Page 2169 - Williams Hematology ( PDFDrive )

2144 Part XII: Hemostasis and Thrombosis Chapter 124: Inherited Deficiencies of Coagulation Factors II, V, V+VIII, VII, X, XI, and XIII 2145

PROTEIN insertion in exon 14 (c.2116insAAGA) introducing a frameshift that
Factor XIII (fibrin-stabilizing factor) is a plasma transglutaminase that after seven altered amino acids results a stop codon and a protein
299
crosslinks γ-glutamyl–ε-lysine residues of fibrinogen chains, thereby with AQ3 truncated second β-barrel domain (p.Pro675TyrfsX7) has
stabilizing the fibrin clot. Plasma factor XIII is an Mr 340,000 hetero- been reported to cause an extremely rare type II variant. The mutant
tetramer composed of two catalytic A subunits and two carrier B sub- protein lost its activity, but the plasma factor XIII antigen level was at
units linked by noncovalent bonds. The average concentration of the the lower limit of the reference interval. This finding suggests that the
A B tetramer in plasma is approximately 22 mcg/mL, and its half-life C-terminal part of β-barrel 2 is essential for the expression of factor
2
2
is 9 to 14 days. Intracellularly, factor XIII is found as a homodimer XIII activity.
265
composed of two A subunits (A ). 266,267 Factor XIII-A subunit is mainly Splice-site mutation in intron 5 (IVS5–1 G>A) seems to be the
2
synthesized in macrophages and megakaryocytes. 266,267 Because factor most common mutation as it has already been reported in six unrelated
XIII-A subunit lacks a signal sequence, it cannot be released by the families from six different European countries, whereas the Arg660Pro
264,300
classic secretory pathway through the Golgi apparatus. Conceivably, was found in Palestinian Arabs, consistently with founder effects. It
factor XIII-A subunit is released into the circulation from cells as a is likely that the Arg661stop mutation in Finnish patients and the Arg-
consequence of cell injury. Structurally, each A monomeric subunit 77Cys mutation in Swiss patients are also a result of founder effects,
268
(Mr ~82,000) is composed of an activation peptide, that is removed although both are at CpG dinucleotides and therefore can be consid-
264,301,302
by thrombin cleavage of an Arg37-Gly38 bond in the presence of cal- ered recurrent mutations. Another mutation, Ser295Arg, was
cium ions, and four distinct domains: β-sandwich, central core, barrel identified in six Pakistani families and may also stem from a common
303
1, and barrel 2 regions. The central core domain contains a catalytic founder, but this remains to be established. Six nonsynonymous/cod-
25
triad (common to the transglutaminase family) formed through hydro- ing polymorphisms in the factor XIIIA1 (F13A1) gene, Val34Leu in
gen bond interactions between Cys314, His373, and Asp396. 269–271 It is exon 2, Tyr204Phe in exon 5, Pro(CCA)331(CCC)Pro in exon 8, Glu(-
structurally homologous with the α chain of tissue transglutaminase, GAA)567Glu(GAG) and Pro564Leu in exon 12, and Val650Ile and
272
the α chain of keratinocyte transglutaminase, and band 4.2 of ery- Glu651Gln in exon 14 have been analyzed in an association study. The
273
throcytes, although the latter lacks transglutaminase activity. study showed that only the Val34Leu is a true functional polymorphism
274
The site of synthesis for factor XIII-B subunit has been suggested and the rest are in linkage disequilibrium with this polymorphism. In
to be the liver. The B subunit (Mr 76,500) is composed of 10 tandem this study, only haplotypes containing the “34L” allele affected factor
275
298,304
repeats of complement control protein (CCP) modules designated as XIII function. However, a larger number of synonymous/noncod-
304
Sushi domains, which are also observed in proteins of the complement ing polymorphisms (>500) are known for the F13A1 gene. Only 16
298
system. 276,277 The two B subunits of factor XIII function as carrier pro- different mutations have been reported so far for the FXIIIB gene.
teins for the A subunits, 278,279 stabilizing them in the circulation and reg-
ulating the calcium-dependent activation of factor XIII.
On activation by thrombin and Ca the A and B subunits dis- CLINICAL MANIFESTATIONS
2+
sociate. Proteolytic activation by thrombin involves the cleavage of a Factor XIII deficiency causes formation of blood clots that are unsta-
N-terminal 37-residue activation peptide. The cleavage and the calcium ble and susceptible to fibrinolytic degradation by plasmin. As a result,
binding both serve to induce structural changes that open up the cata- affected individuals have an increased tendency to bleed and rebleed-
lytic triad to substrate access. This process is accelerated by fibrin. 281–283 ing. Delayed umbilical cord bleeding reported in 80 percent of patients
280
The clot stabilizing effect of factor XIII is achieved by the crosslinking of with factor XIII deficiency can be considered as diagnostic symp-
fibrinogen chains, between the γ-carbonyl group of glutamine and the tom of the deficiency. CNS bleeding is reported in approximately 30
ε-amino group of lysine. In fibrin, this amide bond is located between percent of cases, 305,306 making primary prophylaxis mandatory in
Aα-chain sequences and between γ-chain sequences 284–288 ; factor XIIIA patients affected with severe factor XIII deficiency. Ecchymoses, intra-
also crosslinks α antiplasmin to the α-chain fibrin, thereby increasing muscular and subcutaneous hematomas, oral cavity, mouth and gingival
289
2
the resistance of fibrin to plasmin degradation, and crosslinks fibronec- bleeding, and prolonged bleeding following trauma are also character-
tin to the α-chain of fibrin, thereby affecting the mechanical proper- istic symptoms. 305
290
ties of the clot and increasing cell adhesion. 291 Delayed wound healing occurs in approximately 15 percent
In addition to fibrinogen and α -antiplasmin, factor XIII has many of patients deficient in factor XIII. The exact mechanism by which
2
other substrates, including fibronectin, vitronectin, collagen, factor V, factor XIII, or factor XIIIa, exerts its beneficial effect on wound healing
von Willebrand factor, α -antiplasmin, actin, myosin, vinculin, throm- is unknown. A proangiogenic effect of factor XIIIa was described, sug-
2
bospondin, plasminogen-activating inhibitor (PAI), TAFI 2, and AT1 gesting that decreased vascularization of wounds results in improper
receptor dimers of monocytes, implicating multiple and different roles repair. 306
for factor XIII in various systems other than coagulation. 292 In a review of the literature on 121 women with factor XIII defi-
ciency, menorrhagia and ovulation bleeding were found to be common
gynecologic problems, affecting 26 and 8 percent of women, respec-
GENETICS tively. Of 192 pregnancies, 127 (66 percent) resulted in a miscarriage
307
The gene for the factor XIII A-subunit is located on chromosome 6p24- and 65 (34 percent) reached viability stage, whereas of 136 pregnancies
p25. 293,294 It spans more than 170 kb and is composed of 15 exons. The without prophylactic therapy, 124 (91 percent) resulted in a miscarriage
295
B-subunit gene is located on chromosome 1q31-q32.1. 296,297 The gene for and 12 (9 percent) progressed to viability stage. In affected women, for-
the B subunit spans 28 kb and is composed of 12 exons. 297 mation of the cytotrophoblastic shell is impaired. Conceivably, fac-
308
One hundred and twenty-one mutations causing factor XIII tor XIII A-subunit deficiency at the implantation site abrogates fibrin/
A-subunit deficiency have been reported as of this writing, of which fibronectin crosslinking, which is essential for attachment of the pla-
only one maps to the promoter region, 57 are missense, 11 are non- centa to the uterus. 309
sense, 17 are splice-site, and 35 are del/ins mutants (http://www.isth. Placental abruption, preterm delivery, and PPH could be also
org/?MutationsRareBleedin and Ref. 298). A homozygous four-bases problem if not adequately treated. 309

Kaushansky_chapter 124_p2133-2150.indd 2144 17/09/15 3:42 pm