Chapter 129: Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is a clinicopathologic syndrome in which widespread intravascular coagulation occurs as a result of exposure or production of procoagulants insufficiently balanced by natural anticoagulant mechanisms and endogenous fibrinolysis. Perturbation of the endothelium in the microcirculation along with stimulated inflammatory cells and release of inflammatory mediators play a key role in this mechanism. DIC may cause tissue ischemia from occlusive microthrombi, and bleeding from the consumption of platelets and coagulation factors and, in some cases, an excessive fibrinolytic response. DIC complicates a variety of disorders, and the complexity of its pathophysiology has made it the subject of a voluminous literature.^{1,2,3,4,5,6,7}

In 1834, Dupuy reported that injection of brain material into animals caused widespread clots in blood vessels, thus providing the first description of DIC.⁸ In 1865, Trousseau described the tendency to thrombosis, sometimes disseminated, in cachectic patients with malignancies.⁹ In 1873, Naunyn showed that disseminated thrombosis could be evoked by intravenous injection of dissolved red cells, and Wooldridge demonstrated that the procoagulant involved was a substance contained in the stroma of the red cells.^10,11,12

In 1955, Ratnoff and associates described the hemostatic abnormalities, which we would currently classify as DIC, that occur in women with fetal death or amniotic fluid embolism.¹³ The mechanism by which DIC can lead to bleeding was clarified only in 1961, when Lasch and coworkers introduced the concept of consumption coagulopathy, and McKay established that DIC is a pathogenetic feature of a variety of diseases.^1,14 Sizable series of cases were first described in the late 1960s, following the introduction of defined laboratory criteria for DIC.¹⁵ Yet despite the vast experience that has been accumulated, DIC still constitutes a major clinicopathologic and therapeutic challenge.

Diffuse multiorgan bleeding, hemorrhagic necrosis, microthrombi in small blood vessels, and thrombi in medium and large blood vessels are common findings at autopsy, although patients who had unequivocal clinical and laboratory signs of DIC may not have had confirming postmortem findings.^16,17 Conversely, some patients in whom clinical and laboratory signs were not consistent with DIC had typical autopsy findings.^18,19 This occasional lack of correlation among clinical, laboratory, and pathologic findings is partly a result of extensive postmortem changes in the blood, for example, excessive fibrinolysis, but remains unexplained in most instances.¹⁷ Organs most frequently involved by diffuse microthrombi are the lungs and kidneys, followed by the brain, heart, liver, spleen, adrenal glands, pancreas, and gut. Specific immunohistologic techniques and ultrastructural analysis have revealed that most thrombi consist of fibrin monomers or polymers in combination with platelets. In addition, involvement of activated mononuclear cells and other signs of inflammatory activation are frequently present.²⁰ In cases of long-lasting DIC, organization and endothelialization of the microthrombi are often observed. Acute tubular necrosis is more frequent than renal cortical necrosis.¹⁶

A significant proportion of patients with chronic DIC have nonbacterial thrombotic endocarditis involving mainly the mitral and aortic valves.¹⁹ Moreover, in a retrospective pathologic study, approximately 50 percent of patients with nonbacterial thrombotic endocarditis had DIC.¹⁸ These heart lesions can be a source of arterial embolization, leading to infarction of the brain, kidneys, and myocardium.

INFLAMMATION AND ENDOTHELIUM IN DISSEMINATED INTRAVASCULAR COAGULATION

Various triggers cause an hemostatic imbalance that gives rise to a procoagulant state (Fig. 129–1). The most important mediators responsible for this imbalance are cytokines.²¹ There is an extensive crosstalk between coagulation and inflammatory systems, whereby inflammation leads to activation of coagulation, and coagulation stimulates inflammatory activity.²² These interactions are highlighted in sepsis-induced systemic activation of coagulation and inflammation that lead to specific organ dysfunctions.²³ The endothelium of the capillary bed is the most important interface in which the interaction between inflammation and coagulation takes place. Endothelial cells may be a source of tissue factor and can thereby be involved in the initiation of coagulation activation. All physiologic anticoagulant systems and various adhesion molecules that may modulate both inflammation and coagulation are connected to the endothelium. In sepsis, endothelial glycosaminoglycans present in the glycocalyx are downregulated by proinflammatory cytokines, thereby impairing the functions of antithrombin (AT), tissue factor pathway inhibitor (TFPI), leukocyte adhesion, and leukocyte transmigration. Because the glycocalyx also plays a role in other endothelial functions, including maintenance of the vascular barrier function, nitric oxide–mediated vasodilation, and antioxidant activity, all these processes can be impaired in DIC (see “Role of Oxidative Stress and Vasoactive Molecules” below).^24,25 Moreover, specific disruption of the glycocalyx results in thrombin generation and platelet adhesion within a few minutes.^26,27

Endothelial perturbation constitutes a sine qua non for most patients with DIC. Following injury or infection, the integrity of the endothelium is compromised, mononuclear cells are activated by cytokine and hormonal signals, additional cytokines and surface receptors are upregulated, procoagulant proteins and platelets are activated, the endothelium changes from an anticoagulant to procoagulant surface, and fibrinolysis is impeded. This sequence of events is typical for the systemic inflammatory response syndrome and can lead to microvascular thrombosis with ensuing multiorgan dysfunction and eventually to multiorgan failure.

ROLE OF CYTOKINES AND TISSUE FACTOR

Tissue factor (TF) plays a central role in the initiation of inflammation-induced coagulation in DIC.²⁸ Blocking TF activity completely inhibits inflammation-induced thrombin generation in experimental models of endotoxemia or bacteremia.^29,30 Most cells constitutively expressing TF are found in tissues not in direct contact with blood, such as the adventitial layer of larger blood vessels. TF becomes exposed to blood upon disruption of the vascular integrity, or when cells present in the circulation, such as monocytes, are triggered to express TF. The in vivo expression of TF is dependent on interleukin (IL)-6 generation; inhibition of IL-6, unlike inhibition of other proinflammatory cytokines, completely abrogates TF-dependent thrombin generation in experimental endotoxemia.^21,31 In severe sepsis, monocytes, stimulated by proinflammatory cytokines, express TF, which leads to systemic activation of coagulation.³² Even in experimental low-dose endotoxemia in healthy subjects, a 125-fold increase in TF mRNA levels in blood monocytes can be detected.³³ A potential alternative source of TF may be endothelial cells, polymorphonuclear cells, and other cell types. It is hypothesized that TF from these sources is shuttled between cells through microparticles derived from activated mononuclear cells.³⁴ However, it is unlikely that cells other than monocytes synthesize TF in substantial quantities.^32,35 Tumor necrosis factor (TNF)-α and IL-1, also generated during inflammation, impair the physiologic anticoagulant pathways.^31,36,37

AMPLIFYING ROLE OF THROMBIN AND PLATELETS

The TF–factor VIIa complex catalyzes the conversion of factor X to Xa, and factor Xa, in turn, forms the prothrombinase complex with factor Va, prothrombin (factor II), and calcium ions, thereby generating thrombin, and converting fibrinogen into fibrin. The TF–factor VIIa complex can also activate factor IX, and factor IXa forms the tenase complex with activated factor VIII and calcium ions, generating additional factor Xa, thereby forming an essential amplification loop of thrombin generation. The assembly of the prothrombinase and tenase complexes are markedly facilitated if a suitable phospholipid surface is available, such as the membrane of activated platelets. In the setting of inflammation-induced activation of coagulation, platelets can be activated directly by endotoxin or by proinflammatory mediators, such as the membrane of platelet-activating factor. Thrombin itself is one of the strongest platelet activators (Chap. 115).

Activation of platelets may also accelerate fibrin formation by another mechanism. The expression of TF on monocytes is markedly stimulated by the presence of platelets and granulocytes in a P-selectin–dependent reaction.³⁸ This effect may be the result of nuclear factor kappa B (NF-κB) activation induced by binding of activated platelets to neutrophils and mononuclear cells.³⁹ This cellular interaction also markedly enhances the production of IL-1β, IL-8, monocyte chemotactic protein (MCP)-1, and TNF-α.⁴⁰

Thrombin generated by the TF pathway amplifies both clotting and inflammation through the following activities: (1) it activates platelets, giving rise to platelet aggregation and augmenting platelet functions in coagulation; (2) it activates factors VIII, V, and XI, yielding further thrombin generation; (3) it activates proinflammatory factors via protease-activated receptors (PARs); (4) it activates factor XIII to factor XIIIa, which crosslinks fibrin clots; (5) it activates thrombin-activatable fibrinolysis inhibitor (TAFI), making clots resistant to fibrinolysis; and (6) it increases expression of adhesion molecules, such as L-selectin, thereby promoting the inflammatory effects of leukocytes.⁴¹

Paradoxically, at low concentrations, thrombin exhibits both antiinflammatory and anticoagulant effects because it binds to thrombomodulin and activates protein C to the activated form, which, in turn, downregulates inflammation and serves as an “off switch” for further thrombin generation (Chap. 116).

ROLE OF COAGULATION PROTEASES IN UPREGULATING INFLAMMATION

Coagulation proteases and protease inhibitors not only interact with coagulation proteins, but also with specific cell receptors to induce signaling pathways. In particular, protease interactions that affect inflammatory processes may be important in critically ill patients. Coagulation of whole blood in vitro results in a detectable expression of IL-1β mRNA in blood cells,⁴² and thrombin markedly enhances endotoxin-induced IL-1 activity in culture supernatants of guinea pig macrophages.⁴³ Similarly, clotted blood produces IL-8 in vitro.⁴⁴

Factor Xa, thrombin, and fibrin can also activate endothelial cells, eliciting the synthesis of IL-6 and IL-8.^45,46 Coagulation proteases such as thrombin, factor Xa, and factor VIIa–TF complex induce inflammatory upregulation via leukocyte, endothelial cell, and platelet PAR-1, PAR-2, PAR-3, and PAR-4, which are located on leukocytes, endothelial cells, and platelets.⁴⁷ PARs have an extracellular domain, seven transmembrane domains, and an intracellular domain that is coupled to specific G-proteins that transmit signaling. PAR-1, PAR-3, and PAR-4 are activated by thrombin through cleavage of a specific aminoterminus bond creating a tethered ligand that activates the receptor. PAR-2 can be cleaved by factor Xa–TF–factor VIIa complex and by other proteases.⁴⁸ Activated PARs then lead through mitogen-activated protein kinase and NF-κB signaling pathways to cell motility, shape change, proliferation, endogenous secretagogue release, and apoptosis. The activated protein C (APC)–endothelial protein C receptor complex (see “Role of Natural Anticoagulant Pathways” below) appears to be the “off switch” for PAR activation by the proteases. These counterbalances determine the magnitude of coagulation and inflammatory upregulation by PARs. For example, factor VIIa–TF binding to PAR-2 in the lungs is proinflammatory and appears to play a role in acute respiratory distress syndrome (ARDS), raising the possibility that TFPI might be therapeutic in this circumstance.⁴⁹ This finding is consistent with data from animal studies demonstrating that TFPI can protect baboons from a LD100 of Escherichia coli, likely by impeding factor VIIa–TF activation of PAR-2 and thereby attenuating release of IL-6 and other proinflammatory agents.

ROLE OF FIBRINOGEN AND FIBRIN

Fibrinogen and fibrin directly influence the production of proinflammatory cytokines and chemokines (including TNF-α, IL-1β, and MCP-1) by mononuclear cells and endothelial cells.⁵⁰ Fibrinogen-deficient mice display inhibition of macrophage adhesion and less thrombin-mediated cytokine production in vivo. The effects of fibrinogen on mononuclear cells seem to be mediated by toll-like receptor-4, which is also the receptor of endotoxin.

ROLE OF NATURAL ANTICOAGULANT PATHWAYS

Procoagulant activity is regulated by three important anticoagulant pathways: AT, the protein C system, and TFPI. In DIC, the function of all three pathways can be impaired (Fig. 129–2).⁵¹

The serine protease inhibitor AT is the main inhibitor of thrombin and factor Xa. Without heparin, AT neutralizes coagulation enzymes in a slow, progressive manner.⁵² Heparin induces conformational changes in AT that result in at least a 1000-fold enhancement of AT activity. Thus, the clinical efficacy of heparin is attributed to its interaction with AT. Endogenous glycosaminoglycans, such as heparan sulfate, also promote on the vessel wall AT-mediated inhibition of thrombin and other coagulation enzymes. During severe inflammatory responses, AT levels are markedly decreased because of impaired synthesis, degradation by elastase from activated neutrophils, and consumption as a consequence of ongoing thrombin generation.⁵³ Proinflammatory cytokines also cause reduced synthesis of glycosaminoglycans on the endothelial surface, thereby reducing AT function.⁵⁴

APC appears to play a central role in the pathogenesis of sepsis and associated organ dysfunction.⁵⁵ There is ample evidence that decreased function of the protein C pathway contributes to the derangement of coagulation in sepsis.^49,56 The circulating zymogen protein C is activated by thrombin when it is bound to thrombomodulin at the endothelial cell surface.⁵⁷ APC acts with its cofactor protein S and degrades the essential cofactors Va and VIIIa, and hence, is an effective anticoagulant. The endothelial protein C receptor (EPCR) accelerates the activation of protein C several-fold, and also serves as a receptor for APC, thereby augmenting APC’s anticoagulant and antiinflammatory activities.⁵⁸

In patients with severe inflammation, the protein C pathway malfunctions at virtually all levels. Plasma levels of the zymogen protein C are decreased because of impaired synthesis, consumption, and degradation by proteolytic enzymes, such as neutrophil elastase.^59,60,61 Furthermore, a significant downregulation of thrombomodulin, caused by proinflammatory cytokines such as TNF-α and IL-1, results in diminished protein C activation.^62,63 Low levels of free protein S may further compromise the function of the protein C system. In plasma, 60 percent of protein S is complexed with a complement regulatory protein, C4b-binding protein (C4bBP), and exhibits no activity. The remaining protein S in plasma is free and functional. It was suggested that increased plasma levels of C4bBP caused by the acute phase reaction in inflammatory diseases results in a relative protein S deficiency, which further contributes to a procoagulant state during sepsis. Indeed, infusion of C4bBP in combination with a sublethal dose of E. coli into baboons resulted in a lethal response with severe organ damage because of DIC.⁶⁴

In sepsis, the EPCR is downregulated, which further impairs the function of the protein C pathway.⁶⁵ Sepsis can also cause resistance toward APC because of a substantial increase in factor VIII levels.⁶⁶

A third inhibitory mechanism of thrombin generation involves TFPI, the main inhibitor of the TF–factor VIIa complex and factor Xa. The role of TFPI in the regulation of inflammation-induced coagulation activation is not completely clear. Administration of recombinant TFPI blocks inflammation-induced thrombin generation in humans, and pharmacologic doses of TFPI prevent mortality during systemic infection and inflammation in experimental animals suggesting that TFPI can modulate TF-mediated coagulation.^67,68

NATURAL ANTICOAGULANTS AND INFLAMMATION

AT possesses antiinflammatory properties, many of which are mediated by its actions in the coagulation cascade.⁶⁹ By inhibiting thrombin, AT blunts activation of many inflammatory mediators released by platelets and endothelial cells that recruit and activate leukocytes.⁷⁰ At high concentrations, AT also possesses potent antiinflammatory properties that are independent of its anticoagulant activity.⁷⁰ Another effect of AT is the induction of prostacyclin release from endothelial cells.^71,72,73 Prostacyclin inhibits platelet activation and aggregation, blocks neutrophil tethering to blood vessels, and decreases endothelial cell production of various cytokines and chemokines.⁷⁴

AT also interacts directly with leukocytes and lymphocytes. It binds to receptors, such as syndecan-4, on the cell surfaces of neutrophils, monocytes, and lymphocytes, thereby blocking the adhesion of these cells to endothelial cells, their activation and migration. This effect, in turn, ameliorates the severity of capillary leakage and subsequent organ damage.

The protein C system also has an important function in modulating inflammation.^75,76 Blocking the protein C pathway in septic baboons exacerbates the inflammatory response, and in contrast, administration of APC ameliorates the inflammatory activation upon the intravenous infusion of E. coli.⁷⁷ Support for the notion that APC has antiinflammatory properties comes from in vitro observations, demonstrating an APC binding site on monocytes, that may mediate downstream inflammatory processes,^78,79 and from experiments showing that APC can block NF-κB nuclear translocation, which is a prerequisite for increased proinflammatory cytokine levels and adhesion molecules.⁸⁰ These in vitro findings are supported by in vivo studies in mice with targeted disruption of the protein C gene. In these mice with genetic deficiencies of protein C, endotoxemia was associated with a more marked increase in proinflammatory cytokines and other inflammatory responses as compared with wild-type mice.^81,82

It is likely that the antiinflammatory effects of APC are mediated by the EPCR.⁷⁵ Binding of APC to EPCR influences gene expression profiles of cells by inhibiting NF-κB nuclear translocation.^79,80 The EPCR-APC complex itself can translocate from the plasma membrane into the cell nucleus, which may be another mechanism of modulating gene expression, although the relative contribution of this nuclear translocation and cell surface signaling is uncertain.⁵⁶ Like APC, EPCR itself may have antiinflammatory properties. Blocking the EPCR with a specific monoclonal antibody aggravates both the coagulation and the inflammatory response to E. coli infusion.⁶⁵

Apart from the effect on cytokine levels, APC causes diminished leucocyte chemotaxis and adhesion to the activated endothelium.^83,84,85 A localized antiinflammatory effect of APC has been demonstrated in the lung.⁸⁶ One mechanism for this effect may be inhibition of the expression of platelet-derived growth factor in the lung.⁸⁷ Also, APC protects against the disruption of endothelial cell barrier in sepsis.^88,89,90 APC also inhibits endothelial cell apoptosis by a mechanism that seems to be mediated by binding of APC to EPCR and requires PAR-1.^91,92 Signaling through this pathway can affect Bcl-2 homologue protein, which can inhibit apoptosis, and further suppresses p53, that is a proapoptotic transcription factor.^93,94

DYSREGULATION OF FIBRINOLYSIS

In experimental models of DIC, fibrinolysis is initially activated but subsequently inhibited, because of an increased release of plasminogen activator inhibitor-I (PAI-1) by endothelial cells.⁹⁵ These effects are mediated by TNF-α and IL-1.^96,97 In a study of 69 DIC patients (31 with multiorgan failure), higher levels of tissue-type plasminogen activator (t-PA) antigen and PAI-1 with depressed levels of α₂-antiplasmin were observed in patients with DIC and multiorgan failure compared to DIC patients without multiorgan failure.⁹⁸ This finding supports the conclusion that fibrinolysis is an important mechanism in preventing multiorgan failure.

Experiments in mice with targeted disruptions of genes encoding components of the plasminogen–plasmin system confirm that fibrinolysis plays a major role in inflammation. Mice with a deficiency of plasminogen activators have more extensive fibrin deposition in organs when challenged with endotoxin, whereas PAI-1 knockout mice, in contrast to wild-type controls, have no microvascular thrombosis upon endotoxin administration.⁹⁹

TAFI, like PAI-1, may play a role in impeding fibrinolysis and in augmenting formation of microvascular thrombi. Studies in a DIC cohort demonstrated very low levels of TAFI proportionate to thrombin generation in such patients, particularly in those with infection-associated DIC.¹⁰⁰ Hence, TAFI may contribute (along with PAI-1) to microvascular thrombosis-induced ischemia in organs resulting in multiorgan dysfunction.

ROLE OF OXIDATIVE STRESS AND VASOACTIVE MOLECULES

Superoxides and hydroxyl radicals are generated during sepsis and other organ injury states that predispose to DIC. Each is a proinflammatory agent that may lead to recruitment of neutrophils, formation of chemotactic factors, lipid peroxidation, and stimulation of NF-κB, which induces cytokine upregulation.¹⁰¹ In addition, formation of peroxynitrite by these radicals exacerbates inflammation by (1) deactivating superoxide dismutase, which ordinarily would eliminate these superoxides and other radicals, and (2) exerting damaging effects on deoxyribonucleic acid, nicotinamide adenine dinucleotide, and ATP. For example, evidence indicates that the poor response to pressors in shock-like states associated with DIC may be directly related to their deactivation by superoxides.

Adding further insult, high levels of superoxide impair vascular response to nitrous oxide, thereby creating an imbalance in the signaling to vascular cells. Because of the strategic importance of an intact endothelium for attenuating any microangiopathic process, the most devastating effect of excessive generation of superoxides and associated free radicals may be their role in inducing endothelial apoptosis, which exacerbates capillary leak.¹⁰¹

Vasoactive substances play a critical role in the evolution of DIC. The vasodilatory agent nitric oxide (NO) and the vasoconstrictor endothelin have been measured in experimental rat models of DIC induced by both TF infusion and lipopolysaccharide (LPS) infusion.¹⁰² LPS infusion increased both NO and endothelin remarkably, whereas TF infusion increased NO more than did LPS but did not stimulate endothelin significantly. The differential stimuli–response mechanisms may explain why LPS-induced DIC so prominently displays tissue infarction leading to multiorgan dysfunction (e.g., sepsis) compared to DIC that is predominately induced by TF exposure (e.g., head trauma).

METABOLIC MODULATION OF COAGULATION IN DISSEMINATED INTRAVASCULAR COAGULATION

Because there is a tight relationship between plasma lipoproteins and coagulation, it has been suggested that lipoprotein metabolism modulates coagulation in DIC.¹⁰³ In vitro experiments showed that plasma large very-low-density lipoprotein, small very-low-density lipoprotein, intermediate-density lipoprotein, and low-density lipoprotein stimulate activation of coagulation by supporting factor VII activation or by stimulating monocytes to express TF.¹⁰⁴ Lipid infusion potentiates in animals endotoxin-induced coagulation activation, as indicated by increased plasma levels of prothrombin fragments 1 and 2, thrombin–AT III complex, and PAI-1.¹⁰⁵ High-density lipoprotein (HDL) exerts opposite effects. Administration of recombinant HDL (rHDL) ameliorates the inflammatory response, inhibits coagulation, and augments fibrinolysis,¹⁰⁶ as reflected by reduced thrombin generation and increased levels of t-PA antigen following administration of endotoxin.

Endogenous lipid levels may have similar effects. Human subjects with low endogenous HDL-cholesterol plasma levels injected with small doses of endotoxin had a more pronounced increase in markers of coagulation activation in comparison with subjects with high endogenous HDL levels.¹⁰⁷ Also, patients heterozygous for familial hypercholesterolemia whose low-density lipoproteins level is increased were more prone to activation of coagulation upon an inflammatory stimulus.¹⁰⁸

Hyperglycemia and hyperinsulinemia, as seen in type 2 diabetes mellitus and the associated metabolic syndrome, affect hemostasis.^109,110,111 In these circumstances, there is a marked decrease of endogenous fibrinolysis because of increased upregulation of plasma levels of PAI-1. Also, a modulatory effect of glucose/insulin on coagulation in an inflammatory setting has been described. Inflammation-induced TF gene expression was elevated in the brain, lung, kidney, heart, liver, and adipose tissues of diabetic mice compared with controls. Administration of insulin to lean mice induced enhanced inflammation-driven TF mRNA in the kidney, brain, lung, and adipose tissue.¹¹² In a hyperglycemic normoinsulinemic study in healthy subjects, there was an increased sensitivity toward endotoxin exhibited by upregulation of TF expression.¹¹³ Strict glucose regulation in critically ill patients improves survival and reduces morbidity that is probably related to a better control of the derangement of coagulation and a faster resolution of coagulation abnormalities.¹⁰³

CONSUMPTION OF HEMOSTATIC FACTORS

The widespread generation of thrombin in DIC induces deposition of fibrin, which leads to the consumption of substantial amounts of platelets, fibrinogen, factors V and VIII, protein C, AT, and components of the fibrinolytic system. This situation results in massive depletion of these components that is further aggravated because of their decreased synthesis by the liver, which frequently is affected in DIC. Depending on the magnitude and nature of component depletion, bleeding, enhanced thrombosis, or both can result. Bleeding can be promoted by fibrinolysis-derived fibrin degradation products (FDPs) that exhibit anticoagulant and antiplatelet aggregation effects (see Fig. 129–1). Microangiopathic hemolytic anemia also occurs as a result of blood cells passing through vessels that are partially occluded by thrombi.

Numerous disorders can provoke DIC, but only a few constitute major causes, as can be inferred from retrospective clinical studies (Table 129–1).¹¹⁴ Infectious diseases and malignant disorders together account for approximately two-thirds of DIC cases in the major series (Table 129–2). Trauma was a major cause of DIC in some series, probably reflecting the specialized nature of the clinical practice in those centers.¹¹⁵

Clinical manifestations are attributable to DIC, the underlying disease, or both (Table 129–3). 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. These variations probably reflect the different nature of the underlying disorders in the respective series.

BLEEDING

Acute DIC frequently is heralded by hemorrhage into the skin at multiple sites.¹¹⁵ Petechiae, ecchymoses, and oozing from venipunctures, arterial lines, catheters, and injured tissues are common. Bleeding also may occur on mucosal surfaces. Hemorrhage may be life-threatening, with massive bleeding into the gastrointestinal tract, lungs, central nervous system, or orbit. Patients with chronic DIC usually exhibit only minor skin and mucosal bleeding.

THROMBOSIS AND THROMBOEMBOLISM

Extensive organ dysfunction can result from microvascular thrombi or from venous and/or arterial thromboembolism (Table 129–4). For example, involvement of the skin can cause hemorrhagic bullae, acral necrosis, and gangrene. Thrombosis of major veins and arteries and pulmonary embolism occur but are rare. Cerebral embolism can complicate nonbacterial thrombotic endocarditis in patients with chronic DIC.

SHOCK

Both the diseases underlying DIC and the DIC itself can cause shock. For example, septicemia and excessive blood loss because of trauma or obstetric complications by themselves can cause shock. Whatever the cause of shock, its advent in cases with DIC is a serious adverse event.

RENAL DYSFUNCTION

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 cases in all series (see Table 129–3).

LIVER DYSFUNCTION

Hepatocellular dysfunction sufficient to cause jaundice has been reported in 20 to 50 percent of patients with DIC.^4,115 Infectious diseases and prolonged hypotension contribute to hepatic dysfunction.

CENTRAL NERVOUS SYSTEM DYSFUNCTION

Microthrombi, macrothrombi, emboli, and hemorrhage in the cerebral vasculature all have been held responsible for the nonspecific neurologic symptoms and signs displayed by patients with DIC.¹¹⁶ These manifestations include coma, delirium, transient focal neurologic symptoms, and signs of meningeal irritation. Careful exclusion of causes other than DIC is essential.

PULMONARY DYSFUNCTION

Symptoms and signs of respiratory dysfunction in DIC range from transient hypoxemia in mild cases to pulmonary hemorrhage and ARDS in severe cases.^117,118,119 Pulmonary hemorrhage is heralded by hemoptysis, dyspnea, and chest pain. Physical examination reveals rales, wheezing, and occasionally a pleural friction rub. Chest imaging shows diffuse infiltration resulting from excessive intraalveolar hemorrhage. ARDS is characterized by tachypnea, auscultatory silence, hypoxemia, low lung compliance, normal wedge pressure, and “white lungs” on chest images.¹²⁰ It stems from severe damage to the pulmonary vascular endothelium, which permits egress of blood components into the pulmonary interstitium and alveoli. This situation leads to intraalveolar 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. When DIC and ARDS are simultaneously triggered, each aggravates the other. Regardless of the mechanism, ARDS is a serious complication in patients with DIC.

MORTALITY

Both DIC and its underlying disorders contribute to the high mortality rate. Mortality correlates independently with the extent of organ dysfunction,¹¹⁵ the degree of hemostatic failure,¹²¹ and increasing age.¹²² Mortality rates in major series of patients with DIC ranged from 31 to 86 percent,^{121,122,123,124} whether or not heparin was administrated. Of note, there is a clear correlation between the severity of DIC and the mortality rate.^121,123,124 In patients with sepsis, the presence of DIC is one of the strongest predictors of 28-day mortality.¹²⁴

No single laboratory test is sensitive or specific enough to allow a definite diagnosis of DIC (Table 129–5). However, some sophisticated laboratory tests, for example, thrombin–AT complex, prothrombin fragment 1.2, are sensitive to ongoing activation of coagulation pathways. Determination of soluble fibrin in plasma is one of the best parameters for detection of ongoing DIC^{125,126,127,128}; when the concentration is above a defined threshold, a diagnosis of DIC is likely.^129,130 Most of the other parameters show a sensitivity of 90 to 100 percent for the diagnosis of DIC but have a rather low specificity,¹³¹ and a wide discordance among various assays.¹³² FDPs may be detected by specific enzyme-linked immunosorbent assays or by latex agglutination assays, allowing rapid and bedside determination.¹³³ None of the available assays discriminates between degradation products of crosslinked fibrin and fibrinogen, a situation that may cause spuriously high results.^134,135 The specificity of high levels of FDPs is therefore limited and many other conditions, such as trauma, recent surgery, inflammation or venous thromboembolism, are associated with elevated FDPs.

Newly developed tests are aimed at the detection of neoantigens on degraded crosslinked fibrin, one of which detects an epitope related to plasmin-degraded crosslinked γ-chain, associated with D-dimer formation. These tests better differentiate degradation of crosslinked fibrin from fibrinogen or fibrinogen degradation products.¹³⁶ D-dimer level is substantially elevated in patients with DIC, but this poorly distinguishes patients with DIC from patients with venous thromboembolism, recent surgery, or inflammatory conditions.^133,137

In routine practice, simple laboratory tests in conjunction with clinical considerations are used for establishing the diagnosis of DIC. The simple tests include platelet count, prothrombin time, fibrinogen level, and fibrin-related markers, such as FDP or D-dimer. Caution should be exercised when using these laboratory parameters in the algorithms described below, because an underlying disease by itself can cause an abnormality. For example, impairment of hemostasis and/or thrombocytopenia unrelated to DIC can arise from hepatic disease and from marrow involvement by leukemia. Impaired hemostasis also may 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 repeated testing, thereby following the dynamics of the process.

A scoring system utilizing the simple laboratory tests has been developed by the subcommittee on DIC of the International Society on Thrombosis and Haemostasis,¹³⁸ and Table 129–6 summarizes a five-step diagnostic algorithm to calculate a DIC score. Tentatively, a score of 5 or more is compatible with DIC, whereas a score of less than 5 may be indicative but is not affirmative for nonovert DIC. By using receiver-operating characteristics curves, an optimal cutoff for a quantitative D-dimer assay was determined, thereby optimizing sensitivity and the negative predictive value of the system.¹³¹ Prospective studies show that the sensitivity of the DIC score is 93 percent, and the specificity is 98 percent.¹²³ The severity of DIC according to this scoring system is related to the mortality in patients with sepsis (Fig. 129–3).¹²⁴ Linking prognostic determinants from critical care measurement scores such as acute physiology and chronic health evaluation (APACHE-II) to DIC scores is an important means to assess prognosis in critically ill patients. In addition, certain biochemical indicators of organ dysfunction may imply a DIC risk. For example, serial assessment of arterial lactate has proved to be a reliable prognostic indicator of DIC development among patients with the systemic inflammatory response syndrome.¹³⁹

Criteria for less-overt DIC have been more difficult to establish.^138,140 In the algorithm for nonovert DIC, the global coagulation tests are scored as with the overt DIC algorithm; however, when scoring by the algorithm is being serially repeated, improvement in any laboratory test confers a negative score (rather than a zero or neutral score). This “trend” scoring allows longitudinal assessment of the patient’s microangiopathy and, when therapy has been instituted, inference on whether the therapy has improved the course of the disease.^121,141 Measurements of several markers for assessing the risk of progression from nonovert to overt DIC and prediction of multiorgan dysfunction are potentially valuable and in the future can be accommodated in the nonovert DIC score. For example, impaired fibrinolysis may play a particularly important role in multiorgan dysfunction resulting from DIC of sepsis.¹⁴² Therefore, assaying PAI-1, plasmin–antiplasmin complexes, or TAFI in septic patients may be important. Another highly sensitive early marker of impending DIC is a monoclonal antibody against APC that identifies a calcium ion-dependent epitope involved in factor Va inactivation.¹⁴³ Whether serial measurement of von Willebrand factor-cleaving protease also will identify individuals at risk early in their disease course, or will help differentiate individuals with microangiopathy who are not prone to progress, needs further data.^144,145

Techniques, such as rotational thrombelastography (ROTEM) enable bedside performance of this test and has again become popular recently in acute care settings.¹⁴⁶ The theoretical advantage of thrombelastography (TEG) over conventional coagulation assays is that is provides an idea of platelet function as well as fibrinolytic activity. Hyper- and hypocoagulability as demonstrated with TEG was shown to correlate with clinically relevant morbidity and mortality in several studies, although its superiority over conventional tests has not unequivocally been established.¹⁴⁷ Even though there are no systematic studies on the diagnostic accuracy of TEG for the diagnosis of DIC, the test may be useful for assessing the global status of the coagulation system in critically ill patients.¹⁴⁸

INFECTIOUS DISEASES

Bacterial infections are among the most common causes of DIC.^5,149 Certain patients are particularly vulnerable to infection-induced DIC, such as immune-compromised hosts, asplenic patients whose ability to clear bacteria, particularly pneumococci and meningococci, is impaired, and newborns whose coagulation inhibitory systems are immature. Infections are frequently superimposed on trauma and malignancies, which themselves are potential triggers of DIC. In addition, infections can aggravate bleeding and thrombosis by directly inducing thrombocytopenia, hepatic dysfunction, and shock associated with diminished blood flow in the microcirculation.¹⁵⁰ Clinically overt DIC may occur in 30 to 50 percent of patients with Gram-negative sepsis.^151,152 DIC is similarly common in patients with Gram-positive sepsis.^153,154 Extreme examples of sepsis-related DIC are (1) group A streptococcus toxic shock syndrome, characterized by deep tissue infection, vascular collapse, vascular leakage, and multiorgan dysfunction; a streptococcal M protein forms complexes with fibrinogen, and these complexes bind to β₂ integrins of neutrophils leading to their activation¹⁵⁵; and (2) meningococcemia, a fulminant Gram-negative infection characterized by extensive hemorrhagic necrosis, DIC, and shock. The extent of hemostatic derangement in patients with meningococcemia correlates with prognosis.^156,157 More frequent Gram-negative infections associated with DIC are caused by Pseudomonas aeruginosa, E. coli, and Proteus vulgaris. Patients affected by such bacteremias may have only laboratory signs of activated coagulation or may present with severe DIC, especially when shock develops.^158,159

Severe secondary deficiency of a disintegrin-like metalloprotease with thrombospondin type 1 repeats (ADAMTS13), the von Willebrand cleaving protease, occurs in patients with sepsis-induced DIC and is associated with a high incidence of acute renal failure.¹⁶⁰

Among the Gram-positive infections, Staphylococcus aureus bacteremia can cause DIC accompanied by renal cortical and dermal necrosis. The mechanism by which DIC is elicited may be related to an α-toxin that activates platelets and induces IL-1 secretion by macrophages.¹⁶¹ Streptococcus pneumoniae infection is associated with the Waterhouse-Friderichsen syndrome,¹⁶² particularly in asplenic patients. Initiation of DIC in these conditions is ascribed to the capsular antigen of the bacterium and to antigen–antibody complex formation.¹⁶³ Other Gram-positive bacteria that can cause DIC are the anaerobic clostridia. Clostridial bacteremia is a highly lethal disease characterized by septic shock, DIC, renal failure, and hemolytic anemia.¹⁶⁴

Activation of the coagulation system has also been documented for nonbacterial pathogens, that is, viruses (causing hemorrhagic fevers),^164,165 protozoa (Malaria),^166,167 and fungi.¹⁶⁸ Common viral infections, such as influenza, varicella, rubella, and rubeola, rarely are associated with DIC.¹⁶⁹ However, purpura fulminans associated with DIC has been reported in patients with infections and either hereditary thrombophilias,^170,171 or acquired antibodies to protein S.¹⁷² Other viral infections can cause “hemorrhagic fevers” characterized by fever, hypotension, bleeding, and renal failure. Laboratory evidence of DIC can accompany Korean, rift valley, and dengue-related hemorrhagic fevers.^173,174,175 Release of TF from cells in which viruses replicate²⁸ and increased levels of proinflammatory cytokines have been suggested as mechanisms for initiation of the TF pathway in these conditions.¹⁶³

PURPURA FULMINANS

Purpura fulminans is a severe, often lethal form of DIC in which extensive areas of the skin over the extremities and buttocks undergo hemorrhagic necrosis.¹⁷⁶ The disease affects infants and children predominantly, and occasionally adults.^177,178 Diffuse microthrombi in small blood vessels, necrosis, and occasionally vasculitis are present in biopsies of skin lesions. Onset can be within 2 to 4 weeks of a mild infection such as scarlet fever, varicella, or rubella, or can occur during an acute viral or bacterial infection in patients with acquired or hereditary thrombophilias affecting the protein C inhibitory pathway.^156,177 Homozygous protein C deficiency presents in neonates soon after birth as purpura fulminans, with or without extensive thrombosis.^179,180 Patients affected by purpura fulminans are acutely ill with fever, hypotension, and hemorrhage from multiple sites; they frequently have typical laboratory signs of DIC.¹⁷⁷ Excision of necrotic skin areas and grafting are indispensable at a later stage.

SOLID TUMORS

Trousseau was the first to describe the propensity to thrombosis of patients with cancer and cachexia, and evidence for malignancy-related primary fibrinolysis and/or DIC was provided 75 years ago.^9,181,182

In 182 patients with malignant disorders, excessive bleeding was recorded in 75 cases, venous thrombosis in 123, migratory thrombophlebitis in 96, arterial thrombosis in 45, and arterial embolism resulting from nonbacterial thrombotic endocarditis in 31.¹⁸³ Multifocal hemorrhagic infarctions of the brain, caused by fibrin microemboli and manifested as disorders of consciousness, have been described. Patients with solid tumors and DIC are more prone to thrombosis than to bleeding, whereas patients with leukemia and DIC are more prone to hemorrhage. The incidence of DIC in consecutive patients with solid tumors was 7 percent.¹⁸⁴

Solid-tumor cells can express different procoagulant molecules including TF, which forms a complex with factor VII(a) to activate factors IX and X, and a cancer procoagulant, a cysteine protease with factor X activating properties.^185,186 In breast cancer, TF is expressed by vascular endothelial cells as well as the tumor cells.^187,188 TF also appears to be involved in tumor metastasis and angiogenesis.^189,190,191 Cancer procoagulant is an endopeptidase that can be found in extracts of neoplastic cells but also in the plasma of patients with solid tumors.^192,193 The exact role of cancer procoagulant in the pathogenesis of cancer-related DIC is unclear.

Interactions of P- and L-selectins with mucin from mucinous adenocarcinoma can induce formation of platelet microthrombi and probably constitute a third mechanism of cancer-related thrombosis.¹⁹⁴ Depending on the rate and quantity of exposure or influx of shed vesicles from tumors containing TF, a nonovert or overt DIC develops.^39,195,196 For instance, a patient may be asymptomatic or present with venous thromboembolism if the tumor cells expose or release TF slowly or intermittently and the ensuing utilization of fibrinogen and platelets is compensated by increased production of these components. Conversely, massive thrombosis or severe bleeding may supervene in a patient whose circulation is deluged by TF.^184,186

Another mechanism by which tumor cells may contribute to the pathogenesis of DIC is by expressing fibrinolytic proteins.^197,198 Despite the ability of many malignant cells to express urokinase-type plasminogen activator and t-PA, most tumors induce a hypofibrinolytic state. Because DIC is commonly characterized by a shutdown of the fibrinolytic system, mostly because of high levels of PAI-1, this may represent an alternative mechanism for the development of DIC in cancer.

Virtually all pathways that contribute to the occurrence of DIC are driven by cytokines. IL-6 has been identified as one of the most important proinflammatory cytokines that is able to induce TF expression on cells.^21,199 Indeed, inhibition of IL-6 results in an inhibition of endotoxin-stimulated activation of coagulation. In contrast, changes in fibrinolysis and microvascular physiologic anticoagulant pathways are mostly dependent on TNF-α.^200,201,202 Other cytokines that participate in the systemic activation of coagulation are IL-1β and IL-8, whereas antiinflammatory cytokines, such as IL-10, are able to inhibit DIC.^203,204,205 Because many types of tumors have the ability to synthesize and release cytokines or to stimulate other cells to activate the cytokine network, it is likely that cytokine-dependent modulation of coagulation and fibrinolysis plays a role in cancer-related DIC.

Patients with solid tumors are vulnerable to risk factors and additional triggers of DIC that can aggravate thromboembolism and bleeding.¹⁸² Risk factors include advanced age, stage of the disease, and use of chemotherapy or antiestrogen therapy.¹⁹⁷ Triggers include septicemia, immobilization, and involvement of the liver by metastases that impede the function of the liver in controlling DIC. Microangiopathic hemolytic anemia frequently is induced by DIC in patients with malignancies and is particularly severe in patients with widespread intravascular metastases of mucin-secreting adenocarcinomas.²⁰⁶

LEUKEMIAS

Numerous reports on DIC and fibrinolysis complicating the course of acute leukemias have been published. In 161 consecutive patients who presented with acute myeloid leukemia, DIC was diagnosed in 52 (32 percent).²⁰⁷ In acute lymphoblastic leukemia, DIC was diagnosed in 15 to 20 percent.²⁰⁸ Some reports indicate that the incidence of DIC in acute leukemia patients might further increase during remission induction with chemotherapy.²⁰⁹ In patients with acute promyelocytic leukemia (APL), DIC is present in more than 90 percent of patients at the time of diagnosis or after initiation of remission induction.^210,211

The pathogenesis of hemostatic disturbance in APL is related to properties of the malignant cells and their interaction with the host’s endothelial cells.^192,208 APL cells express TF and the cancer procoagulant that can initiate coagulation, and they release IL-1β and TNF-α, which downregulate endothelial thrombomodulin, thereby compromising the protein C anticoagulant pathway. APL cells also express increased amounts of annexin II, which mediates augmented conversion of plasminogen to plasmin (Chap. 135). The overall results of these processes are DIC and hyperfibrinolysis, followed by major bleeding that can lead to death.²¹² All-trans-retinoic acid, used for induction and maintenance therapy of APL, inhibits in vitro and in vivo the deleterious effect of APL cells and has led to a reduced frequency of early hemorrhagic death; however, all-trans-retinoic acid may induce thrombotic complications.^192,213

TRAUMA

When DIC complicates trauma, it usually occurs in severely injured patients. Extensive exposure of TF to the blood circulation and hemorrhagic shock probably are the most immediate triggers of DIC in such instances, although direct proof of this mechanism is lacking. An alternative hypothesis is that cytokines play a pivotal role in the occurrence of DIC in trauma patients. In fact, the changes in cytokine levels are virtually identical in trauma patients and septic patients.²¹⁴ The levels of TNF-α, IL-1β, PAI-1, circulating TF, plasma elastase derived from neutrophils, and soluble thrombomodulin all can be elevated in patients with signs of DIC, predicting multiorgan dysfunction (ARDS included) and death.^215,216 Careful monitoring of laboratory signs of DIC, reduced fibrinolytic activity, and perhaps low AT levels also are useful for predicting the outcome of such patients.²¹⁷

DIC can be aggravated in patients with severe trauma who require massive blood replacement because stored blood components are diluted and do not contain sufficient amounts of viable platelets and factors V and VIII. Moreover, in such patients, there is an activation of fibrinolysis that further aggravate bleeding in combination with acidosis, and hypotension.^{218,219,220,221} Infection commonly occurs in such patients and may contribute to the DIC.

The time interval between trauma and medical intervention correlates with the development and magnitude of DIC. Experience during wars proved that fast evacuation and prompt medical care reduce the risk of DIC.^222,223,224

BRAIN INJURY

Brain injury can be associated with DIC, most likely because the injury exposes the abundant TF of brain to blood. Specimens of contused brain, obtained during surgery in patients with head injury and of liver, lungs, kidneys, and pancreas obtained during autopsy, revealed microthrombi in arterioles and venules.^225,226 In adults and children with head injuries, a high rate of mortality occurred when DIC was present.²²⁷ A laboratory DIC score has predictive value for prognosis in patients with head injuries, thereby supplementing the Glasgow coma score.²²⁸ Bleeding in patients with DIC that is related to brain injury can be managed by replacement therapy.

BURNS

TF exposed to blood at sites of burned tissue, the systemic inflammatory response syndrome induced by the burn, and the common presence of superimposed infections, all can trigger DIC.²²⁹ Bleeding, laboratory tests indicative of DIC, and vascular microthrombi in biopsies of undamaged skin have been described in patients with extensive burns.²³⁰ Kinetic studies with labeled fibrinogen and labeled platelets disclosed that, in addition to systemic consumption of hemostatic factors, significant local consumption occurs in burned areas.²³¹ Laboratory signs of DIC are associated with organ failure; the extent of protein C and AT deficiencies correlates with a poor outcome.²³⁰ A clinicopathologic study of 139 patients who died during treatment for a severe burn disclosed that 18 percent had cerebral infarctions caused by septic arterial occlusions or DIC and approximately 4 percent had intracranial hemorrhage.²³²

LIVER DISEASES

Very complicated derangements of hemostasis occur in patients with severe liver disease and during liver transplantation (Chap. 129). Synthesis of most coagulation factors and natural anticoagulants (protein C, protein S, and AT) and of the main components of the fibrinolytic system (plasminogen, TAFI, and α₂-antiplasmin) is reduced. The capacity of the liver to clear the circulation of activated factors IX, X, and XI, and of t-PA is decreased. Moreover, thrombocytopenia is common as a result of hypersplenism and decreased production of thrombopoietin by the liver. The similarities between the hemostatic defects observed in patients with liver disease and in patients with DIC are striking and have evoked an ongoing controversy as to whether or not DIC contributes to hemostatic derangements associated with liver disease.²³³

Several laboratory and clinical observations support the hypothesis that DIC accompanies hepatic disorders. They include a shortened half-life of radiolabeled fibrinogen and prolongation of fibrinogen half-life by administration of heparin^234,235; failure of replacement therapy to significantly increase the levels of hemostatic factors (suggesting continuous consumption); and increased blood levels of D-dimer, thrombin–AT (TAT) complexes, and fibrinopeptide A, all consistent with ongoing thrombin generation.^236,237,238

Other observations and considerations argue against the hypothesis that DIC accompanies liver diseases. They include (1) a very low incidence (2.2 percent) of microthrombosis in the tissues of patients who die of liver disease and (2) causes other than, or inconsistent with, DIC for the deranged findings in liver disease.²³⁷ Examples of alternative explanations include the following: (1) a prolonged thrombin time may result from acquired dysfibrinogenemia²³⁹; (2) low levels of coagulation factors and inhibitors may result from reduced synthesis²⁴⁰; (3) increased FDP levels may be a consequence of primary fibrinogenolysis induced by reduced synthesis of α₂-antiplasmin and PAI-1 and by decreased clearance of t-PA; (4) factor VIII levels are commonly increased rather than decreased²⁴¹; (5) the kinetic data show that the apparently excessive consumption of fibrinogen can be explained by loss of fibrinogen into extravascular spaces²⁴²; and (6) fibrinogen and plasminogen do not appear to be removed rapidly when labeled endogenously by ⁷⁵Se-selenomethionine.²⁴³

A third hypothesis maintains that patients with liver disease usually do not present with DIC but are extremely sensitive to the various triggers of DIC because of their impeded capacity to clear procoagulants and to synthesize essential components of the coagulation, inhibitory, and fibrinolytic systems. Patients with primary or metastatic liver disease who undergo a peritoneovenous shunt operation for severe ascites are more likely to develop DIC than are patients with ascites who undergo the same procedure because of other causes.²⁴⁴

What, then, should be the approach to patients with liver disease and bleeding without an apparent local cause? First, possible underlying causes of DIC should be considered and identified, and then a hemostatic profile should be examined at frequent intervals so as to detect any dynamic changes that may be helpful in recognizing DIC. The sensitive assays that reflect thrombin generation (TAT complex and prothrombin fragments 1.2) or concomitant thrombin and plasmin generation (D-dimer), as well as finding a normal or decreased level of factor VIII may help establish the diagnosis of DIC in a patient with liver disease.²⁴⁵

HEAT STROKE

In 1841, James Wellstead published his book Travels to the City of the Caliphs (currently known as Baghdad) and vividly described that on an extremely hot day in the Persian Gulf the decks of the ship Liverpool resembled a slaughterhouse, so numerous were the bleeding patients.²⁴⁶ This is probably one of the first written reports on the occurrence of DIC in humans who suffer from heatstroke.²²⁹ Heat stroke is a syndrome characterized by a rise in body temperature to higher than 42°C, which follows collapse of the thermoregulatory mechanism. The following predisposing factors have been identified: high environmental temperature, strenuous physical activity, infection, dehydration, and lack of acclimatization.^247,248 Extensive hemorrhage, unclottable blood, and venous engorgement were found as early as 1838 in postmortem examinations of patients who died of heat stroke.²⁴⁶ Investigations confirm that a severe hemorrhagic diathesis and multiple organ failure often accompany heat stroke.^{229,249,250,251} Diffuse fibrin deposition and hemorrhagic infarctions are found in fatal human cases. DIC associated with profound fibrin(ogen)olysis is evident in patients with heat stroke. The possible triggers of DIC in patients with heat stroke include endothelial cell damage and TF released from heat-damaged tissues.²⁴⁹

In a series of 18 critically ill patients from Paris with heat stroke during the 2003 heat wave in Western Europe that caused numerous deaths in France alone,²⁵¹ patients had very high levels of IL-6 and IL-8. In addition, there was a striking activation of white blood cells, as demonstrated by β₂-integrin upregulation and increased production of reactive oxygen species. All patients also had evidence of a significant systemic activation of coagulation and DIC was present in approximately 35 percent of patients. There was a marked correlation between the extent of inflammation and coagulation activation and the clinical severity of the heat stroke.

The severity of the syndrome and the stage of its development affect the type and magnitude of hemostatic alterations. Thus, in a study of 56 patients, three groups were discernible: nonbleeders, bleeders without DIC but with slight consumption of hemostatic factors, and bleeders with typical signs of DIC.²⁵² Prompt cooling and support of vital functions have substantially reduced the high mortality that was commonly observed in early studies.

SNAKE BITES

Several species of snakes belonging to the Viperidae family produce venoms that have a wide range of activities affecting hemostasis. Prominent among these species are the Vipera, Echis (E. carinatus or E. coloratus), Aspis, Crotalus, Bothrops, and Agkistrodon. Venoms of these snakes contain enzymes or peptides that exert the following activities^253,254,255: (1) thrombin-like activity, cleaving fibrinopeptide A from the Aα chain of fibrinogen (Agkistrodon rhodostoma); (2) activation of prothrombin even in the absence of calcium ions (E. carinatus); (3) activation of factors X and V (Russell viper venom); (4) fibrinogenolytic activity (Agkistrodon acutus); (5) induction of thrombocytopenia by platelet aggregation; (6) inhibition of platelet aggregation by the low-molecular-weight arginine-glycine-aspartic acid–containing peptides from a variety of snake species; (7) activation of protein C; and (8) activities causing damage to endothelial cells, leading to bleeding, tissue ischemia, and edema. Interestingly, victims of snake bites rarely experience excessive bleeding or thromboembolism, in spite of the serious derangements in hemostatic tests and findings that are sometimes consistent with DIC.^256,257,258

The major symptoms and signs related to envenomation are vomiting, diarrhea, apprehension, hypotension, local swelling, ischemia, and necrosis. Consequently, treatment for victims of snake bites consists of immediate immobilization, administration of antivenom and fluids, and other general measures to preserve vital functions. Local incisions, cooling, and application of tourniquet should be avoided.²⁵³

HEMANGIOMAS

In 1940, Kasabach and Merritt described the association between giant hemangioma and a bleeding tendency occurring mainly in infants. The pathogenesis and management of this syndrome have been reviewed.²⁵⁹ Studies using radiolabeled fibrinogen and platelets provided evidence that within the hemangioma, consumption of platelets and fibrinogen occurs because of localized intravascular clotting and excessive fibrinogenolysis.^260,261 Conceivably, concomitant local activation of the coagulation pathway and release of large amounts of t-PA by the abnormal endothelium lining the tumor vessels occur. Microangiopathic hemolytic anemia and laboratory signs of DIC and fibrinolysis have been demonstrated in patients with giant hemangiomas.²⁶² Accelerated growth of these hemangiomas in infants is associated with augmented consumption of hemostatic factors, and can be effectively treated with glucocorticoids. Radiotherapy and interferon-α are also effective, but should only be used in life-threatening circumstances after failure of glucocorticoid therapy because of severe adverse events.²⁶³ Spontaneous mild to moderate bleeding manifestations have been observed, but severe bleeding generally occurs only after surgery or trauma.

Extensive vascular malformation may persist and cause pain, probably resulting from thrombosis, and bleeding following trauma, which is related to the localized or generalized consumption of clotting factors and platelets and hyperfibrinolysis.²⁶⁴ Graded permanent elastic compression, when possible, and low-molecular-weight heparin constitute the only effective treatment in such cases.

AORTIC ANEURYSM

An association between aortic aneurysm and DIC is well documented.^265,266 In a series of patients with aortic aneurysm, 40 percent had elevated levels of FDPs, but only 4 percent had significant bleeding and laboratory evidence of DIC.²⁶⁵ Several factors predispose patients with aortic aneurysms to the development of DIC: a large surface area, dissection, and expansion of the aneurysm.²⁶⁷ Clinical and laboratory signs of DIC should be carefully sought in patients with an aortic aneurysm because bleeding may seriously complicate surgical repair of the aneurysm.^267,268 The initiation of localized and generalized intravascular coagulation can be ascribed to activation of the TF pathway by the abundant amounts of TF present in atherosclerotic plaques.²⁶⁹ When patients present with significant bleeding or when surgery is planned, hemostatic defects should be sought and ongoing coagulation activation may be corrected by (low-molecular-weight) heparin.²⁷⁰ Stent-grafting, which is a common procedure for repair of aortic aneurysms, was complicated by DIC and death in two patients, of whom one had cirrhosis and the other underwent a lengthy procedure.²⁷¹ However, a study of 31 such patients failed to detect DIC following stent-grafting of thoracic aneurysms.²⁷²

TRANSFUSION REACTION

DIC accompanies incompatible blood transfusion, in which massive hemolysis is commonly associated with excessive bleeding with widespread thrombosis in fatal cases (Chap. 138). The trigger of DIC in these cases cannot be simply ascribed to the release of red cell stroma, as patients with massive oxidative hemolysis because of glucose-6-phosphate dehydrogenase deficiency do not develop DIC.²⁷³ Rather, extensive antigen–antibody reaction appears to cause DIC as a result of release of elastase and TNF-α from neutrophils, and activation of monocytes that release TNF-α express TF and complement, with assembly of the membrane attack complex inflicting damage to endothelial cells.^274,275

DISSEMINATED INTRAVASCULAR COAGULATION DURING PREGNANCY

Pregnancy predisposes patients to DIC for at least four reasons: (1) pregnancy itself produces a hypercoagulable state, manifested by evidence of low-grade thrombin generation, with elevated levels of fibrin monomer complexes and fibrinopeptide A; (2) during labor, leakage of TF from placental tissue into the maternal circulation causes a hypercoagulable state; (3) pregnancy is associated with reduced fibrinolytic activity because of increased plasma levels of PAI-1; and (4) pregnancy is associated with a decline in the plasma level of protein S. DIC may be difficult to diagnose during pregnancy because of the high initial levels of coagulation factors such as fibrinogen, factor VIII, and factor VII.^276,277 Progressive reductions in these factors, however, can confirm or exclude the diagnosis of DIC in suspected cases. Thrombocytopenia may be particularly helpful in determining whether DIC is present, provided other causes of thrombocytopenia are excluded.²⁷⁸

Abruptio Placentae

The dramatic clinical presentation of abruptio placentae was first reported by DeLee in 1901,²⁷⁹ but the immediate cause of sudden rupture of uterine spiral arteries and detachment of the placenta is still unknown. Placental abruption is a leading cause of perinatal death.²⁸⁰ Older multiparous women or patients with one of the hypertensive disorders of pregnancy are thought to be at highest risk. The severe hemostatic failure accompanying abruptio placentae is the result of acute DIC emanating from the introduction of large amounts of TF into the blood circulation from the damaged placenta and uterus.²⁸¹ Amniotic fluid is able to activate coagulation in vitro, and the degree of placental separation correlates with the extent of DIC, suggesting that leakage of thromboplastin-like material from the placental system is responsible for the occurrence of DIC. Abruptio placentae occurs in 0.2 to 0.4 percent of pregnancies,²⁸² but only 10 percent of these cases are associated with DIC.²⁷⁸ Different grades of severity are found among those who develop DIC, with only the more severe forms resulting in shock and fetal death. Rapid volume replenishment and evacuation of the uterus is the treatment of choice.²⁸⁰ Transfusion of cryoprecipitate, fresh-frozen plasma, and platelets should be given when profuse bleeding occurs. However, in the absence of severe bleeding, administration of blood components may not be necessary because depleted coagulation factors increase rapidly following delivery. Heparin or antifibrinolytic agents are not indicated.

Amniotic Fluid Embolism

This rare catastrophic disorder, described by Steiner and Lushbaugh in 1941, occurs only in one in 8000 to one in 80,000 deliveries.²⁸³ A maternal mortality rate of 86 percent was reported in a 1979 review of 272 cases, but in a later population-based study, the maternal mortality (26.4 percent) was significantly lower.^284,285 Patients predisposed to amniotic fluid embolism are multiparous women whose pregnancies are postmature with large fetuses and women undergoing a tumultuous labor after pharmacologic or surgical induction. Apparently, amniotic fluid is introduced into the maternal circulation through tears in the chorioamniotic membranes, rupture of the uterus, and injury of uterine veins.²⁸⁴ The trigger of DIC probably is TF present in amniotic fluid.^286,287 The mechanical obstruction of pulmonary blood vessels by fetal debris, meconium, and other particulate matter in the amniotic fluid enhances local fibrin–platelet thrombus formation and fibrinolysis. The extensive occlusion of the pulmonary arteries and an acute anaphylactoid response reminiscent of severe systemic inflammatory response syndrome provoke sudden dyspnea, cyanosis, acute cor pulmonale, left ventricular dysfunction, shock, and convulsions. These symptoms are followed within minutes to several hours by severe bleeding in 37 percent of patients.²⁸⁴ Hemorrhage is particularly severe from the atonic uterus, puncture sites, gastrointestinal tract, and other organs. The best prospect for decreasing mortality lies in early termination of parturition in patients at high risk and prevention of hypertonic and tetanic uterine contractions during labor. When the syndrome is recognized, immediate termination of pregnancy under pulmonary and cardiovascular support is essential.

Preeclampsia and Eclampsia

Thrombocytopenia described in early reports of eclampsia and widespread deposition of fibrin in blood vessels observed in fatal cases were interpreted as evidence of DIC triggered by placental TF exposure to the circulation.¹ A critical analysis of the literature concluded that the thrombocytopenia in these patients stems from endothelial injury rather than DIC.²⁸⁸ However, other investigators provided evidence for significant DIC in preeclampsia and eclampsia.^289,290 Moreover, in a large series of patients, a good correlation was noted between the clinical severity and abnormalities in platelet counts and FDPs.²⁹¹ Also consistent with DIC were results of assays of sensitive parameters of thrombin generation and activation of fibrinolysis, such as TAT complexes, D-dimer, and fibrinopeptide Bβ1–42. Despite these observations, administration of heparin to patients with preeclampsia and eclampsia has not resulted in convincing benefits.²⁹²

HELLP Syndrome

The syndrome of hemolysis (H), elevated liver enzymes (EL), low platelet count (LP), and severe epigastric pain is a complication of pregnancy-induced hypertension.²⁹³ Seventy percent of the cases occur during the third trimester of pregnancy and 30 percent occur during the postpartum period.²⁹⁴ HELLP syndrome occurs more often in whites, multipara, and women older than 35 years.²⁹² Liver biopsy findings of fibrin deposition in hepatic blood vessels and laboratory tests consistent with DIC in a significant proportion of patients imply that DIC plays a role in the pathogenesis of the syndrome.^294,295,296 Hepatic imaging in 33 patients revealed subcapsular hematomas in 13 and intraparenchymal hemorrhage in 6.²⁹⁷ What actually triggers DIC in these cases is not known but has been related to endothelial dysfunction.²⁹² Multiple organ dysfunctions manifested by acute renal failure, ascites, pulmonary edema, and severe hemorrhage resulting from DIC may develop, leading to significant maternal and perinatal mortality rates. Management of patients with HELLP syndrome consists of supportive care, careful monitoring, and blood component replacement therapy. With few exceptions, immediate delivery, not necessarily by cesarian section, is indicated. HELLP syndrome tends to recur in subsequent gestations.²⁹⁸

Sepsis During Pregnancy

Gram-negative bacteria, group A streptococci, and Clostridium perfringens are among the more common causes of sepsis during pregnancy. These infections are frequently associated with fulminant DIC. The pathogens gain entry into the circulation during abortion, via amnionitis that may follow invasive procedures or rupture of membranes, by endometritis developing during labor, and by way of the urinary tract. Approximately 40 percent of bacteremic patients experience shock, which is associated with significant mortality.²⁹⁹ In addition, a high rate of bleeding and organ dysfunction affects the kidneys, lungs, and central nervous system.

Treatment of all cases of sepsis-related DIC should include antibiotics, support of vital functions, and surgical intervention to remove any local nidus of infection. Abortion or hysterectomy may be considered.

Dead Fetus Syndrome

Several weeks after intrauterine fetal death, approximately one-third of patients may exhibit laboratory signs of DIC, occasionally accompanied by bleeding.^278,300 Apparently, TF from the retained dead fetus or placenta slowly enters the maternal circulation and initiates DIC, which sometimes is accompanied by significant fibrinolysis.¹³ This complication currently is rarely observed because labor is induced promptly after the diagnosis of fetal death is made. However, if labor induction is unavoidably delayed, serial blood coagulation tests should be performed.

The entity of fetal death and DIC can occur following the demise of one of multiple gestations. If it occurs at term, therapy is started as discussed. If it occurs prior to fetal maturity, prolonged administration of heparin can be useful. Interestingly, when selective termination of the life of an anomalous fetus is performed in women with multiple pregnancies, hemostatic abnormalities develop in only approximately 3 percent of cases.³⁰¹

Acute Fatty Liver

Acute fatty liver of pregnancy is a rare disorder that occurs during the third trimester of pregnancy.³⁰² It can lead to hepatic failure, encephalopathy, and death of the mother and fetus.^{303,304,305,306} In 15 to 20 percent of cases, acute fatty liver of pregnancy is associated with fetal homozygosity or compound heterozygosity for long-chain acyl-coenzyme A dehydrogenase (LCAD) deficiency.³⁰⁷ Infants born with LCAD deficiency fail to thrive and are prone to liver failure and death. LCAD is one of four enzymes taking part in β-oxidation of fatty acids in mitochondria. When it is deficient, accumulation of medium- and long-chain fatty acid occurs. One predominant mutation (G1528C) accounts for 65 to 90 percent of cases with the deficiency. The precise mechanism by which LCAD deficiency in the fetus causes the severe liver disease in the heterozygous mother is unclear. The acute fatty liver disease of pregnancy is characterized by severe liver dysfunction, renal failure, hypertension, and signs of DIC.^304,308 The typical histologic feature is microvesicular fatty infiltration of the liver. Exceedingly low levels of AT and other laboratory signs of DIC were observed in a series of 28 patients, but no definite clinical benefit from AT concentrate infusion was achieved.³⁰⁸ The primary therapy for these patients is early delivery and supportive care, which yield a maternal survival of 90 percent and perinatal survival of more than 85 percent.^304,309 Pancreatitis is a potentially lethal complication of acute fatty liver of pregnancy.³¹⁰

NEWBORNS

Newborns have a limited capacity to cope with triggers of DIC for several reasons: (1) their ability to clear soluble fibrin and activated factors is reduced; (2) their fibrinolytic potential is decreased because of a low plasminogen level; and (3) their capacity to synthesize coagulation factors and inhibitors is limited.^311,312 Criteria for diagnosis of DIC in newborns are different from those for diagnosis in adults.³¹³ Important to consider are the physiologic hemostatic findings common at this age, which include low levels of the vitamin K–dependent factors, reduced AT and protein C levels, and prolonged thrombin time. The laboratory evidence of DIC in the newborn is based on the progressive decline of hemostatic parameters, thrombocytopenia, and reduced levels of fibrinogen, factor V, and factor VIII.^311,314,315

DIC occurs in sick neonates and particularly in those who are premature. More than one underlying cause usually can be identified in newborns with DIC. The most frequent underlying conditions are sepsis, hyaline membrane disease (respiratory distress syndrome), asphyxia, necrotizing enterocolitis, intravascular hemolysis, abruptio placentae, and eclampsia.^312,316

Bleeding from multiple sites is the most common manifestation of DIC in newborns, with intracranial hemorrhage being the most life-threatening condition. No clinical manifestations of DIC are apparent in approximately 20 percent of neonates,³¹⁴ so a high index of suspicion in patients at risk is essential.

Controlled studies of patients with DIC are difficult to perform in view of the variabilities in DIC triggers, clinical presentations, and grades of severity. Figure 129–4 shows general guidelines for management of patients with DIC, but decisions regarding treatment must be individualized after careful consideration of all clinically important aspects.

TREATMENT OF UNDERLYING DISORDERS AND VITAL SUPPORT

The survival of patients with DIC depends on vigorous treatment of the underlying disorder to alleviate or remove the inciting injurious cause. For sepsis-induced DIC, treatment includes aggressive use of intravenous organism-directed antibiotics and source control (e.g., by surgery or drainage). Other examples of vigorous treatment of underlying conditions are cancer surgery or chemotherapy, uterus evacuation or even hysterectomy in patients with abruptio placentae, resection of aortic aneurysm, and debridement of crushed tissues.

Intensive support of vital functions is required. Volume replacement and correction of hypotension, acidosis, and oxygenation may improve blood flow and oxygen delivery to the microcirculation. Careful monitoring of pulmonary, cardiac, and renal function enables prompt institution of supportive measures, such as use of a respirator for respiratory support, inotropic and vasoactive drugs for improvement of organ perfusion, renal function, and maintenance of electrolyte balance.

BLOOD COMPONENT THERAPY

Treatment of the underlying disease and vital support are necessary but usually insufficient to treat DIC or forestall progression of nonovert DIC to overt DIC. Additional supportive treatment directly aimed at the coagulation system may be required. These interventions include replacing the coagulation factors, natural anticoagulant, fibrinolytic proteins, and platelets that are actively consumed during DIC.³¹⁷

Low levels of platelets and coagulation factors may increase the risk of bleeding. However, plasma or platelet substitution therapy should not be instituted on the basis of laboratory results alone; it is indicated only in patients with active bleeding and in those requiring an invasive procedure or are at risk for bleeding complications.^318,319 The suggestion that administration of blood components might “add fuel to the fire” has never been proven in clinical or experimental studies. The presumed efficacy of treatment with plasma, fibrinogen concentrate, cryoprecipitate, or platelets is not based on randomized controlled trials but appears to be rational therapy in bleeding patients or in patients at risk of bleeding who have a significant depletion of these hemostatic factors.³¹⁹ One of the major challenges of infusion of fresh-frozen plasma in these dire circumstances is the propensity of the added volume, which is necessary to correct the coagulation defect, to exacerbate capillary leak. This situation can increase the risk of inducing or worsening pulmonary edema and, by extension, predispose to ARDS, and induce ascites. Coagulation factor concentrates, such as prothrombin complex concentrate, may partially overcome this obstacle, but do not contain essential factors, such as factor V. Moreover, caution is advocated with the use of prothrombin complex concentrates in DIC, as it may worsen the coagulopathy because of traces of activated factors that are present in these concentrates. Specific deficiencies of coagulation factors, such as fibrinogen, may be corrected by administration of purified coagulation factor concentrates.

Platelet transfusion is often required in patients with DIC to prevent bleeding into already ischemic or damaged organs (particularly the central nervous system). The threshold platelet count that should prompt transfusion is patient and disease specific. Cryoprecipitate can be used to rapidly raise the fibrinogen and factor VIII levels, particularly when bleeding is part of the DIC and fibrinogen level is less than 1 g/L. Cryoprecipitate has at least four to five times the mass of fibrinogen per milliliter of infusate compared to fresh-frozen plasma. Fresh-frozen plasma contains fibrinogen in sufficient amounts for treatment of patients with mild to moderate hypofibrinogemia.

Replacement therapy for thrombocytopenia should consist of 5 to 10 units of platelet concentrate or single-donor apheresis-derived platelets to raise the platelet count to 20 to 30 × 10⁹/L, and in patients who need an invasive procedure, to 50 × 10⁹/L.

RESTORATION OF PHYSIOLOGIC ANTICOAGULANT PATHWAYS

Because the levels of the physiologic anticoagulants are reduced in patients with DIC, restoration of these inhibitors may be a rational approach.^49,320 Based on successful preclinical studies, the use of AT concentrates and heparin in patients with DIC has been examined mainly in randomized controlled trials, that included patients with sepsis, septic shock, or both. All trials have shown some beneficial effect in terms of improvement of laboratory parameters, shortening of the duration of DIC, or even improvement in organ function.^6,321,322 In several small clinical trials, use of very high doses of AT concentrate showed a modest reduction in mortality, but without being statistically significant.^323,324,325 A large-scale, multicenter, randomized controlled trial also showed no significant reduction in mortality of patients with sepsis.³²⁶ Interestingly, post hoc subgroup analyses of the latter study indicated some benefit in patients who did not receive concomitant heparin, but this observation needs validation. In a small randomized trial in patients with burns and DIC, AT administration decreased mortality, reduced multiple organ failure, and improved coagulation parameters compared to placebo-control patients.³²⁷

Because a decreased function of the protein C system contributes to the pathogenesis of DIC, therapy by an APC concentrate was predicted to be beneficial.³²⁸ Indeed, a dose-ranging controlled trial using continuous infusion of recombinant human APC disclosed that a dose of 24 mcg/kg per hour was optimal, judged by a decrease of D-dimer level in plasma.³²⁹ A subsequent phase III trial of APC concentrate in patients with sepsis was prematurely stopped because of efficacy in reducing mortality in these patients.³³⁰ All-cause mortality at 28 days after inclusion was 24.7 percent in the APC group versus 30.8 percent in the control group (a 19.4 percent relative risk reduction). Amelioration of coagulation abnormalities and less organ failure were noted in patients who received the concentrate.³³¹ However, meta-analyses of subsequent trials concluded that the basis for treatment with APC, even in patients with a high disease severity, was not very strong.^332,333 A recently completed placebo-controlled trial in patients with severe sepsis and septic shock was prematurely stopped because of the lack of any significant benefit of APC.³³⁴ Subsequently, the manufacturer of APC has decided to withdraw the product from the market, which has resulted in a revision of current guidelines for treatment of DIC.³³⁵

HEPARIN ADMINISTRATION AND OTHER ANTICOAGULANTS

Although the question of heparin therapy in patients with DIC has been studied by several investigators, this therapy remains controversial. Experimental studies show that heparin can at least partly inhibit the activation of coagulation in DIC.^336,337 However, a beneficial effect of heparin on clinically important outcome events in patients with DIC has not been demonstrated in controlled clinical trials.³³⁸ Also, the safety of heparin treatment is debatable in DIC patients who are prone to bleeding. A large trial in patients with severe sepsis showed a slight, but nonsignificant benefit, of low-dose heparin on 28-day mortality in patients with severe sepsis.³³⁹

Notwithstanding these considerations, administration of heparin is beneficial in some categories of chronic DIC, such as metastatic carcinomas, purpura fulminans, and aortic aneurysm (prior to resection). Heparin also is indicated for treating thromboembolic complications in large vessels and before surgery in patients with chronic DIC (see Fig. 129–4). Heparin administration may 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 these conditions. In patients with chronic DIC because of metastatic carcinoma or aortic aneurysm, continuous infusion of heparin 500 to 750 U/h without a bolus injection may be sufficient. If no response is obtained within 24 hours, escalating dosages can be used. In hyperacute DIC cases, such as mismatched transfusion, amniotic fluid embolism, septic abortion, and purpura fulminans, intravenous bolus injection of 5000 to 10,000 U heparin may be given simultaneously with replacement therapy with blood products. Some experts would not administer a bolus dose of heparin even under these circumstances. Continuous infusion of 500 to 1000 U/h heparin may be necessary to maintain the benefit until the underlying disease responds to treatment.³³⁹

Theoretically, the most logical anticoagulant agent to use in DIC is directed against TF activity. Potential agents include recombinant TFPI, inactivated factor VIIa, and recombinant nematode anticoagulant protein c2 (NAPc2), a potent and specific inhibitor of the ternary complex of TF–factor VIIa and factor Xa.³⁴⁰ Phase II trials of recombinant TFPI in patients with sepsis showed promising results,³⁴¹ but a phase III trial did not show an overall survival benefit in patients who were treated with TFPI.^341,342

Recombinant human soluble thrombomodulin binds to thrombin to form a complex that inactivates thrombin’s coagulant activity and activates protein C, and thus, is a potential drug for the treatment of patients with DIC. In a phase III randomized double-blind clinical trial in patients with DIC, administration of the soluble thrombomodulin had a significantly better effect on bleeding manifestations and coagulation parameters than heparin.³⁴³ Ongoing trials with soluble thrombomodulin focus on DIC, organ failure, and mortality rate.

INHIBITORS OF FIBRINOLYSIS

Patients with DIC should not be treated with antifibrinolytic agents such as ε-aminocaproic acid or tranexamic acid because these drugs block fibrinolysis that preserves tissue perfusion in patients with DIC. Use of these agents in patients with DIC has been complicated by severe thrombosis.^344,345

A different situation prevails in patients with DIC accompanied by primary fibrino(geno)lysis, as in some cases of APL, 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,³⁴⁶ provided (1) the patient is bleeding profusely and has not responded to replacement therapy and (2) excessive fibrino(geno)lysis is observed, that is, rapid whole blood clot lysis or a very short euglobulin lysis time. In such circumstances, use of antifibrinolytic agents should be preceded by replacement of depleted blood components and continuous heparin infusion (see Fig. 129–4).