DIC is also not a syndrome that has altogether been ignored in the medical literature. Most of the published literature concerns case reports and studies regarding the pathophysiology of DIC. Recently, however, the pathogenesis of DIC has largely been clarified and these novel insights may lead to more adequate management strategies.
Disseminated intravascular coagulation
Some of these strategies are currently being tested in clinical trials. In addition, the improved knowledge on the pathogenesis of DIC may facilitate the development of more accurate diagnostic tests to ascertain or reject the diagnosis of DIC. This article briefly discusses the definition, clinical setting and relevance of DIC, and current insights in the pathogenesis of the syndrome.
Subsequently, currently available knowledge regarding the clinical management of patients with DIC will be discussed. Disseminated intravascular coagulation is not a disease or a symptom but a syndrome, which is always secondary to an underlying disorder. Obviously, the clinical importance of a severe depletion of platelets and coagulation factors in patients with diffuse, widespread bleeding or in patients that need to undergo an invasive procedure is indisputable. There is some debate as to what extent the intravascular deposition of fibrin, as a result of the systemic activation of coagulation, contributes to organ failure and mortality.
The presence of these intravascular thrombi appears to be clearly and specifically related to the clinical dysfunction of the organ. Taking this data together, there appears to be sufficient evidence for a pathogenetic role of DIC in organ failure and related mortality.
Several disease states may lead to the development of DIC. In addition, systemic infections with other microorganisms, such as viruses and parasites, may also lead to DIC. Factors involved in the development of DIC in patients with infections may be specific cell membrane components of the microorganism lipopolysaccharide or endotoxin or bacterial exotoxins e.
Severe trauma is another clinical condition frequently associated with DIC Gando, A combination of mechanisms including release of tissue material fat, phospholipids into the circulation, haemolysis and endothelial damage may contribute to the systemic activation of coagulation. In fact, systemic cytokine patterns have been shown to be virtually identical in trauma patients and septic patients.
Some tumours are associated with a form of DIC that is characterized by severe hyperfibrinolysis on top of an activated coagulation system. Although clinically bleeding predominates in this situation, disseminated thrombosis is found in a considerable number of patients at autopsy. Acute DIC occurs in obstetrical calamities such as placental abruption and amniotic fluid emboli Weiner, Although some characteristics of microangiopathic haemolytic anaemia and the resulting thrombotic occlusion of small and midsize vessels leading to organ failure may mimic the clinical picture of DIC, these disorders in fact represent a distinct group of diseases.
Materials and Methods
Clinically, normal global clotting times, such as the prothrombin time PT and the activated partial thromboplastin time aPTT , are helpful in distinguishing microangiopathic haemolytic anaemia from DIC. In addition to enhanced fibrin formation, fibrin removal is impaired as a result of depression of the fibrinolytic system.
As mentioned before, in exceptional forms of DIC, fibrinolytic activity may be increased and contribute to bleeding. In somewhat more detail, the following processes are involved:. Schematic representation of pathogenetic pathways in disseminated intravascular coagulation. During systemic inflammatory response syndromes, both perturbed endothelial cells and activated mononuclear cells may produce proinflammatory cytokines that mediate coagulation activation. Activation of coagulation is initiated by tissue factor expression on activated mononuclear cells and endothelial cells.
Disseminated intravascular coagulation - Wikipedia
In addition, downregulation of physiological anticoagulant mechanisms and inhibition of fibrinolysis by endothelial cells will further promote intravascular fibrin deposition. An impaired function of various natural regulating pathways of coagulation activation may amplify the further thrombin generation and contribute to fibrin formation Esmon, Plasma levels of the most important inhibitor of thrombin, antithrombin III, are usually markedly reduced in septic patients.
This reduction is caused by a combination of consumption, as a result of ongoing thrombin generation, degradation by elastase, which is released from activated neutrophils, and impaired synthesis. In addition to the decrease in antithrombin III, a significant depression of the protein C system may occur.
This, in combination with low levels of zymogen protein C because of similar mechanisms as described for antithrombin , results in diminished protein C activation, which will enhance the procoagulant state. The third significant inhibitor of coagulation is tissue factor pathway inhibitor TFPI. Experimental models indicate that at the time of maximal activation of coagulation, the fibrinolytic system is largely shut off.
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PARs are localized in the vasculature on endothelial cells, mononuclear cells, platelets, fibroblasts and smooth muscle cells Coughlin, In addition, all three physiological anticoagulant pathways are capable of influencing inflammatory activity. This is most prominently shown for the protein C pathway Okajima, ; Esmon, Infusion of activated protein C abrogates inflammatory activity and improves organ function and survival in an experimental E. It is likely that the effects of activated protein C on inflammation are mediated by the endothelial protein C receptor EPCR Esmon, The close relationship between coagulation, anticoagulant, and fibrinolytic pathways and inflammation.
To establish a diagnosis of DIC, it is of utmost important to assess the whole clinical picture, taking into account the clinical condition of the patient, the diagnosis, and all available laboratory results. No single routinely available laboratory test is sufficiently sensitive or specific to enable a diagnosis of DIC. In a specialized setting, molecular markers for activation of coagulation or fibrin formation may be the most sensitive assays. Indeed, these markers are notably elevated in patients with DIC but again the specificity is a problem.
In addition to these shortcomings, most of the sensitive and sophisticated tests described above are not available to general haematology laboratories. Although these tests may be very helpful in clinical trials or other research, they cannot often be used in a routine setting. It has been shown that a biphasic waveform is a specific and reasonably sensitive marker for incipient DIC. While promising, the specialized equipment to perform this waveform analysis will not be available at most sites.
A score of 5 or greater was concluded to have a positive result. Autopsy results of patients who died of DIC manifested by disseminated intravascular coagulation, DIC, or disseminated intravascular coagulopathy in the final anatomic diagnosis [FAD] and with micro-thrombi described in 1 or more organs were extracted by retrospective review of the anatomic pathology database.
The cases were re-reviewed to confirm the presence of fibrin thrombi in the microvasculature of organs, most often the liver sinusoids, adrenal glands, or kidneys. Their last set of coagulation tests right before death was retrospectively collected from the clinical pathology database used for routine reporting of test results. Two logistic regression models were built by including independent variables—namely, fibrinogen, PT, platelet, and D-dimer—to compare the TCH method of diagnosis with the ISTH scoring method.
Next, stepwise logistic regression analysis was done to assess the ability of the independent variables, such as PT, D-dimer, platelet count, and fibrinogen, to predict overt DIC according to the ISTH and TCH criteria and also to identify the best set of predictors of DIC in both systems. In addition, sensitivity and specificity, which are statistical measurements of a binary classification test presence or absence of DIC , were calculated according to their specific criteria and compared with the autopsy diagnosis of DIC, which is the global gold standard of diagnosis. A total of 2, DIC panels from patients There was a significant difference in the coagulation parameters between patients with and without a diagnosis of DIC.
Forward stepwise logistic regression analysis was performed to examine the impact of the coagulation variables on the diagnosis of DIC Table 4. However, only a few studies have validated the scoring method in children. Hence, we investigated its usefulness in the pediatric age group and compared it with our diagnostic criteria and a gold standard pathologic confirmation of DIC. Several other studies have confirmed similar results in the adult population. The results presented here indicate that PT, D-dimer, and platelet count are significant predictors in both models. However, fibrinogen does not seem have a significant impact on the prediction of DIC.
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Fibrinogen adds no further effect to the stepwise logistic regression risk factor modeling, and it is therefore excluded while developing a parsimonious model. This is consistent with the results of the study done by Bakhtiari and colleagues, 9 who concluded that the ISTH DIC scoring system was very reliable in confirming or rejecting a diagnosis of DIC in critically ill patients and that inclusion or exclusion of fibrinogen levels did not affect the accuracy of the scoring system. Fibrinogen levels have been known to be insensitive indicators of DIC, primarily due to its increase during the acute-phase response.
So, even though DIC may cause intense consumption of fibrinogen, levels do not typically fall below the normal range. However, sequential measurement of fibrinogen, as performed in TCH, is useful in detecting decreasing trends of fibrinogen and, therefore, is more predictive of overt DIC.
In our institution, serial values are evaluated to detect successive drops in the count, and DIC is diagnosed when a trend emerges. A single measurement reflecting moderate thrombocytopenia is found in many critically ill patients due to their underlying disease; hence, the platelet count at a single time point is not a sensitive predictor of overt DIC.
In addition, patients with leukemia commonly have thrombocytopenia related to the disease condition or chemotherapy. Because those patients frequently receive platelet transfusions, an evaluation of platelet count must include a careful review of transfusion history. However, sequential measurements of platelet counts that show a decrease from normal or low-normal baseline values are indicative of DIC.
Hence, our comparison of both diagnostic algorithms against the autopsy gold standard has clinical implications that will influence the diagnosis and treatment of DIC in children. Our results indicate that comparing the presence or absence of DIC by the TCH criteria with the autopsy results displays a sensitivity and specificity of 0.
Current consideration and management of disseminated intravascular coagulation
When the analysis was done for the ISTH system, the cutoff for sensitivity and specificity was 0. On the contrary, the TCH scoring system displays significantly higher sensitivity due to the inclusion of sequential testing that determines the rate of change in coagulation physiology, alerting the diagnostician to the possibility of an evolving overt DIC.
PICU patients show minimal or mild derangement in their coagulation profiles due to the activation of the coagulation system by their disease process. It is therefore critical to delineate evolving DIC from other disease conditions. Thus, the TCH scoring system, with its high degree of sensitivity, is able to recognize a trend in the evolution from an early-phase DIC to overt DIC, an advantage in accurately capturing the pathobiochemical scenario.
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This is consistent with results of the study done by Wilde et al, 12 who elucidated the association between coagulation parameters obtained before death and evidence of DIC in adult autopsies. They reported that coagulation tests reflective of a single time point—whether individual or combinations of coagulation tests—were not sensitive predictors of DIC. Most of the published literature concerns the pathophysiology of DIC, which in its main features is now well understood.
Other aspects of DIC, however, particularly those related to the definition, the relevance of the syndrome, and clinical management, remain unclear. Taking an evidence-based approach to the appropriate diagnosis and treatment of patients with DIC is difficult, in view of the lack of sound clinical trials.
This is probably due to the fact that DIC is a poorly-defined syndrome with a widely variable intensity, often complicating a diversity of severe disorders that are themselves related to extensive morbidity and mortality.