Advance in the Management of Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation

Abstract

Coagulopathy commonly occurs in sepsis as a critical host response to infection that can progress to disseminated intravascular coagulation (DIC) with an increased mortality. Recent studies have further defined factors responsible for the thromboinflammatory response and intravascular thrombosis, including neutrophil extracellular traps, extracellular vesicles, damage-associated molecular patterns, and endothelial glycocalyx shedding. Diagnosing DIC facilitates sepsis management, and is associated with improved outcomes. Although the International Society on Thrombosis and Haemostasis (ISTH) has proposed criteria for diagnosing overt DIC, these criteria are not suitable for early detection. Accordingly, the ISTH DIC Scientific Standardization Committee has proposed a new category termed "sepsis-induced coagulopathy (SIC)" to facilitate earlier diagnosis of DIC and potentially more rapid interventions in these critically ill patients. Therapy of SIC includes both treatment of the underlying infection and correcting the coagulopathy, with most therapeutic approaches focusing on anticoagulant therapy. Recently, a phase III trial of recombinant thrombomodulin was performed in coagulopathic patients. Although the 28-day mortality was improved by 2.6% (absolute difference), it did not reach statistical significance. However, in patients who met entry criteria for SIC at baseline, the mortality difference was approximately 5% without increased risk of bleeding. In this review, we discuss current advances in managing SIC and DIC.

Keywords: antithrombin; coagulopathy; disseminated intravascular coagulation; sepsis; thrombomodulin.

Figure 1

Three major factors contribute to DIC that include coagulation activation, platelet aggregation, and endothelial damage. Tissue factor expressed on the leukocytes and phosphatidylserine on the damaged cell membrane activate coagulation, decreased physiologic anticoagulant systems accelerate clot formation, and platelet aggregation is stimulated by thrombin and other inflammatory mediators. Endothelial damage reduces the antithrombotic milieu of the vascular lumen. PAMPs: pathogen-associated molecular patterns, NETs: neutrophil extracellular traps, DAMPs: damage-associated molecular patterns, ADAMTS13: a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, NO: nitric oxide, PGI₂: prostagrandin I₂, DIC: disseminated intravascular coagulation.

Figure 2

The coagulation, fibrinolytic, and natural anticoagulant systems. Both the extrinsic pathway and contact pathway are activated in sepsis. Tissue factor, expressed on the monocytes, endothelial cells, and extracellular vesicles triggers the extrinsic pathway, while the phosphatidylserine residue present in various cell membranes initiates the contact pathway of coagulation. Antithrombin/heparin, thrombomodulin/protein C, and tissue factor pathway inhibitor (TFPI) are the three major physiologic anticoagulant systems. FDP: fibrin/fibrinogen degradation products.

Figure 3

The sequential change from sepsis-induced coagulopathy to disseminated intravascular coagulation. Sepsis-induced coagulopathy progresses to disseminated intravascular coagulation (DIC) if the infection/inflammation is severe enough. Transient activation of fibrinolysis is observed initially, due to the release of tissue-type plasminogen activator (t-PA) from the vascular endothelial cells. Subsequently, the fibrinolytic system is suppressed by the production of plasminogen activator inhibitor-1. The imbalance between coagulation and fibrinolysis leads to a hypercoagulable state and organ dysfunction in sepsis.