Disseminated Intravascular Coagulation: What's New?
Section snippets
Clinical setting
DIC is not a disease in itself, but is always secondary to an underlying disorder. The underlying disorders most commonly known to be associated with DIC are listed in Box 1.
Bacterial infection, in particular septicemia, is often associated with DIC [3], [4]. However, systemic infections with other microorganisms, such as viruses and parasites, may lead to DIC as well. Endotoxins (eg, from Gram negative bacteria) or exotoxins (eg, staphylococcal alpha toxin) may contribute to the development of
Clinical presentation
Patients with severe forms of DIC may present with manifest thrombo-embolic disease, or clinically less apparent microvascular fibrin deposition, which predominantly presents as multiple organ dysfunction [2]. Alternatively, severe bleeding may be the leading symptom, but quite often a patient with DIC has simultaneous thrombosis and bleeding. In its most severe form, this combination may present as Waterhouse-Friderichsen syndrome, most commonly seen during fulminant meningococcal septicemia;
Pathogenesis
In recent years, the mechanisms involved in pathological microvascular fibrin deposition in DIC have become increasingly clear. Initiation of coagulation is tissue factor-dependent; amplification of thrombin generation is caused by defective physiological anticoagulant mechanisms; and propagation of fibrin deposition in the microvasculature is caused by insufficient fibrin degradation, as a result of an inhibited fibrinolytic system (Fig. 1).
Traditionally, DIC was thought to be the result of
Propagation of coagulation activation
Regulation of thrombin generation normally occurs at three levels in the coagulation system: at the level of thrombin and factor Xa by antithrombin, at the level of the essential cofactors V and VIII by activated protein C, and at the level of the tissue factor/factor VIIa complex by tissue factor pathway inhibitor (TFPI). In DIC, each of these three major physiological anticoagulant mechanisms is defective (Fig. 2).
For several reasons, antithrombin appears to be incapable of adequate
Fibrinolysis
Experimental models indicate that at the time of maximal activation of coagulation, the fibrinolytic system is largely shut off. Experimental bacteremia and endotoxemia result in a rapidly occurring increase in fibrinolytic activity, most probably caused by the release of plasminogen activators from endothelial cells. This profibrinolytic response is almost immediately followed by a suppression of fibrinolytic activity because of a sustained increase in plasma levels of plasminogen activator
Systemic versus localized responses
Although the mechanisms mentioned above have been demonstrated to occur in vivo as a general response upon pro-inflammatory stimuli, it is likely that marked differences in the procoagulant response as well as the underlying pathogenetic pathway may exist between cells and tissues [42]. This may be caused by differences in cell-specific gene expression, environmental factors, and organ specific differences. First, localization of coagulation activity may relate to a cell specific gene
Diagnosis of DIC
No single laboratory test available today is sensitive or specific enough to allow a definite diagnosis of DIC. According to the current understanding of sepsis-associated coagulation abnormalities, the determination of soluble fibrin in plasma appears to be crucial [49], [50], [51], and clinical studies indicate that if the concentration is above a defined threshold, a diagnosis of DIC can be made [52], [53]. Most of the clinical studies show a sensitivity of 90%-100% for the diagnosis of DIC
DIC scoring system
Without a specialized laboratory, the diagnosis of DIC may be made by a combination of platelet count, prothrombin time (PT), measurement of fibrinogen and fibrin degradation products [62]. A scoring system, using these simple laboratory tests, has been reviewed by the subcommittee on DIC of the International Society on Thrombosis and Haemostasis [63]. A five-step diagnostic algorithm to calculate a DIC score is summarized in Box 2, and is based partly on a similar model of the Japanese
Management of disseminated intravascular coagulation
The fundament of DIC treatment is the specific and vigorous treatment of the underlying disorder. In some cases, the DIC will completely resolve within hours after resolution of the underlying condition (for example, in cases of DIC induced by abruptio placentae). However, in other cases, such as in patients with sepsis and a systemic inflammatory response syndrome, DIC may proceed, even after proper treatment has been given. In those cases, supportive measures to manage the DIC may be required
Plasma and platelet substitution therapy
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, but is only indicated in patients with active bleeding and in those requiring an invasive procedure or otherwise at risk for bleeding complications [66]. The suggestion that administration of blood components might add “fuel to the fire” has in fact never been proven in clinical or experimental
Anticoagulants
Experimental studies have shown that heparin can at least partly inhibit the activation of coagulation in sepsis and other causes of DIC [68]. It has been claimed that uncontrolled case series in patients with DIC have been successful. However, a beneficial effect of heparin on clinically important outcome events in patients with DIC has never been demonstrated in controlled clinical trials [69]. Also, the safety of heparin treatment is debatable in DIC patients who are prone to bleeding.
Restoration of anticoagulant pathways
Since antithrombin is one of the most important physiological inhibitors of coagulation, and based on successful pre-clinical results, the use of antithrombin III concentrates in patients with DIC has been studied relatively intensively. Most of the randomized controlled trials concern patients with sepsis or septic shock. All trials show some beneficial effect in terms of improvement of laboratory parameters, shortening of the duration of DIC, or even improvement in organ function [3]. In the
Summary
DIC is a syndrome characterized by systemic intravascular activation of coagulation, leading to widespread deposition of fibrin in the circulation. There is good experimental and pathological evidence that the fibrin deposition contributes to multiple organ failure. The massive and ongoing activation of coagulation may result in depletion of platelets and coagulation factors, which may cause bleeding (consumption coagulopathy). DIC is not a disease in itself but is invariably seen as a
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