Factor XIII Deficiency – Congenital

At a Glance

Hereditary factor XIII deficiency can be considered in a patient with delayed bleeding after minor trauma in whom more common etiologies have been excluded. Hereditary factor XIII deficiency is rare, affecting 1 in 2-5 million persons.

Umbilical stump bleeding as a newborn is a characteristic feature. The risk for spontaneous intracranial hemorrhage is increased, which is the most feared complication. Patients may also experience bruising, intramuscular hematomas, menorrhagia and poor wound healing. Hemarthrosis is not common. Pregnant women with this disorder commonly have miscarriages. Inheritance is autosomal recessive; thus, the parents typically have no bleeding symptoms and a family history of bleeding might therefore be absent. Siblings, however, have a 25% chance of being similarly affected. A survey of affected families suggested that heterozygous carriers might have bleeding symptoms.

The prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The PT and aPTT will not detect factor XIII deficiency. Most laboratories use a factor XIII screening assay, called the clot solubility test, which can only detect severe deficiencies with less than approximately 2% factor XIII. To perform this test, a clot is formed by adding calcium (most commonly) or thrombin to the patient plasma sample. The clot is then immersed for 24 hours in urea (most commonly), acetic acid or chloroacetic acid. If factor XIII is present, the clot remains intact because factor XIII will have stabilized the clot by incorporating covalent bonds between the fibrin strands. If factor XIII is severely reduced (e.g. <2%), the clot lyses and disappears.

An antiplasmin activity assay should be performed if the clot lyses in the clot solubility assay because antiplasmin deficiency can also cause an abnormal clot solubility result. This is because factor XIII also crosslinks antiplasmin to fibrin, protecting the fibrin clot from fibrinolysis by plasmin.

A mixing study can be performed if the clot lyses in the clot solubility assay to exclude the possibility of an acquired factor XIII deficiency due to an auto-antibody against factor XIII. The mixing study involves mixing patient plasma with normal plasma and then performing the clot solubility assay on the mix. The clot solubility results should be normal in the mix if the deficiency is hereditary but should remain abnormal if the deficiency is acquired due to an antibody.

Quantitative factor XIII activity and antigen assays are commercially available but are largely limited to reference laboratories at present. The advantage of these methods is they can detect mild or moderate deficiencies as well as severe deficiencies.

Factor XIII consists of two catalytic A subunits and two noncatalytic carrier B subunits. Most mutations causing factor XIII deficiency have, so far, been found in the A subunit. (Table 1)

Table 1.

Tests Results indicative of Hereditary Factor XIII Deficiency
Clot Solubility Clot Solubility in Mix Factor XIII Activity Factor XIII Antigen (using anti-subunit A antibodies)
Abnormal (clot lysed) Normal (clot remained intact) <5% <5% with A subunit deficiencies; significantly reduced with B subunit deficiencies

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Transfusions within the preceding 1-4 months prior to specimen collection can cause falsely normal results in the clot solubility assay because only a small amount of factor XIII is needed to keep the clot intact and factor XIII has a long half-life.

With the clot solubility assay, the use of thrombin and acetic acid or chloroacetic acid instead of calcium and urea might be less specific (falsely abnormal results) but may be more sensitive in detecting a deficiency.

A citrated (blue top) tube is typically used for factor XIII assays. Do not submit an EDTA specimen for the clot solubility assay because it causes falsely abnormal results when the laboratory uses thrombin to generate the clot in this assay (due to a lack of calcium, which is necessary for factor XIII activity).

A variety of conditions can cause acquired, usually mild decreases of factor XIII, including liver dysfunction, Crohn's disease, ulcerative colitis, disseminated intravascular coagulation (DIC) or surgery. The normal range (reference range) is lower in newborns than adults. These conditions are not expected to cause a severe decrease in factor XIII and, therefore, should not cause falsely abnormal clot solubility results, but quantitative assays may show results below the reference range.

With one type of quantitative activity assay, falsely decreased results may occur with high ammonia levels and very high or very low fibrinogen. In this quantitative activity assay, factor XIII is activated by thrombin. Activated factor XIII then attaches glycine ethyl ester to a specific peptide substrate, releasing ammonia. The released ammonia generates a subsequent reaction detected by a photometer. This assay tends to overestimate low levels of factor XIII, but a newer version of this assay that claims to have accurate results even at very low levels has recently become available.

A latex agglutination-based factor XIII antigen assay is the only currently FDA-approved quantitative factor XIII assay, and it uses antibodies that detect the A subunit of factor XIII. The results are markedly low if the patient has homozygous mutation(s) in the A subunit with little or no A subunit detected. If the patient has homozygous mutation(s) in the B subunit, which is uncommon, the results are significantly low because the half-life of subunit A is short when not protected by subunit B. Enzyme linked immunosorbent assays (ELISA) using antibodies against the A subunit or the B subunit are also available on a research basis.

What Lab Results Are Absolutely Confirmatory?

An abnormal clot solubility assay is essentially confirmatory if the limitations described are addressed, including testing for antiplasmin. Very low to undetectable factor XIII in a quantitative assay is also essentially confirmatory if the limitations described are addressed (e.g. measuring fibrinogen if the factor XIII assay is affected by fibrinogen).

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