Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation
© Franchini et al; licensee BioMed Central Ltd. 2006
Received: 03 January 2006
Accepted: 21 February 2006
Published: 21 February 2006
Disseminated intravascular coagulation (DIC) is a disorder characterized by both acute generalized, widespread activation of coagulation, which results in thrombotic complications due to the intravascular formation of fibrin, and diffuse hemorrhages, due to the consumption of platelets and coagulation factors. Systemic activation of coagulation may occur in a variety of disorders, including sepsis, severe infections, malignancies, obstetric or vascular disorders, and severe toxic or immunological reactions.
In this review, we briefly report the present knowledge about the pathophysiology and diagnosis of DIC. Particular attention is also given to the current standard and experimental therapies of overt DIC.
Clinical conditions associated with disseminated intravascular coagulation.
Gram-positive bacteria, Gram-negative bacteria, spirochetes, rickettsiae, protozoa, fungi, viruses
Polytrauma, neurotrauma, fat embolism, burns
Solid tumors, myeloproliferative/lymphoproliferative malignancies
Amniotic fluid embolism, abruptio placentae, placenta previa, retained dead fetus syndrome
Large vascular aneurysms, Kasabach-Merritt syndrome
Severe pancreatitis, severe hepatic failure
Snake bites, recreational drugs
Hemolytic transfusion reaction, transplant rejection
In the following sections we briefly discuss the current knowledge on the pathogenesis, diagnosis and treatment of DIC.
Pathogenesis of DIC
Most of the recent advances in our understanding ofthe pathogenesis of DIC are derived from studies in animal models and humans with severe sepsis . These studies have demonstrated that the systemic formation of fibrin observed in this setting is the result of the simultaneous coexistence of four different mechanisms: increased thrombin generation, a suppression of the physiologic anticoagulant pathways, impaired fibrinolysis and activation of the inflammatory pathway [1, 8, 21].
The systemic generation of thrombin has been shown to be mediated predominantlyby the extrinsic (factor VIIa) pathway. In fact, while the abrogation of the tissue factor/factor VIIa pathway resulted in complete inhibition of thrombin generation in experimental animal models of endotoxemia, the inhibition of the contact system did not prevent systemic activation of coagulation [22, 23].
Impaired function of physiological anticoagulant pathways may amplify thrombin generation and contribute to fibrin formation . Plasma levels of antithrombin are markedly reduced in septic patients as a result of a combination of increased consumption by the ongoing formation of thrombin, enzyme degradation by elastase released from activated neutrophils, impaired synthesis due to liver failure and vascular capillary leakage [6, 7, 25]. Likewise, there may be significant depression of the protein C system, caused by enhanced consumption, impaired liver synthesis, vascular leakage and a down-regulation of thrombomodulin expression on endothelial cells by pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin(IL)-1β [26–28]. Moreover, the evidence that administration of recombinant tissue factor pathway inhibitor (TFPI) results in complete inhibition of endotoxin-induced thrombin generation suggests that tissue factor is involved in the pathogenesis of DIC [29, 30]. Although no acquired or deficiency or functional defect of TFPI has been identified in patients with DIC, there is evidence that the inhibitor does not regulate tissue factor activity sufficiently in such patients.
As regards impaired fibrinolysis, experimental models of bacteremia and endotoxemia are characterized by rapidly increasing fibrinolytic activity, most probably due to the release of plasminogen activators from endothelial cells. However, this initialhyperfibrinolytic response is followed by an equally rapid suppression of fibrinolytic activity, due to the increase in plasma levels of plasminogen activator inhibitor type 1 (PAI-1) [31–33]. The importance of PAI-1 in the pathogenesis of DIC is further demonstrated by the fact that a functional mutation in the PAI-1 gene, the 4G/5G polymorphism, which causes increased plasma levels of PAI-1, was linked to a worse clinical outcome in patients with meningococcal septicemia .
Finally, another important mechanism in the pathogenesis of DIC is the parallel and concomitant activation of the inflammatory cascade mediated by activated coagulation proteins, which in turn can stimulate endothelial cells to synthesize pro-inflammatory cytokines. In fact, while cytokines and inflammatory mediators can induce coagulation, thrombin and other serine proteasesinteract with protease-activated receptors on cell surfaces to promote further activation and additional inflammation . Furthermore, since activated protein C has an anti-inflammatory effect through its inhibition of endotoxin-induced production of TNF-α, IL-1β, IL-6 and IL-8 by cultured monocytes/macrophages, depression of the protein C system may result in a pro-inflammatory state .
Pathogenesis of disseminated intravascular coagulation in sepsis.
1) Increased thrombin generation
Mediated predominantlyby tissue factor/factor VIIa pathway
2) Impaired function of physiological anticoagulant pathway
a) Reduction of antithrombin levels
The result of a combination of increased consumption, enzyme degradation, impaired liver synthesis and vascular leakage
b) Depression of protein C system
The result of a combination of increased consumption, impaired liver synthesis, vascular leakage and down- regulation of thrombomodulin
c) Insufficienttissue factor pathway inhibitor (TFPI)
3) Impaired fibrinolysis
Mediated by release of plasminogen activators from endothelial cells immediately followed by an increase in the plasma levels of plasminogen activator inhibitor type 1 (PAI-1)
4) Activation of inflammatory pathway
Mediated by activated coagulation proteins and by depression of the protein C system
However, there is evidence that various events, including the release of tissue material (fat, phospholipids, cellular enzymes) into the circulation, hemolysis and endothelial damage may promote the systemic activation of coagulation in severe trauma and burns through a mechanism similar to that observed in septic patients (i.e., systemic activation of cytokines)[14, 15]. Nevertheless, there may also be specific variations in the pathogenesis if DIC due to different underlying disorders. For example, in some patients with cancer the initiation of coagulation activation is not only due to tissue factor expression on the surface of the malignant cells but in this case also involves a specific cancer procoagulant, a cysteine protease with factor X activating properties. Patients with acute promyelocytic leukemia have a peculiar form of DIC characterized by a severe hyperfibrinolytic state associated with systemic activation of coagulation.
Diagnosis of DIC
Treatment of DIC
Treatment modalities for disseminated intravascular coagulation.
1) Replacement therapy
- Fresh-frozen plasma
- Unfractionated and low-molecular-weight heparin
- Danaparoid sodium
- Recombinant hirudin
- Recombinant tissue factor pathway inhibitor
- Recombinant nematode anticoagulant protein c2
3) Restoration of anticoagulant pathways
- Recombinant human activated protein C
4) Other agents
- Recombinant activated factor VII
- Antifibrinolytic agents
- Antiselectin antibodies
- Recombinant interleukin-10
- Monoclonal antibodies against TNF and CD14
a) Replacement therapy
The aim of replacement therapy in DIC is to replace the deficiency due to the consumptionof platelets, coagulation factors and inhibitors in order to prevent or arrest the hemorrhagic episodes . Platelet concentrates and fresh frozen plasma (FFP) were, in the past, used very cautiously because of the fear that they might "feed the fire" and worsen thrombosis in patients with active DIC. However, this fear was not confirmed by clinical practice and nowadays replacement therapy is a mainstay of the treatment of patients with significant bleeding and coagulation parameters compatible with DIC. Transfusion of platelet concentrates at 1–2 U/10 Kg body weight should be considered when the platelet count is less than 20 × 109/L or if there is major bleeding and the platelet count is less than 50 × 109/L. When there is significant DIC-associated bleeding and fibrinogen levels are below 100 mg/dL, the use of FFP, at a dose of 15–20 mL/Kg, is justified. Alternatively, fibrinogen concentrates (total dose 2–3 g) or cryoprecipitates (1 U/10 Kg body weight) may be administered. However, FFP should be preferred to specific coagulation factor concentrates since the former contains all coagulation factors and inhibitors deficient during active DIC and lacks traces of activated coagulation factors, which may instead contaminate the concentrates and exacerbate the coagulation disorder.
The role of heparin in the treatment of DIC remains controversial [55–62]. In fact, although from a theoretical point of view interruption of the coagulation cascade should be of benefit in patients with active DIC , the clinical studies carried out so far have not been conclusive and indeed have often yielded contradictory results . However, on the basis of the few data available in the literature, heparin treatment is probably useful in patients with acute DIC and predominant thromboembolism, such as those with purpura fulminans [2, 56]. The use of heparin in chronic DIC is better established and it has been successfully employed in patients with chronic DIC associated with those diseases in which recurrent thrombosis predominates, such as solid tumors, hemangiomas, and dead fetus syndrome . The role of heparin in the treatment of DIC associated with acute promyelocytic leukemia (APL) is another controversy, since some authors support its use whereas other studies failed to demonstrate its efficacy [57–59]. However, the use of heparin in this setting has declined in the last few years thanks to the introduction of all-trans retinoic acid therapy which has led to the reduction of APL-associated coagulopathy. Heparin is usually given at relatively low doses (5–10 U/Kg of body weight per hour) by continuous intravenous infusion and may be switched to subcutaneous injection for long-term outpatient therapy (i.e. for those patients with chronic DIC associated with solid tumors). Alternatively, low-molecular-weight heparin may be used, as supported by the positive results in both experimental and clinical DIC studies [60–63].
A newer anticoagulant agent with direct thombin inhibitory activity, recombinant hirudin (r-hirudin) [67, 68], was recently shown to be effective in treating DIC in animal studies, although a study of the effect of this thrombin inhibitor in a sheep model of lethal endotoxemia showed no benefit . Preliminary experimental human studies proved that this drug attenuated endotoxin-induced coagulation activation .
Since activation of the coagulation cascade during DIC occurs predominantlythrough the extrinsic pathway, theoretically the inhibition of tissue factor should block endotoxin-associated thrombin generation . In vivo experiments in baboon models of lethal DIC showed that TFPI is a potent inhibitor of sepsis-related mortality . De Jonge and colleagues  first demonstrated in humans that recombinant TFPI dose-dependently inhibits coagulation activation during endotoxemia. Recombinant TFPI was evaluated in a phase II randomized trial in patients with severe sepsis . Although the study did not have the statistical power to demonstrate a survival benefit, it did show a trend toward a reduction in 28-day all-cause mortality together with an improvement in organ dysfunction in the group of patients treated with the recombinant TFPI. No evidence of a survival advantage was observed in patients with severe sepsis who received recombinant TFPI in a recent phase III large clinical trial.
Inhibition of the tissue factor/factor VIIa pathway is an another strategy that has been explored. Moons and colleagues demonstrated the efficacy of recombinant nematode anticoagulant protein c2 (NaPc2), a potent and specific inhibitor of the ternary complex between tissue factor/factor VIIa and factor Xa, in inhibiting coagulation activation in a primate model of sepsis . Other authors have experimented with anti-tissue factor/factor VIIa antibodies in animal models with promising results .
c) Restoration of anticoagulant pathways
Since patients with active DIC have an acquired deficiency of coagulation inhibitors, restoration of the physiologic anticoagulation pathways seems to be an appropriate aim of the treatment of DIC . Considering that antithrombin (AT) is the primary inhibitor of circulating thrombin, its use in DIC is certainly rational . Recent studies in animals and humans with severe sepsis have demonstrated that antithrombin also has anti-inflammatory properties (reduction of C-reactive protein and IL-6 levels), which may further justify its utilization during DIC [78, 79]. The administration of antithrombin concentrates infused at supraphysiologic concentrations was shown to reduce sepsis-related mortality in animal models . Several small clinical trials have been conducted in humans, mostly in patients with sepsis-related DIC, and have shown beneficial effects in terms of improvement of coagulation parameters and organ function [81, 82]. An Italian multicenter, randomized, double-blind study conducted in 1998 by Baudo et al. , evaluating the role of antithrombin in patients with sepsis or post-surgical complications, showed a net beneficial effect on survival in those patients receiving the concentrate. These findings were confirmed in 1999 by Levi et al. in their meta-analysis of all so far published human clinical trials of antithrombin treatment of DIC . By contrast, a large randomized, controlled multicenter trial of supraphysiologic doses of AT concentrates conducted in 2144 patients with sepsis and DIC did not show a beneficial effect of antithrombin treatment . However, a retrospective analysis of the same trial showed that the subgroup of patients who did not receive concomitant heparin had a potential benefit from antithrombin III in terms of mortality reduction.
Based on the fact that the protein C system is impaired during DIC some authors have investigated the therapeutic efficacy of exogenous administration of this protein in patients with DIC [86–98]. The infusion of activated protein C (APC) concentrates was shown to prevent DIC and mortality in an animal model of sepsis . A study conducted in 1998 on patients with severe sepsis suggested a trend toward improved survival in the group treated with APC . In a dose-ranging clinical trial, 131 patients with sepsis received recombinant human APC by continuous infusion at doses ranging from 12μg/Kg/hour to 30 μg/Kg/hour or placebo . A 40 percent reduction in mortality was observed in those patients who received the higher doses of activated protein C. Similarly, another recent multicenter clinical trial  determined that treatment with recombinant human APC, given intravenously at a dose of 24 μg/Kg of body weight per hour, significantly reduced mortality in patients with severe sepsis, in spite of a higher rate of serious bleeding in the APC-treated group. A double-blind randomized trial compared the safety and efficacy of APC and unfractionated heparin in the treatment of DIC and concluded that the former improved DIC, and finally the survival, more efficiently than did heparin . The recently published results of the trial conducted by the Human Recombinant Activated Protein C Worldwide Evaluation in Sepsis (PROWESS) Study Group showed a significant reduction in 28-day mortality and a quicker resolution of organ dysfunction in the group of patients with severe sepsis treated with APC [92, 93]. These results were confirmed by the ENHANCE trial which also suggested that recombinant APC might be more effective is therapy is started earlier . By contrast, a very recent trial on 2640 patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score <25 or single organ failure) did not find a statistically significant difference in 28-day mortality rate between the placebo and APC-treated groups, suggesting that APC is of benefit only in patients at high risk of death from sepsis.Ongoing studies are focusing on the concomitant use of heparin in patients with DIC who receive activated protein C .
d) Other agents
Recombinant factor VII activated (rFVIIa) may be used in patients with severe bleeding who are not responsive to other treatment options. Bolus doses of 60–120 μg/Kg, possibly repeated after 2–6 hours, have been found to be effective in controlling refractory hemorrhagic episodes associated with DIC [100, 101]. Antifibrinolytic agents, such as epsilon-aminocaproic acid or tranexamic acid, given intravenously at a dose of 10–15 mg/Kg/h, are occasionally used in patients resistant to replacement therapy who are bleeding profusely or in patients with disease states associated with intense fibrinolysis (prostate cancer, Kasabach-Merrit syndrome, acute promyelocytic leukemia) . However, since these agents are very effective in blocking fibrinolysis, they should not be administered unless heparin has been previously infused in order to block the prothrombotic component of DIC. The use of these drugs in APL has declined in the last few years, given the efficacy of all-trans-retinoic-acid in preventing the majority of the hemorrhagic complications of this malignancy .
The advances in the understanding of the pathophysiology of DIC have resulted in novel preventive and therapeutic approaches to this disease. Based on the fact that tissue inflammation is a fundamental mechanism in DIC associated with sepsis or major trauma, some researchers have successfully employed the combined blockade of leukocyte/platelet adhesion and coagulation in a murine model by using antiselectin antibodies and heparin and have suggested the potential clinical use of such a strategy . Based on the same rationale, other researchers have demonstrated that the administration of recombinant IL-10, an anti-inflammatory cytokine which may modulate the activation of coagulation, completely abrogated endotoxin-induced effects on coagulation in humans . By contrast, the use of monoclonal antibodies against tumor necrosis factor has shown disappointing or at best modest results in septic patients[105–107]. More recently, Branger and colleaguesfound that an inhibitor of p38 mitogen-activated protein kinase (MAPK), an important component of intracellular signaling cascades that mediate the inflammatory response to infectious and non-infectious stimuli, attenuated the activation of coagulation, fibrinolysis and endothelial cells during human endotoxemia. Finally, although studies using antibodies against the receptor for bacterial endotoxins (CD14) produced positive results, other studies using endotoxin antibodies failed to improve outcome[110, 111].
Disseminated intravascular coagulation is a syndrome characterized by systemic intravascular activation of coagulation leading to bleeding (due to depletion of platelets and coagulation factors) and thrombosis(due to widespread deposition of fibrin in the circulation).
The diagnosis of DIC is usually made by a combination of routinely available laboratory tests, using a validated diagnostic algorithm.
In recent years, the mechanisms involved in pathological microvascular fibrin deposition in DIC have become progressively clear, resulting in novel preventive and therapeutic approaches to patients with DIC.
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