Disseminated intravascular coagulation and its immune mechanisms

Abstract

Disseminated intravascular coagulation (DIC) is a syndrome triggered by infectious and noninfectious pathologies characterized by excessive generation of thrombin within the vasculature and widespread proteolytic conversion of fibrinogen. Despite diverse clinical manifestations ranging from thrombo-occlusive damage to bleeding diathesis, DIC etiology commonly involves excessive activation of blood coagulation and overlapping dysregulation of anticoagulants and fibrinolysis. Initiation of blood coagulation follows intravascular expression of tissue factor or activation of the contact pathway in response to pathogen-associated or host-derived, damage-associated molecular patterns. The process is further amplified through inflammatory and immunothrombotic mechanisms. Consumption of anticoagulants and disruption of endothelial homeostasis lower the regulatory control and disseminate microvascular thrombosis. Clinical DIC development in patients is associated with worsening morbidities and increased mortality, regardless of the underlying pathology; therefore, timely recognition of DIC is critical for reducing the pathologic burden. Due to the diversity of triggers and pathogenic mechanisms leading to DIC, diagnosis is based on algorithms that quantify hemostatic imbalance, thrombocytopenia, and fibrinogen conversion. Because current diagnosis primarily assesses overt consumptive coagulopathies, there is a critical need for better recognition of nonovert DIC and/or pre-DIC states. Therapeutic strategies for patients with DIC involve resolution of the eliciting triggers and supportive care for the hemostatic imbalance. Despite medical care, mortality in patients with DIC remains high, and new strategies, tailored to the underlying pathologic mechanisms, are needed.

Graphical abstract

Figure 1.

Incidence of DIC in critically ill patients grouped according to the main underlying disease.

Figure 2.

Interactions of cellular and molecular components of host defense in the pathogenesis of DIC.

Figure 3.

Initiation of coagulation in DIC. Pathogens, dead cells, and their derived molecular pattern molecules (PAMPs and DAMPs) can signal through PRRs to induce TF expression and microparticle release from monocytes, and to promote synthesis of proinflammatory cytokines that further amplify TF expression, thus initiating coagulation via the extrinsic pathway. In parallel, contact activation with FXIIa generation can occur on the surface of the pathogens, PAMPs, DAMPs, and cell debris. In particular, bacteria-derived long-chain polyphosphates (LC-poly-Ps) and platelet-derived short-chain polyphosphates (SC-poly-P), and the extracellular nucleic acids (DNA/RNA) can induce contact-mediated autoactivation of FXII and trigger coagulation via the intrinsic pathway. Both pathways converge into the common coagulation mechanism, leading to thrombin generation and downstream platelet activation and fibrin and thrombus formation.

Figure 4.

Interactions of complement with coagulation and microvasculature in DIC. Pathogens, PAMPs, NETs, cell debris, and DAMPs can activate the complement cascade via 3 pathways, classic (CP), lectin (LP), or alternative (AP), all of which converge at C3. Formation of the C3 convertase of classic and lectin pathways involves cleavage of C4 with formation of C4b convertase component and C4a, an anaphylatoxin that can increase endothelial permeability by signaling through PAR-1 and -4. C3 convertases generated through the 3 pathways, cleave C3 to C3a and C3b. C3a anaphylatoxin activates platelets and leukocytes. C3b is a potent opsonin that contributes to opsonophagocytosis of pathogens, cell debris, and circulating erythrocytes and platelets contributing to extravascular hemolysis and thrombocytopenia. C3b is also a component of C5 convertase, which cleaves C5 into C5a and C5b. C5a anaphylatoxin is a potent chemoattractant and activator of leukocytes and an inducer of TF on monocytes and PAI-1 on endothelial cells (not shown). C5b initiates the formation of C5b-9 terminal complement complex (also known as a membrane attack complex), which makes cytolytic pores in cell membranes, inducing bacteriolysis or cell death in host organs. C5b-9 can activate platelets and induce monocyte TF expression and microparticle release. MASP, mannose-associated serine protease; MBL, mannose binding lectin.

Figure 5.

Involvement of immune mechanisms in the propagation of coagulation in DIC. Interaction of pathogens with neutrophils, macrophages, and platelets induces formation of NETs. Components of NETs, such as histones and DNA/nucleosomes, can further amplify the coagulation pathway leading to thrombin generation. NETs and proinflammatory cytokines promote TF expression on monocytes and TF-mediated coagulation. Cell-free DNA supports contact activation and intrinsic coagulation, whereas extracellular histones activate platelets and induce exocytosis of endothelial storage granules, including WPBs and subsequent release of von Willebrand factor and P-selectin, which promote microvascular thrombosis. Thrombin has a similar secretagogue effect. PSGL-1, P-selectin glycoprotein ligand-1.

Figure 6.

Pathogenesis of thrombotic and fibrinolytic phenotypes of DIC. DIC with a thrombotic phenotype is induced by the exposure of pathogens/PAMPs, cell debris/DAMPs, and NETs to circulating blood, leading to systemic inflammation and endothelial injury. These events promote activation of coagulation and depression of anticoagulant and fibrinolytic activities, leading to uncontrolled thrombin generation and microvascular thrombosis. When fibrinogen and other clotting factors are consumed; bleeding is a frequent outcome. Microvascular thrombosis and bleeding can be equally damaging to the tissues and organs, frequently contributing to death. DIC with fibrinolytic phenotype occurs more frequently in trauma and APL. In these cases, excessive fibrinolysis due to massive release of t-PA and plasmin generation can destroy the early hemostatic clots releasing fibrin fragment D-dimer. In APL, cell surface annexin II binds t-PA and protects its action from inhibitors, thus enhancing plasmin generation and fibrin degradation. Proteases, such as neutrophil elastase and cathepsins, released by leukocytes during inflammation and trauma, degrade fibrinogen and fibrin, leading to the formation of fibrinogen degradation products that further increase bleeding risk and contribute to organ failure and death. TAFI, thrombin activatable fibrinolysis inhibitor.