At a Glance

Severe acquired factor XIII deficiency is very rare and can be caused by a factor XIII auto-antibody (inhibitor). There have been at least 36 cases of factor XIII inhibitors reported, with additional cases that have not been published. A factor XIII inhibitor can be considered in a patient who develops a severe, unexplained bleeding tendency with no prior history or family history of bleeding. Intracranial and/or intramuscular bleeding is common with factor XIII inhibitors.

Systemic lupus erythematosus (SLE) was associated with approximately one-third of reported cases. Various medications, including isoniazid, procainamide, penicillin, phenytoin and valproate have been implicated.

Unrelated to inhibitors, mild acquired decreases in factor XIII can occur with a variety of conditions, such as liver dysfunction, Crohn’s disease, ulcerative colitis, disseminated intravascular coagulation (DIC), surgery, Henoch Schoenlein purpura, myeloproliferative and myelodysplastic disorders and leukemia, and in these cases, the decrease in factor XIII is usually too mild to cause bleeding or account for bleeding that occurs.

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Factor XIII inhibitors have also arisen in a small number of patients with severe hereditary factor XIII deficiency who received multiple transfusions and developed an anti-factor XIII antibody after exposure to the normal factor XIII in the transfused product.

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

The prothrombin time (PT) and activated partial thromboplastin time (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. This screening assay should be adequate in detecting a clinically-significant factor XIII inhibitor.

An antiplasmin activity assay should be performed if the clot solubility assay result is abnormal, because antiplasmin deficiency can also cause an abnormal result.

A mixing study to assess for an inhibitor can be performed if the clot solubility result is abnormal and antiplasmin is normal. If there is no inhibitor, clot solubility should be normal in the mixing study. If a factor XIII inhibitor is present, clot solubility should remain abnormal (i.e. the clot lyses). However, some inhibitors can give falsely normal results in the mixing study (e.g. if they only cause accelerated clearance of factor XIII rather than inhibition of factor XIII activity).

Quantitative factor XIII assays are also available, usually in large reference laboratories. If a severe deficiency of factor XIII is detected by a quantitative assay, a mixing study can be performed using a quantitative factor XIII activity assay to assess for an inhibitor. (Table 1)

Table 1.
Clot Solubility Factor XIII Activity, quantitative Mixing Study
Abnormal (clot lysed) <5% Clot solubility: abnormal (clot lysed)
Quantitative assay: activity remains < 5% in the mix

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?

As noted, some medications have been implicated in triggering the development of a factor XIII inhibitor, and some conditions (e.g. liver disease) can cause mild decreases in factor XIII unrelated to an inhibitor. Mild acquired decreases in factor XIII will not affect the clot solubility assay but could cause quantitative results to be mildly below the normal range. In addition, newborns have a lower normal range than adults in quantitative assays, but this should not affect the clot solubility assay.

The clot solubility assay might be less specific (generating falsely abnormal results), albeit more sensitive, if thrombin and acetic acid or chloroacetic acid are used instead of calcium and urea.

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 lack of calcium, which is necessary for factor XIII activity).

With one type of quantitative activity assay, falsely decreased results may occur with high ammonia levels and very high or very low fibrinogen. This assay tends to overestimate low levels of factor XIII, but a newer version of this assay that claims to be accurate even at very low levels has recently become available.

What Lab Results Are Absolutely Confirmatory?

An abnormal clot solubility assay (the clot lysed) or quantitative factor XIII activity levels less than 5%, with a positive mixing study (clot lysed in the clot solubility mixing study or quantitative factor XIII activity remaining <5% or significantly less than expected in a mixing study), confirms the presence of a factor XIII inhibitor, if the limitations described are taken into account.

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

If a factor XIII inhibitor is confirmed, a few reference laboratories can determine the titer of the inhibitor if requested.