Disseminated Intravascular Coagulation in Sepsis
1Acute and Critical Care Medicine, Sapporo Higashi Tokushukai, Japan
Disseminated intravascular coagulation (DIC) has been recognized as a dysregulated coagulofibrinolytic responses against the insults such as sepsis, trauma, and cardiac arrest and resuscitation.
Definition: The Standardization Subcommittee on DIC of the International Society on Thrombosis and Haemostasis (ISTH) defined DIC as follows: DIC is an acquired syndrome characterized by the intravascular activation of coagulation with a loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which, if sufficiently severe, can produce organ dysfunction. The important point in above definition is that the “activation of coagulation with a loss of localization” means systemic thrombin generation. Another point is that “damage to the microvasculature” suggests neutrophil activation associated with endothelial injury.
Phenotypes: DIC is always thrombotic, however it can be subdivided intro thrombotic and fibrinolytic phenotypes. DIC with a fibrinolytic phenotype is defined as an underlying condition of DIC simultaneously stimulating the release of stored tissue-type plasminogen activator (t-PA) from endothelial Weibel-Palade bodies, which enhance systemic fibrin(ogen)olysis associated with the consumption of alpha2-plasmin inhibitor. Sepsis-induced DIC is a representative entity of thrombotic DIC, and the early phase of trauma and cardiac arrest evoke DIC with the fibrinolytic phenotype.
Diagnosis: The ISTH and the Japanese Association for Acute Medicine (JAAM) DIC diagnostic criteria have been prospectively validated in patients with critical illness, including sepsis. The ISTH scoring system is recognized as specific for diagnosing DIC, while the JAAM scoring system is sensitive for diagnosing DIC.
Pathophysiology: Damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) induce the expression of inflammatory cytokines. These inflammatory mediators trigger the activation of coagulation through the expression of tissue factor on monocytes. In addition, DAMPs and PAMPs induce neutrophils to release neutrophil extracellular traps (NETs) presenting matrix DNA and histones with neutrophil components, such as neutrophil elastase. Histones and DNA further enhance coagulation by impairing anticoagulation pathways such as tissue factor pathway inhibitor (TFPI) and thrombomodulin. Furthermore, activated neutrophil-released elastase nonspecifically degrades TFPI, thrombomodulin and antithrombin. DAMPs and inflammatory cytokines induce plasminogen activator inhibitor-1 (PAI-1) mRNA, which inhibits fibrinolysis. Therefore, the persistent activation of coagulation, impairment anticoagulation pathways and suppression of fibrinolysis by PAI-1 are the main pathophysiology of DIC.
Treatment: The guidance for the treatment of DIC published by the ISTH recommends the specific and vigorous treatment of the underlying conditions of DIC, substitution therapy, anticoagulants, and anticoagulant factor concentrates. Recent evidence has shown that the treatment target is sepsis-induced DIC, especially in those with severe sepsis. Neither the overall sepsis population nor sepsis-induced “coagulopathy” patients are suitable for the treatment, as the physiologically formed immunothrombi at the site of infection may be deteriorated and systemically disseminate the thrombosis.