Disseminated Intravascular Coagulation: A Disease-Specific Approach

Disseminated intravascular coagulation (DIC) is an extreme form of systemic coagulation activation. Systemic activation of coagulation may occur in the context of a variety of disorders. This coagulation activation may only be detectable by measuring sensitive molecular markers for activation of coagulation factors and pathways, but it can become clinically manifest as changes in routine coagulation tests may occur.[1] The spectrum of clinically manifest coagulation activation ranges from a small decrease in platelet count and subclinical prolongation of global clotting times to fulminant DIC, characterized by simultaneous widespread microvascular thrombosis and profuse bleeding from various sites.[2] [3]

DIC is not a disease or a symptom but a syndrome that is always secondary to an underlying disorder. In general, two major pathways may cause DIC[4]: (1) a systemic inflammatory response, leading to activation of the cytokine network and subsequent activation of coagulation (such as in sepsis or major trauma) and/or (2) release or exposure of procoagulant material (in)to the bloodstream (such as in cancer or in obstetric cases). Although these conditions may be very different, the pathogenesis of DIC seems to follow similar lines. Briefly, intravascular fibrin deposition is a result of tissue factor–mediated thrombin generation that is insufficiently balanced by dysfunctional physiological anticoagulant mechanisms, such as the antithrombin system and the protein C system.[5] In addition to enhanced fibrin formation, fibrin removal is impaired due to depression of the fibrinolytic system. This impairment of endogenous thrombolysis is mainly caused by high circulating levels of the fibrinolytic inhibitor plasminogen activator inhibitor 1.

Despite the common pathways in the development of DIC, the specific underlying disease may have impact on the clinical manifestation of the coagulopathy and has certainly therapeutic consequences. Therefore, this issue of Seminars in Thrombosis and Hemostasis is devoted to the specific underlying conditions that may cause DIC and how these disease states may modulate the clinical picture and affect our diagnostic and therapeutic management strategies.

The most common underlying disorder of DIC is usually severe infectious disease, and this condition as a precipitating factor for DIC is reviewed in the first article of this issue.[6] Bacterial infection, in particular septicemia, is commonly associated with DIC.[7] There is no difference in the incidence of DIC in patients with gram-negative or gram-positive sepsis.[8] In addition, systemic infections with other microorganisms, such as viruses and parasites, may lead to DIC as well. 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.g., staphylococcal α toxin). These components cause a generalized inflammatory response, characterized by the systemic occurrence of proinflammatory cytokines.[4]

Severe trauma is another clinical condition frequently associated with DIC.[9] A combination of mechanisms—including release of tissue material (fat, phospholipids) into the circulation, hemolysis, and endothelial damage—may contribute to the systemic activation of coagulation. In addition, solid evidence indicates that cytokines play a pivotal role in the occurrence of DIC in trauma patients as well.[10] [11] Traumatic injury as underlying cause for DIC is discussed by Lippi and Cervellin.[12]

Both solid tumors and hematological malignancies may be complicated by DIC.[13] The mechanism of the derangement of the coagulation system in this situation is only partially understood. Solid tumor cells can express different procoagulant molecules, including tissue factor and a cancer procoagulant, a cysteine protease with factor X activating properties.[14] In addition, hemato-oncological diseases are often complicated by DIC.[15] This latter group is extensively described in a contribution of Franchini et al in this issue.[16]

Montagnana discusses DIC as a consequence of obstetric and gynecological complications.[17] Acute DIC occurs in obstetric calamities such as placental abruption and amniotic fluid emboli.[18] Amniotic fluid has been shown to be 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.[19] Although the coagulation system may be activated in patients with preeclampsia, and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, clinically significant DIC only occurs in a small percentage of patients, usually with secondary complications.

DIC in neonates is a common complication of many conditions and has specific features that are discussed in the article by Veldman et al in this issue.[20] In this particular situation adequate management of the coagulopathy is thought to be of utmost importance for the overall outcome and long-term prognosis.

Burn injury is increasingly recognized as an important underlying disorder that may lead to DIC. Lippi et al review the epidemiology of DIC as a consequence of burn injury and describe the specific pathogenetic pathways that may play a role in this condition.[21] With the rapidly improving management and outcome of severe burn injuries, complications such as DIC and their management are getting increasingly more important for the outcome in these patients.

Another form of traumatic injury that is connected to DIC is related to acute organ damage, in particular acute liver failure and acute pancreatitis. New insights into the pathogenesis of coagulopathy in these conditions is discussed by Lisman and Porte.[22] Much of the knowledge in this area has been obtained by careful coagulation studies in patients undergoing orthotopic liver transplantation, and it seems that these insights can be extrapolated to other situations, such as acute liver failure.

In most textbooks on DIC, snake bites are mentioned as an underlying cause of DIC. However, Isbister makes a case that snake bites do not cause DIC in sensu stricto.[23] In his contribution he carefully describes the coagulopathy and thrombotic microangiopathy that may result after a venomous snake bite, a disease state that may mimic DIC but can indeed be distinguished from this condition.

In the rapidly progressive research on the interaction between inflammation and coagulation, it is increasingly recognized that chronic inflammatory conditions, such as rheumatoid arthritis or inflammatory bowel disease, are associated with not only accelerated cardiovascular disease but also systemic activation of coagulation. Bisoendial et al review the available evidence and come to the conclusion that the prothrombotic state in rheumatoid arthritis is indeed an additive risk factor for adverse atherothrombotic events.[24]

Lastly, the optimal laboratory approach in DIC is presented by Favaloro.[25] Tests for the detection of coagulation activation or fibrin degradation products play an important role in the diagnosis of DIC and have a sensitivity from 90% to 100% but generally a low specificity.[26] In addition, there is quite some discordance among various assays. A scoring system, using such simple laboratory tests, has been developed by the subcommittee on DIC of the International Society on Thrombosis and Haemostasis,[27] and it has been prospectively validated in various studies, indicating a sensitivity and specificity ~95%.[28]

Taken together, this issue of Seminars in Thrombosis and Hemostasis presents the state-of-the-art in current thinking on underlying causes of DIC and how these conditions may modulate the clinical presentation but also may affect the optimal diagnostic and therapeutic management of these patients. I would like to thank the various contributors for providing excellent review articles that will be helpful for clinicians and researchers alike and may contribute to the further development of research in this area.

REFERENCES

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