From: Elizabeth M. Van Cott, M.D., and Michael Laposata, M.D., Ph.D., “Coagulation.” In: Jacobs DS et al, ed. The Laboratory Test Handbook, 5th Edition. Lexi-Comp, Cleveland, 2001; 327-358.
Related Information
Synonyms Fibrin Stabilizing Factor; Fibrinoligase; Laki-Lorand Factor
Abstract Activated factor XIII stabilizes fibrin clots by cross-linking fibrin strands. Factor XIII deficiency can cause a hereditary bleeding disorder with features including delayed bleeding, umbilical stump bleeding, and miscarriages.
Specimen Plasma
Container One blue top (sodium citrate) tube
Collection Routine venipuncture. If multiple tests are being drawn, draw blue top tubes after any red top tubes but before any lavender top (EDTA), green top (heparin), or gray top (oxalate/fluoride) tubes. Immediately invert tube gently at least 4 times to mix. Tubes must be appropriately filled. Deliver tubes immediately to the laboratory.
Storage Instructions Separate plasma from cells as soon as possible. Plasma may be stored on ice for up to 4 hours; otherwise, store frozen.
Causes for Rejection Specimen received more than 4 hours after collection, tubes not filled, clotted specimens
Turnaround Time Screening assay: 24 hours after incubation begins; quantitative assay: several days (typically it is a send-out test)
Reference Interval Screening assay: Clot stable in 5 M urea for at least 24 hours. If factor XIII deficiency is present, clot will usually dissolve in 1-2 hours. Quantitative assay: 70% to 140% of normal (some newborns have lower levels than adults).1
Use Consider this test in patients with evidence for a familial bleeding disorder and a normal PT, PTT, and von Willebrand panel (because factor XIII deficiencies do not prolong the PT or PTT, and von Willebrand disease is a much more common disorder than factor XIII deficiency).
Factor XIII deficiency is rare. It causes delayed bleeding because although fibrin clots can form initially, they are weak and subsequently lyse. Factor XIII consists of two catalytic A subunits and two noncatalytic B subunits. Most mutations causing factor XIII deficiency have so far been found in the A subunit. The PT and PTT are normal in factor XIII deficiency because factor XIII stabilizes the clot after a fibrin clot has formed, whereas the PT and PTT measure the clotting time through initial fibrin formation. Inheritance is autosomal. Formerly, it was believed that heterozygotes are asymptomatic, but more recent evidence suggests they can have bleeding symptoms.2 Symptoms include poor wound healing, umbilical stump bleeding, miscarriage, prolonged bleeding from superficial wounds, and intracranial hemorrhage, in addition to a number of other bleeding symptoms.
Limitations Screening assay: will not detect heterozygotes; quantitative assay: expensive, not readily available, and high ammonia levels may falsely decrease the result
Methodology A qualitative factor XIII assay evaluates clot stability in 5 M urea. The patient sample is clotted by adding calcium, and then after 30 minutes at 37degrees C the clot is placed in 5 M urea for 24 hours at room temperature. Clots formed by normal individuals remain stable in 5 M urea, while clots from factor XIII deficient patients dissolve in urea. This assay detects only the most severely affected homozygous patients with 1% to 2% factor XIII activity or less. A quantitative assay can detect heterozygous deficiencies (with values of ~50%), but this test is not yet readily available in most U.S. laboratories. In the quantitative 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 that is detected by a photometer.
Additional Information When fibrin initially forms, fibrin monomers are held together by weak noncovalent hydrogen bonds. Factor XIII is a transglutaminase that stabilizes fibrin clot by cross-linking fibrin monomers with covalent bonds. Calcium is required for its activation by thrombin as well as its activity. It also cross-links antiplasmin to fibrin, which protects the clot from fibrinolysis by plasmin.
A factor XIII polymorphism (Val34Leu), present in nearly half of the population, is suspected to protect against deep venous thrombosis and is somewhat more frequent in patients with intracranial hemorrhage.3,4 Factor XIII has a long half-life of 10-12 days. Therefore, treatment of factor XIII deficiency can be successful with infrequent doses of cryoprecipitate, fresh frozen plasma, or if available, factor XIII concentrates. Acquired decreases in factor XIII can arise in liver disease (decreased hepatic synthesis), disseminated intravascular coagulation (DIC), certain inflammatory diseases (Crohn, ulcerative colitis, Henoch-Schönlein purpura), leukemia, myelodysplasia, and myeloproliferative disorders. Over 25 cases of inhibitors (antibodies) against factor XIII have been reported.5,6
Footnotes
1. Andrew M, Paes B, and Johnston M, “Development of the Hemostatic System in the Neonate and Young Infant,”Am J Pediatr Hematol Oncol, 1990,12(1):95-104.
2. Seitz R, Duckert F, Lopaciuk S, et al, “ETRO Working Party on Factor XIII Questionnaire on Congenital Factor XIII Deficiency in Europe: Status and Perspectives,”Semin Thromb Hemost, 1996, 22(5):415-8.
3. Catto AJ, Kohler HP, Coore J, et al, “Association of a Common Polymorphism in the Factor XIII Gene With Venous Thrombosis,”Blood, 1999; 93(3):906-8.
4. Catto AJ, Kohler HP, Bannan S, et al, “Factor XIII Val 34 Leu: A Novel Association With Primary Intracerebral Hemorrhage,”Stroke, 1998, 29(4):813-6.
5. Standen G, Birchall J, Morse C, et al, “A Large Bruise,”Lancet, 1999, 353(9168):1934.
6. Lorand L, Velasco PT, Murthy P, et al, “Autoimmune Antibody in a Hemorrhagic Patient Interacts With Thrombin-Activated Factor XIII in a Unique Manner,”Blood, 1999, 93(3):909-17.
References
Egbring R, Kroniger A, and Seitz R, “Factor XIII Deficiency: Pathogenic Mechanisms and Clinical Significance,”Semin Thromb Hemost, 1996, 22(5):419-25.
Mikkola H and Palotie A, “Gene Defects in Congenital Factor XIII Deficiency,”Semin Thromb Hemost, 1996, 22(5):393-8.
