The first clinical report of factor XIII deficiency was in 1960265; since then, more than 500 cases of factor XIII deficiency have been identified worldwide, with an incidence of one individual in 1 to 3 million population.22,264 Congenital factor XIII deficiency is characterized by severe delayed spontaneous bleeding and recurrent abortion with normal coagulation screening tests.
Factor XIII (fibrin-stabilizing factor) is a plasma transglutaminase that crosslinks γ-glutamyl–ε-lysine residues of fibrinogen chains, thereby stabilizing the fibrin clot. Plasma factor XIII is an Mr 340,000 heterotetramer composed of two catalytic A subunits and two carrier B subunits linked by noncovalent bonds. The average concentration of the A2B2 tetramer in plasma is approximately 22 mcg/mL, and its half-life is 9 to 14 days.265 Intracellularly, factor XIII is found as a homodimer composed of two A subunits (A2).266,267 Factor XIII-A subunit is mainly synthesized in macrophages and megakaryocytes.266,267 Because factor XIII-A subunit lacks a signal sequence, it cannot be released by the classic secretory pathway through the Golgi apparatus. Conceivably, factor XIII-A subunit is released into the circulation from cells as a consequence of cell injury.268 Structurally, each A monomeric subunit (Mr ~82,000) is composed of an activation peptide, that is removed by thrombin cleavage of an Arg37-Gly38 bond in the presence of calcium ions, and four distinct domains: β-sandwich, central core, barrel 1, and barrel 2 regions. The central core domain contains a catalytic triad (common to the transglutaminase family) formed through hydrogen bond interactions between Cys314, His373, and Asp396.269,270,271 It is structurally homologous with the α chain of tissue transglutaminase,272 the α chain of keratinocyte transglutaminase,273 and band 4.2 of erythrocytes,274 although the latter lacks transglutaminase activity.
The site of synthesis for factor XIII-B subunit has been suggested to be the liver.275 The B subunit (Mr 76,500) is composed of 10 tandem repeats of complement control protein (CCP) modules designated as Sushi domains, which are also observed in proteins of the complement system.276,277 The two B subunits of factor XIII function as carrier proteins for the A subunits,278,279 stabilizing them in the circulation and regulating the calcium-dependent activation of factor XIII.
On activation by thrombin and Ca2+ the A and B subunits dissociate. Proteolytic activation by thrombin involves the cleavage of a N-terminal 37-residue activation peptide. The cleavage and the calcium binding both serve to induce structural changes that open up the catalytic triad to substrate access.280 This process is accelerated by fibrin.281,282,283 The clot stabilizing effect of factor XIII is achieved by the crosslinking of fibrinogen chains, between the γ-carbonyl group of glutamine and the ε-amino group of lysine. In fibrin, this amide bond is located between Aα-chain sequences and between γ-chain sequences284,285,286,287,288; factor XIIIA also crosslinks α2 antiplasmin to the α-chain fibrin,289 thereby increasing the resistance of fibrin to plasmin degradation, and crosslinks fibronectin to the α-chain of fibrin,290 thereby affecting the mechanical properties of the clot and increasing cell adhesion.291
In addition to fibrinogen and α2-antiplasmin, factor XIII has many other substrates, including fibronectin, vitronectin, collagen, factor V, von Willebrand factor, α2-antiplasmin, actin, myosin, vinculin, thrombospondin, plasminogen-activating inhibitor (PAI), TAFI 2, and AT1 receptor dimers of monocytes, implicating multiple and different roles for factor XIII in various systems other than coagulation.292
The gene for the factor XIII A-subunit is located on chromosome 6p24-p25.293,294 It spans more than 170 kb and is composed of 15 exons.295 The B-subunit gene is located on chromosome 1q31-q32.1.296,297 The gene for the B subunit spans 28 kb and is composed of 12 exons.297
One hundred and twenty-one mutations causing factor XIII A-subunit deficiency have been reported as of this writing, of which only one maps to the promoter region, 57 are missense, 11 are nonsense, 17 are splice-site, and 35 are del/ins mutants (http://www.isth.org/?MutationsRareBleedin and Ref. 298). A homozygous four-bases insertion in exon 14 (c.2116insAAGA) introducing a frameshift that after seven altered amino acids results a stop codon and a protein with AQ3 truncated second β-barrel domain (p.Pro675TyrfsX7)299 has been reported to cause an extremely rare type II variant. The mutant protein lost its activity, but the plasma factor XIII antigen level was at the lower limit of the reference interval. This finding suggests that the C-terminal part of β-barrel 2 is essential for the expression of factor XIII activity.
Splice-site mutation in intron 5 (IVS5–1 G>A) seems to be the most common mutation as it has already been reported in six unrelated families from six different European countries, whereas the Arg660Pro was found in Palestinian Arabs, consistently with founder effects.264,300 It is likely that the Arg661stop mutation in Finnish patients and the Arg77Cys mutation in Swiss patients are also a result of founder effects, although both are at CpG dinucleotides and therefore can be considered recurrent mutations.264,301,302 Another mutation, Ser295Arg, was identified in six Pakistani families and may also stem from a common founder, but this remains to be established.303 Six nonsynonymous/coding polymorphisms in the factor XIIIA1 (F13A1) gene,25 Val34Leu in exon 2, Tyr204Phe in exon 5, Pro(CCA)331(CCC)Pro in exon 8, Glu(GAA)567Glu(GAG) and Pro564Leu in exon 12, and Val650Ile and Glu651Gln in exon 14 have been analyzed in an association study. The study showed that only the Val34Leu is a true functional polymorphism and the rest are in linkage disequilibrium with this polymorphism. In this study, only haplotypes containing the “34L” allele affected factor XIII function.298,304 However, a larger number of synonymous/noncoding polymorphisms (>500) are known for the F13A1 gene.304 Only 16 different mutations have been reported so far for the FXIIIB gene.298
Factor XIII deficiency causes formation of blood clots that are unstable and susceptible to fibrinolytic degradation by plasmin. As a result, affected individuals have an increased tendency to bleed and rebleeding. Delayed umbilical cord bleeding reported in 80 percent of patients with factor XIII deficiency can be considered as diagnostic symptom of the deficiency. CNS bleeding is reported in approximately 30 percent of cases,305,306 making primary prophylaxis mandatory in patients affected with severe factor XIII deficiency. Ecchymoses, intramuscular and subcutaneous hematomas, oral cavity, mouth and gingival bleeding, and prolonged bleeding following trauma are also characteristic symptoms.305
Delayed wound healing occurs in approximately 15 percent of patients deficient in factor XIII. The exact mechanism by which factor XIII, or factor XIIIa, exerts its beneficial effect on wound healing is unknown. A proangiogenic effect of factor XIIIa was described, suggesting that decreased vascularization of wounds results in improper repair.306
In a review of the literature on 121 women with factor XIII deficiency, menorrhagia and ovulation bleeding were found to be common gynecologic problems, affecting 26 and 8 percent of women, respectively.307 Of 192 pregnancies, 127 (66 percent) resulted in a miscarriage and 65 (34 percent) reached viability stage, whereas of 136 pregnancies without prophylactic therapy, 124 (91 percent) resulted in a miscarriage and 12 (9 percent) progressed to viability stage. In affected women, formation of the cytotrophoblastic shell is impaired.308 Conceivably, factor XIII A-subunit deficiency at the implantation site abrogates fibrin/fibronectin crosslinking, which is essential for attachment of the placenta to the uterus.309
Placental abruption, preterm delivery, and PPH could be also problem if not adequately treated.309
No large clinical reports on heterozygous patients with factor XIII deficiency are available, thus not allowing to draw evidence-based conclusion on the prevalence of clinical symptoms in this group of patients. Recently, a subset of 28 heterozygotes for factor XIII deficiency among 350 carriers of an autosomal recessive inherited coagulation disorders show an association with prolonged or massive bleeding after minor trauma.310 However, these data need to be confirmed in other cohorts of patients.
Factor XIII A-subunit knockout mice manifest no excess embryonic lethality or bleeding into the thoracic cavity, peritoneum, or skin, compatible with survival to adulthood. However, the survival rate of knockout males was markedly lower than that of the wild-types.311 Female factor XIII knockout mice show intrauterine bleeding during pregnancy, similar to women with severe factor XIII A-subunit deficiency who experience the same problem, as well as recurrent abortions. Factor XIIIB knockout mice show a prolonged bleeding time at variance with patients with a complete factor XIII B-subunit deficiency, who report only mild bleeding symptoms and display normal bleeding times.312,313
According to the EN-RBD results, blood levels of factor XIII that are 30 percent of normal are necessary to assure an asymptomatic state. This goal may be reached via a number of options. Many case reports show improved bleeding symptoms in patients on prophylactic therapy.314 Plasma replacement therapy is highly satisfactory because of the long half-life of factor XIII (9 to 12 days). Plasma-derived, virus-inactivated concentrates of factor XIII are available315 and are the treatment of choice. The development of adverse events after treatment is rare. The most dreaded adverse event is the development of inhibitors, although its incidence is rare.316 A RBD registry created in North America discovered that 3 percent of factor XIII–deficient patients who received FFP or factor XIII concentrate treatment developed inhibitors.102 A new rFXIIIA2 concentrate has become available and a phase III clinical trial (ClinicalTrials.gov identifier: 00713648) has been completed, establishing that rFXIII is safe and effective in preventing bleeding episodes in patients with congenital factor XIII A-subunit deficiency. The rFXIII was recently approved for the treatment of factor XIIIA deficiency in Australia, Canada, the European Union, Switzerland, and the United States.317