PAMPs and DAMPs as triggers for DIC

Abstract

Thrombosis is generally considered harmful because it compromises the blood supply to organs. However, recent studies have suggested that thrombosis under certain circumstances plays a major physiological role in early immune defense against invading pathogens. This defensive role of thrombosis is now referred to as immunothrombosis. Activated monocytes and neutrophils are two major inducers of immunothrombosis. Monocytes and neutrophils are activated when they detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Detection of PAMPs and DAMPs triggers tissue factor expression on monocytes and neutrophil extracellular trap (NET) release by neutrophils, promoting immunothrombosis. Although tissue factor-mediated and NET-mediated immunothrombosis plays a role in early host defense against bacterial dissemination, uncontrolled immunothrombosis may lead to disseminated intravascular coagulation.

Keywords: Damage-associated molecular patterns (DAMPs); Disseminated intravascular coagulation (DIC); Immunothrombosis; Neutrophil extracellular traps (NETs); Pathogen-associated molecular patterns (PAMPs); Tissue factor.

Figure 1

Basic mechanisms of coagulation. Coagulation factor VII searches for sites of vascular damage where subendothelial tissue factor is exposed. Tissue factor is expressed on the surface of fibroblasts and pericytes in the subendothelial space. Binding of coagulation factor VIIa to tissue factor results in a cascade of blood-clotting reactions, leading to thrombin generation (the initiation pathway). Once small amounts of thrombin are generated in this pathway, thrombin plays a crucial role in the amplification and propagation phases of coagulation by activating coagulation factors V, VIII, and XI (the amplification pathway). This leads to a burst of additional thrombin generation, which is essential for forming sufficient fibrin and sealing the sites of vascular damage. Coagulation factor XIII then crosslinks fibrin fibers, a fundamental process for stabilizing fibrin clots. Contact activation of coagulation factor XII, another important trigger of coagulation in laboratory tests, is not considered essential for hemostasis.

Figure 2

Anticoagulant properties of endothelial cells. Endothelial cells express several anticoagulants, including thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), and heparan sulfate. Upon binding to TM, thrombin loses its ability to activate platelets, fibrinogen, and coagulation factors V, VIII, XI, and XIII. Furthermore, the thrombin-TM complex activates protein C, which in turn stops thrombin generation by inactivating coagulation factors Va and VIIIa. Endothelial cells also synthesize and display heparan sulfate proteoglycans on their surface, which bind to TFPI and antithrombin (AT), inhibiting the factor VIIa-tissue factor complex, factor Xa, and thrombin activity. IIa thrombin, PS protein S.

Figure 3

Four mechanistic models explaining how immunothrombosis provides protection against invading pathogens. (1) Immunothrombosis limits microbial dissemination by containing microbes within thrombi. (2) Thrombi form protective barricades inside and/or around blood vessels that limit microbial movement in and out of the vessels. (3) Fibrin, fibrinogen, and fibrin/fibrinogen degradation products promote recruitment and activation of leukocytes, such as neutrophils and macrophages, coordinating cellular immune responses to pathogens at sites of infection. (4) Intravascular thrombi yield a distinct compartment where antimicrobial peptides are concentrated and have increased opportunities to come into contact with pathogens.

Figure 4

Triggers for immunothrombosis. Detection of PAMPs and DAMPs triggers NET release by neutrophils and tissue factor expression on monocytes, promoting immunothrombosis. NETs are able to activate coagulation factor XII, inactivate anticoagulant TFPI, and provide a scaffold for platelet binding and aggregation, all of which promote thrombus formation. A part of monocyte-associated tissue factor is released in the form of microparticles and delivered into developing thrombi.