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DIC at the Intersection of the Thrombotic, Fibrinolytic and Inflammatory Axes

and .


Disseminated intravascular coagulation (DIC) is a common clinical syndrome with dichotomous presentations of hemorrhage and thrombosis with a common underlying pathophysiology. As a syndrome, DIC presents a spectrum of severity ranging from a chronic disorder with minimal hemolysis and coagulation to a fulminant disorder with uncontrollable hemorrhage and major organ failure from small vessel thrombosis. DIC occurs in many different diseases (Table 1). In its severest form it is one of the final steps leading to multi-system failure. In each case derangement of the normally dynamic complex balance between thrombosis and fibrinolysis results in either a dominant phenotype of microvascular clotting or hemorrhage. In the thrombotic phenotype, unregulated fibrin generation results in widespread coagulation, while in the hemorrhagic phenotype, unregulated plasmin generation results in fibrinolysis and proteolysis of all soluble clotting factors. Paradoxically, the hemorrhage associated with DIC is clinically more obvious, but the microvascular clotting is far more lethal. Several recent discoveries about prognosis and therapy in patients with DIC emphasize the fundamental importance of the microvascular clotting over that of hemorrhage. In DIC the diversity of causes makes a unifying description of its pathophysiology difficult. However, focussing on several of the more important cell types and enzymes clarifies how a group of diverse diseases causes this syndrome.

Hanging in the Balance: Fibrinolysis and Thrombosis in the Quiescent Vasculature

Under homeostatic conditions, endothelial cells play an integral role in maintaining fluidity of blood in transit. They mediate interactions between blood, tissue, leukocytes and platelets. Other cells in the vascular wall and at the blood interface (particularly monocytes), are also critical regulators of this homeostasis. Endothelial cells possess an array of antithrombotic defenses. Von Willebrand factor (vWF) is a multimeric high molecular weight protein that participates in the binding of activated platelets to exposed collagen through common RGD receptors, such as GP Ib on the platelet surface.1 It also binds and stabilizes the circulating clotting factor VIII. In the quiescent endothelial cell vWF is sequestered in sub-plasmalemmal cigar-shaped storage vesicles called Weibel-Palade bodies. Embedded within the endothelial cell plasmalemma is a thrombin receptor, thrombomodulin (TM). TM opposes coagulation by accelerating thrombin's conversion of the precursor protein C to the active anticoagulant activated protein C (APC). Activated protein C, a serine protease, inactivates Factors Va and VIIIa and is a potent anticoagulant and anti-inflammatory molecule.

Endothelial cells also synthesize glycocalyx material in the form of large negatively charged heparan sulfate proteoglycans, which maintain the anti-thrombotic character of the endovascular wall. These heparan molecules have an important immunologic role in tissue. When broken down into their constituent parts, they also can induce tissue dendritic cell maturation and migration to lymph nodes, making them fully potent antigen-presenting cells.2 Although endothelial cells synthesize tissue factor (TF), they also sequester it in the abluminal basement membrane. The maintenance of the TF gradient and its directional secretion prevents activation of the extrinsic clotting cascade. Thrombomodulin expression, sequestration of TF and vWF, and expression of a glycocalyx are some of the essential endothelial functions that prevent fibrin-mediated thrombosis.

Endothelial cells also must keep platelet-driven thrombosis at bay. Paracrine secretion of eicasanoids, most notably PGI2 (prostacylin) and nitric oxide, not only vasodilate subjacent vascular smooth muscle, but also suppress platelet aggregation. The constitutive endothelial isoform of nitric oxide synthase (NOS3) produces nitric oxide after increases in shear forces or after receptor-mediated activation. Of the known platelet-inhibitory mechanisms, arguably the most potent is CD39 (NTPDase I). CD39 is a highly conserved 78 kDa membrane-spanning glycoprotein that functions as an ectoapyrase, rapidly catabolizing ADP and ATP. It is constitutively expressed on the endothelial plasmalemma. When platelets are activated at the endovascular surface, they release ADP, further activating nearby platelets. CD39 prevents this secondary recruitment through the breakdown of ADP/ATP.3 CD39 also has potent anti-inflammatory effects modulating endothelial IL 1α expression and possibly leukocyte adhesion to activated endothelial cells. Endothelial cells that over-express recombinant CD39 produce less IL 1α after lipopolysaccharide (LPS) stimulation.4

Until recently, thrombosis was thought to occur only under pathological conditions, however experimental data suggest that both a low level of thrombosis and fibrinolysis are ongoing at all times. These processes are in a dynamic equilibrium. Levels of fibrin degradation products from fibrin's β chain are always detectable in blood from this ongoing thrombosis and fibrinolysis.5 While a many factors trigger the low level thrombosis, endothelial cells must drive the low level of fibrinolysis. Endothelial cells synthesize tissue plasminogen activator (tPA). This enzyme, both in plasma-membrane-bound and circulating soluble forms, constantly activates small amounts of plasminogen to form plasmin. Plasmin is the key serine protease that degrades fibrin. tPA and plasmin balance the thrombotic stimuli maintaining the vascular lumen's patency and preserving the free flow of blood.

Perturbation of the Balance: Activated Cells in the Vascular Wall

A number of divergent environmental stimuli disturb the endothelial micro-environment leading to disruption of the thrombotic/fibrinolytic balance. Although the stimuli are often very different, the pattern of vascular responses is very limited. Hypoxia, ischemia, exposure to endotoxin, pro-inflammatory cytokines, mechanical injury, thermal injury, infectious, immunologic processes, or activation of coagulation at remote sites all trigger a final common vascular phenotype: a vasodilated, porous, procoagulant, proinflammatory and anti-fibrinolytic vessel. The convergence of these pathways into a single vascular phenotype has only recently appreciated to be important. Endothelial cells and the cells of the vessel wall are the link between these divergent injuries and this vascular phenotype.


Endothelial cells exposed to LPS or hypoxia elaborate (de novo) a variety of cytokines that promulgate inflammation, such as IL-1α, TNF-α, IL-6, MCP-1 and other chemokines. As part of their role in inflammation, stimulated endothelial cells also express CD40 and CD154, providing required secondary signals for T cell activation.6 The CD40-CD154 interaction not only stimulates the T cell but also enhances the endothelial stimulation.7 In addition, exposure to hypoxia or endotoxin can elicit endothelial expression of a multitude of glycoprotein adhesion receptors at the luminal surface. These include members of the selectin family of glycoprotein adhesion receptors, P-and E-selectin, and immunoglobulin class family members such as ICAM-1 and VCAM-1.8-11 Other paracrine modulators of vascular tone and the inflammatory response, such as thromboxane A2 and endothelin, superoxide and nitric oxide (made in large quantities by the inducible isoform of nitric oxide synthase, NOS2) are also synthesized in this deranged environment.

Induction of Coagulation

In terms of the coagulant phenotype, endothelial surface levels of thrombomodulin decline precipitously after any of these stimuli. Coincident with this decline in thrombomodulin levels is an equal and opposite increase in secreted plasminogen activator inhibitor-1 (PAI-1) and membrane TF expression. PAI-1, a 52-kDa serine protease inhibitor, circulates predominantly complexed with tPA, inhibiting tPA's ability to produce plasmin, effectively suppressing fibrinolysis. TF is a transmembrane receptor for factors VII and VIIa. Exposure of TF to blood leads to rapid activation of the extrinsic pathway of coagulation. In vivo, TF is the single most potent stimulus for coagulation. TF-binding enhances factor VII's susceptibility to activation and factor VIIa's ability to enzymatically activate factors IX and X triggering the intrinsic clotting cascade. Although the soluble form of TF cannot regulate factor VII, soluble TF still enhances factor VIIa's function. Activated monocytes also express TF in large quantities, and their presence in the vessel wall significantly amplifies coagulation (Fig. 1).

Figure 1a. Shows plasma PAI-1 levels by ELISA in mice exposed to hypoxia.

Figure 1a

Shows plasma PAI-1 levels by ELISA in mice exposed to hypoxia.

Platelet Adhesion

A variety of signals including hypoxia and cytokine exposure can cause endothelial cells to exocytose the preformed stores of vWF.12 When released, free vWF increases platelet adhesivity under conditions of low shear. This allows platelets to bind exposed collagen through a variety of collagen receptors on their surface. In addition vWF binds and stabilizes factor VIII markedly prolonging its half-life. Activated platelets secrete thromboxane A2 and exocytose granules containing other platelet agonists, particularly ADP. The presence of thrombin, vWF and the platelet agonists makes the stimulated region of the vessel strongly favor platelet aggregation.

Fibrinolytic Suppression

The ability of endothelial cells to recruit monocytes is also an important mechanism that amplifies coagulation. Once activated, these cells collaborate to suppress fibrinolysis, promote inflammation and thrombosis. Monocytes exposed to LPS or hypoxia express large amounts of TF, as well as PAI-1 (Fig. 1).13,14 In a murine hypoxia model, depletion of the monocytes reduces in situ fibrin formation in the lungs.15 In parallel with endothelial cells, monocytes release numerous proinflammatory cytokines providing autocrine amplification of their procoagulant phenotype. Recent studies have elucidated a key environmental response pathway transcription factor, early growth response-1 (Egr-1), critical in monocyte and endothelial stimulation. The Egr-1 gene encodes a stress response zinc finger transcription factor, which binds to the promoter regions of TF, PAI-1, IL-1α, MCP-1, TF and other genes. This transcription factor binds to the promoter region of many procoagulant and proinflammatory genes. Hypoxia-driven production of this transcription factor directly up-regulates TF and PAI-1 levels on monocytes and endothelial cells. When mice lacking the Egr-1 gene are exposed to LPS, hypoxia, or ischemia, the procoagulant and inflammatory responses are markedly suppressed.16,17 In the cellular environment oxidative stress stimulates the enzyme protein kinase C β II (PKCβ II) which seems to trigger a cascade of kinase activity resulting in Egr-1 production (Fig. 2).18 Egr-1 production appears to transduce the environmental stressor at the genetic level, linking the stressor and cellular stress response.

Figure 2. Schematic representation of the proposed Egr-1 pathway inside a mononuclear phagocyte.

Figure 2

Schematic representation of the proposed Egr-1 pathway inside a mononuclear phagocyte. In the schematic, environmental stressors stimulate the intracellular kinase pathway, which results in the production of the proinflammatory, prothrombotic transcription (more...)

Figure and c. B shows the PAI-1 mRNA levels, determined by Northern blotting, of in lung homogenates from mice exposed to hypoxia.

Figure and c

B shows the PAI-1 mRNA levels, determined by Northern blotting, of in lung homogenates from mice exposed to hypoxia. C shows the PAI-1 mRNA levels in a macrophage cell line, RAW cells, after the cells were exposed to hypoxia in vitro. Adapted from reference (more...)

Barrier Function

As the physical mediator of the interface between blood and tissue, damage to the barrier function of the endothelium also occurs when these stressors activate the vessel wall. Even when present in sublytic amounts, terminal components of the complement cascade can elicit both TF and P-selectin expression on endothelial cells.19 Bradykinin, the complement-derived anaphylatoxin C5a, IL-1α, TNF-α and other factors degrade the physical barrier function of the endothelium.20,21 Under quiescent conditions, the lateral margins of endothelial cells are juxtaposed tightly, creating a semi-permeable membrane and permitting only restricted diffusion. Downstream thrombosis and local stasis create conditions of local hypoxia, causing levels of cAMP to fall within the endothelial cell. This alters activity of myosin light chain kinase in the cells, causing changes in the endothelial actin-based cytoskeleton resulting in centripetal retraction of endothelial cell edges.22 After gaps form between adjacent endothelial cells, diffusion is no longer restricted, and mass transport of solutes and macromolecules transpires.23 Additionally, inter-endothelial gap formation places the procoagulant subendothelial cell basement membrane in direct contact with blood. This triggers tissue factor/VIIa-mediated activation of the extrinsic cascade of coagulation. With increasing vascular permeability and an increasingly porous basement membrane, the local tissue becomes edematous and flow through the vessel is compromised.

These data indicate that both endothelial cells and monocytes are critical mediators of the vascular response to environmental stress. DIC represents the clinical manifestation of the perturbation of these pathways. Underlying the diverse causes of DIC is the common feature of damage to, or activation of, cells in the vascular wall. These pathways have come into recent focus with the discovery that activated protein C and suppression of PAI-1 prevent the lethal consequences of activation of these pathways.

Coagulation and Fibrinolysis in DIC

DIC was described first as a hemorrhagic complication of obstetrics with an attendant 50% mortality. Dr. Charles Schneider, an obstetrician, performed many of the fundamental experiments that led to major breakthroughs in understanding this syndrome. TF obtained from homogenized organs, when infused rapidly into rabbits, produced pulmonary artery thrombosis and immediate death of the animal. A slow infusion of the same material produced no effect. An intermediate rate of infusion of TF over 20 minutes produced no immediate effect, however several hours later, the rabbit developed pulmonary hemorrhage. Measurement of clotting factor levels revealed a rapid decline in Factors V, VII and XII as well as a decline in clotting inhibitors antithrombin III, proteins C and S within two hours leading to this hemorrhage. This led to the understanding of DIC as a “consumptive coagulopathy.”24

Following the observation in obstetrics, the syndrome was identified in a host of other disorders (Table 1), most frequently in sepsis. DIC occurs in 7.5–49% of patients with sepsis. This association forced the recognition of the links between infection, inflammation and coagulation. The classic experimental model of DIC, infusion of endotoxin into non-human primates, underscores the close relationship between infection, inflammation and coagulation. Exposure of endothelial cells and monocytes to either IL-1α or TNF-α stimulates coagulation and further inflammation,25,26 and infusion of IL-6, IL-1α and TNF-α into non-human primates produces DIC.24 These are the key cytokines linking inflammation and clotting. Endothelial cells and monocytes mediate this link between clotting and inflammation.

Endothelial Contribution to DIC

Diffuse endothelial damage or activation represents a feature common to many of the conditions resulting in DIC. Regardless of the insult, the endothelium in DIC has a limited repertoire of responses. After the insult, the careful balance achieved by the quiescent endothelium tips rapidly out of balance, allowing either fibrinolysis or thrombosis to proceed unchecked (Fig. 3). The fibrinolytic state has been more amenable to treatment than the thrombotic state. FFP and transfusions frequently can support the patient through bleeding complications. Clinical trials of heparin, anti-thrombin III and tPA to treat the thrombotic phenotype have produced inconsistent results. The recent randomized trial of APC in sepsis, a therapy with both anticoagulant and anti-inflammatory effects, was the first to demonstrate a large mortality benefit in humans for this intractable illness.27

Figure 3. The dynamic balance of coagulation (red= prothrombotic, blue= profibrinolytic).

Figure 3

The dynamic balance of coagulation (red= prothrombotic, blue= profibrinolytic). The highlighted portions of the pathways are those reviewed in this Chapter.

Although the clinical presentations of the two patterns of DIC appear to be polar opposites, at the level of the endothelial cell they share a number of similarities. During the initial phases of DIC, the outpouring of cytokines (particularly IL-6, IL-1α and TNF-α), vasoactive mediators and platelet agonists and the creation of large amounts of activated clotting factors at the initial injury's nidus determine whether the injury will be generalized into DIC. Activated clotting factors in general and factor Xa in particular have only recently been implicated in the generalization of the vascular dysfunction. Circulating Xa stimulates previously uninvolved endothelial cells binding specific endothelial receptors such as EPR-1. Stimulation of this receptor has been shown to result in perivascular accumulation and degranulation of mast cells.28 Understanding the vessel response to these stimuli is crucial to predicting whether this balance will tip towards either thrombosis or fibrinolysis.

The Thrombotic Phenotype

The patients who develop the thrombotic phenotype of fulminant DIC may not die as a consequence of their DIC, but there is mounting evidence that they have a more severe form of this illness. The factors that play a critical role in clotting are also involved in creating multi-system organ failure (ARDS, renal failure, etc). Two well-understood forces drive thrombosis in these patients, inhibition of fibrinolysis and initiation of new thrombosis.

PAI-1 is the major inhibitor of fibrinolysis both in normal subjects and in patients with DIC. Produced in monocytes, macrophages and endothelial cells, PAI-1 is the most potent of three inhibitors of plasminogen activation (PAI-1, 2 and 3). Activated platelets not only secrete PAI-1, but also induce endothelial cells to express PAI-1. PAI-1 binds to single and double chain tPA and uPA inactivating them, preventing the conversion of plasminogen to plasmin. Entrapment of PAI-1 in platelet-rich thrombi represents a major factor leading to fibrinolysis resistance. In DIC from multiple causes, PAI-1 levels correlate closely with mortality.29,30

Further investigation of this observation led to the discovery of the 4G allelic polymorphism in the PAI-1 promoter region. This polymorphism is associated with a gene-dose dependent increase in PAI-1 levels in children with meningococcemia, the homozygous individuals had an increased risk of death.31 The 4G polymorphism has been shown to increase the promoter's sensitivity to IL-1a stimulation. Interestingly, in the children with meningitis without sepsis/DIC, the 4G polymorphism was not associated with a worse clinical outcome. Recently, in another DIC-associated inflammatory condition, severe pre-eclampsia, heterozygous individuals (4G/5G) and homozygous individuals (4G/4G) were at increased risk for severe pre-eclampsia.32 This promoter polymorphism has been studied in other non-inflammatory thrombotic diseases (stroke and myocardial infarction). In these conditions the polymorphism is not associated with incidence or severity. These data seem to suggest the PAI-1 promoter's response to inflammation may play a critical role determining which direction the coagulation balance will tip. Patients with the 4G polymorphism and higher PAI-1 levels may be more prone to the fatal thrombotic form of this illness.

In DIC, protein C deficiency is an important cause of inhibited fibrinolysis. Protein C is synthesized in the liver in precursor form. Thrombin-TM complexes and factor Xa activate the precursor form of protein C. Activated protein C (APC) is a serine protease with anticoagulant and anti-inflammatory effects. It degrades factors Va and VIIIa, inhibiting production of new activated clotting factors and new fibrin monomers. More importantly, APC enhances fibrinolysis, binding to PAI-1 and inactivating it. Although the signaling details remain obscure, APC can bind to endothelial cells through endothelial protein C receptor directly down-regulating endothelial PAI-1 expression. An analogous protein C receptor exists on human mononuclear phagocytes. The receptor seems to allow APC to inhibit monocyte proliferative responses and cytokine elaboration. In humans APC specifically inhibits monocyte TNF-a production, endothelial expression of E-selectin, neutrophil activation and mast cell degranulation in response to a variety of stimuli.33

TM also likely plays an important role in the fibrinolytic response to DIC. TM is a high affinity transmembrane receptor for thrombin expressed on the surface of endothelial cells. When bound to TM, thrombin undergoes an important conformational change and develops several anticoagulant properties including the ability to activate protein C. TM bound to thrombin exists in clathrin-coated pits and eventually the complex is endocytosed. In DIC, although blood levels of soluble TM increase, endothelial sloughing at the locus of vessel injury is the most likely explanation. On viable endothelial cells stimulated by a number of stressors, the TM/PAI-1 ratio actually declines, reflecting the endothelial cell's shift toward a pro-thrombotic phenotype.34,35 Together, TM and APC cooperate to check the progression of thrombosis and promote fibrinolysis.

Repletion of the APC deficiency and direct suppression of PAI-1 restores endogenous fibrinolysis. This strategy appears to work better than direct anti-coagulation, which has produced mixed results in animal models and clinical trials. Although thrombosis is an easily measurable side effect of diffuse vascular activation, it may only be a confounding marker for disease severity. The improved understanding of the consequences of inflammation have emphasized the importance of the anti-inflammatory effects of APC and TM. In a recent trial, patients with severe sepsis (defined as sepsis with organ dysfunction) received either APC or albumin for 96 hours. Therapy with APC was associated with a 6.1% reduction in absolute mortality. Treatment with APC also reduced levels of IL-6 and D-dimers.27 Recent data in a murine stroke model extends the evidence for anti-inflammatory effects of APC as a therapy. Ten minutes after the middle cerebral artery occlusion, APC was infused. The arterial occlusion was relieved after one hour and followed by 24 hours of reperfusion. APC not only limited thrombosis and ischemic injury, but also completely prevented migration of neutrophils into the damaged tissue.36

Attempts to suppress PAI-1 expression have met with more limited success than its inactivation. In a rabbit model of endotoxin-induced DIC, treatment with a monoclonal antibody to PAI-1, MA-33B8, completely prevented glomerular fibrin deposition in the rabbit kidneys, however, it did not improve survival.37 A more direct method of suppressing PAI-1 production has met with recent success. In a murine model of pulmonary ischemia-reperfusion and also in endotoxemia, pre-treatment with inhaled low doses carbon monoxide (CO) suppressed PAI-1 expression in both alveolar macrophages and endothelial cells. This observation provides a novel mechanism of PAI-1 suppression, a novel therapy for thrombosis and also insights about the molecular biology of the stress response. PAI-1 suppression decreased fibrin deposition, improved pulmonary function and increased survival (Fig. 4).38

Figure 4a. Mouse Kaplan-Meier survival curve after lung ischemia-reperfusion injury.

Figure 4a

Mouse Kaplan-Meier survival curve after lung ischemia-reperfusion injury. The dashed line represents wild type mice treated with CO; the dotted line represents wild type mice treated with CO and ODQ (a cGMP inhibitor).

Figure b and c. PAI-1 mRNA levels by Northern blotting in mice injected with LPS with or without CO therapy.

Figure b and c

PAI-1 mRNA levels by Northern blotting in mice injected with LPS with or without CO therapy. PAI-1 mRNA levels by Northern blotting in mice subjected to lung ischemia-reperfusion injury with or without CO therapy. Adapted from reference .

In vivo hypoxia, ischemia reperfusion, inflammation and other environmental stressors upregulate hemoxygenase I (Hmox-1). Hmox-1 cleaves the α-meso carbon of the heme molecule producing equimolar amounts of iron, CO and biliverdin. This is the major source of endogenous CO. Pretreating Hmox-1 knockout mice with CO prior to lung ischemia-reperfusion injury partially rescues them. As fibrin deposition is known to be one of the critical elements to ischemia-reperfusion injury, CO's effects in this injury that suggest Hmox-1's role in stress may be promotion of fibrinolysis.38

Future Directions

Several trials have evaluated heparin and heparinoids in the treatment of endotoxin-induced DIC. These are the most completely tested of the therapies available, consistently improving surrogate markers of DIC such as fibrinogen, fibrinogen degradation products, coagulation times, and bleeding complications. However, neither therapy has been shown to improve mortality in animals or humans.39

In human case reports and in rat models, TM appears to be useful in the treatment of DIC. In a rat model of endotoxemia, infusion of purified human urinary soluble TM reduced edema and reduced fibrinogen levels in the rats. TM did not change intrapulmonary macrophage accumulation as measured by tissue myeloperoxidase levels.40

The stress-response enzyme Hmox-1 has recently received a great deal of attention for its protective role in the vasculature. Biliverdin and CO, two byproducts of heme's catabolism by Hmox-1, have beneficial effects on the vasculature in pre-clinical studies. Blocking Hmox activity with zinc protoporphyrin IX (or using Hmox-1 null mice) worsens the vascular response to mechanical injury.41 Increasing CO levels with exogenous inhalation enhances Hmox-1's protective effect in an LPS model of DIC. Treatment with CO suppresses the increase in PAI-1 levels usually observed in the lungs of mice injected with LPS (Fig. 4).38 Both CO's and Hmox-1's effect on the vasculature depend on cyclic GMP, sharing this pathway with NO. Further experiments are required to establish whether this therapy shares the anti-inflammatory benefits of APC.

Other promising therapies in this area include inhibition of the Egr-1 pathway either at the level of the Egr-1 transcription factor or upstream in the pathway through PKCβ II inhibition. Theoretically, inhibition of this pathway might prevent induction of the conserved vascular responses to environmental stressors, maintaining the quiescent phenotype at non-injured loci. NTPDase I CD39 also has significant promise for similar conditions. Like APC, CD39 appears to modulate both coagulation and inflammation. However, soluble CD39 has the theoretical advantage of preventing platelet activation, without disabling the platelet's response to vascular injury.


Although DIC inevitably results in the unchecked activation of numerous coagulation factors, emerging data points to a new conceptual framework for DIC's pathogenesis. Cells of the vascular wall normally maintain the intricate homeostatic balance protecting the unimpeded flow of blood and cells through the vascular tree. In the severest form of DIC, activation of these same cells profoundly disrupts this balance, altering the microvascular milieu to favor thrombosis and inflammation. Perpetuation of the inflammatory cascade by activated vascular wall cells in the amplification of DIC has gone under-recognized. Recent therapeutic strategies targeting these cells and their products for inhibition have shown initial promise for treating this previously untreatable illness. Recognition of the critical molecular pathways in the induction of thrombosis and inflammation and the suppression of fibrinolysis has finally provided hope for the treatment of DIC.


APC, activated protein C; DIC, disseminated intravascular coagulation; Hmox-1, heme oxygenase type 1; IL-1α, interleukin-1α; LPS, lipopolysaccharide; PAI-1, plasminogen activator inhibitor-1; PKCb II, protein kinase C b II; TF, tissue factor; TM, thrombomodulin; TNF-α, tumor necrosis factor α; tPA, tissue plasminogen activator; vWF, von Willebrand's factor


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