Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 10 Hemostasis
TABLE 10-6 Major Inhibitors of Coagulation and Fibrinolysis
Inhibitor Target Enzymes Cofactor(s)
TFPI Factor Xa Calcium
Tissue factor/factor VIIa
Antithrombin Thrombin, factor Xa Heparin/heparan sulfate
Factors IXa, XIa, XIIa
Heparin cofactor II Thrombin Heparin/heparan sulfate
α 1 -Antitrypsin/α 1 -protease inhibitor Thrombin, factors Xa, XIa —
Activated protein C, plasmin
α 2 -Macroglobulin Factor Xa, thrombin —
Activated protein C, plasmin
C1 inhibitor Factors XIa, XIIa, —
kallikrein
Protein C inhibitor Thrombin, factors Xa, XIa Thrombomodulin
Activated protein C
Heparin/heparan sulfate
tPA, uPA
Activated protein C Factor VIIIa, factor Va Protein S, thrombomodulin, EPCR
TAFI, PAI-1
TAFI tPA Fibrin
PAI-1 tPA, uPA —
α 2 -Antiplasmin Plasmin Fibrin
Abbreviations: EPCR, endothelial cell protein C receptor; PAI-1, plasminogen activator inhibitor -1; TAFI, thrombin activatable fi brinolysis inhibitor;
tPA, tissue-type plasminogen activator; u-PA, urokinase-type plasminogen activator.
proteins such as plasmin. One way this occurs is by FXIIIamediated
incorporation of plasmin inhibitor into the developing
fibrin meshwork (see Section II.D.3). Plasmin
inhibitor becomes bound to α -chains of both fibrinogen and
fibrin and prevents the absorption of plasminogen to fibrin.
FXIIIa can also cross-link other plasma proteins to fibrin
strands (see Section II.C.4) ( Sidelmann et al ., 2000 ). Once
the lesion has been repaired, which may also be partly mediated
by FXIIIa ( Barry and Mosher, 1988 ), a process called
fibrinolysis dissolves the fibrin clot (see Section II.D).
5. Inhibitors of Coagulation
Several biochemical mechanisms exist that function to
keep the formation of a blood clot localized to a site of
vascular injury, to prevent the excessive growth of the
clot, and to prevent thrombin generation and fibrin formation
from becoming generalized to nondamaged areas of
the vascular system. The target enzymes and cofactors for
these and other circulating inhibitors are summarized in
Table 10-6 .
a. Tissue Factor Pathway Inhibitor (TFPI)
TFPI is the principal endogenous inhibitor of the tissue
factor pathway. TFPI is a Kunitz-type serine protease
inhibitor that has a double inhibitory effect: it inhibits
both FXa and the TF/FVIIa complex ( Golino et al ., 2002 ;
Lindhahl, 1997). Between 75% and 90% of the total body
TFPI is located in endothelial cells; the remaining 10% to
25% circulates bound to plasma lipoproteins with only trace
amounts being detectable free in plasma or in platelet cytosol.
Because of its association with lipoproteins, TFPI was
formerly known as lipoprotein-associated coagulation inhibitor
(LACI). TFPI is a single-chain 32-kDa glycoprotein that
has a highly negatively charged N-terminus connected to
three tandem domains that show homology to Kunitz-type
protease inhibitors and a highly positively charge C-terminal
region ( Broze, 1992 ). Multiple forms of TFPI have been
identified in human plasma with 36- and 43-kDa forms
predominating. This size variation appears to be due to the
formation of disulfide bonds and glycosolation of the TFPI
molecule ( Broze, 1992 ; Lindahl, 1997 ). A 34-kDa form of
TFPI circulates in association with plasma LDL, and a 40-
kDa form associates with HDL. TFPI is not uniformly dispersed
in the vasculature. It is constitutively expressed by
endothelial cells of the microvasculature but not by endothelial
cells of larger vessels ( Doshi and Mamur, 2002 ).
A localized increase of TFPI can occur at the site of a clot
because thrombin is able to induce the release of TFPI from
activated platelets ( Novotny et al ., 1988 ). TFPI is stored on