Page 1983 - Williams Hematology ( PDFDrive )

1958 Part XII: Hemostasis and Thrombosis Chapter 114: Control of Coagulation Reactions 1959

opposite functional effects, as thrombin peptide and TRAP cause endo- cascade by binding to C4b and promoting its proteolytic inactivation
thelial barrier disruption and proinflammatory effects whereas APC and by the protease, factor I. C4b-binding protein reversibly binds protein S
the TR47 peptide cause barrier-protective and antiinflammatory effects. with high affinity, 282–284 and formation of this complex affects some but
Thus, PAR-1 displays biased signaling depending on the activation cleav- not all of the anticoagulant activities of protein S. 71,198,271,285 Because of
age sites and the generated tethered-ligand with absolutely opposing the influence of C4b-binding protein on protein S activities and plasma
outcomes for the cell, the tissue, and the host depending on which coag- levels, interpretation of clinical assays for protein S requires evaluation
ulation system protease, thrombin or APC, is cleaving PAR-1. of free and bound protein S as plasma contains approximately 240 nM
Other receptors are recognized that may also play key roles for protein S–C4b-binding protein complexes and 120 nM free protein S.
283
APC’s beneficial signaling effects, including PAR-3 and sphingosine-1- C4b-binding protein is a heteropolymer containing six or seven α chains
phosphate receptor-1. 249,250,257,258 ApoER2 can initiate Disabled-1-depen- that are disulfide-linked to a single β chain that binds protein S. 286,287
dent pathway activation of the PI3K-Akt cell-survival pathway, which Residues 30 to 45 of the β chain bind with high affinity to the C-ter-
may ultimately help explain additional aspects of APC’s cytoprotection. 259 minal SHBG domain of protein S. 65,288,289 During an acute phase reac-
Although most studies demonstrating the cell-signaling activities tion, the level of the C4b-binding protein α chain, but not the β chain,
of APC have focused on pharmacologic levels of APC, several reports is increased, so that the acute phase change in total C4b-binding protein
of murine injury models demonstrate the physiologic importance of does not alter the level of free and bound protein S. 290
cell signaling by endogenous APC, 260–262 implying that defects in APC’s Another potential mechanism for the antithrombotic actions pro-
endogenous cytoprotective actions might have pathophysiologic rele- tein S is based on its APC-independent direct interactions with cells

vance. Future investigations on APC cellular receptors and on intracel- that might contribute to its antithrombotic actions. Protein S promotes
lular mechanisms involved in the protein C cellular pathway will likely clearance of apoptotic cells, 68,71,198,291–294 and this antiapoptotic activity of
provide novel clinical insights with diagnostic and therapeutic potential. protein S might contribute to its antithrombotic activity. Protein S has
direct effects on cells by activating one or more transmembrane receptor
tyrosine kinases. 68,198,292 Protein S is a potent neuroprotectant as it can pro-
INHIBITION OF ACTIVATED PROTEIN C tect brain endothelium against ischemic injury in murine stroke models
and can protect neurons against NMDA-induced excitotoxic injury, pre-
Blood contains circulating APC in a well-defined normal concentration sumably acting via transmembrane receptor tyrosine kinases. 295–299
range that contributes to antithrombotic surveillance mechanisms and
possibly to homeostatic cell signaling. 15,142,144 Circulating APC levels
are determined by the balance between countervailing mechanisms for INHIBITION OF COAGULATION
APC generation and for APC inhibition and clearance. APC genera- PROTEASES BY PROTEASE INHIBITORS
tion is influenced by protein C zymogen levels, endogenous thrombin
generation, and the availability of thrombomodulin and EPCR. Clear- Antithrombin, initially designated antithrombin III, is clinically the best
ance of circulating APC is based on inhibition of APC by protease known inhibitor of clotting factor proteases. Antithrombin can neutral-
inhibitors and clearance of APC:inhibitor complexes. 263–269 The major ize all coagulation proteases in reactions that are enhanced by hepa-
plasma inhibitors of APC include α -antitrypsin, protein C inhibitor, rin and related glycosaminoglycans (see Chap. 113 and Fig. 113–28).
300
1
and α -macroglobulin. However, antithrombin does not inhibit the anticoagulant protease
2
APC. TFPI can neutralize factors VIIa and Xa, proteases of the extrin-
sic coagulation pathway. 277,278,301–303 In addition, other plasma protease
ACTIVATED PROTEIN C–INDEPENDENT inhibitors such as α -antitrypsin, heparin cofactor II, protein C inhib-
1
ANTICOAGULANT ACTIVITY OF itor, α -macroglobulin, or protein Z–dependent protease inhibitor, can
2
neutralize various coagulation proteases, although the ultimate clinical
PROTEIN S significance of these reactions is less-well defined than the clinical rele-
vance of antithrombin for thrombophilia (Chap. 130). Antithrombin is
Because hereditary protein S deficiency 270,271 is strongly linked to key for anticoagulant therapy based on the heparin-stimulated inhibi-
increased venous thrombosis risk (Chap. 130), protein S is a significant tion of thrombin and factor Xa.
physiologic anticoagulant factor. 71,198 In addition to its anticoagulant
cofactor activity for APC, protein S can also inhibit coagulation reac-
tions independently of APC. Several plausible mechanisms have been ANTITHROMBIN AND HEPARINS
described for protein S’s anticoagulant activity independent of APC. Antithrombin is synthesized in the liver and is present in plasma at
First, protein S can bind directly to procoagulant factors Xa and Va and 150 mcg/mL, and it is a typical member of the serine protease inhibitor
thereby inhibit directly the activity of the prothrombinase complex. 11–13 (SERPIN) superfamily and is denoted as SERPINC1. 300,304–306 Based on
The thrombin-sensitive region and the EGF3 domains of protein S X-ray crystallographic studies, 307–311 models of serpin–protease com-
(see Fig. 114–5) likely bind factor Xa, contributing to APC-indepen- plexes in various reaction states have emerged and the mechanism for
dent anticoagulant activity. 206,272,273 Second, protein S can also bind fac- the effects of heparin on the reaction of thrombin with antithrombin is
tor VIIIa and inhibit activation of factor X by factor IXa–factor VIIIa reasonably clear.
complexes. 274–276 Third, protein S binds tissue factor pathway inhibitor The neutralization of proteases by antithrombin is a result of a
(TFPI) and enhances its ability to inhibit factor Xa. 277–279 Zn ions might stable enzyme–antithrombin complex that is formed by a molecular
2+
280
play a key role for APC-independent protein S activity. It is not easy to mechanism characteristic of inhibitory serpins. 304–307,309–312 Following
decipher the relative importance of each of these or other mechanisms binding of a protease to a “reactive site” loop in a serpin, a single pep-
for APC-independent anticoagulant activities of protein S or to estab- tide bond in the serpin is cleaved with formation of an acyl-enzyme
lish their physiologic relevance, but infusions of protein S without APC intermediate via the active site Ser residue. This metastable enzyme–
are antithrombotic in baboon thrombosis models. 281 serpin complex can either break apart because of deacylation, or it can
The activities of protein S can be strongly influenced by C4b-binding form a more stable covalent enzyme–serpin complex. To break apart
protein, a plasma protein that enhances inactivation of the complement the enzyme–serpin covalent complex, deacylation liberates the cleaved

Kaushansky_chapter 114_p1949-1966.indd 1958 9/18/15 10:06 AM