Prevention of Unwanted Blood Clotting

If thrombin and factor Xa, the major activated blood coagulation factors (Fig. 11.6), escape into healthy blood vessels, blood clots will develop and occlude capillaries throughout the body. Direct inhibition of these activated enzymes in the blood flow utilizes serine protease inhibitors, of which there are two common types a Kunitz inhibitor and a serpin. The former possess a Kunitz domain, a convex antiparallel (1-sheet that exactly fits into the concave active site of a serine protease, directly blocking it (lock and key mechanism). By contrast, serpins undergo complex interactions with other proteins to cause conformational changes that bait and block the catalytic action (Fig. 11.12 shows the bait). Table 11.3 fists the major coagulation inhibitors and cofactors, their targets and mechanisms of action. 

Thrombin and factor Xa that have escaped into the blood flow are both inhibited by serpins, anti-thrombin III (ATIII) and heparin cofactor II (HCII). These proteins bind to heparin sulfate or dermatan sulfate (Sect. 6.3.1), glycosaminoglycans which are secreted onto the luminal surface of healthy endothelial cells and also released into the blood from mast cells activated by an injury. Among the heparin molecules is a pentaglycan sequence 

The activity of surface-bound factor Xa is controlled by a third serpin, Z-dependent protease inhibitor (ZPI) which circulates in blood along with protein Z. The latter has a gla domain and it attaches to the activated platelet surface alongside the activated clotting factors. Protein Z attaches ZPI in which it alters the conformation of a surface loop and causes a residue, not arginine, to protrude and inactivate the bound factor Xa. Protein Z dissociates from the ZPI-factor Xa complex, but ZPI itself gets cut by factor Xa into two fragments that soon dissociate from the complex. Protein Z replaces a glycosaminoglycan in the previous mechanism, but ZPI inhibition of factor Xa is transient. ZPI may work best where an 

Tissue factor pathway inhibitor (TFPI) TF-VIIa, Xa 

Tissue factor pathway inhibitor (TFPI) is a Kunitz type inhibitor composed of three Kunitz domains. The N-terminal Kunitz domain binds to and inhibits the VHa-TF complex that activates factor X (Fig. 11.6a), whereas the downstream Kunitz domain binds directly to factor Xa and inhibits it strongly and permanently. No function has yet been demonstrated for the third Kunitz domain. The C-terminal region of TFPI is basic and remains attached to endothelial cell surfaces where it inhibits inadvertent factor Xa activation. Studies in mice indicate that knocking out the gene for TFPI stops fetal development. Indeed, clotting diseases such as a stroke and heart attacks are associated with mutations of AITH, HCII and ZPI, but not of TFPI. Like TF (Sect. 11.3.1), diminished TFPI activity may be incompatible with life. 

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