Page 1955 - Williams Hematology ( PDFDrive )

1930 Part XII: Hemostasis and Thrombosis Chapter 113: Molecular Biology and Biochemistry of the Coagulation Factors 1931

domain; Mr ≈28,000) are linked via a Cys340–Cys467 disulfide bond tissue, particularly fibroblasts and smooth muscle cells, where it serves
(see Fig. 113–15). Once activated, α-factor XIIa activates factor XI to as a hemostatic “envelope,” poised to activate coagulation upon vas-
factor XIa. Furthermore, α-factor XIIa activates PK, thereby contribut- cular damage. Generally, tissue factor is not exposed to the blood, but
ing to its own feedback activation. 232 endothelial cells and adhered leukocytes may express tissue factor in
Factor XII is also known to acquire α-factor XIIa activity upon response to injury or stimuli such as endotoxin or cytokines.
contact with a negatively charged surface, the latter inducing a confor-
mational change in factor XII. This conformational change induces Protein Structure
233
a limited amount of proteolytic activity in factor XII, known as auto- Although many of the coagulation factors share some degree of homol-
activation. 234,235 Furthermore, the surface-induced active conforma- ogy, the structure of tissue factor is unique. It is the only procoagulant
tion of factor XII is suggested to enhance the proteolytic conversion to protein that is an integral membrane protein and shares structural
236
α-factor XIIa. The fibronectin types I and II domains, EGF-2, the homology with class II interferon receptors. Tissue factor consists of
kringle domain, and the proline-rich region are reported to contribute 263 amino acids (Mr ≈47,000) and comprises a 219-residue extracel-
to interaction with a negatively charged surface. 237–240 These naturally lular domain, a 23-residue hydrophobic transmembrane portion, and
occurring surfaces include platelet polyphosphate (poly-P), micropar- a short 21-residue intracellular tail. The extracellular domain is made
252
ticles derived from platelets and erythrocytes, RNA, and collagen. 241–244 up of two fibronectin type III domains, which each comprise a disulfide
Further cleavage of α-factor XIIa by kallikrein at Arg334 and bond (Cys49–Cys57, Cys186–Cys209). Elimination of the second disul-
Arg343 in the light chain (proline-rich region) results in the generation fide link distorts the coagulant activity of tissue factor.
of β-factor XIIa, which comprises a nine-residue heavy-chain fragment
230
that is disulfide-linked to the light chain. Given the absence of the Tissue Factor Activation and Cofactor Function
heavy chain, β-factor XIIa does not interact with anionic surfaces. Even The tissue factor–factor VIIa complex is generally acknowledged to
though β-factor XIIa is still capable of activating PK, it no longer acti- be the major physiologic initiator of blood coagulation. The process
vates factor XI. 245 of coagulation is initiated when an injury ruptures a vessel and allows
Despite its contribution to fibrin formation in vitro, factor XII has blood to come into contact with extravascular tissue factor. Escape of
long been considered to be dispensable for coagulation in vivo, because blood from the vessel allows factor VII to bind to extravascular tissue
factor XII deficiency is not associated with a bleeding. 229,246 However, factor and initiate coagulation. However, it is very likely that in the
newer in vivo studies indicate that factor XII contributes to surface- absence of injury, tissue factor located in close proximity of the vessels is
induced pathologic thrombosis via activation of factor XI. 215,242,247,248 already associated with factor VIIa. An injury allows the extravascular
253
The serpin C1 inhibitor is the main plasma inhibitor of α-factor tissue factor–factor VIIa complexes to come into contact with blood and
XIIa and β-factor XIIa. In addition, antithrombin (AT) and PAI-1 also initiate thrombin generation on activated platelet surfaces. Interaction
inhibit factor XIIa activity. Conditions in which the factor XIIa activity of tissue factor with factor VII induces conformational changes in the
is not properly controlled, such as in C1 inhibitor deficiency states or serine protease domain of factor VIIa (see Fig. 113–6), thereby allowing
in case of a constitutively active form of factor XIIa, can result in the the latter to proteolytically activate factors IX and X. 11
disorder hereditary angioedema. 249
Tissue factor does not require proteolytic activation to express its
activity. However, it appears that tissue factor can occur in an inactive or
Gene Structure and Variations “encrypted” state, and procoagulant activity follows after an appropriate
The gene for factor XII is located on chromosome 5q35.3, spans approx- stimulus. Even though the exact nature of the molecular mechanism
imately 12 kb, and contains 14 exons. The intron–exon structure of the remains to be identified, several models explaining tissue factor decryp-
250
gene is similar to the plasminogen activator family of serine proteases. tion have been put forward.
Portions of the gene are homologous to domains found in fibronectin Originally, it was assumed that tissue factor encryption–decryption
and tissue-type plasminogen activator. depends on the phospholipid environment, with decryption follow-
Loss-of-function mutations in the factor XII gene do not cause clini- ing upon expression of negatively charged phosphatidylserine on the
cal symptoms in the form of a bleeding tendency in homozygous or com- membrane surface. Interaction of tissue factor with phosphatidylser-
pound heterozygous individuals, although they have a prolonged APTT. ine restricts the orientation of the tissue factor–factor VIIa complex,
Several common allelic variations in the factor XII gene have been thereby ensuring correct alignment of the factor VIIa active site with
examined to determine whether these variations influence plasma fac- the membrane-bound substrates factors X and IX. Encryption of tis-
254
tor XII levels and whether these are associated with thrombotic risk. sue factor has been proposed to occur upon localization into lipid rafts,
Best studied is a 46C>T transition four nucleotides upstream of the start which are known to be poor in phosphatidylserine. In endothelial cells,
codon. TT homozygotes have lower plasma factor XII levels than CC assembly of the ternary tissue factor–factor VIIa–factor X complex does
homozygotes, but there was no relationship with risk for venous throm- result in tissue factor translocation to caveolae, which renders tissue fac-
bosis or myocardial infarction. 251
255
tor inactive. In addition, cell-membrane anchoring of tissue factor via
acylation of palmitic and stearic acids may serve to target tissue factor
THE CELL-ASSOCIATED COFACTORS to specific lipid domains. 256
In a second model, the tissue factor–dependent procoagulant
TISSUE FACTOR, THROMBOMODULIN, activity is explained by oxidation and reduction of the Cys186–Cys209
AND ENDOTHELIAL PROTEIN C bond. This disulfide bond is less stable because of its strained conforma-
RECEPTOR tion, and disruption of this link may cause conformational changes that
The breaking and
257,258
alter the affinity of tissue factor for factor VIIa.
formation of this disulfide link is suggested to be modulated by protein
TISSUE FACTOR disulfide isomerases. 255
Tissue factor, also known as thromboplastin or CD142, is the cellular A final model assumes that decryption relies on the dimerization
receptor and cofactor for factors VII and VIIa (see Fig. 113–6) and was of tissue factor. Like other members of the class II interferon receptors,
first described in 1905. Tissue factor is expressed in extravascular tissue factor is capable of dimerization in a manner determined by the
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Kaushansky_chapter 113_p1915-1948.indd 1930 9/21/15 2:40 PM