There are a few parameters that are not measured in the routine screening tests of the PT and aPTT. One are platelets and the other is a FXIII deficiency. Fibrin Stabilizing Factor was discovered in 1944 by Robbins. It occurs in 1 in 2 million births and the inheritance pattern is autosomal recessive.
Factor XIII role in hemostasis catalysis the cross linking of fibrinogen, platelet membrane and proteins during thrombus formation. This is known as stabilizing the fibrin clot. This is a tetrameric zymogen which is converted to an active transglutaminase. Fibrin chains and alpha 2 plasmin inhibitor cross link to fibrin in which active FXIII will stabilize fibrin and protect it from fibrinolysis.
Factor XIII deficiency is a rare bleeding disorder. Patients present with umbilical cord bleeding, delayed soft tissue bruising, mucosal bleeding and life threatening intracranial hemorrhage. Patients also present with poor wound healing and recurrent miscarriages. While the deficiency is rare, there are 2 subunits FXIII-A which results in severe bleeding and FXIII-B that presents with milder bleeding symptoms. The A subunit is the enzymatic component and is responsible for the linking of fibrin. The B-subunit is a protective component that combines with the A subunit and protects it from being broken down and allows it to stay in the blood stream longer. The A subunit is produced in the bone marrow and the B subunit is made in the liver. Most FXIII deficient patient have a missing or non-functional A part which occurs in 95% of patients. The International FXIII Deficiency Registry includes 104 people with congenital factor XIII deficiency. In that registry just over half have severe bleeding, and most of the rest have moderate or mild bleeding.
Normal levels of Factor XIII activity are between 53-221%. There are 2 types of deficiencies. Type 1 is a quantitative defect due to decreased synthesis of the protein. Type 2 presents with a normal concentration of functionally defective FXIII A. Classification of disorders are based on the level of XIII and symptoms. This is not as straightforward as other disorders since FXIII is difficult to measure. The following classifications have been proposed:
- Mild: >30% activity: patients are asymptomatic and may have bleeding during trauma, or during a surgical procedure or with pregnancy/delivery.
- Moderate: <30% activity: patients have mild spontaneous bleeding,or bleeding triggered by trauma, surgery of pregnancy/delivery.
- Severe: undetectable: patients present with severe, spontaneous and life threatening bleeding.
There has been 70 mutations identified in Factor XIIIA deficient patients and only 5 mutations in the FXIIIB deficient patients.
Acquired deficiency of FXIII have been reported in patients in conjunction with drugs, lymphoproliferative disorders, chronic renal failure and cirrhosis. Most inhibitors are IgG antibodies and develop in patients without preexisting FXIII deficiency.
TESTING FACTOR XIII
When testing patients for F XIII deficiency, screening tests of the PT, aPTT and platelet counts will be normal. To evaluate the stability of a clot, most laboratories will perform a clot solubility test. This is based on the principle that the clots from a FXIII patient are unstabilized and will rapidly dissolve in either 5 M urea or 1% monochloroacetic acid in contrast to a normal patient which will not dissolve during testing and will remain stable for 24 hours. A deficient patient will dissolve a clot in minutes. In order for this test to be abnormal, patients must have a severe deficiency with levels in the ranges of 1-3%.
A functional FXIII assay uses immobilized fibrinogen on the wells of a microtiter plate. Plasma is added and FXIII is activated by the addition of calcium and thrombin. FXIIIa is then assayed either by incorporation of a substrate into the fibrin clot and measuring the amount of substrate or by measuring the amount of ammonia generated based on the transglutamidase activity of XIIIa. The measurement range is from 0-250%.
FXIII can also be measured by a chromogenic assay based on its transglutamidase activity. Thrombin activated FXIII to FXIIIa which links the amine substrate glycine-ethylene-ester with the glutamine residual of the specific peptide substrate. Ammoniac is released. In the measurement reaction the released ammoniac is demonstrated in a glutamate dehydrogenase catalyzed NADPH dependent reaction. The consumption of NADPH is spectrometrically measured by decrease of extinction at 340 nm. which uses a chromogenic substrate to determine levels. It is accurate for levels above 10-20%, and less precise in low levels. Immunological assay can also help to identify patients that are missing A or B part of factor XIII. Genotyping can also be performed to determine if there are abnormalities of the sequencing. Thromboelastography (TEG) can also detect significant FXIII deficiency - the TEG shows reduced clot formation and increased fibrinolysis.
Factor XIII (Corifact) concentrate was approved by the FDA in 2011 to be used to prevent bleeding in patients with congenital FXIII deficiency. In 2013, its use was expanded the use to include peri-operative management of surgical bleeding in adults and children.
The product is administered by intravenous infusion. It is made from pooled plasma of healthy donors. It is possible to develop antibodies against Corifact and if higher then recommended doses are given, the patient is at risk for a thrombotic event. For patients with FXIII A-subunit deficiency Tretten by Novo Nordisk has been FDA approved as an IV infusion product. It is the onl recombinant product approved to treat these patients. Cryoprecipitate should only be used to treat FXIII deficient patients in life threatening emergencies.
FXIII is a rare disorder, but may be one that is underdiagnosed in patients. There is a case report of a young child who fell and had a severe bleed. Child abuse was suspected, however the patient really had a FXIII deficiency. Unexplained bleeding, umbilical cord bleeding and delayed bleeding should all be investigated for a possible FXIII deficiency.