FXIII Deficiency

Pattern of Inheritance

It is now evident that some mild to moderate forms of Factor XIII deficiency may have gone unrecognized. Broader approaches to the evaluation of all patients with bleeding or know carriers have identified individuals with more bleeding than their FXIII activity level in vitro would predict. This may be due to mutations in a functional site, such as the catalytic moiety or the activation peptide, which may be missed in our conventional assays but still result in significant bleeding in vivo.

This finding is particularly pertinent to the Factor XIII B subunit deficient patients. While true deficiency of B subunit is much less common than an absent A subunit, mutations in a B subunit resulting in a milder form of FXIII deficiency or dysfunction may be more common than originally thought. Recent prospective evaluation of all patients evaluated for bleeding disorders showed a higher incidence of FXIII B subunit mutations in mild to moderate patients compared to the severe patients. This study was done in Germany and may relate to that specific population.34,35 The trend, however, is likely to hold up when tested elsewhere among the mild to moderate patients. The patients with mild to moderate deficiencies due to B subunit mutations could use the plasma derived FXIII concentrate, but not the recombinant form.

To date, there are only four known mutations for FXIII-B, leading to the more rare form of FXIII deficiency. The few defects that have been reported in the B chain lead to a deficiency of the carrier protein (subunit B), which then leads to instability and reduction of plasma subunit A levels despite the presence of functional intracellular subunit A (type 1 defect).17 Most recently, three unrelated patients with severe FXIII deficiency were reported with failure of hepatocyte secretion of a truncated form of FXIII subunit B. This mutation, derived from a single-base deletion in the B subunit gene, resulted in impaired intracellular transport from the endoplasmic reticulum to the Golgi apparatus.

Certain gene variants exhibit a single nucleotide change or polymorphism (SNP), which results in the substitution of one amino acid for another. This is considered a polymorphism rather than a mutation due to the fact that it occurs at a fairly high frequency in certain populations.  Variants from one individual to the next are common, but certain SNPs result in increased or decreased function of the protein encoded on that particular allele. With the advent of whole genome sequencing more and more variants are being noted (currently > 297), but without the associated clinical findings or patient phenotype, these molecular variants are hard to categorize as pathologic or not.  Globally, all submitted requests for sequencing should be accompanied by a clinical report and trio family studies be performed to help distinguish pathologic variants from those which are benign.36

The FXIII gene has several common single nucleotide sequence variations, which encode amino acid substitutions. Five common coding polymorphisms have been identified in the FXIII-A subunit: Val34Leu, Tyr204Phe, Pro564Leu, Val650Ile and Glu651Gln. The Val34Leu variant is the most studied FXIII-A subunit polymorphism, with the amino acid substitution occurring in the activation peptide sequence, three amino acids upstream from the thrombin-cleavage site. This polymorphism exists in approximately 20% of white European, 40% of Pima Native American and 13% of South Asian populations.37,38

Studies have shown that the Leu34 allele variant actually promotes accelerated cleavage of the activation peptide once triggered by thrombin.39 On the other hand, two other polymorphisms, Tyr204Phe and Pro564Leu, have been linked with increased risk of hemorrhagic stroke in young women.40 The Tyr204Phe substitution has also been reported to be associated with an increased risk of miscarriages.41

Some studies have shown that the Leu34 variant was associated with a decreased risk of myocardial infarction in several different human studies,42-44 but other scientists have not found this association.45-48 Controversy has surrounded the role of Val34Leu in coronary artery disease, with the literature supporting both sides of the debate. The FXIII-B subunit also has common polymorphisms, His95Arg being the most well known. No known change of function in the FXIII-B subunit has been associated with this polymorphism to date although murine studies suggest a shortened FXIII half-life due to weakened association of the A and B subunits when this SNP is present.

The FXIII gene mutations and polymorphisms result in a high level of heterogeneity of disease presentation and overall phenotype. Mutations occurring along the gene can affect different areas of the protein, such as the B subunit binding site or the A subunit activation site. In combination, heterogeneity in the gene and FXIII proteins is responsible in large part for the wide range of clinical manifestations in patients with mild, moderate or severe FXIII deficiency.

A number of excellent reviews have recently been published that document the higher rate of mild FXIII deficiencies due to variants that result in a partially dysfunctional molecule, or who simply manifest bleeding symptoms with levels in the range of 5-30% due to carrier status.   This reaffirms the importance of sequencing patients with rare blood disorders as it is key to our understanding of how genetic variants impact the bleeding phenotype, especially in the Factor XIII molecule which is involved in so many different activities.49-51