Antithrombin is a complex glycoprotein with multiple pharmacologically important activities in both the coagulation and inflammatory cascades. Normal serum AT levels range between 12.5 – 15 mg/dL.1 It is the most critical modulator of coagulation (Figure 1) and has potent anti-inflammatory properties (Figure 2) independent of its effects on coagulation.2

AT is a serine protease inhibitor (Figure 1) that is the principal inhibitor of the blood coagulation serine proteases thrombin and Factor Xa, and to a lesser extent, Factors IXa, XIa, XIIa, trypsin, plasmin, and kallikrein.3-7 Binding of heparin to AT results in a conformational change that greatly increases the activity of AT toward thrombin (1000 fold) and other serine proteases. AT neutralizes the activity of thrombin as well as other serine proteases by forming a 1:1 stoichiometric complex between enzyme and inhibitor.8 In the case of thrombin inhibition, the complex formed is thrombin-antithrombin (TAT), which is rapidly removed from the circulatory compartment (t1/2 = 5 min). Complex formation occurs at a relatively slow rate in the absence of heparin. When heparin is present, however, it binds to lysyl residues on AT and dramatically accelerates the rate of complex formation.8 The localization of a fraction of the AT bound to heparan sulfate proteoglycans (HSPG) on the endothelial surface, where enzymes of the intrinsic coagulation cascade are commonly generated, enables AT to rapidly neutralize these hemostatic enzymes and protect natural surfaces against thrombus formation.9

Antithrombin has been shown to have significant anti-inflammatory properties. AT binds to heparin-like glucosaminoglycans on the surface of endothelial cells in vitro10-11 and in vivo.12  This binding promotes endothelial cell release of prostacyclin (PGI2), which, in turn, impacts a variety of inflammatory processes.

It has been demonstrated that both endotoxin-induced pulmonary vascular injury13 and ischemia/ reperfusion-induced liver injury12 were reduced by AT treatment through its promotion of endothelial PGI2 production (Figure 3). These effects were not observed with a Trp49-modified AT, which is incapable of promoting the endothelial release of PGI2 due to its lack of affinity for heparin.

Ostrovsky et al.,14 using a cat mesentery ischemia-reperfusion injury model, showed that AT inhibits leukocyte rolling and adhesion that are characteristic of inflammatory reactions. This effect was independently confirmed by Hoffman et al.15 and Nevière et al.16 using intravital videomicroscopy to assess small intestine injury in endotoxemic rats treated with AT. In both cases, co-treatment with indomethacin, an inhibitor of PGI2production, abolished the effect of AT on leukocytes. Specific interaction with cell-surface glycosaminoglycans on the endothelium is also the mechanism of antithrombin-mediated attenuation of leukocyte-endothelial cell interaction.17

Examining the intracellular mechanism of AT anti-inflammatory activity, Oeschlager et al.18 used cultured human monocytes and endothelial cells to show that AT inhibits NF-κB induction. Since the NF-κB transcription factor activates genes that encode defense and signaling molecules in response to various inflammatory stimuli,19 inhibition of this signaling pathway represents a plausible mechanism for AT’s anti-inflammatory effects.

In summary, it is clear that AT, in addition to its central role in the coagulation cascade, has potent anti-inflammatory activities (Figure 4). Since the anti-inflammatory properties of AT are mediated through its interaction with heparin-like receptors such as syndecan-4, located on endothelial surfaces and leukocytes, supra-physiological doses are necessary to achieve a significant effect.

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