Antithrombin and Its Role in Host Defense and Inflammation

Abstract

Antithrombin (AT) is a natural anticoagulant that interacts with activated proteases of the coagulation system and with heparan sulfate proteoglycans (HSPG) on the surface of cells. The protein, which is synthesized in the liver, is also essential to confer the effects of therapeutic heparin. However, AT levels drop in systemic inflammatory diseases. The reason for this decline is consumption by the coagulation system but also by immunological processes. Aside from the primarily known anticoagulant effects, AT elicits distinct anti-inflammatory signaling responses. It binds to structures of the glycocalyx (syndecan-4) and further modulates the inflammatory response of endothelial cells and leukocytes by interacting with surface receptors. Additionally, AT exerts direct antimicrobial effects: depending on AT glycosylation it can bind to and perforate bacterial cell walls. Peptide fragments derived from proteolytic degradation of AT exert antibacterial properties. Despite these promising characteristics, therapeutic supplementation in inflammatory conditions has not proven to be effective in randomized control trials. Nevertheless, new insights provided by subgroup analyses and retrospective trials suggest that a recommendation be made to identify the patient population that would benefit most from AT substitution. Recent experiment findings place the role of various AT isoforms in the spotlight. This review provides an overview of new insights into a supposedly well-known molecule.

Anti-inflammatory role of SGLT2 inhibitors as part of their anti-atherosclerotic activity: Data from basic science and clinical trials

“…Pro-inflammatory cytokines, such as IL-1, IL-6, Interferons (IFN) gamma, metalloproteases-2 and 9 (MMP-2 and MMP-9), and metallopeptidase inhibitors (TIMP-1, TIMP-2), are responsible for plaque erosion/rupture. Specifically, IL-6 plays a crucial role in inducing a prothrombotic state by positive regulation of plasminogen activator inhibitor type 1 (PAI-1) during the acute inflammation phase response and negative regulation of antithrombin and protein S ( 24 ). Moreover, IL-6 induces the up-regulation of adhesion molecules in the endothelial cells and increases vascular permeability and cellular dysfunction ( 25 ).…”

Antithrombin as Therapeutic Intervention against Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation: Lessons Learned from COVID-19-Associated Coagulopathy

“…As a serine protease inhibitor, AT manifests as an anticoagulant, primarily by inhibiting thrombin and activated factor X. AT also has direct inflammation-modulating properties and may produce antimicrobial effects that all provide biological plausibility to the therapeutic effectiveness of AT as an anti-DIC intervention in SIC ( Figure 2 ) [ 50 ]. AT interacts with activated proteases of the coagulation system and heparan sulfate proteoglycans on the cell surface.…”

The relationship between antithrombin administration and inflammation during veno-venous ECMO

“…Antithrombin, a circulating protein that inactivates thrombin and other coagulation factors, is essential to the therapeutic effects of heparin and is often supplemented during ECMO 8 . In addition to its serine-protease inhibitor anti-coagulant role 9 , AT also has anti-microbial and inflammatory properties 10 . Antithrombin can bind to and perforate bacterial cell walls.…”