Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 548

innate immunity. Binding of thrombomodulin to HMGB1 prevents signaling from
HMGB1 receptor, the receptor for advanced glycation end products (RAGE). 123
Thrombomodulin secretion depends on hemodynamic stress.
Protein-C 124 is a vitamin-K-dependent circulating zymogen. It is activated once
bound to thrombin. Its activation is improved by thrombomodulin and endothelial
protein-C receptors (EPCR). It then acts as a serine peptidase and inactivates
activated clotting factors-Va and -VIIIa.
Thrombin, thrombomodulin, and endothelial protein-C receptor together activate
protein-C. Both protein-C and activated protein-C interact with EPCR with a similar
affinity. Both thrombin and activated protein-C cleave peptidase-activated receptor-
1(PAR 1 ), but PAR 1 cleavage by thrombin can be more efficient than that of activated
protein-C. 125 Cleavage of PAR 1 by thrombin yields thrombotic and inflammatory
responses. Both endothelial protein-C receptor and peptidase-activated receptor-1,
colocalized in membrane rafts of endothelial cell plasma membrane, are implicated
in protein-C signaling [ 1003 ]. Thrombomodulin that localizes with endothelial
protein-C receptor and peptidase-activated receptor-1 in the same membrane raft,
can recruit thrombin, then generates a thrombin-thrombomodulin complex to
activate EPCR-bound protein-C. Anti-inflammatory and cytoprotective properties of
activated protein-C are due to EPCR-dependent PAR 1 cleavage by activated protein-
C in endothelial cells. Anticoagulant function of activated protein-C results from
degradation of activated clotting factor-Va and -VIIIa, hence preventing thrombin
generation by activated protein-C that is stimulated by protein-S.
Protein-S of the anticoagulation pathway is a vitamin-K-dependent plasma
glycoprotein synthesized in endothelial cells. Protein-S circulates in 2 forms: free
and bound to C4b complement protein. This free cofactor of protein-C participates
in the inactivation of clotting factor-Va and -VIIIa.
Tissue factor pathway inhibitor , (TFPI), also termed lipoprotein-associated
coagulation inhibitor (LACI) and extrinsic pathway inhibitor (EPI), can reversibly
inhibit clotting factor-Xa and thrombin (or factor-IIa), in addition to tissue factor.
The majority of tissue factor pathway inhibitor is bound to the endothelium, as
plasma and platelet pools account for less than half the vascular content. 126 Tissue
factor pathway inhibitor reduces activation of factor-X, without abolishing it, in
123 Receptor RAGE is a pro-inflammatory transmembrane molecule of the immunoglobulin
superfamily for non-enzymatically altered proteins and other ligands, in addition to HMGB1
protein.
124 A.k.a. autoprothrombin-2A and blood-coagulation factor-XIV.
125 Endogenous activated protein-C generated by thrombin on the endothelial cell surface has
greater effects than exogenous activated protein-C.
126 Platelets contain TFPI, the amount of which is estimated at 5-10% of the plasma level [ 1004 ]. In
endothelial cells, TPFI-containing vesicles can be linked to plasmalemmal caveolae. Agent TFPI
is released when intracellular calcium level rises.