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Chapter 126 Molecular Basis of Blood Coagulation 1893

Tissue factor pathway inhibitor
FVIIa FXa Heparin
binding binding binding

NH 2 Kunitz 1 Kunitz 2 Kunitz 3 COOH
Cell-binding
domain
Antithrombin

Heparin Serine protease
binding target site

NH 2 CHO domain COOH
S S S S
S S

Heparin Serine protease
Heparin cofactor II binding target site

NH 2 Hirudin like – Acidic region COOH

Protein C inhibitor
Serine protease
target site

NH 2 COOH
Fig. 126.7 SCHEMATIC REPRESENTATION OF SEVERAL PROTEINASE INHIBITORS. Tissue
factor pathway inhibitor (TFPI) contains three Kunitz domains. TFPI inhibits the serine proteases FVIIa and
FXa, shutting down the extrinsic pathway of coagulation. Kunitz 1 domain binds FVIIa, and Kunitz 2 domain
binds FXa. The COOH-terminus of TFPI contains a basic region, the cell-binding domain, which binds to
heparin. Antithrombin (AT) contains two intrachain disulfide bonds (-S-S-) in its NH 2-terminus and one in
its COOH-terminus with a carbohydrate-rich domain (CHO) in between. The region of interaction between
the active sites of target proteases and AT is illustrated (reactive center loop). Heparin binding occurs in the
NH 2-terminus and enhances the rate of inhibition of serine proteases. Heparin cofactor II inhibits thrombin.
Structurally, the inhibitor contains an NH 2 -terminus hirudin-like region, a heparin or dermatan sulfate binding
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region, and a reactive center loop. The reactive site is shown at Leu . Protein C inhibitor is a serine protease
inhibitor that inhibits several proteases, including activated protein C, thrombin, and FXa. It is also a potent
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inhibitor of the thrombin–thrombomodulin complex. The reactive bond (Arg ) in the reactive center loop
is shown. FVIIIa, Factor VIIa; FXa, factor Xa.

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inhibition of the factor VIIa–tissue factor complex depends on thrombosis, the physiologic role of heparin cofactor II as a systemic
the presence of factor Xa. Thus inhibition of the extrinsic factor thrombin inhibitor has been questioned.
tenase by TFPI occurs only after significant factor IXa and factor In vitro, heparin cofactor II inhibition of thrombin is accelerated
Xa formation. Inhibition by TFPI is achieved by formation of by dermatan sulfate proteoglycans synthesized by fibroblasts and
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the stable quaternary, by tissue factor–factor VIIa–TFPI–factor vascular smooth muscle cells. Thus heparin cofactor II may be
Xa complex, and by formation of the factor Xa–TFPI complex uniquely suited to regulate extravascular thrombin in areas of vascular
directly. endothelium disruption in which heparin cofactor II would be
exclusively stimulated by dermatan sulfate in the subendothelium. In
Heparin Cofactor II addition, heparin cofactor II may participate in regulation of acute
Heparin cofactor II is a member of the serpin family (see Fig. 126.7). inflammation and wound healing by harboring a peptide chemotactic
The plasma concentration of heparin cofactor II is 0.5–1.4 µmol/ for neutrophils and monocytes that is released by leukocyte
L 166,167 (see Table 126.1). Its plasma half-life is approximately 2.5 proteolysis. 172
days. Similar to antithrombin, heparin cofactor II inhibits thrombin Heparin cofactor II may also have a role in protection from
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in a reaction that is accelerated more than 1000-fold by heparin. thrombosis during pregnancy. Increased levels of dermatan sulfate in
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However, unlike antithrombin, the only coagulation enzyme inhib- the maternal and fetal circulation along with increased levels of
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ited by heparin cofactor II is thrombin. The rate of thrombin heparin cofactor II in pregnant women have been reported. 174,175 Low
inhibition by heparin cofactor II in the absence or presence of heparin levels of thrombin–heparin cofactor II complexes are detected in
or heparin-like molecules is significantly slower than by antithrombin normal plasma samples; elevated levels were detected in patients with
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under similar conditions. Considering that the plasma concentration disseminated intravascular coagulation. Although inherited defi-
of heparin cofactor II is 25%–50% that of antithrombin and that ciency of heparin cofactor II has been associated with thrombosis,
low levels of heparin cofactor II are not strongly associated with this is not always the case. 177–179