Page 1960 - Williams Hematology ( PDFDrive )

1934 Part XII: Hemostasis and Thrombosis Chapter 113: Molecular Biology and Biochemistry of the Coagulation Factors 1935

Crosslinks stabilize a clot by incorporation of the plasmin inhibi- 1 234 5 6 78 910 1112
tor α -antiplasmin which makes it resistant to fibrinolytic attack by Gene 28 kb
2
plasmin. 304
Several other processes during clotting are factor XIII-dependent,
305
among which red blood cell incorporation in clots, complement fac-
306
307
tor 3 (C3) crosslinking to fibrin, and clot retraction by platelets. mRNA 2.2 kb
Factor XIII also plays a role in the functioning of multiple adhesive and
308
contractile proteins and in angiotensin type I receptor crosslinking.
Fetal specific crosslinking of Fas by factor XIII dampens apoptosis,
309
suggesting that factor XIII may play a role in cell survival prenatally. Exon 1 2 3 4 5 6 7 8 9 1011 12
Related to its expression by monocytes/macrophages, factor XIII levels Protein ProS1S2S3S4S5S6S7 S8S9S10 Carb
may drop after inhibition of IL-6 receptor signalling by tocilizumab. Figure 113–25. Relationship of gene structure to protein structure in
310
Besides its crucial role in hemostasis, factor XIII has important func- the factor XIIIB chain. The exons, introns, mRNA, and protein structure
311
tions during tissue regeneration and infection. Factor XIII is neces- are as indicated. The mRNA is 2.2 kb with small 3′ and 5′ untranslated
sary to prevent bleeding/stroke, maintain pregnancy, and aids in wound noncoding regions (light blue). In the protein, Pro indicates the propep-
healing. 298 tide, S1 to S10 indicates the Sushi 1 to 10 domains, and the C-terminal
region is indicated by Carb.
Gene Structure and Function
The factor XIIIA chain gene (F13A1) has been localized to chromosome A Val34Leu polymorphism associated with fatal atherothrom-
6 p25.1. It contains 15 exons, and is larger than 160 kb (Fig. 113–24). botic ischemic stroke results in a faster factor XIIIA activation rate by
312
The fibrin-binding domain is encoded by exons 2 to 12. The active site, thrombin, which affects clot structure. 316
with its reactive thiol at Cys314, is present in exon 7. The gene encod-
ing the factor XIIIB (F13B) chain has been localized to chromosome THROMBIN-ACTIVATABLE FIBRINOLYSIS
1q31.3. It has 12 exons and is approximately 28 kb (Fig. 113–25). Each INHIBITOR
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Sushi domain is encoded by a single exon. The regulation of factor XIIIB TAFI is the zymogen of a zinc-bound metalloprotease, and is also
expression is poorly understood. A total of 30 potential start sites are known as carboxypeptidase B, R, or U. TAFI is synthesized in the liver.
located upstream of the initial methionine. Most TAFI present in the blood is in the plasma compartment, which
Homozygosity or compound heterozygosity for loss-of-function circulates at 70 to 275 nM (see Table 113–1).
mutations in the factor XIIIA or XIIIB genes leads to a severe bleeding
314
disorder that is rare (1 in 2,000,000 of the population). Factor XIII– Protein Structure
deficient newborns often present with bleeding from the umbilical cord. TAFI is a 401-amino-acid proenzyme (Mr ≈60,000) and consists of an
The natural course is characterized by a life-long bleeding tendency and N-terminal activation peptide (residues 1 to 76), a linker region (res-
spontaneous miscarriages in affected women. Acquired factor XIII idues 77 to 92), and a catalytic domain (residues 93 to 401). Twenty
deficiency by development of an inhibitory antibody may lead to fatal percent of the protein mass of TAFI is accounted for by carbohydrate
bleeding if not treated. 315 side chains that are attached to four sites within the activation pep-
Mutations underlying factor XIII deficiency are more commonly tide (Asn22, Asn51, Asn63) and linker region (Asn86). The active site
found in the gene encoding factor XIIIA than the one encoding factor residues (Glu271, Arg125) and zinc-binding residues (His67, Glu70,
XIIIB. In accordance with this, the human gene mutation database lists His196) in TAFI are conserved between other members of the carboxy-
107 mutations in the factor XIIIA gene and 19 mutations in the factor peptidase A family.
XIIIB gene. Mutations in the gene encoding factor XIIIB often lead low
levels of both factor XIII subunits. This is probably because free factor Thrombin-Activatable Fibrinolysis Inhibitor Activation and
XIIIA has a short plasma half-life. Thrombin-Activatable Fibrinolysis Inhibitor-a Activity
TAFI is proteolytically activated by plasmin or thrombin, reactions that
are accelerated 1000-fold when thrombin is bound to thrombomod-
ulin. Both enzymes cleave TAFI at Arg92 to give rise to activated TAFI
12 34 5 6 7 8 9 1011 12 131415 (TAFIa; Mr ≈37,000) upon release of the activation peptide. TAFIa cat-
Gene 160 kb alyzes removal of C-terminal lysine and arginine residues from fibrin
and fibrin cleavage products. These residues are important for binding
and activation of plasminogen, and removal of these residues by TAFIa
reduces formation of plasmin on clots resulting in decreased clot lysis.
mRNA 4 kb TAFIa may also have an antiinflammatory role as it can efficiently
cleave C-terminal arginines of anaphylatoxins such as bradykinin and
the complement activation peptides C3a and C5a.
Inhibitors of TAFIa have not been identified. Rather, the primary
Exon 2 3 4 56 78 9 10 11 12 13 14 15 regulatory mechanism of TAFI activity involves its intrinsic thermal
Protein AP Catalytic domain instability with a half-life of less than 15 minutes at 37 C.
o
Figure 113–24. Relationship of gene structure to protein structure
in the factor XIIIA chain. The exons, mRNA, and protein structure of the Gene Structure and Variations
factor XIIIA chain are shown. The mRNA is 4 kb with some 5′ untrans- The gene for TAFI (CPB2) has been localized to 13q14.13. The gene con-
lated sequence coded in exon 1 and a large 3′ untranslated region (light tains 11 exons with 10 introns and spans 48 kb. Homozygosity or com-
blue). In the protein, AP indicates the activation peptide, and the cata- pound heterozygosity for mutations in the gene encoding TAFI have
lytic domain is indicated. not been described.

Kaushansky_chapter 113_p1915-1948.indd 1935 9/21/15 2:40 PM