Natural anticoagulants appear to possess unique, anti-inflammatory activities distinct from their anticoagulant activities. Antithrombin, TFPI and APC have all been shown to protect baboons from E. coli sepsis when given prior to the challenge. In this and several rodent models  either synthetic FXa inhibitors  or active site-blocked FXa, a potent inhibitor of prothrombin activation in vivo, failed to protect the animals or modulate cytokine elaboration. Thus current data suggest that the anti-inflammatory activities of the natural anticoagulants may be very important to their physiological functions.
In experimental animal settings, antithrombin has been shown to protect from septic shock . Heparin appears to prevent protection despite increasing the antithrombotic activity of antithrombin, and a similar negative effect of heparin in combination with antithrombin was observed in clinical trials . In vitro, supra-physiological levels of antithrombin have been shown to have anti-inflammatory activity . Antithrombin has been found to inhibit endotoxin-induced interleukin-6 formation by mononuclear cells and endothelium . These activities appear to be mediated through interaction of antithrombin with proteoglycans, like syndecan-4 . Antithrombin interaction with the cell surfaces appears to be able to block NFκB nuclear translocation  and the subsequent release of cytokines and induction of adhesion molecules. In addition, antithrombin stimulates prostacyclin release from endothelial cells in culture , which appears to contribute to the protective effects of antithrombin in lung injury models .
Protein C pathway
APC has been shown to protect non-human primates from E. coli-induced sepsis, whether given before or after the E. coli challenge. APC binding to monocytic cells has been shown to block agonist-induced calcium transients  and to inhibit NFκB-mediated signaling [50–53] and mRNA levels . In endothelium, APC reduces the expression of cell surface adhesion molecules and cytokine formation, and elevates molecules involved in preventing apoptosis . APC has also been shown to dampen both basal levels and the phorbol-induced expression of tissue factor on U937 cells . The latter activities are EPCR dependent. Under appropriate conditions, APC can also cleave protease-activated receptors (PARs) . It remains unclear to the author how this form of cell surface activation can elicit anti-inflammatory functions, since most of the downstream events following activation of these receptors enhance inflammation . It is possible that activation of the PARs is a negative side reaction occurring under the in vitro conditions.
TM has also been found to exhibit anti-inflammatory properties. In part, this is mediated by protein C activation, but recent studies have identified additional pathways. TM also accelerates thrombin activation of a plasma procarboxypeptidase B, sometimes referred to as thrombin activatable fibrinolysis inhibitor (TAFI) . TAFI was named for its ability to remove terminal Lys residues in fibrin. Since these lysine residues are important in binding plasminogen/plasmin and tissue plasminogen activator (TPA), removal of the lysines slows, but does not eliminate, clot lysis . Originally, these activities were thought to stabilize the clot and therefore this activity of TM appeared to be thrombogenic.
Carboxypeptidase B enzymes remove C terminal Arg residues from vasoactive peptides like the complement anaphylatoxin C5a. C5a is generated during complement activation. Recent studies have found that TAFI is the major enzyme responsible for the inactivation of C5a [59,60]. In this context, the thrombin–TM complex protects the microvasculature by accelerating the clearance by activated TAFI and possibly other vasoactive peptides. Further linking this pathway to inflammation, C reactive protein, a strong acute phase reactant, has been found to initiate complement activation . Inflammation leading to downregulation of TM, decreases in TAFI activation and increased complement activation could work together to injure the vessel wall and expose coagulant phospholipid surfaces.
Very recently, an additional potent anti-inflammatory activity of TM has been revealed by Conway et al. . TM is composed of several domains. The N terminal domain has homology to the C type lectins. Conway et al. found that this domain dampened activation of the MAP kinase and NFκB signaling systems. Interestingly, TM had these activities whether on the cell surface or in solution.
This finding is potentially quite important as a contributing factor to arterial, venous and microvascular thrombosis. TM appears to be downregulated on endothelium overlying atherosclerotic plaques, vein bypass grafts, in diabetes, and by acute inflammatory insults like bacterial infection . Loss of the TM would not only reduce protein C activation, but would also increase the sensitivity of the endothelium to phenotype modulation by inflammatory mediators. The net effect would be to promote leukocyte adhesion, increase permeability and reduce the natural antithrombotic surface. Consistent with this prediction, overexpression of TM has been shown to reduce thrombosis, restenosis and leukocyte infiltration in rabbits with deep arterial injury [64,65].
In addition to the anti-inflammatory activities of TM, EPCR has recently been found to exhibit anti-inflammatory activity. Inhibition of EPCR-protein C binding increased the coagulant and cytokine responses in animals challenged with low dose E. coli. In addition, leukocyte migration into the tissues was increased substantially. A potential mechanism for the increased leukocyte migration came from the observations that soluble EPCR, released by a metalloproteinase in endothelium , can bind to selectively activated neutrophils and that the binding appears to involve interaction with proteinase 3 bound to Mac-1 (CD11b/CD18) . In vivo data suggest that this interaction reduces tight binding of neutrophils to activated endothelium.
It has been recognized since EPCR was cloned  and the gene structure determined  that EPCR was closely related to the MHC class 1/CD1 family of proteins. The crystal structure confirmed and expanded this view by showing that EPCR has a tightly bound phospholipid in the ‘antigen-presenting groove’. CD1 family members are antigen-presenting molecules, but unlike the MHC class 1 family, they present lipid antigens. For instance in the case of CD1c, this is a lipid derived from tuberculosis . The CD1 series of proteins then instruct T cells and modulate the cellular and humoral response to inflammation. Furthermore, they appear likely candidates to be involved in autoimmunity . Whether EPCR plays similar roles should become clear through analysis of genetically modified mice .