiology, a pattern of DIC associated with primary fibrino(geno)lysis occurs in acute promyelocytic leukemia, heat stroke, metastatic prostatic carcinoma, and amniotic fluid embolism (see the discussions of these conditions under Specific Underlying Disorders, below).
Primary fibrinogenolysis occurs when plasmin is generated in the absence of DIC. This has been described in hepatic disorders, prostatic carcinoma, and cases without an apparent cause. At present, most cases of primary fibrinogenolysis are iatrogenically induced during thrombolytic therapy (see Chap. 134). Primary fibrinogenolysis can be distinguished from DIC by finding a normal platelet count, rapid whole blood clot lysis, shortened euglobulin lysis time, and greatly elevated fibrinogen degradation products. Theoretically, D-dimer levels should be normal, but elevated levels are often found in states of primary fibrino(geno)lysis such as t-PA therapy.
No controlled studies of patients with DIC have been performed. Such studies are difficult to carry out in view of the variabilities in DIC triggers, clinical presentations, and grades of severity. Fig. 126-2 shows general guidelines for management of patients with DIC, but decisions regarding treatment must be individualized after all clinically important aspects have been carefully considered.

FIGURE 126-2 General guidelines for initial treatment and follow-up of patients with DIC. The success of management is related to taking rapid, vigorous measures against the underlying disease; close clinical observation; thoughtful consideration in each individual patient; availability of 24-h coagulation laboratory services; and an adequate supply of platelet concentrates, cryoprecipitate, fresh-frozen plasma, and packed red cells for replacement therapy. Heparin, when indicated, should be administered by continuous infusion. The basis and limitations of each of the outlined recommendations are detailed throughout the text.

The survival of patients with DIC depends on vigorous treatment of the underlying disorders so as to curtail the triggers of blood coagulation. Examples of such treatment are intensive antibiotic treatment in patients with gram-negative bacteremia, hysterectomy in patients with abruptio placentae, resection of an aortic aneurysm, and debridement of crushed tissues.
The underlying disease and DIC itself frequently compromise the patient’s vital functions. This results in further aggravation of DIC, and therefore intensive support of vital functions is required. Volume replacement and correction of hypotension and oxygenation will improve blood flow through the microcirculation, thus restoring the functions of blood coagulation inhibitory systems. Careful monitoring of pulmonary, cardiac, and renal function enables prompt institution of supportive measures, such as use of a respirator for better oxygenation, inotropic drugs for improvement of cardiac output, and maintenance of electrolyte balance.
Although commonly quoted as fact, the hypothesis that hemostatic replacement therapy in DIC “fuels the fire” has never been proved. Platelet concentrates, cryoprecipitate, and fresh-frozen plasma contain the hemostatic factors and inhibitors of blood coagulation commonly depleted in patients with DIC. In general, patients should be transfused with blood components only when they have bleeding and depleted hemostatic factors. Also eligible are patients being prepared for emergency surgery and patients with gunshot-induced brain injury. Replacement therapy for thrombocytopenia should consist of 6 to 10 units of platelet concentrate, ideally attempting to raise the platelet count to more than 50,000 to 100,000/µl; for hypofibrinogenemia (<100 mg/dl), 8 to 10 units of cryoprecipitate; and for depletion of other coagulation factors, 1 to 2 units of fresh-frozen plasma depending on the severity of the depletion and the patient’s body weight. Replacement therapy may need to be repeated every 8 h, with adjustment of doses according to the platelet count, PT, aPTT, fibrinogen level, and volume status. Fibrin(ogen) degradation products and D-dimer are not very useful for monitoring therapy because their clearance can be delayed, especially in cases of renal dysfunction, and because fibrinogen degradation products can be elevated due to earlier transfusion of stored plasma products. Infusions should be stopped as soon as normal or near-normal values of hemostatic factors are attained. Prothrombin complex concentrates are contraindicated in view of their potential prothrombotic effect.
In most clinical circumstances, patients with DIC are seen when the process is already well established. None of the clinical reports has shown a reduction in mortality in patients with DIC treated with heparin; heparin has, at best, improved the levels of hemostatic factors in the treated patients.68 In contrast, heparin administration can seriously aggravate bleeding in such patients,9,11 especially when the patients have severe hemostatic failure due to consumption and when there is hepatic or renal dysfunction. Moreover, heparin can exacerbate bleeding from sites of traumatic injury. Heparin may, in fact, have reduced anticoagulant effect in DIC, since AT-III is commonly depleted and fibrin monomers, which are produced during DIC, protect thrombin from inactivation by heparin-AT-III complex.69
Notwithstanding these considerations, administration of heparin is beneficial in some categories of chronic DIC, e.g., metastatic carcinomas, purpura fulminans, dead fetus syndrome (at time of removal), and aortic aneurysm (prior to resection). Heparin is also indicated for treating thromboembolic complications in large vessels and before surgery in patients with chronic DIC (see Fig. 126-2). Heparin administration may also be helpful in patients with acute DIC when intensive blood component replacement fails to improve excessive bleeding, or when thrombosis threatens to cause irreversible tissue injury (e.g., acute cortical necrosis of the kidney or digital gangrene).
Heparin should be used cautiously in all the above conditions. In chronic DIC a continuous infusion of heparin, 500 to 750 U/h without a bolus injection, may be sufficient. If no response is obtained within 24 h, escalating dosages can be used. In hyperacute DIC cases, such as mismatched transfusion, amniotic fluid embolism, septic abortion, and purpura fulminans, an intravenous bolus injection of 5000 to 10,000 units of heparin may be given simultaneously with replacement therapy with blood products; some experts would not give a bolus dose of heparin even under these circumstances. A continuous infusion of 500 to 1000 U/h of heparin may be necessary to maintain the benefit until the underlying disease responds to treatment.
AT-III concentrate infusion has been used in the treatment of patients with DIC, either alone or in combination with heparin,70,71 but only small numbers of patients have been studied. In one double-blind controlled study of patients with DIC and septic shock, large doses of AT-III concentrate caused a shortening of the duration of DIC and lowered the mortality by 44 percent, but this decline did not reach statistical significance.72 Two additional trials that await completion show similar trends.73 Thus, no definitive recommendations regarding the clinical use of AT-III concentrate can be made at present.
Patients with DIC should not be treated with antifibrinolytic agents like e-aminocaproic acid or tranexamic acid since these drugs block the secondary fibrinolysis that accompanies DIC and presumably helps to preserve tissue perfusion. Indeed, the use of these agents in patients with DIC has been complicated by severe thrombosis.74,75
A different situation prevails in patients with DIC accompanied by primary fibrino(geno)lysis, as in some cases of acute promyelocytic leukemia, giant hemangioma, heat stroke, amniotic fluid embolism, some forms of liver disease, and metastatic carcinoma of the prostate. In these conditions the use of fibrinolytic inhibitors can be considered, provided that (1) the patient is bleeding profusely and has not responded to replacement therapy; and (2) excessive fibrino(geno)lysis is observed, i.e., rapid whole blood clot lysis or a very short euglobulin lysis time. In such circumstances the use of antifibrinolytic agents should be preceded by replacement of depleted blood components and continuous heparin infusion.
Gabexate mesilate and nafamostat mesilate76,77 are synthetic serine protease inhibitors that have been used in Japan for the treatment of patients with DIC. A study of 395 DIC patients given gabexate mesilate for 1 week demonstrated improvement in 58 percent of the cases, mainly in their hemostatic factors.18 Other preparations have been successfully tested in animals and in a few patients. For example, a protein C concentrate appeared to be helpful in four children with DIC induced by meningococcemia.78 Other agents, such as anti-tissue-factor antibodies79,80 or active-site-inhibited factor VIIa,81 have been shown in experimental animals not only to prevent endotoxin-induced DIC but also to attenuate the lethal inflammatory effects of E. coli. Similarly, recombinant tissue factor pathway inhibitor (TFPI) produced good results in animals, and clinical trials are in progress.82 Clinical trials employing antiendotoxin monoclonal antibodies in patients with gram-negative septicemia have been described, but the efficacy of this treatment modality is inconclusive.83,84 and 85 More promising results have been obtained with recombinant IL-10 in human subjects injected with small doses of endotoxin.86 IL-10 not only inhibited the release of TNF-a and IL-1b, but was found to inhibit the coagulant and fibrinolytic responses.86
Bacterial infections are among the most common causes of DIC. Certain clinical conditions make patients particularly vulnerable to infection-induced DIC. For instance, pregnant women, who have reduced plasma PS levels and diminished fibrinolytic activity, are predisposed to severe infection-induced DIC; asplenic patients have a tendency to develop fulminant DIC, which is related to their inability to clear bacteria, particularly pneumococci87; and newborns have a similar vulnerability, which is probably related to immaturity of their coagulation inhibitory systems. Infections are also frequently superimposed on trauma and malignancies, which are themselves potential triggers of DIC. In addition, infections can aggravate bleeding and thrombosis by directly inducing thrombocytopenia, hepatic dysfunction, and shock, with diminished blood flow in the microcirculation.
Meningococcemia is a fulminant gram-negative infection characterized by extensive hemorrhagic necrosis, DIC, and shock. The extent of the hemostatic derangement in patients with meningococcemia correlates with prognosis.88,89 Heparin treatment is of questionable benefit in meningococcemia.
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 DIC10 or may have severe DIC, especially when shock develops.90 Under the latter conditions, persistently low levels of AT-III and PC predict a fatal outcome.72 The presentation in extreme cases may be reminiscent of the generalized Shwartzman reaction.91 Mortality is very high, even if vigorous antibiotic therapy and supportive measures are promptly instituted. Heparin administration has, so far, not been shown to have a clear benefit. Some investigators failed to demonstrate any effect of heparin on mortality, though they did show a slight improvement in laboratory findings,18,68 while others62 found an increased rate of survival in patients who had received heparin. In view of these conflicting reports, heparin therapy should only be considered in special cases such as pregnant women with gram-negative septicemia92 and patients who present with skin necrosis.
Staphylococcus aureus bacteremia can cause DIC48 accompanied by renal cortical and dermal necrosis.93 The mechanism by which DIC is produced may be related to an a toxin that activates platelets and induces IL-1 secretion by macrophages.94 Streptococcus pneumoniae infection has been associated with the Waterhouse-Friderichsen syndrome95 and with acral gangrene,96 particularly in asplenic patients.87 Initiation of DIC in these conditions is ascribed to the capsular antigen of the bacterium and to antigen-antibody complex formation.97
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.98,99
Common viral infections such as influenza, varicella, rubella, and rubeola have rarely been associated with DIC.100 However, purpura fulminans associated with DIC has been reported in patients with infections and either hereditary thrombophilias101 or acquired antibodies to PS.102 Other viral infections can cause “hemorrhagic fevers” characterized by fever, hypotension, bleeding, and renal failure. Laboratory evidence of DIC can accompany Korean and dengue-related hemorrhagic fevers103,104 but apparently not the Argentine hemorrhagic fever.105 Release of tissue factor from cells in which viruses replicate106 and increased levels of TNF-a have been suggested as mechanisms for initiation of the tissue factor pathway in these conditions.107
Fungal infections108,109 and miliary tuberculosis110 have also at times been associated with DIC. In falciparum malaria, thrombocytopenia is common but overt DIC is very rare.111 However, activation of the coagulation system with elevated levels of TAT complexes has been reported.112
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. The disease affects infants and children predominantly113,114 but occasionally also adults.115 Biopsy of the skin lesions reveals diffuse microthrombi in small blood vessels and vasculitis. Its 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 acquired114 or hereditary thrombophilias101 affecting the PC inhibitory pathway. Homozygous PC deficiency presents in neonates soon after birth as purpura fulminans,116 with or without thrombosis.117
Patients affected by purpura fulminans are acutely ill with fever, hypotension, and hemorrhage from multiple sites; they frequently have typical laboratory signs of DIC.113,114 Full heparinization can be beneficial in these patients113,114 and should be supplemented by transfusion of the depleted hemostatic components. PC concentrate has been reported to be beneficial both in cases due to inherited deficiency of PC and in cases in which acquired PC deficiency accompanies purpura fulminans.78,114 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 cancerous cachexia,20 and evidence for malignancy-related primary fibrino(geno)lysis and/or DIC was provided 70 years ago.118 A recent review of the subject is available.119
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 due to nonbacterial thrombotic endocarditis in 31.120 Multifocal hemorrhagic infarctions of the brain, caused by fibrin microemboli and manifested as disorders of consciousness, have also been described.121 Patients with solid tumors and DIC are more prone to thrombosis than to bleeding, while patients with leukemia and DIC are more prone to hemorrhage.
Both bleeding and thromboembolism stem from the DIC that is initiated by exposure of the blood to tissue factor present in carcinomas.122,123,124 and 125 A factor X–activating procoagulant present in the mucin secreted by adenocarcinomas was postulated as a cause of DIC in some patients,126 but this observation could not be confirmed.125 A third postulated mechanism for triggering the coagulation system is via activation of factor X by a cysteine proteinase or “cancer procoagulant.”127 However, this material was found to contain tissue factor and to exert only a weak effect on activation of factor X.125
Depending on the rate and quantity of exposure or influx of shed vesicles from tumors containing tissue factor,128 a decompensated, compensated, or overcompensated hemostatic state develops.126 For instance, a patient may be asymptomatic or present with venous thromboembolism (Trousseau syndrome) if the tumor cells expose or release tissue factor slowly or intermittently and the ensuing utilization of fibrinogen and platelets is compensated by increased production of these components. Conversely, massive thrombosis130 or severe bleeding9,11 may supervene in a patient whose circulation is deluged by tissue factor.
Patients with solid tumors are vulnerable to additional triggers of DIC that can aggravate thromboembolism and bleeding. These triggers include septicemia, immobilization, suppression of platelet production by chemotherapy, and involvement by metastases of the liver, which impede the role of the liver in the control of DIC.
Microangiopathic hemolytic anemia is frequently induced by DIC in patients with malignancies and is particularly severe in patients with widespread intravascular metastases of mucin-secreting adenocarcinomas.131
Chronic DIC associated with malignancy can be treated successfully by heparinization.120,125 The indications include arterial or venous thrombosis, significant bleeding, preparation for surgery, and prophylaxis before institution of intensive chemotherapy. Replacement of depleted blood components may be required during initial heparinization, but once appropriate anticoagulation has been achieved DIC usually abates. Treatment can then be followed by subcutaneous unfractionated heparin125 or low molecular weight heparin,132 but not warfarin.125 Patients with neoplastic disorders who develop acute severe DIC can also be treated by heparinization, but the results are only partially successful.9 Patients with prostatic carcinoma exhibiting primary fibrinogenolysis or DIC with extensive secondary fibrinolysis can be treated successfully by e-aminocaproic acid133 or by tranexamic acid, but only after heparin has begun to mitigate the DIC. However, the diagnosis should be unequivocal in view of the hazards involved when antifibrinolytic agents are used in patients with DIC and secondary fibrinolysis,74,75 and other precautions should be taken as well (see “Therapy”).
In 1935, bleeding together with a low fibrinogen level was noted in a patient with acute myelocytic leukemia.134 Since then, numerous reports have been published on DIC and fibrinolysis complicating the course of acute leukemias. Although relatively uncommon among the acute leukemias, acute promyelocytic leukemia (APL) is the entity most frequently associated with life-threatening hemorrhage. The pathogenesis of the hemostatic disturbance in APL and the implied therapeutic approach are complex.135,136 One school of thought maintains that severe DIC accompanied by profound secondary fibrinolysis is responsible for the abnormalities, and therefore heparin should be administered during induction therapy. This hypothesis is based upon (1) postmortem examinations that showed widespread thrombosis in such patients137,138 and 139; (2) finding tissue factor in cells of patients with APL,140,141 a factor X–activating proteinase,142 and excessive IL-1 production that induces tissue factor synthesis in monocytes and endothelial cells143; and (3) demonstration of increased levels of prothrombin fragment 1.2 and TAT complexes.144 However, clinical experience in patients with APL failed to show an unequivocal advantage for heparin therapy over support by blood products145,146 or use of antifibrinolytic agents.146
Other authorities regard primary fibrinogenolysis as the predominant cause of the serious bleeding in patients with APL.147 This hypothesis is based on finding (1) urokinase-type plasminogen activator148 and t-PA149 in leukemic cells from patients with APL; (2) low plasma levels of a2-antiplasmin150; and (3) decreased activity of plasminogen activator inhibitor.151 Consequently, treatment with antifibrinolytic agents has been recommended.146,147,150
It is not unlikely that patients with APL may have concomitant DIC and primary fibrino(geno)lysis and that both processes are triggered by the leukemic cells to variable extents. Introduction of sensitive tests recording the relative magnitude of thrombin and of plasmin generation (TAT and PAP assays)67 may provide information as to when, in a given patient, one should administer heparin, when to use an antifibrinolytic agent, or perhaps both. In any case, treatment should always include blood component replacement until balanced hemostasis is achieved.
The introduction of all-trans-retinoic acid (ATRA) in the treatment of patients with APL raised hopes that the APL coagulopathy might be ameliorated, since it was shown in vitro that ATRA therapy decreased the production of tissue factor by leukemic cells and increased thrombomodulin expression.152 Indeed, in several uncontrolled studies the hemostatic abnormalities have improved when ATRA was used.135,136 However, in a controlled study of 346 patients with APL, early mortality from hemorrhage was similar in patients whose induction therapy consisted of ATRA (6%) or chemotherapy (7%).153 Moreover, thrombotic events were also observed by several authors in patients who received ATRA, and these events were either related or unrelated to the “ATRA syndrome.”154,155,156 and 157
A high incidence of DIC, particularly during induction therapy without L-asparaginase, has also been described in adult patients with acute lymphoblastic leukemia.158 The pathogenesis of DIC in these patients is not clear at present. Platelet transfusions and cryoprecipitate and plasma replacement seem effective in such patients.158
When DIC complicates trauma it usually occurs in severely injured patients. Extensive exposure of tissue factor to the blood circulation and hemorrhagic shock are probably the most immediate triggers of DIC in such instances. Later, however, DIC can be induced within the framework of the systemic inflammatory response syndrome (SIRS) that not infrequently accompanies multiorgan trauma. A series of elegant studies has demonstrated that the levels of TNF-a, IL-1b, PAI-1, circulating tissue factor, plasma elastase derived from neutrophils, and soluble thrombomodulin are all elevated in patients who have signs of DIC.159,160 and 161 Moreover, DIC is a predictor of the multiple organ dysfunction syndrome (ARDS included) and death. Careful monitoring of laboratory signs of DIC, of reduced fibrinolytic activity, and perhaps of AT-III level162 are useful for predicting the outcome of such patients.
DIC can be aggravated in patients with severe trauma who require massive blood replacement since stored blood does not contain platelets or sufficient amounts of factors V or VIII. Moreover, infection is common 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 the Vietnam war proved that fast evacuation and prompt medical care reduces the risk of DIC.163 Debridement of damaged tissues to arrest the influx of tissue factor into the circulation is of paramount importance. Vital functions such as blood flow through the microcirculation and respiratory, cardiac, and renal performance must be monitored and supported; measures also need to be taken against potential infections. Transfusion of appropriate blood components should be given to replenish the consumed or lost clotting factors and platelets. Use of an AT-III concentrate has been tried,70,71,164 but the limited data currently available do not provide unequivocal evidence for its efficacy.
Brain injury can be associated with DIC, most likely because the injury exposes the abundant tissue factor of brain tissue to blood. The DIC can cause serious bleeding,165 but transfusion of platelets and plasma components can effectively arrest bleeding.166 In fatal cases DIC was confirmed by the presence of microthrombi in the brain, liver, lungs, kidneys, and pancreas.167 Studies of adults and children with head injuries have shown a high rate of mortality when DIC is present.168 In fact, a laboratory DIC score has predictive value for prognosis of patients with head injuries, thereby supplementing the Glasgow coma score.168,169 Hence, though bleeding in patients with DIC related to brain injury can be managed by replacement therapy, it carries a grave prognosis.
Tissue factor exposed to blood at sites of burned tissue, the systemic inflammatory response syndrome induced by the burn, and the commonly present superimposed infections can all trigger DIC in patients with burns. Bleeding, laboratory tests indicative of DIC, and vascular microthrombi in biopsies of undamaged skin have all been described in patients with extensive burns.170 Kinetic studies with labeled fibrinogen and labeled platelets disclosed that in addition to systemic consumption of hemostatic factors, significant local consumption also takes place in burned areas.171 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 about 4 percent had intracranial hemorrhage.172
Replacement therapy with blood components is the treatment of choice in patients with burns and bleeding, due to low levels of hemostatic components. Heparin should be avoided if possible.
Very complicated derangements of hemostasis occur in patients with severe liver disease and during liver transplantation (see also Chap. 125). There is reduced synthesis of most coagulation factors and natural anticoagulants (PC, PS, and AT-III) and of the main components of the fibrinolytic system (plasminogen and a2-antiplasmin). In addition, there is decreased capacity of the liver to clear the circulation of activated factors IX, X, and XI as well as t-PA.57,58,173 Moreover, thrombocytopenia is common as a result of hypersplenism. The similarities between the hemostatic defects observed in patients with liver disease and in patients with DIC are therefore striking and have evoked an ongoing controversy as to whether DIC contributes to hemostatic derangements associated with liver disease.174,175
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 heparin176,177; failure of replacement therapy to significantly increase the levels of hemostatic factors (suggesting continuous consumption)178; and increased blood levels of D-dimer,179 TAT complexes,180,181 and fibrinopeptide A182—all indicative of ongoing thrombin generation.
Other observations and considerations argue against the hypothesis that DIC accompanies liver diseases. They include: (1) There is an extremely low incidence (2.2%) of microthrombosis in the tissues of patients who die of liver disease183; and (2) Many of the hemostatic abnormalities of patients with hepatic disorders can stem from causes other than DIC or are not consistent with DIC. Examples of alternative explanations include: (a) A prolonged thrombin time may be due to acquired dysfibrinogenemia.184 (b) Low levels of coagulation factors and inhibitors may be due to reduced synthesis. (c) Increased FDP levels may be a consequence of primary fibrinogenolysis induced by reduced synthesis of a2-antiplasmin and of plasminogen activator inhibitor-1 along with decreased clearance of t-PA. (d) Factor VIII levels are commonly increased rather than decreased.185 (e) The kinetic data show that the apparently excessive consumption of fibrinogen can be explained by loss of fibrinogen into extravascular spaces.186 (f) Fibrinogen and plasminogen do not appear to be removed rapidly when labeled endogenously by 75Se-selenomethionine.187
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 in view of their impeded capacity to clear procoagulants and to synthesize essential components of the coagulation, inhibitory, and fibrinolytic systems. Indeed, 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.188
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 carefully considered and identified, and then a hemostatic profile should be examined at frequent intervals in order to detect any dynamic changes that may be helpful for recognizing DIC. The sensitive assays that reflect thrombin generation (TAT complex) or concomitant thrombin and plasmin generation (D-dimer) may help to establish the diagnosis of DIC in a patient with liver disease.189
Given the present diagnostic limitations and therefore the uncertainty as to whether a patient is bleeding because of liver disease per se or because of superimposed DIC, the treatment should consist of replacement of hemostatic factors, and if a DIC trigger is identified specific vigorous treatment should be instituted. Prothrombin complex concentrates containing activated clotting factors should be avoided in view of their potential thrombogenic effects. Antifibrinolytic agents can be considered in patients with severe bleeding who do not respond to replacement therapy, but evidence of fibrinolysis should be obtained and treatment preceded by continuous heparin infusion.
Clinical and laboratory signs of DIC have been observed in some patients after a peritoneovenous shunt procedure (the LeVeen shunt) for ascites associated with liver disease. In an early review of 278 patients with the LeVeen shunt, DIC was observed postoperatively in only 10 cases,190 but other investigators have reported higher frequencies, with the shunt apparently contributing to death in some cases.191 A review reported the elimination of the postshunt DIC by careful removal of the ascites fluid at the time of surgery.192
Heat stroke is a syndrome characterized by a rise in body temperature to over 42°C that follows collapse of the thermoregulatory mechanism. The following predisposing factors have been identified: a high environmental temperature, strenuous physical activity, infection, dehydration, and lack of acclimatization.193,194 Extensive hemorrhage, unclottable blood, and venous engorgement were found as early as 1838 in postmortem examination of patients who had died of heat stroke.195 Investigations have confirmed that a severe hemorrhagic diathesis and multiple organ failure often accompany heat stroke.193,196,197,198 and 199 Diffuse fibrin deposition and hemorrhagic infarctions are found in fatal human cases197,200 and in dogs with experimental heat stroke.201 DIC associated with profound fibrino(geno)lysis is evident in patients with heat stroke.199,202,203 and 204 The possible triggers of DIC in patients with heat stroke include endothelial cell damage205 and tissue factor released from heat-damaged tissues.
Both the severity of the syndrome and the stage of its development affect the type and magnitude of hemostatic alterations.199,203,204 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.199 Prompt cooling and support of vital functions have substantially reduced the high mortality that was commonly observed in early studies.193 Replacement of hemostatic components is the treatment of choice when bleeding occurs.194 Heparin administration may be beneficial206,207,208 and 209 but carries a high risk,210 as does treatment with antifibrinolytic agents.
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. Several reviews are available on the biochemistry, pathophysiology, and clinical aspects of snake bites.211,212,213,214,215,216 and 217
Venoms of the above-mentioned snakes contain enzymes or peptides that exert the following activities: (1) thrombin-like activity, cleaving fibrinopeptide A from the Aa chain of fibrinogen (Agkistrodon rhodostoma); (2) activation of prothrombin even in the absence of calcium ions (Echis carinatus); (3) activation of factors X and V (Russell viper venom); (4) fibrinogenolytic activity (Agkistrodon acutus)214; (5) induction of thrombocytopenia by platelet aggregation214; (6) inhibition of platelet aggregation by the low molecular weight arginine-glycine-aspartic acid-containing peptides from a variety of snake species218; (7) activation of protein C219; 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,211,212,215,216,220 in spite of the serious derangements in hemostatic tests and findings that are sometimes consistent with DIC.220,221 and 222
The major symptoms and signs, which are related to other effects of envenomation, are vomiting, diarrhea, apprehension, hypotension, local swelling, ischemia, and necrosis. Consequently, treatment for victims of snake bites should consist 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.212,214 Two controlled trials showed no advantage of administering heparin and antivenom compared to antivenom alone.223,224 In the event of bleeding, replacement with platelet concentrates and plasma components is advisable.
Concentrates of the vitamin K-dependent clotting factors are used to treat patients with hemophilia B and patients with other hereditary or acquired coagulation factor deficiencies. Instances of severe DIC225,226 have been reported in patients after the administration of these concentrates, and these reactions may be related to the presence of factors IXa, VIIa, and Xa in the concentrates.227 Factor VIIa has a relatively long T1/2 (2.5 h) in vivo.228 A contributing factor in these patients is hepatic dysfunction,225,226 which impedes the capacity of the liver to neutralize and remove factors IXa and Xa.57,58 Newly prepared factor IX concentrates appear to be less thrombogenic229 because they are almost completely free of activated clotting factors. Nevertheless, prothrombin complex concentrates should not be given as replacement therapy to patients with DIC, and patients with hepatic dysfunction should receive prothrombin complex concentrates only as a last resort, preferably only after their nonthrombogenicity has been established.
Two factor XI concentrates produced in England and France, respectively, have been shown to induce activation of the coagulation and fibrinolytic systems.230,231 Infusions of these concentrates have been associated with severe thrombotic events in several patients,232 but no instances of severe DIC have been observed. Contributing factors in the development of DIC are cardiovascular diseases, cancer, and surgery.
In 1940 Kasabach and Merritt described the association between giant hemangioma and a bleeding tendency.233 Studies employing radiolabeled fibrinogen234,235 and platelets236 provided evidence that within the hemangioma there is consumption of platelets and fibrinogen due to localized intravascular clotting and excessive fibrinogenolysis. Conceivably, there is concomitant local activation of the coagulation pathway, as well as release of large amounts of t-PA by the abnormal endothelium lining the tumor vessels. Microangiopathic hemolytic anemia and laboratory signs of DIC and fibrinolysis have been demonstrated in patients with giant hemangiomas.237,238 and 239
Accelerated growth of hemangiomas in infants is associated with augmented consumption of hemostatic factors, which can be effectively treated with irradiation, glucocorticoids, and interferon. Spontaneous mild to moderate bleeding manifestations have been observed, but severe bleeding generally occurs only after surgery.240 Therefore, extreme caution should be exercised with invasive procedures.
Signs of DIC have also been associated with other vascular lesions, such as the Klippel-Trenaunay syndrome,241,242 hemangioendothelioma of the liver243 and spleen,244 hemangioendotheliosarcoma,245 and even hereditary hemorrhagic telangiectasis.246
In patients with the Kasabach-Merritt syndrome, tumor regression and improvement of hemostatic parameters have been attained by means of inducing thrombosis in the hemangioma with antifibrinolytic agents alone247 or in combination with cryoprecipitate.248 When successful, this results in correction of the coagulation abnormalities.
An association between aortic aneurysm and DIC has been well documented.249 In a series of patients with aortic aneurysm, 40 percent had elevated levels of fibrin(ogen) split products, but only 4 percent had significant bleeding and laboratory evidence of DIC.250 Several factors predispose patients with aortic aneurysms to the development of DIC: a large surface area,250 dissection,249 and expansion of the aneurysm.251 Clinical and laboratory signs of DIC should be carefully sought in patients with an aortic aneurysm since bleeding may seriously complicate surgical repair of the aneurysm.250,252,253 The initiation of localized and generalized intravascular coagulation can be ascribed to activation of the tissue factor pathway by the abundant amounts of tissue factor present in atherosclerotic plaques.254 Spontaneous correction of the abnormal coagulation tests can take place and is attributed to packing of the aneurysm with blood clots.255 When patients present with significant bleeding or when surgery is planned, the hemostatic defects should be corrected by replacement therapy and continuous infusion of heparin.256 Surgical resection produces a permanent solution.
Early studies22,23,257,258 described the strong in vitro and in vivo procoagulant effect of the stroma of red cells, and conversely, fibrin deposition in the vasculature induced by injections of thrombin or thromboplastin was shown to induce intravascular hemolysis.259,260 Hence, it was suggested that a vicious cycle of DIC causing hemolysis and hemolysis aggravating DIC could develop in certain circumstances.261 Whether this actually occurs in cases of DIC causing hemolysis has not been rigorously proved. A possible example of a relationship between DIC and hemolysis is incompatible blood transfusion, in which massive hemolysis is commonly associated with excessive bleeding and DIC, with widespread thrombosis in fatal cases.262,263 and 264 However, the trigger of DIC in these cases could not simply be ascribed to the release of red cell stroma, since patients with massive hemolysis due to favism do not develop DIC.265 It rather appears that the antigen-antibody reaction results in activation of monocytes (which release cytokines and express tissue factor) and complement (with the assembly of the membrane attack complex inflicting damage to endothelial cells266), all leading to DIC.
Microangiopathic hemolytic anemias and disseminated or localized intravascular coagulation may be initiated by disseminated cancer131 and giant hemangioma.238 In these circumstances hemolytic anemia may be aggravated by intravascular coagulation, but there is little to suggest that the hemolysis aggravates or initiates DIC.
Pregnancy predisposes patients to DIC for at least three 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) Pregnancy is associated with reduced fibrinolytic activity due to increased plasma levels of PAI-1; and (3) Pregnancy is associated with a decline in the plasma level of PS. DIC may be difficult to diagnose during pregnancy due to the high initial levels of coagulation factors like fibrinogen, factor VIII, and factor VII. Progressive reductions in these factors, however, can confirm or exclude the diagnosis of DIC in suspected cases.267 Thrombocytopenia may be particularly helpful in determining whether DIC is present, provided other causes of thrombocytopenia are excluded.
The dramatic clinical presentation of abruptio placentae was first reported by DeLee in 1901,268 but the immediate cause for sudden detachment of the placenta is still unknown. Older multiparous women or patients with one of the hypertensive disorders of pregnancy are thought to be at highest risk.269,270 The severe hemostatic failure accompanying abruptio placentae is the result of acute DIC emanating from the introduction of large amounts of placental tissue factor into the blood circulation.270,271
In two large series of deliveries, abruptio placentae occurred in 0.2 to 0.4 percent of pregnancies,269,272 and of these only 38 percent were associated with hypofibrinogenemia.269 Thus, not all patients with abruptio placentae develop DIC, and among those who do, different grades of severity are found, 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.270 Transfusion of cryoprecipitate, fresh-frozen plasma, and platelets should be given when profuse bleeding occurs.273,274 However, in the absence of severe bleeding, administration of blood components may not be necessary since depleted coagulation factors increase rapidly following delivery.275 Heparin or antifibrinolytic agents are not indicated. Following a cesarean section it is advisable to give either low-dose heparin 5000 U twice a day subcutaneously or low molecular weight heparin, continuing treatment until the patient is completely mobile to prevent venous thrombosis.
This rare catastrophic disorder described by Steiner and Lushbaugh in 1941276 occurs only in 1 in 8000 to 1 in 80,000 deliveries. A mortality rate of 86 percent was reported in a 1979 review of 272 cases.277 A 1995 review of 46 cases found a mortality rate of 61 percent,278 demonstrating that the mortality remains extraordinarily high. Patients predisposed to amniotic fluid embolism are multiparous women whose pregnancies are postmature with large fetuses and woman undergoing a tumultuous labor after pharmacologic or surgical induction.276,277,279 A recent registry, however, failed to show a correlation between prolonged labor or oxytocin use and the occurrence of the syndrome.278 Apparently, amniotic fluid is introduced into the maternal circulation through tears in the chorioamniotic membranes, rupture of the uterus, and injury of uterine veins.277 Possible triggers of DIC are tissue factor280 and an activator of factor X281 present in amniotic fluid. The mechanical obstruction of pulmonary blood vessels by fetal debris, meconium, and other particulate matter in the amniotic fluid also 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 syndrome278 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 the cases.277 Hemorrhage is particularly severe from the atonic uterus, from puncture sites, and from the gastrointestinal tract and other organs.
The best prospect for decreasing mortality lies in early elective termination of parturition in patients at high risk and prevention of hypertonic and tetanic uterine contractions during labor. When the syndrome is recognized, immediate pulmonary and cardiovascular support is essential. At present, insufficient data are available on the use of heparin or antifibrinolytic agents. Platelet concentrates, fresh-frozen plasma, and cryoprecipitate are given when bleeding and profound hemostatic impairment supervene.
Thrombocytopenia described in early reports of eclampsia282 and widespread deposition of fibrin in blood vessels observed in fatal cases283 were interpreted as evidence of DIC triggered by placental tissue factor becoming exposed to the circulation.284 A critical analysis of the literature concluded that the thrombocytopenia in these patients stems from endothelial injury rather than DIC.285 However, other investigators have provided evidence for significant DIC in preeclampsia and eclampsia.286,287,288,289,290 and 291 Moreover, in a large series of patients there was a good correlation between the clinical severity and abnormalities in platelet counts and fibrin(ogen) degradation products.288 Also consistent with DIC were results of assays of sensitive parameters of thrombin generation and activation of fibrinolysis, such as TAT, D-dimer, and fibrinopeptide Bb1–42.289,290,291 and 292 Despite these observations, administration of heparin to patients with preeclampsia and eclampsia has not resulted in convincing benefits.293
The syndrome of hemolysis (H), elevated liver enzymes (EL), low platelet count (LP), and severe epigastric pain is a complication of pregnancy-induced hypertension294; 70 percent of the cases occur during the third trimester of pregnancy and 30 percent occur during the postpartum period.295 Liver biopsy findings of fibrin deposition in hepatic blood vessels296 and laboratory tests consistent with DIC in a significant proportion of patients295,297,298 imply that DIC may play a role in the pathogenesis of this syndrome. Hepatic imaging in 33 patients revealed subcapsular hematomas in 13 and intraparenchymal hemorrhage in 6.299 What actually triggers DIC in these cases is not known. Multiple organ dysfunctions manifested by acute renal failure, ascites, pulmonary edema, and severe hemorrhage due to DIC may develop, leading to a maternal mortality rate of 1.1 percent.295 Management of patients with HELLP syndrome consists of supportive care, careful monitoring, and blood component replacement therapy. Some authors advocate immediate induction of labor, while others prefer to wait until signs of DIC develop in order to achieve greater fetal maturity.300 In patients with postpartum HELLP syndrome persisting for more than 72 h, plasma exchange seems to be beneficial.301 HELLP syndrome tends to recur in subsequent gestations.302
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 prolonged rupture of membranes, by endometritis developing during labor, and by way of the urinary tract. About 40 percent of bacteremic patients experience shock, which is associated with significant mortality.303 In addition, there is a high rate of bleeding and organ dysfunction affecting the kidneys, lungs, and central nervous system. The human equivalent of the generalized Shwartzman reaction was described in such circumstances.304,305
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 even hysterectomy may need to be considered. If bleeding is brisk or surgery is contemplated, cryoprecipitate, platelet concentrates, and fresh-frozen plasma should be given. Administration of heparin reportedly decreases the rate of DIC after septic abortion,306,307 but controlled trials have not been conducted.
Several weeks after intrauterine fetal death, patients may exhibit laboratory signs of DIC, occasionally accompanied by bleeding.308 Apparently, tissue factor from the retained dead fetus or placenta slowly enters the maternal circulation and initiates DIC, which is sometimes accompanied by significant fibrinolysis.309 Once the diagnosis of intrauterine fetal death is established, serial blood coagulation tests should be performed. A progressive deterioration in these tests calls for immediate evacuation of the uterus. Induction of labor should be preceded by continuous infusion of heparin at a rate of 1000 U/h until normal fibrinogen levels and a normal platelet count are obtained.310,311 At this point, administration of heparin is discontinued, and 8 to 12 h later the uterus evacuated. When patients present with bleeding or induction of labor becomes urgent, replacement therapy with cryoprecipitate is useful. Platelet transfusion is rarely needed.
The entity of fetal death and DIC can occur following the demise of one of multiple gestations. If it occurs at term, therapy is begun as discussed. If it occurs prior to fetal maturity, prolonged administration of heparin can be useful.309 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.312
Acute fatty liver of pregnancy is a rare disorder of unknown etiology that occurs during the third trimester of pregnancy and can lead to hepatic failure, encephalopathy, and death of the mother and fetus.313,314 and 315 The disease is characterized by severe liver dysfunction,314 renal failure, hypertension, and signs of DIC.314,316 The typical histological feature is microvesicular fatty infiltration of the liver. Exceedingly low levels of AT-III and other laboratory signs of DIC were observed in a series of 28 patients, but no definite clinical benefit from AT-III concentrate infusion was achieved.316 The primary therapy for these patients is early delivery and supportive care.
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 due to low plasminogen level; and (3) Their capacity to synthesize coagulation factors and inhibitors is limited.317,318 Criteria for the diagnosis of DIC in newborns are different from those of adults. One must take into account the physiologic hemostatic findings common at this age, which include low levels of the vitamin K–dependent factors, reduced AT-III and PC levels, and a 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.317,319
DIC occurs in sick neonates and particularly in those who are premature. More than one underlying cause can usually 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.317,318,319 and 320
Bleeding from multiple sites is the most common manifestation of DIC in newborns, with intracranial hemorrhage being the most life-threatening condition. In about 20 percent of neonates no clinical manifestations of DIC are apparent,320 and thus a high index of suspicion in patients at risk is essential.
Vigorous therapeutic measures directed toward the underlying disorder, general support of vital functions, and blood component therapy are the best means to treat neonates with DIC. If bleeding persists, a two-volume exchange transfusion with fresh, heparinized whole blood is recommended by some authorities.322 Most studies could not demonstrate any survival benefit from administration of heparin,317,319,320,323,324 although slight improvements in bleeding323 and in coagulation defects324 have been reported.

McKay DG: Disseminated Intravascular Coagulation: An Intermediary Mechanism of Disease. Hoeber Medical Division. Harper and Row. New York, 1965.

Hardaway RM: Syndromes of Disseminated Intravascular Coagulation with Special Reference to Shock and Hemorrhage. Charles C. Thomas, Springfield, IL, 1966.

Mammen EF, Anderson GF, Barnhard MI (eds): Disseminated intravascular coagulation. Thromb Diathes Haemorrh (suppl) 36, 1969.

Minna JD, Robboy SJ, Colman RW: Disseminated Intravascular Coagulation in Man. Charles C. Thomas, Springfield, IL, 1974.

Bick RL: Disseminated Intravascular Coagulation and Related Syndromes. CRC Press, Boca Raton, FL, 1983.

Abe T, Yamanaka M (eds): Disseminated Intravascular Coagulation. Bibliotheca Haematologica, No. 49. Karger, Basel, 1983.

Larcan A, Lambert H, Gerard A: Consumption Coagulopathies. Masson, New York, 1987.

Merskey C, Johnson AJ, Kleiner GJ, et al: The defibrination syndrome: clinical features and laboratory diagnosis. Br J Haematol 13:528, 1967.

Al-Mondhiry H: Disseminated intravascular coagulation. Experience in a major cancer center. Thromb Diathes Haemorrh 34:181, 1975.

Siegal T, Seligsohn U, Aghai E, Modan M: Clinical and laboratory aspects of disseminated intravascular coagulation (DIC): a study of 118 cases. Thromb Haemost 39:122, 1978.

Mant MJ, King EG: Severe, acute disseminated intravascular coagulation. A reappraisal of its pathophysiology, clinical significance and therapy based on 47 patients. Am J Med 67:557, 1979.

Spero JA, Lewis JH, Hasiba U: Disseminated intravascular coagulation. Findings in 346 patients. Thromb Haemost 43:28, 1980.

Bick RL: Disseminated intravascular coagulation: a clinical/laboratory study of 48 patients. Ann NY Acad Sci 370:843, 1981.

Matsuda M, Aoki N: Statistics on underlying and causative diseases of DIC in Japan. A cooperative study, in Disseminated Intravascular Coagulation, edited by T Abe, M Yamanaka, pp 15–22, Karger, Basel, 1983.

Tanaka K, Imamura T: Incidence and clinicopathological significance of DIC in autopsy cases, in Disseminated Intravascular Coagulation, edited by T Abe, M Yamakaka, pp 79–93. Karger, Basel, 1983.

Kobayashi N, Maekawa T, Takada M, Tanaka H: Criteria for diagnosis of DIC on the analysis of clinical and laboratory findings in 345 patients collected by the research committee on DIC in Japan, in Disseminated Intravascular Coagulation, edited by T Abe, M Yamanaka, pp 265–275. Karger, Basel, 1983.

Sharp AA: Diagnosis of disseminated intravascular coagulation, in Disseminated Intravascular Coagulation, edited by T Abe, M Yamanaka, pp 251–263, Karger, Basel, 1983.

Wada H, Wakita Y, Nakase T, et al: Outcome of disseminated intravascular coagulation in relation to the score when treatment was begun. Thromb Haemost 74:848, 1995.

Dupuy M: Injections de matière cerebral dans les veines. Gas Med Paris 2:524, 1834.

Trousseau A: Phlegmasia alba dolens. Clin Med Hotel Dieu Paris, p 695, 1965.

Naunyn C: Untersuchungen über Blutgerinnung im lebeden tiere und ihre Folgen. Arch Exp Pathol Pharmacol, Bd 1, 1873.

Wooldridge LC: Note on the relation of the red blood corpuscles to coagulation. Practitioner 38:187, 1886.

Wooldridge LC: Ueber intravasculare gerinnungen. Arch Ant Physiol Abt (Leipzig) p 397, 1886.

Lasch HG, Krecke HJ, Rodriguez-Erdman F, et al: Verbrauchskoagulopathien (Patogenese und Therapie). Folia Haematol 6:325, 1961.

Robboy SJ, Major MC, Colman RW, Minna JD: Pathology of disseminated intravascular coagulation (DIC). Analysis of 26 cases. Hum Pathol 3:327, 1972.

Kim HS, Suzuki M, Lie JT, Titus JL: Clinically unsuspected disseminated intravascular coagulation (DIC). An autopsy survey. Am J Clin Pathol 66:31, 1976.

Mori K, Hizawa K: Histopathological study of disseminated intravascular coagulation. An analysis of 114 autopsy cases. Tokushima J Exp Med 29:47, 1982.

Watanabe T, Imamura T, Nakagaki K, Tanaka K: Disseminated intravascular coagulation in autopsy cases. Its incidence and clinicopathologic significance. Pathol Res Pract 165:311, 1979.

Shimamura K, Oka K, Nakazawa M, Kojima M: Distribution patterns of microthrombi in disseminated intravascular coagulation. Pathol Lab Med 107:543, 1983.

Wilde JT, Roberts KM, Greaves M, Preston FE: Association between necropsy evidence of disseminated intravascular coagulation and coagulation variables before death in patients in intensive care units. J Clin Pathol 41:138, 1988.

Kojima M, Shimamura K, Mori N, et al: A histological study on microthrombi in autopsy cases of DIC. Bibl Haematol 49:95, 1983.

Kim HS, Suzuki M, Lie JT, Titus JL: Nonbacterial thrombotic endocarditis (NBTE) and disseminated intravascular coagulation (DIC). Arch Pathol Lab Med 101:65, 1977.

Sugiura M, Hiraoka K, Ohkawa S, et al: A clinico-pathological study on cardiac lesions in 64 cases of disseminated intravascular coagulation. Jpn Heart J 18:57, 1977.

Kuramoto K, Matsushita S, Yamanouchi H: Nonbacterial thrombotic endocarditis as a cause of cerebral and myocardial infarction. Jpn Circ J 48:1000, 1984.

Katsumura Y, Ohtsubo K: Incidence of pulmonary thromboembolism, infarction and hemorrhage in disseminated intravascular coagulation: a necroscopic analysis. Thorax 50:160, 1995.

American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864, 1992.

Davies MG, Hagen PO: Systemic inflammatory response syndrome. Brit J Surg 84:920, 1997.

Fourrier F, Chopin C, Goudemand J, et al: Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 101:816, 1992.

Rangel-Frausto MS, Pittet D, Costigan M, et al: The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 273:117, 1995.

Gando S, Kameue T, Nanzaki S, Nakanishi Y: Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome. Thromb Haemost 75:224, 1996.

ten Cate JW, van der Poll T, Levi M, et al: Cytokines: triggers of clinical thrombotic disease. Thromb Haemost 78:415, 1997.

Vervloet MG, Thijs LG, Hack CE: Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost 24:33, 1998.

Muller-Berghaus G: Pathophysiologic and biochemical events in disseminated intravascular coagulation: dysregulation of procoagulant and anticoagulant pathways. Semin Thromb Hemost 15:58, 1989.

Celi A, Pellegrini G, Lorenzet R, et al: P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci USA 91:8767, 1994.

Moore KL, Andreoli SP, Esmon NL, et al: Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest 79:124, 1987.

Kobayashhi M, Shimada K, Ozawa T: Human recombinant interleukin 1-beta and tumor necrosis factor alfa-mediated suppression of heparin-like compounds on cultured porcine aortic endothelial cells. J Cell Physiol 144:383, 1990.

Pixley RA, De La Cadena R, Page JD, et al: The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. J Clin Invest 91:61, 1993.

Mesters RM, Mannucci PM, Coppola R, et al: Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients. Blood 88:881, 1996.

Weiss SJ: Tissue destruction by neutrophils. N Engl J Med 320:365, 1989.

Jordan RE, Nelson RM, Kilpatrick J, et al: Inactivation of human antithrombin by neutrophil elastase. Kinetics of the heparin-dependent reaction. J Biol Chem 264:10493, 1989.

Levin EG, Marzec U, Anderson J, Harker LA: Thrombin stimulates tissue plasminogen activator release from cultured endothelial cells. J Clin Invest 74:1988, 1984.

Rosenberg RD: Biochemistry of heparin antithrombin interactions and the physiologic role of this natural anticoagulant mechanism. Am J Med 87 (suppl 3B):2S, 1989.

Bajzar L, Nesheim ME, Tracy PB: The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood 88:2093, 1996.

Sandset PM, Warn-Cramer BJ, Rao LVM, et al: Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant. Proc Natl Acad Sci USA 88:708, 1991.

Spaet TH, Horowitz HHI, Zucker-Franklin D, et al: Reticuloendothelial clearance of blood thromboplastin by rats. Blood 19:196, 1961.

Sherman LA, Lee J, Jacobson A: Quantitation of the reticuloendothelial system clearance of soluble fibrin. Br J Haematol 37:231, 1977.

Deykin D: The role of the liver in serum-induced hypercoagulability. J Clin Invest 45:256, 1966.

Deykin D, Cochios F, DeCamp G, Lopez A: Hepatic removal of activated factor X by the perfused rabbit liver. Am J Physiol 214:414, 1968.

Bone RC, Francis PB, Pierce AK: Disseminated intravascular coagulation with the adult respiratory distress syndrome. Am J Med 61:585, 1976.

Rinaldo JE, Christman JW: Mechanisms and mediators of the adult respiratory distress syndrome. Clin Chest Med 11:621, 1990.

Kollef MH, Schuster DP: The acute respiratory distress syndrome. N Engl J Med 332:27, 1995.

Colman RW, Robboy SJ, Minna JD: Disseminated intravascular coagulation. A reappraisal. Annu Rev Med 30:359, 1979.

Carr JM, McKinney M, McDonagh J: Diagnosis of disseminated intravascular coagulation. Role of D-dimer. Am J Clin Pathol 91:280, 1989.

Bovill EG: Disseminated intravascular coagulation: pathophysiology and laboratory diagnosis. Fibrinol 7 (suppl 2):17, 1993.

Hoek JA, Sturk A, ten Cate JW, et al: Laboratory and clinical evaluation of an assay of thrombin-antithrombin III complexes in plasma. Clin Chem 34:2058, 1988.

Takahashi H, Hanano M, Takizawa S, et al: Plasmin-alpha 2-plasmin inhibitor complex in plasma of patients with disseminated intravascular coagulation. Am J Hematol 28:162, 1988.

Asakura H, Jokaji H, Saito M, et al: Study of the balance between coagulation and fibrinolysis in disseminated intravascular coagulation using molecular markers. Blood Coag Fibrinol 5:829, 1994.

Corrigan JJ, Jordan CM: Heparin therapy in septicemia with disseminated intravascular coagulation. N Engl J Med 283:778, 1970.

Hogg PJ, Jackson CM: Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: Implications for heparin efficacy. Proc Natl Acad Sci USA 86:3619, 1989.

Blauhut B, Kramar H, Vinazzer H, Bergmann H: Substitution of antithrombin III in shock and DIC: A randomized study. Thromb Res 39:81, 1985.

Vinazzer HA: Antithrombin III in shock and disseminated intravascular coagulation. Clin Appl Thrombosis/Hemostasis 1:62, 1995.

Fourrier F, Chopin C, Huart JJ, et al: Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 104:882, 1993.

Eisele B, Lamy M: Clinical experience with antithrombin III concentrates in critically ill patients with sepsis and multiple organ failure. Semin Thromb Hemost 24:71, 1998.

Naeye RL: Thrombotic state after a hemorrhagic diathesis, a possible complication of therapy with epsilon-aminocaproic acid. Blood 19:694, 1962.

Gralnick HR, Greipp P: Thrombosis with epsilon aminocaproic acid therapy. Am J Clin Pathol 56:151, 1971.

Taenaka N, Shimada Y, Hirata T, et al: Gabexate mesilate (FOY) therapy of disseminated intravascular coagulation due to sepsis. Crit Care Med 11:735, 1983.

Shibata A, Takahashi H, Aoki N, et al: Nafamostat mesilate as a therapy for disseminated intravascular coagulation (DIC): A well-controlled multicenter comparative study. Thromb Haemost 62:371, 1989.

Rivard GE, David M, Farrell C, Schwartz HP: Treatment of purpura fulminans in meningococcemia with protein C concentrate. J Pediatr 126:646, 1995.

Warr TA, Rao LVM, Rapaport SI: DIC in rabbits induced by administration of endotoxin or tissue factor: effect of antitissue factor antibodies and measurement of plasma extrinsic pathway inhibitor activity. Blood 75:1481, 1990.

Taylor FB Jr, Chang AC, Ruf W, et al: Lethal septic shock is prevented by blocking tissue factor. Circ Shock 33:127, 1991.

Taylor FB, Chang ACK, Peer G, et al: Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and -8, but not tumor necrosis factor responses of the baboon to LD100 Escherichia coli. Blood 91:1609, 1998.

Bajaj MS, Bajaj SP: Tissue factor pathway inhibitor: potential therapeutic applications. Thromb Haemost 78:471, 1997.

Warren HS, Danner RL, Munford RS: Anti-endotoxin monoclonal antibodies. N Engl J Med 326:1153, 1992.

Cross AS: Antiendotoxin antibodies: a dead end? Ann Intern Med 121:58, 1994.

Anderson MR, Blumer JL: Advances in the therapy for sepsis in children. Pediat Clin North Am 44:179, 1997.

Pajkrt D, van der Poll T, Levi M, et al: Interleukin-10 inhibits activation of coagulation and fibrinolysis during human endotoxemia. Blood 89:2701, 1997.

Bisno AL, Freeman JC: The syndrome of asplenia, pneumococcal sepsis, and disseminated intravascular coagulation. Ann Intern Med 72:389, 1970.

Vik-Mo H, Lote K, Nordoy A: Disseminated intravascular coagulation in patients with meningococcal infection: laboratory diagnosis and prognostic factors. Scand J Infect Dis 10:187, 1978.

Kornelisse RF, Hazelzet JA, Hop WC, et al: Meningococcal septic shock in children: clinical and laboratory features, outcome, and development of a prognostic score. Clin Infect Dis 25:640, 1997.

Corrigan JJ, Ray WL, May N: Changes in the blood coagulation system associated with septicemia. N Engl J Med 279:851, 1968.

Rapaport SI, Tatter D, Caeur-Barron N, Hjort PF: Pseudomonas septicemia with intravascular clotting leading to the generalized Shwartzman reaction. N Engl J Med 271:80, 1964.

Clarkson AR, Sage RE, Lawrence JR: Consumption coagulopathy and acute renal failure due to gram-negative septicemia after abortion. Complete recovery with heparin therapy. Ann Intern Med 70:1191, 1969.

Murray HW, Tuazon CU, Sheagren JN: Staphylococcal septicemia and disseminated intravascular coagulation. Arch Intern Med 137:844, 1977.

Bhakdi S, Muhly M, Mannhardt U, et al: Staphylococcal alpha toxin promotes blood coagulation via attack on human platelets. J Exp Med 168:527, 1988.

Ratnoff OD, Nebehay WG: Multiple coagulative defects in a patient with Waterhouse-Friderichsen syndrome. Ann Intern Med 56:627, 1962.

Stossel TP, Levy R: Intravascular coagulation associated with pneumococcal bacteremia and symmetrical peripheral gangrene. Arch Intern Med 125:876, 1970.

Rytel MW, Dee TH, Ferstenfeld JE, Hensley GT: Possible pathogenetic role of capsular antigens in fulminant pneumococcal disease with disseminated intravascular coagulation (DIC). Am J Med 57:889, 1974.

De Virgilio C, Klein S, Chang L, et al: Clostridial bacteremia: implications for the surgeon. Am Surg 57:388, 1991.

Yoshikawa T, Tanaka KR, Guze LB: Infection and disseminated intravascular coagulation. Medicine (Baltimore) 50:237, 1971.

Cosgriff TM: Viruses and hemostasis. Rev Infect Dis 11 (suppl 4):S672, 1989.

Inbal A, Kenet G, Zivelin A, et al: Purpura fulminans induced by disseminated intravascular coagulation following infection in two unrelated children with double heterozygosity for factor V Leiden and protein S deficiency. Thromb Haemost 77:1086, 1997.

Levin M, Eley BS, Louis J, et al: Postinfectious purpura fulminans caused by an autoantibody directed against protein S. J Pediatr 127:355, 1995.

Lee M, Lee JS, Kim BK: Disseminated intravascular coagulation in Korean hemorrhagic fever. Bibl Haematol 49:181, 1983.

Isarangkura PB, Pongpanich B, Pintadit P, et al: Hemostatic derangement in dengue haemorrhagic fever. Southeast Asian J Trop Med Public Health 18:331, 1987.

Molinas FC, de Bracco MM, Maiztegui JI: Hemostasis and the complement system in Argentine hemorrhagic fever. Rev Infect Dis 11 (suppl 4):S762, 1989.

Grob C: Tissue factor initiation of disseminated intravascular coagulation in filovirus infection. Med Hypotheses 45:380, 1995.

Vitarana T, de Silva H, Withana N, Gunasekera C: Elevated tumour necrosis factor in dengue fever and dengue haemorrhagic fever. Ceylon Med J 36:63, 1991.

Philippidis P, Naiman JL, Sibinga MS, Valdes-Dapnea MA: Disseminated intravascular coagulation in Candida albicans septicemia. J Pediatr 78:683, 1971.

Fera G, Semeraro N, De Mitrio V, Schiraldi O: Disseminated intravascular coagulation associated with disseminated cryptococcosis in a patient with acquired immunodeficiency syndrome. Infection 21:171, 1993.

Mavligit GM, Binder RA, Crosby WH: Disseminated intravascular coagulation in miliary tuberculosis. Arch Intern Med 130:388, 1972.

Rojanasthien S, Surakamolleart V, Boonpucknavig S, Isarangkura P: Hematological and coagulation studies in malaria. J Med Assoc Thai 75 (suppl 1):190, 1992.

Pukrittayakamee S, White NJ, Clemens R, et al: Activation of the coagulation cascade in falciparum malaria. Tans R Soc Trop Med Hyg 83:762, 1989.

Hjort PF, Rapaport SI, Jorgensen L: Purpura fulminans. Report of a case successfully treated with heparin and hydrocortisone. Review of 50 cases from the literature. Scand J Haematol 1:69, 1964.

Gerson WT, Dickerman JD, Bovill EG, Golden E: Severe acquired protein C deficiency in purpura fulminans associated with disseminated intravascular coagulation: treatment with protein C concentrate. Pediatrics 91:418, 1993.

Tishler M, Abramov AL, Seligsohn U, Kahn Y: Purpura fulminans in an adult. Isr J Med Sci 22:820, 1986.

Branson HE, Katz J, Marble R, Griffin JH: Inherited protein C deficiency and a coumarin-responsive chronic relapsing purpura fulminans syndrome in a newborn infant. Lancet 2:1156, 1983.

Seligsohn U, Berger A, Abend M, et al: Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med 310, 1984.

Jurgens R, Trautwein H: über Fibrinopenie (Fibrinogenopenie) beim Erwaschsenen, nebst Bemerkungen über die herkunft des Fibrinogens. Dtsch Arch Klin Med 169:28, 1930.

Goad KE, Gralnick HR: Coagulation disorders in cancer. Hematol Oncol Clin North Am 10:457, 1996.

Sack GH Jr, Levin J, Bell WR: Trousseau’s syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine (Baltimore) 56:1, 1977.

Collins RC, Al-Mondhiry H, Chernik NL, et al: Neurologic manifestations of intravascular coagulation in cancer: a clinicopathologic analysis of 12 cases. Neurology 25:795, 1975.

Szczepanski M, Bardadin K, Zawadzki J, Pypno W: Procoagulant activity of gastric, colorectal and renal cancer is factor VII-dependent. J Cancer Res Clin Oncol 114:519, 1988.

Gonmori H, Maekawa T, Kobayashi N, et al: The role of tissue thromboplastin in the development of DIC accompanying neoplastic diseases. Bibl Haematol 49:23, 1983

Zacharski LR, Schned AR, Sorenson GD: Occurrence of fibrin and tissue factor antigen in human small cell carcinoma of the lung. Cancer Res 43:3963, 1983.

Callander N, Rapaport SI: Trousseau’s syndrome. West J Med 158:364, 1993.

Pineo GF, Regoeczi E, Hatton MWC, Brain MC: The activation of coagulation by extracts of mucus: a possible pathway of intravascular coagulation accompanying adenocarcinomas. J Lab Clin Med 82:255, 1973.

Falanga A, Gordon SG: Isolation and characterization of cancer procoagulant: a cysteine proteinase from malignant tissue. Biochemistry 24:5558, 985.

Dvorak HF, Quay SC, Orenstein NS, et al: Tumor shedding and coagulation. Science 212:923, 1981.

Owen CA Jr, Bowie EJW: Chronic intravascular coagulation syndromes, a summary. Mayo Clin Proc 49:673, 1974.

Bell WR, Starksen NF, Tong S, Proterfield JK: Trousseau’s syndrome. Devastating coagulopathy in the absence of heparin. Am J Med 79:423, 1985.

Seligsohn U, Weber H, Yoran C, et al: Microangiopathic hemolytic anemia and defibrination syndrome in metastatic carcinoma of the stomach. Isr J Med Sci 4:69, 1968.

Zuger M, Demarmels Biasiutti F, et al: Subcutaneous low-molecular-weight heparin for treatment of Trousseau’s syndrome. Ann Hematol 75:165, 1997.

Cooper DL, Sandler AB, Wilson LD, Duffy TP: Disseminated intravascular coagulation and excessive fibrinolysis in a patient with metastatic prostate cancer. Response to epsilon-aminocaproic acid. Cancer 70:656, 1992.

Risak E: Die Fibrinopenie. Z Klin Med 128:606, 1935.

De Loughery TG, Goodnight SH: Acute promyelocytic leukaemia in the all-trans-retinoic acid era. Med Oncol 13:233, 1996.

Barbui T, Finazzi G, Falanga A: The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukemia. Blood 91:3093, 1998.

Pittman GR, Senhauser DA, Lowney JF: Acute promyelocytic leukemia. A report of 3 autopsied cases. Am J Clin Pathol 46:214, 1966.

Polliak A: Acute promyelocytic leukemia with disseminated intravascular coagulation. Am J Clin Pathol 56:155, 1971.

Gralnick HR, Tan HK: Acute promyelocytic leukemia. A model for understanding the role of the malignant cell in hemostasis. Hum Pathol 5:661, 1974.

Gralnick HR, Abrell E: Studies of the procoagulant and fibrinolytic activity of promyelocytes in acute promyelocytic leukaemia. Br J Haematol 24:89, 1973.

Andoh K, Kubota T, Takada M, et al: Tissue factor activity in leukemia cells. Special reference to disseminated intravascular coagulation. Cancer 59:748, 1987.

Falanga A, Alessio MG, Donati MB, et al: A new procoagulant in acute leukemia. Blood 71:870, 1988.

Cozzolino F, Torcia M, Miliani A, et al: Potential role of interleukin-1 as the trigger for diffuse intravascular coagulation in acute nonlymphoblastic leukemia. Am J Med 84:240, 1988.

Bauer KA, Rosenberg RD: Thrombin generation in acute promyelocytic leukemia. Blood 64:791, 1984.

Tallman MS, Kwaan HC: Reassessing the hemostatic disorder associated with acute promyelocytic leukemia. Blood 79:543, 1992.

Rodeghiero F, Avvisati G, Castaman G, et al: Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia. A GIMENA retrospective study in 268 consecutive patients. Blood 75:2112, 1990.

Avvisati G, ten Cate JW, Mandelli F: Acute promyelocytic leukaemia. Br J Haematol 81:315, 1992.

Bennett B, Booth NA, Croll A, et al: The bleeding disorder in acute promyelocytic leukaemia: fibrinolysis due to u-PA rather than defibrination. Br J Haematol 71:511, 1989.

Francis RB, Seyfert U: Tissue plasminogen activator antigen and activity in disseminated intravascular coagulation. Clinicopathologic correlations. J Lab Clin Med 110:541, 1987.

Schwartz BS, Williams EC, Conlan MG, Mosher DF: Epsilon-aminocaproic acid in the treatment of patients with acute promyelocytic leukemia and acquired alpha-2-plasmin inhibitor deficiency. Ann Intern Med 105:873, 1986.

Sakata Y, Murakami T, Noro A, et al: The specific activity of plasminogen activator inhibitor-1 in disseminated intravascular coagulation with acute promyelocytic leukemia. Blood 77:1949, 1991.

Koyama T, Hirosawa S, Kawamata N, et al: All-trans-retinoic acid upregulates thrombomodulin and downregulates tissue-factor expression in acute promyelocytic leukemia cells: distinct expression of thrombomodulin and tissue factor in human leukemic cells. Blood 84:3001, 1994.

Tallman MS, Andersen JW, Schiffer CA, et al: All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 337:1021, 1997.

Runde V, Aul C, Heyll A, Schneider W: All-trans-retinoic acid: not only a differentiating agent, but also an inducer of thromboembolic events in patients with M3 leukemia. Blood 79:534, 1992.

Hashimoto S, Koike T, Tatewaki W, et al: Fatal thromboembolism in acute promyelocytic leukemia during all-trans-retinoic acid therapy combined with antifibrinolytic therapy for prophylaxis of hemorrhage. Leukemia 8:1113, 1994.

Escudier SM, Kantarjian HM, Estey EH: Thrombosis in patients with acute promyelocytic leukemia treated with and without all-trans-retinoic acid. Leuk Lymphoma 20:435, 1996.

Pogliani EM, Rossini F, Casaroli I, et al: Thrombotic complications in acute promyelocytic leukemia during all-trans-retinoic acid therapy. Acta Haematol 97:228, 1997.

Sarris A, Cortes J, Kantarjian H, et al: Disseminated intravascular coagulation in adult acute lymphoblastic leukemia: frequent complications with fibrinogen levels less than 100 mg/dl. Leuk Lymphoma 21:85, 1996.

Gando S, Nakanishi Y, Tedo I: Cytokines and plasminogen activator inhibitor-1 in posttrauma disseminated intravascular coagulation: relationship to multiple organ dysfunction syndrome. Crit Care Med 23:1835, 1995.

Gando S, Kameue T, Nanzaki S, et al: Increased neutrophil elastase, persistent intravascular coagulation, and decreased fibrinolytic activity in patients with posttraumatic acute respiratory distress syndrome. J Trauma 42:1068, 1997.

Gando S, Kameue T, Nanzaki S, et al: Participation of tissue factor and thrombin in posttraumatic systemic inflammatory syndrome. Crit Care Med 25:1820, 1997.

Owings JT, Bagley M, Gosselin R, et al: Effect of critical injury on plasma antithrombin activity: low antithrombin levels are associated with thromboembolic complications. J Trauma 41:396, 1996.

Simmons RL, Collins JA, Heisterkamp CA, et al: Coagulation disorders in combat casualties: I. Acute changes after wounding. II. Effect of massive transfusion. III. Post-resuscitative changes. Ann Surg 169:455, 1969.

Jochum M: Influence of high-dose antithrombin concentrate therapy on the release of cellular proteinases, cytokines, and soluble adhesion molecules in acute inflammation. Semin Hematol 32 (4 suppl 2):19, 1995.

Goodnight SH, Kenover G, Rapaport SI, et al: Defibrination after brain-tissue destruction. A serious complication of head injury. N Engl J Med 290:1043, 1974.

Scherer RU, Spangenberg P: Procoagulant activity in patients with isolated severe head trauma. Crit Care Med 26:149, 1998.

Kaufman HH, Hui KS, Mattson JC, et al: Clinicopathological correlations of disseminated intravascular coagulation in patients with head injury. Neurosurgery 15:34, 1984.

Olson JD, Kaufman HH, Moake J, et al: The incidence and significance of hemostatic abnormalities in patients with head injuries. Neurosurgery 24:825, 1989.

Selladurai BM, Vickneswaran M, Duraisamy S, Atan M: Coagulopathy in acute head injury—a study of its role as a prognostic indicator. Br J Neurosurg 11:398, 1997.

McManus WF, Eurenius K, Pruitt BA: Disseminated intravascular coagulation in burned patients. J Trauma 13:416, 1973.

Simon TL, Current PW, Harker LA: Kinetic characterization of hemostasis in thermal injury. J Lab Clin Med 82:702, 1977.

Winkelman MD, Galloway PG: Central nervous system complications of thermal burns. A postmortem study of 139 patients. Medicine (Baltimore) 71:271, 1992.

Fletcher AP, Biederman O, Moore D, et al: Abnormal plasminogen-plasmin system activity (fibrinolysis) in patients with hepatic cirrhosis: its cause and consequences. J Clin Invest 43:681, 1964.

Bloom AL: Intravascular coagulation and the liver. Br J Haematol 30:1, 1975.

Carr JM: Disseminated intravascular coagulation in cirrhosis. Hepatology 10:103, 1989.

Tytgat GN, Collen D, Verstraete M: Metabolism of fibrinogen in cirrhosis of the liver. J Clin Invest 50:1960, 1971.

Coleman M, Finlayson N, Bettigole RE, et al: Fibrinogen survival in cirrhosis: improvement by “low dose” heparin. Ann Intern Med 83:79, 1975.

Tytgat GN, Piesens J, Collen D, De Groote J: Experience with exchange transfusion in the treatment of hepatic coma. Digestion 1:257, 1968.

Carr JM, McKinney M, McDonagh J: Diagnosis of DIC: role of D-dimer. Am J Clin Pathol 91;280, 1989.

Paramo JA, Rifon J, Fernandez J, et al: Thrombin activation and increased fibrinolysis in patients with chronic liver disease. Blood Coag Fibrinol 2:227, 1991.

Van Wersch JWJ, Russel MG, Lustermans FA: The extent of diffuse intravascular coagulation and fibrinolysis in patients with liver cirrhosis. Eur J Clin Chem Clin Biochem 30:275, 1992.

Coccheri S, Mannucci PM, Palaret G, et al: Significance of plasma fibrinopeptide A and high molecular weight fibrinogen in patients with liver cirrhosis. Br J Haematol 52:503, 1982.

Oka K, Tanaka K: Intravascular coagulation in autopsy cases with liver diseases. Thromb Haemost 42:564, 1979.

Palascak JE, Martinez J: Dysfibrinogenemia associated with liver disease. J Clin Invest 60:89, 1977.

Corrigan JJ, Bennett BB, Bueffel B: The value of factor VIII levels in acquired hypofibrinogenemia. Am J Clin Pathol 60:897, 1973.

Straub PW: Diffuse intravascular coagulation in liver disease? Semin Thromb Haemost 4:29, 1977.

Canoso RT, Hutton RA, Deykin D: The hemostatic defect of chronic liver disease. Kinetic studies using 75Se-Selenomethionine. Gastroenterology 76:540, 1979.

Tempero MA, Davis RB, Reed E, Edney J: Thrombocytopenia and laboratory evidence of disseminated intravascular coagulation after shunts for ascites in malignant disease. Cancer 55:2718, 1985.

Bakker CM, Knot EA, Stibbe J, Wilson JH: Disseminated intravascular coagulation in liver cirrhosis. J Hepatol 15:330, 1992.

LeVeen HH, Wapnick S, Grosberg S, Kinney MU: Further experience with peritoneovenous shunt for ascites. Ann Surg 184:574, 1976.

Rubinstein D, McInness I, Dudley F: Morbidity and mortality after peritoneovenous shunt surgery for refractory ascites. Gut 26:1070, 1985.

LeVeen EG, LeVeen HH: The place of the peritoneovenous shunt in the treatment of ascites. ASAIO Trans 35:165, 1989.

Shibolet S, Coll R, Gilat T, et al: Heatstroke: its clinical picture and mechanism in 36 cases. Q J Med 36:525, 1967.

Shibolet S, Lancaster MC, Danon Y: Heat stroke: a review. Aviat Space Environ Med 47:280, 1976.

Wakefield EG, Hall WW: Heat injuries: a preparatory study for experimental heat stroke. JAMA 89:92, 1927.

Gauss H, Meyer KA: Heat stroke: report of one hundred and fifty-eight cases from Cook County Hospital, Chicago. Am J Med Sci 154:554, 1917.

Malamud N, Naymaker W, Custer RP: Heat stroke. A clinicopathology study of 125 fatal cases. Milit Surg 99:397, 1946.

Hart GR, Anderson RJ, Crumpler CP, et al: Epidemic classical heat stroke: clinical characteristics and course of 28 patients. Medicine (Baltimore) 61:189, 1982.

Mustafa KY, Omer O, Khogali M, et al: Blood coagulation and fibrinolysis in heat stroke. Br J Haematol 61:517, 1985.

Chao TC, Sinniah R, Pakiam JE: Acute heat stroke deaths. Pathology 13:145, 1981.

Rosenthal T, Shapiro Y, Seligsohn U, Ramot B: Disseminated intravascular coagulation in experimental heatstroke. Thromb Diath Haemorrh 26:417, 1971.

Shibolet S, Fisher S, Gilat T, et al: Fibrinolysis and hemorrhages in fatal heatstroke. N Engl J Med 266:169, 1962.

Al-Mashhadani SA, Gader AG, al-Harthi SS, et al: The coagulopathy of heat stroke: alterations in coagulation and fibrinolysis in heat stroke patients during the pilgrimage (Haj) to Makkah. Blood Coagul Fibrinol 5:731, 1994.

Bouchama A, Bridey F, Hammami MM, et al: Activation of coagulation and fibrinolysis in heatstroke. Thromb Haemost 76:909, 1996.

Sohal RS, Sun SC, Colcolough HL, et al: Heat stroke. An electron microscopy study of endothelial cell damage and disseminated intravascular coagulation. Arch Intern Med 122:43, 1968.

Weber MB, Blakely JA: The haemorrhagic diathesis of heatstroke. A consumption coagulopathy successfully treated with heparin. Lancet 1:1190, 1969.

Cornell CJ, Fein SH, Reilly B, Cornwell GG: Heparin therapy for heat stroke. Ann Intern Med 81:702, 1974.

Perschick JS, Winkelstein A, Shadduck RK: Disseminated intravascular coagulation in heat stroke. JAMA 231:480, 1975.

Knochel JP: Disseminated intravascular coagulation in heat stroke. Response to heparin therapy. JAMA 231:496, 1975.

Shibolet S, Farfel Z: Heparin therapy for heatstroke. Ann Intern Med 82:857, 1975.

De Vries A, Cohen I: Hemorrhagic and blood coagulation disturbing action of snake venoms, in Recent Advances in Blood Coagulation, edited by L Poller, p 277. Churchill, London, 1969.

Efrati P: Snake venoms and blood coagulation, in Snake Venoms, edited by Chen-Yuan Lee, p 956. Springer-Verlag, Berlin, 1979.

Russell EF: Snake venoms and blood coagulation, in Snake Venoms, edited by Chen-Yuan Lee, p 978. Springer-Verlag, Berlin, 1979.

Seegers WH, Ouyang C: Snake venoms and blood coagulation, in Snake Venoms, edited by Chen-Yuan Lee, p 684. Springer-Verlag, Berlin, 1979.

Reid HA: Clinical hemostatic disorders caused by venoms, in Disorders of Hemostasis, edited by OD Ratnoff, CD Forbes, p 511. Grune and Stratton, Orlando, FL, 1984.

Kitchens CS: Hemostatic aspects of envenomation by North American snakes. Hematol Oncol Clin North Am 6:1189, 1992.

Hutton RA, Warrell DA: Action of snake venom components on the haemostatic system. Blood Rev 7:176, 1993.

Huang TF, Holt JC, Lukasiwic H, Niewiarowski S: Trigamin: A low molecular weight peptide inhibiting fibrinogen interaction with platelet receptors expressed on glycoprotein IIb-IIIa complex. J Biol Chem 262:16157, 1987.

Klein JD, Walker FJ: Purification of a protein C activator from the venom of the southern copperhead snake (Agkistrodon contortrix). Biochemistry 25:4175, 1986.

Schulchynska-Castel H, Dvilansky A, Keynan A: Echis colorata bites: clinical evaluation of 42 patients. A retrospective study. Isr J Med Sci 22:880, 1986.

Weiss HJ, Phillips LL, Hopewell WS, et al: Heparin therapy in a patient bitten by a saw-scaled viper (Echis carinatus), a snake whose venom activated prothrombin. Am J Med 54:653, 1973.

Fainaru M, Eisenberg S, Manny N, Hershko C: The natural course of defibrination syndrome caused by Echis colorata venom in man. Thromb Diath Haemorrh 31:420, 1974.

Warrell DA, Pope HM, Prentice CRM: Disseminated intravascular coagulation caused by the carpet viper (Echis carinatus): trial of heparin. Br Haematol 33:335, 1976.

Swe TN, Lwin M, Han KE, et al: Heparin therapy in Russell’s viper bite victims with disseminated intravascular coagulation: a controlled trial. Southeast Asian J Trop Med Public Health 23:282, 1992.

Blatt PM, Lundblad RL, Kingdon HS, et al: Thrombogenic materials in prothrombin complex concentrates. Ann Intern Med 81:766, 1974.

Cederbaum AI, Blatt PM, Roberts HR: Intravascular coagulation with use of human prothrombin complex concentrates. Ann Intern Med 84:683, 1976.

Hultin MB: Activated clotting factors in factor IX concentrates. Blood 54:1028, 1979.

Seligsohn U, Kasper CK, Osterud B, Rapaport SI: Activated factor VII: presence in factor IX concentrate and persistence in the circulation after infusion. Blood 53:828, 1979.

Menache D, Behre HE, Orthner Cl, et al: Coagulation factor IX concentrate: method of preparation and assessment of potential in vivo thrombogenicity in animal models. Blood 64:1220, 1984.

Mannucci PM, Bauer KA, Santagostino E, et al: Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients. Blood 84:1314, 1994.

Richards EM, Makris MM, Cooper P, Preston FE: In vivo coagulation activation following infusion of highly purified factor XI concentrate. Br J Haematol 96:293, 1997.

Bolton-Maggs Ph, Colvin BT, Satchi BT, et al: Thrombogenic potential of factor XI concentrate. Lancet 344:748, 1994.

Kasabach HH, Merritt KK: Capillary hemangioma with extensive purpura. Am J Dis Child 59:1063, 1940.

Blix S, Aas K: Giant hemangioma, thrombocytopenia, fibrinogenopenia, and fibrinolytic activity. Acta Med Scand 169:63, 1961.

Straub PW, Kessler S, Schreiber A, Frick PG: Chronic intravascular coagulation in Kasabach-Merritt syndrome. Preferential accumulation of fibrinogen 131I in a giant hemangioma. Arch Intern Med 129:475, 1972.

Warrell RP, Kempin SJ, Benua RS, et al: Intra-tumoral consumption of indium-111 labeled platelets in a patient with hemangiomatosis and intravascular coagulation (Kasabach-Merritt syndrome). Cancer 52:2256, 1983.

Propp RP, Scharfman WB: Hemangioma-thrombocytopenia syndrome associated with microangiopathic hemolytic anemia. Blood 28:623, 1966.

Inceman S, Tangun Y: Chronic defibrination syndrome due to a giant hemangioma associated with microangiopathic hemolytic anemia. Am J Med 46:997, 1969.

Seligsohn U, Ramot B: Angiopathic hemolytic anemias: report of 5 cases and review of the literature. J Isr Med Assoc 74:39, 1968.

Gilon E, Ramot B, Sheba C: Multiple hemangiomata associated with thrombocytopenia: remarks on the pathogenesis of the thrombocytopenia in this syndrome. Blood 14:74, 1958.

D’Amico JA, Hoffman GC, Dyment PG: Klippel-Trenaunay syndrome associated with chronic disseminated intravascular coagulation and massive osteolysis. Cleve Clin Q 44:181, 1977.

Poon MC, Kloiber R, Birdsell DC: Epsilon-aminocaproic acid in the reversal of consumptive coagulopathy with platelet sequestration in a vascular malformation of Klippel-Trenaunay syndrome. Am J Med 87:211, 1989.

Alpert LI, Benesh B: Hemangioendothelioma of the liver associated with microangiopathic hemolytic anemia. Am J Med 48:624, 1970.

Shanberge JH, Tanaka K, Gruhl MC: Chronic consumption coagulopathy due to hemangiomatous transformation of the spleen. Am J Clin Pathol 56:723, 1971.

Blix S, Jacobsen CD: The defibrination syndrome in a patient with hemangio-endothelio-sarcoma. Acta Med Scand 173:377, 1963.

Bick RL: Hereditary hemorrhagic telangiectasia and disseminated intravascular coagulation: a new clinical syndrome. Ann NY Acad Sci 370:851, 1981.

Bell AJ, Chisholm M, Hickton M: Reversal of coagulopathy in Kasabach-Merritt syndrome with tranexamic acid. Scand J Haematol 37:249, 1986.

Warrell RP, Kempin SJ: Treatment of severe coagulopathy in the Kasabach-Merritt syndrome with aminocaproic acid and cryoprecipitate. N Eng J Med 313:309, 1985.

Fine NL, Applebaum J, Elguezabal A, Castleman L: Multiple coagulation defects in association with dissecting aneurysm. Arch Intern Med 119:522, 1967.

Fisher DI, Yawn DH, Crawford S: Preoperative disseminated intravascular coagulation associated with aortic aneurysm. Arch Surg 118:1252, 1983.

Bieger R, Vreeken J, Stibbe J, Loeliger EA: Arterial aneurysm as a cause of consumption coagulopathy. N Engl J Med 285:152, 1971.

ten Cate JW, Timmers H, Becker AE: Coagulopathy in ruptured or dissecting aortic aneurysm. Am J Med 59:171, 1975.

Mulcare RJ, Royster TS, Phillips LL: Intravascular coagulation in surgical procedures on the abdominal aorta. Surg Gynecol Obstet 143:730, 1976.

Wilcox JN, Smith KM, Schwartz SM, Gordon D: Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 86:2839, 1989.

Straub PW, Kessler S: Umzatz und lokalisation von 1131-Fibrinogen bei chronischer intravasaler Gerinnung. Schweiz med Wochenschr 100:2001, 1970.

Goto H, Kimoto A, Kawaguchi H, et al: Surgical treatment of abdominal aortic aneurysm complicated with chronic disseminated intravascular coagulopathy. J Cardiovasc Surg 26:280, 1985.

Quick AJ, Georgatsos JG, Hussey CV: The clotting activity of human erythrocytes: theoretical and clinical implications. Am J Med 228:207, 1954.

Surgenor DM: Erythrocytes and blood coagulation. Thromb Diathes Hemorrh 32:247, 1974.

Brain MC, Esterly JR, Beck EA: Intravascular haemolysis with experimentally produced vascular thrombi. Br J Haematol 13:868, 1967.

Rubenberg ML, Regoeczi E, Bull BS, et al: Microangiopathic haemolytic anaemia: the experimental production of haemolysis and red-cell fragmentation by defibrination in vivo. Br J Haematol 14:627, 1968.

Baker LRI, Rubenberg ML, Dacie JV, Brain MC: Fibrinogen catabolism in microangiopathic haemolytic anaemia. Br J Haematol 14:617, 1968.

Drinker CK, Brittingham HH: The cause of the reactions following transfusion of citrated blood. Arch Intern Med 23:133, 1919.

Astrowe PS: Hemolysis following transfusion. JAMA 79:1511, 1923.

Krevans JR, Jackson DP, Conley Cl, Hartman RC: The nature of the hemorrhagic disorder accompanying hemolytic transfusion reactions in man. Blood 12:834, 1957.

Mannucci PM, Lobina GF, Caocci L, Dioguardi N: Effect on blood coagulation of massive intravascular haemolysis. Blood 33:207, 1969.

Hamilton K, Hattori R, Esmon C, Sims P: Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for assembly of the prothrombinase enzyme complex. J Biol Chem 265:3809, 1990.

Weiner CP: The obstetric patient and disseminated intravascular coagulation. Clin Perinatol 13:705, 1986.

DeLee JB: A case of fatal hemorrhagic diathesis with premature detachment of the placenta. Am J Obstet Gynecol 44:785, 1901.

Pritchard JA, Brekken AL: Clinical and laboratory studies on severe abruptio placentae. Am J Obstet Gynecol 97:681, 1967.

Eskes TK: Abruptio placentae. A “classic” dedicated to Elizabeth Ramsey. Eur J Obstet Gynecol Reprod Biol 75:63, 1997.

Schneider Cl: Fibrin embolism (disseminated intravascular coagulation) with defibrination as one of the end results during abruptio placentae. Surg Gynecol Obstet 92:27, 1951.

Diekmann WJ: Blood chemistry and renal function in abruptio placentae. Am J Obstet Gynecol 31:734, 1936.

Weiner CP: The obstetric patient and disseminated intravascular coagulation. Clin Perinatol 13:705, 1986.

Crane S, Chun B, Acker D: Treatment of obstetrical hemorrhagic emergencies. Curr Opin Obstet Gynecol 5:675, 1993.

Kleiner GJ, Merskey C, Johnson AJ, Markus WD: Defibrination in normal and abnormal parturition. Br J Haematol 19:159, 1970.

Steiner PE, Lushbaugh CC: Maternal pulmonary embolism by amniotic fluid as a cause of obstetric shock and unexpected deaths in obstetrics. JAMA 117:1245, 1340, 1941.

Morgan M: Amniotic fluid embolism. Anaesthesia 34:20, 1979.

Clark SL, Hankins GD, Dudley DA, et al: Amniotic fluid embolism: analysis of the national registry. Am J Obstet Gynecol 172:1158, 1995.

Peterson EP, Taylor HB: Amniotic fluid embolism. An analysis of 40 cases. Obstet Gynecol 35:787, 1970.

Yaffe H, Eldor A, Hornshtein E, Sadovsky E: Thromboplastic activity in amniotic fluid during pregnancy. Obstet Gynecol 50:454, 1977.

Phillips LL, Davidson EC: Procoagulant properties of amniotic fluid. Am J Obstet Gynecol 113:911, 1972.

Stahnke E: Über das Verhalten der blutplattchen bei Eklampsie. Zentralbl Gynak 46:391, 1922.

McKay DG, Marrill SJ, Weiner AE, et al: The pathologic anatomy of eclampsia, bilateral renal cortical necrosis, pituitary necrosis, and other acute fatal complications of pregnancy, and its possible relationship to the generalized Shwartzman phenomenon. Am J Obstet Gynecol 55:507, 1953.

Page EW: On the pathogenesis of pre-eclampsia and eclampsia. J Obstet Gynecol Br Commonwealth 79:883, 1972.

Gibson B, Hunter D, Neame PB, Kelton JG: Thrombocytopenia in pre-eclampsia and eclampsia. Semin Thromb Haemost 8:234, 1982.

McKay DG: Chronic intravascular coagulation in normal pregnancy and pre-eclampsia. Contr Nephrol 25:108, 1981.

Bonnar J, McNichol GP, Douglas AS: Coagulation and fibrinolytic systems in pre-eclampsia and eclampsia. Br Med J 2:12, 1971.

Giles C: Intravascular coagulation in gestational hypertension and pre-eclampsia: The value of haematological screening tests. Clin Lab Haematol 4:351, 1982.

Kobayashi T, Terao T: Preeclampsia as chronic disseminated intravascular coagulation. Study of two parameters–thrombin-antithrombin III complex and D-dimers. Gynecol Obstet Invest 24:170, 1987.

Metz J, Cincotta R, Francis M, et al: Screening for consumptive coagulopathy in preeclampsia. Int J Gynaecol Obstet 46:3, 1994.

Schjetlein R, Haugen G, Wisloff F: Markers of intravascular coagulation and fibrinolysis in preeclampsia: association with intrauterine growth retardation. Acta Obstet Gynecol Scand 76:541, 1997.

Borok Z, Weitz J, Owen J, et al: Fibrinogen proteolysis and platelet alpha granule release in pre-eclampsia/eclampsia. Blood 63:525, 1984.

Broughton Pipkin F, Rubin PC: Pre-eclampsia—the “disease of theories.” Br Med Bull 50:381, 1994.

Weinstein L: Syndrome of hemolysis, elevated liver enzymes, and low platelet count; a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 142:159, 1982.

Sibai BM, Ramadan MK, Usta I, et al: Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets. Am J Obstet Gynecol 169:1000, 1993.

Aarnoudse JG, Houthoff JH, Weits K, et al: A syndrome of liver damage and intravascular coagulation in the last trimester of normotensive pregnancy. A clinical and histopathological study. Br J Obstet Gynaecol 93:145, 1986.

De Boer K, Buller HR, ten Cate JW, et al: Coagulation studies in the syndrome of haemolysis, elevated liver enzymes and low platelets. Br J Obstet Gynecol 98:42, 1991.

Audibert F, Friedman SA, Frangieh AY, Sibai BM: Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 175:460, 1996.

Barton JR, Sibai BM: Hepatic imaging in HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). Am J Obstet Gynecol 174:1820, 1996.

Van Dam PA, Renier M, Backelandt M, et al: Disseminated intravascular coagulation and the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe pre-eclampsia. Obstet Gynecol 73:97, 1989.

Martin JN Jr, Files JC, Blake PG, et al: Postpartum plasma exchange for atypical preeclampsia-eclampsia as HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 172:1107, 1995.

Sullivan CA, Magann EF, Perry KG Jr, et al: The recurrence risk of the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP) in subsequent gestations. Am J Obstet Gynecol 171:940, 1994.

Lee W, Clark SL, Cotton DB, et al: Septic shock during pregnancy. Am J Obstet Gynecol 159:410, 1988.

McKay DC, Jewett JF, Reid DE: Endotoxin shock and the generalized Shwartzman reaction in pregnancy. Am J Obstet Gynecol 78:546, 1959.

Pfau von P, Lasch HG, Gunther O: Sanarelli-Shwartzmann-Phaenomen bei febrilen Fehlgeburten und Schweren Schock und Blutungs-zustanden in der Geburtshilfe. Gynaecologia 150:17, 1960.

Kuhn W, Graeff H: Infizierter Abort und disseminierte intravaskulare Gerinnung (DIG). Med Welt 22:1199, 1971.

Koch HH, Keller O: Unsere Erfahrungen mit den prophylaktischen massnahmen zur Verhinderung des Sanarelli-Shwartzman Phaenomen (SSP) beim infizierten Abort. Geburtshilfe Frauenheilkd 33:460, 1973.

Pritchard JA, Ratnoff OD: Studies of fibrinogen and other hemostatic factors in women with intrauterine death and delayed delivery. Surg Gynecol Obstet 101:467, 1955.

Romero R, Copel JA, Hobbins JC: Intrauterine fetal demise and hemostatic failure: the fetal death syndrome. Clin Obstet Gynecol 28:24, 1985.

Lerner R, Margolin M, Slate WG, et al: Heparin in the treatment of hypofibrinogenemia complicating fetal death in utero. Am J Obstet Gynecol 97:373, 1967.

Gallup DG, Lucas WE: Heparin treatment of consumption coagulopathy associated with intrauterine fetal death. Obstet Gynecol 35:690, 1970.

Berkowitz RL, Stone JL, Eddleman KA: One hundred consecutive cases of selective termination of an abnormal fetus in a multifetal gestation. Obstet Gynecol 90:606, 1997.

Bacq Y, Riely CA: Acute fatty liver of pregnancy: the hepatologist’s view. Gastroenterologist 1:257, 1993.

Usta IM, Barton JR, Amon EA, et al: Acute fatty liver of pregnancy: an experience in the diagnosis and management of fourteen cases. Am J Obstet Gynecol 171:1342, 1994.

Pereira SP, O’Donohue J, Wendon J, Williams R: Maternal and perinatal outcome in severe pregnancy-related liver disease. Hepatology 26:1258, 1997.

Castro MA, Goodwin TM, Shaw KJ, et al: Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy. Am J Obstet Gynecol 174:211, 1996.

Hathaway WE, Mull MM, Peschet GS: Disseminated intravascular coagulation in the newborn. Pediatrics 43:233, 1969.

Corrigan JJ: Activation of coagulation and disseminated intravascular coagulation in the newborn. Am J Pediat Hematol Oncol 1:245, 1979.

Woods WG, Luban NL, Hilgartner MW, Miller DR: Disseminated intravascular coagulation in the newborn. Am J Dis Child 133:44, 1979.

Corrigan JJ: Disseminated intravascular coagulopathy. Pediatr Rev 1:37, 1979.

Gross SJ, Filston HC, Anderson JC: Controlled study of treatment for disseminated intravascular coagulation in the neonate. J Pediatr 100:445, 1982.

Emery ML: Disseminated intravascular coagulation in the neonate. Neonatal Netw 11:5, 1992.

Markarian M, Lubchenko LO, Rosenblut E, et al: Hypercoagulability in premature infants with special reference to the respiratory distress syndrome and hemorrhage: II. The effect of heparin. Biol Neonate 17:98, 1971.

Gobel U, von Voss H, Jurgens H, et al: Efficiency of heparin in the treatment of newborn infants with respiratory distress syndrome and disseminated intravascular coagulation. Eur J Pediatr 133:47, 1980.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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