A Consensus Statement from the ISTH FXIII Joint SSC Committee has recently recommended that patients being evaluated for possible FXIII deficiency should have an initial assay to determine FXIII activity followed by antigenic studies to confirm the level of the complex along with A and B subunits. The molecular or genetic studies would be encouraged to further understand genotype-phenotype associations. Furthermore, the typing of FXIII deficiencies was also simplified and placed in line with other clotting protein classifications. Type 1 is now a combined loss of activity as well as FXIII protein. In Type 2 deficiency FXIII-A2B2 hetero-tetramer is normal to mildly reduced antigen level, but activity is low, suggesting a dysfunctional protein variant with no loss in detectable antigen.
The results of standard laboratory clotting tests, such as prothrombin time, activated partial thromboplastin time, fibrinogen level, platelet count and bleeding time, are all normal in FXIII-deficient patients. The first case of FXIII deficiency was detected by an abnormal urea clot lysis test result. Using a solution of 1% monochloracetic acid or 5 M urea, clots will undergo lysis if a patient has FXIII levels of < 1%. The clot solubility test is only sensitive at very low levels of FXIII (zero or very close to zero) and will be normal if the FXIII activity level rises to 1-3%.8
It is critical to stress that a normal clot lysis assay does NOT rule out FXIII deficiency, as this assay may be falsely normal under a number of scenarios due to sample handling or other factor level changes such as, for example, elevated fibrinogen levels. The clot lysis assay is a quick screening tool and useful if abnormal, but a quantitative, specific measurement of FXIII activity should also be determined as well. Patients with mild disease, or individuals that carry on dysfunctional or absent gene for FXIII may also have very low FXIII levels, with a normal clot lysis. For all these reasons a quantitative analysis of FXIII should always be performed along with the clot lysis assay.
Quantitative Analysis
There are at least four quantitative assay kits commercially available in Europe: the Berichrom FXIII (Dade Behring, Marburg, Germany), the REA-chrom FXIII (Reanal-Ker, Budapest, Hungary) and the Pefakit Factor XIII (Pentapharm, Basel, Switzerland), and a new fluorometric assay developed by N-zyme BioTec (Darmstadt, Germany). The Berichrom FXIII and the REA-chrom both use photometric methods to measure the ammonia released in the first step of the transglutaminase reaction. The Pefakit uses an amine incorporation assay to measure amines covalently cross-linked to a protein substrate.
Development of the new fluorometric test was based on isopeptidase activity of FXIII-A described by Parameswaran et al.57,58 Normal FXIII activity levels range from 50-220%. Plasma levels between 5% and 30% have been shown to be sufficient in preventing spontaneous bleeding, but maybe associated with miscarriage, and trauma or surgically induced hemorrhage. At this time only the Berichrom assay is most commonly used in commercial labs within the US. Genetic analysis is performed to aid in family counseling, prenatal screening and further characterization of specific bleeding risk. Laboratories performing specific FXIII gene mutational analysis are listed in the Resources section.
Any child who presents with spontaneous or recurrent intracranial or spinal hemorrhage should be evaluated for Factor XIII deficiency. Urgent CT scan with subsequent MRI once stabilized is key to tracking response to therapy in patients newly diagnosed with FXIII deficiency while waiting for FXIII levels or pharmacokinetic studies to become available.
In addition, close monitoring for intrauterine bleeds or early placental abruption is critically important during pregnancy, especially in the first trimester. In the case of families where there is a previous child diagnosed with FXIII deficiency, monitoring the fetus closely is also recommended, although the incidence of prenatal ICH or bleeding is very rare. Infants with prenatal diagnosis of FXIII deficiency should be considered for C-section if a complicated and protracted vaginal delivery is suspected.
Rare Coagulation Disorders Resource Room, an extension of the RBDD Registry (eu.rbdd.org), was developed in collaboration with the Indiana Hemophilia & Thrombosis Center (www.innovativehematology.org).
The Resource Room serves as a platform to promote international collaboration to increase knowledge of these very rare disorders and to improve the care of affected individuals. The international RBDD mission, under the leadership of Dr. Peyvandi, will continue to be expanded over time.
The Resource Room thanks all contributing authors of the website articles that have made this valuable information available to the global community of both individuals affected with rare coagulation disorders and their healthcare providers.
