Download PDF
Semin Thromb Hemost 2009; 35(4): 426-438
DOI: 10.1055/s-0029-1225765
© Thieme Medical Publishers

Factor XIII Deficiency

Mehran Karimi1 , Zsuzsanna Bereczky2 , Nader Cohan1 , László Muszbek2
  • 1Hematology Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
  • 2Clinical Research Center and Thrombosis, Haemostasis and Vascular Biology Research Group of the Hungarian Academy of Sciences, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
Further Information

Publication History

Publication Date:
13 July 2009 (online)

    Permissions and Reprints

ABSTRACT

Factor XIII (FXIII) is a tetrameric zymogen (FXIII-A2B2) that is converted into an active transglutaminase (FXIIIa) by thrombin and Ca2+ in the terminal phase of the clotting cascade. By cross-linking fibrin chains and α2 plasmin inhibitor to fibrin, FXIIIa mechanically stabilizes fibrin and protects it from fibrinolysis. Severe deficiency of the potentially active A subunit (FXIII-A) is a rare but severe hemorrhagic diathesis. Delayed umbilical stump bleeding is characteristic, and subcutaneous, intramuscular, and intracranial bleeding occurs with a relatively high frequency in nonsupplemented patients. In addition, impaired wound healing and spontaneous abortion in women are also features of FXIII deficiency. The extremely rare B subunit deficiency results in milder bleeding symptoms. FXIII concentrate is now available for on-demand treatment and primary prophylaxis. A quantitative FXIII activity assay is recommended as a screening test for the diagnosis of FXIII deficiency. For classification purposes, FXIII-A2B2 antigen in the plasma is first determined, and if decreased, further measurement of the individual subunits is recommended in the plasma and FXIII-A in platelet lysate. Analytical aspects of FXIII activity and antigen assays are discussed in this article. There are no hot-spot mutations in the F13A1 and F13B genes, and the majority of causative mutations are missense/nonsense point mutations.

KEYWORDS

Bleeding diathesis - factor XIII deficiency - factor XIII measurements - pregnancy loss - wound healing

REFERENCES

  • 1 Muszbek L, Yee V C, Hevessy Z. Blood coagulation factor XIII: structure and function.  Thromb Res. 1999;  94 271-305
    CrossrefPubMedGoogle Scholar
  • 2 Greenberg C S, Sane D C, Lai T. Factor XIII and fibrin stabilization. In: Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ Hemostasis and Thrombosis. Philadelphia, PA; Lippincott Williams & Wilkins 2006: 317-334
    Google Scholar
  • 3 Muszbek L, Bagoly Z, Bereczky Z, Katona É. The involvement of blood coagulation factor XIII in fibrinolysis and thrombosis.  Cardiovasc Hematol Agents Med Chem. 2008;  6 190-205
    CrossrefPubMedGoogle Scholar
  • 4 Duckert F, Jung E, Shmerling D H. A hitherto undescribed congenital haemorrhagic diathesis probably due to fibrin stabilizing factor deficiency.  Thromb Diath Haemorrh. 1960;  5 179-186
    PubMedGoogle Scholar
  • 5 Seitz R, Duckert F, Lopaciuk S, Muszbek L, Rodeghiero F, Seligsohn U. Study Group . ETRO Working Party on Factor XIII questionnaire on congenital factor XIII deficiency in Europe: status and perspectives.  Semin Thromb Hemost. 1996;  22 415-418
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Inbal A, Lubetsky A, Krapp T et al.. Impaired wound healing in factor XIII deficient mice.  Thromb Haemost. 2005;  94 432-437
    PubMedGoogle Scholar
  • 7 Dardik R, Loscalzo J, Inbal A. Factor XIII (FXIII) and angiogenesis.  J Thromb Haemost. 2006;  4 19-25
    CrossrefPubMedGoogle Scholar
  • 8 Inbal A, Muszbek L. Coagulation factor deficiencies and pregnancy loss.  Semin Thromb Hemost. 2003;  29 171-174
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Muszbek L, Bagoly Z. Fibrin formation disorders and pregnancy loss.  Thromb Res. 2007;  119(Suppl 1) S69-S70
    CrossrefPubMedGoogle Scholar
  • 10 Koseki-Kuno S, Yamakawa M, Dickneite G, Ichinose A. Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages.  Blood. 2003;  102 4410-4412
    CrossrefPubMedGoogle Scholar
  • 11 Asahina T, Kobayashi T, Takeuchi K, Kanayama N. Congenital blood coagulation factor XIII deficiency and successful deliveries: a review of the literature.  Obstet Gynecol Surv. 2007;  62 255-260
    CrossrefPubMedGoogle Scholar
  • 12 Lauer P, Metzner H J, Zettlmeissl G et al.. Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit.  Thromb Haemost. 2002;  88 967-974
    PubMedGoogle Scholar
  • 13 Board P G, Losowsky M S, Miloszewski K JA. Factor XIII: inherited and acquired deficiency.  Blood Rev. 1993;  7 229-242
    CrossrefPubMedGoogle Scholar
  • 14 Anwar R, Miloszewski K J. Factor XIII deficiency.  Br J Haematol. 1999;  107 468-484
    CrossrefPubMedGoogle Scholar
  • 15 Ivaskevicius V, Seitz R, Kohler H P Study Group et al. International registry on factor XIII deficiency: a basis formed mostly on European data.  Thromb Haemost. 2007;  97 914-921
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Lak M, Peyvandi F, Ali Sharifian A, Karimi K, Mannucci P M. Pattern of symptoms in 93 Iranian patients with severe factor XIII deficiency.  J Thromb Haemost. 2003;  1 1852-1853
    CrossrefPubMedGoogle Scholar
  • 17 Anwar R, Minford A, Gallivan L, Trinh C H, Markham A F. Delayed umbilical bleeding—a presenting feature for factor XIII deficiency: clinical features, genetics, and management.  Pediatrics. 2002;  109 E32
    CrossrefPubMedGoogle Scholar
  • 18 Gerlach R, Raabe A, Zimmermann M, Siegemund A, Seifert V. Factor XIII deficiency and postoperative hemorrhage after neurosurgical procedures.  Surg Neurol. 2000;  54 260-264; discussion 264–265
    CrossrefPubMedGoogle Scholar
  • 19 Dardik R, Krapp T, Rosenthal E, Loscalzo J, Inbal A. Effect of FXIII on monocyte and fibroblast function.  Cell Physiol Biochem. 2007;  19 113-120
    CrossrefPubMedGoogle Scholar
  • 20 Nahrendorf M, Hu K, Frantz S et al.. Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial infarction.  Circulation. 2006;  113 1196-1202
    CrossrefPubMedGoogle Scholar
  • 21 Souri M, Koseki-Kuno S, Takeda N et al.. Male-specific cardiac pathologies in mice lacking either the A or B subunit of factor XIII.  Thromb Haemost. 2008;  99 401-408
    PubMedGoogle Scholar
  • 22 Nahrendorf M, Aikawa E, Figueiredo J L et al.. Transglutaminase activity in acute infarcts predicts healing outcome and left ventricular remodelling: implications for FXIII therapy and antithrombin use in myocardial infarction.  Eur Heart J. 2008;  29 445-454
    CrossrefPubMedGoogle Scholar
  • 23 Hashiguchi T, Saito M, Morishita E, Matsuda T, Ichinose A. Two genetic defects in a patient with complete deficiency of the b-subunit for coagulation factor XIII.  Blood. 1993;  82 145-150
    PubMedGoogle Scholar
  • 24 Koseki S, Souri M, Koga S et al.. Truncated mutant B subunit for factor XIII causes its deficiency due to impaired intracellular transportation.  Blood. 2001;  97 2667-2672
    CrossrefPubMedGoogle Scholar
  • 25 Izumi T, Hashiguchi T, Castaman G et al.. Type I factor XIII deficiency is caused by a genetic defect of its b subunit: insertion of triplet AAC in exon III leads to premature termination in the second Sushi domain.  Blood. 1996;  87 2769-2774
    PubMedGoogle Scholar
  • 26 Chanarin I. Laboratory Haematology. An Account of Laboratory Techniques. Edinburgh, Scotland; Churchill Livingstone 1989
    Google Scholar
  • 27 Francis J L. The detection and measurement of factor XIII activity: a review.  Med Lab Sci. 1980;  37 137-147
    PubMedGoogle Scholar
  • 28 Jakobsen E, Godal H C. Simple, semiquantitative test for partial factor XIII (FSF) deficiency.  Scand J Haematol. 1974;  12 366-368
    PubMedGoogle Scholar
  • 29 Jennings I, Kitchen S, Woods T AL, Preston F E. UK NEQAS . Problems relating to the laboratory diagnosis of factor XIII deficiency: a UK NEQAS study.  J Thromb Haemost. 2003;  1 2603-2608
    CrossrefPubMedGoogle Scholar
  • 30 Muszbek L, Polgár J, Fésüs L. Kinetic determination of blood coagulation Factor XIII in plasma.  Clin Chem. 1985;  31 35-40
    PubMedGoogle Scholar
  • 31 Fickenscher K, Aab A, Stüber W. A photometric assay for blood coagulation factor XIII.  Thromb Haemost. 1991;  65 535-540
    PubMedGoogle Scholar
  • 32 Kárpáti L, Penke B, Katona É, Balogh I, Vámosi G, Muszbek L. A modified, optimized kinetic photometric assay for the determination of blood coagulation factor XIII activity in plasma.  Clin Chem. 2000;  46 1946-1955
    PubMedGoogle Scholar
  • 33 Schmidt E, Schmidt F W. Glutamate dehydrogenase. In: Bergmeyer HU Methods of Enzymatic Analysis, Vol. III. Enzymes 1: Oxidoreductases, Transferases, 3rd ed. Weinheim, Germany; Verlag Chemie GmbH 1983: 216-227
    Google Scholar
  • 34 Recommendations of the German Society for Clinical Chemistry . Standardisation of methods for the estimation of enzyme activity in biological fluids.  Z Klin Chem Klin Biochem. 1970;  8 658-660
    PubMedGoogle Scholar
  • 35 da Fonseca-Wollheim F. Deamidation of glutamine by increased plasma γ-glutamyltransferase is a source of rapid ammonia formation in blood and plasma specimens.  Clin Chem. 1990;  36(8 Pt 1) 1479-1482
    PubMedGoogle Scholar
  • 36 Ajzner É, Muszbek L. Kinetic spectrophotometric factor XIII activity assays: the subtraction of plasma blank is not omissible [corrected].  J Thromb Haemost. 2004;  2 2075-2077
    CrossrefPubMedGoogle Scholar
  • 37 Lorand L, Urayama T, De Kiewiet J WC, Nossel H L. Diagnostic and genetic studies on fibrin-stabilizing factor with a new assay based on amine incorporation.  J Clin Invest. 1969;  48 1054-1064
    CrossrefPubMedGoogle Scholar
  • 38 Dvilansky A, Britten A FH, Loewy A G. Factor XIII assay by an isotope method. I. Factor XIII (transamidase) in plasma, serum, leucocytes, erythrocytes and platelets and evaluation of screening tests of clot solubility.  Br J Haematol. 1970;  18 399-410
    CrossrefPubMedGoogle Scholar
  • 39 Lorand L, Campbell-Wilkes L K, Cooperstein L. A filter paper assay for transamidating enzymes using radioactive amine substrates.  Anal Biochem. 1972;  50 623-631
    CrossrefPubMedGoogle Scholar
  • 40 Lee K N, Birckbichler P J, Patterson Jr M K. Colorimetric assay of blood coagulation factor XIII in plasma.  Clin Chem. 1988;  34 906-910
    PubMedGoogle Scholar
  • 41 Song Y C, Sheng D, Taubenfeld S M, Matsueda G R. A microtiter assay for factor XIII using fibrinogen and biotinylcadaverine as substrates.  Anal Biochem. 1994;  223 88-92
    CrossrefPubMedGoogle Scholar
  • 42 Wilmer M, Rudin K, Kolde H J et al.. Evaluation of a sensitive colorimetric FXIII incorporation assay. Effects of FXIII Val34Leu, plasma fibrinogen concentration and congenital FXIII deficiency.  Thromb Res. 2001;  102 81-91
    CrossrefPubMedGoogle Scholar
  • 43 Kohler H P, Ariëns R AS, Whitaker P, Grant P J. A common coding polymorphism in the FXIII A-subunit gene (FXIIIVal34Leu) affects cross-linking activity.  Thromb Haemost. 1998;  80 704
    PubMedGoogle Scholar
  • 44 Ariëns R A, Philippou H, Nagaswami C, Weisel J W, Lane D A, Grant P J. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure.  Blood. 2000;  96 988-995
    CrossrefPubMedGoogle Scholar
  • 45 Balogh I, Szôke G, Kárpáti L et al.. Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia.  Blood. 2000;  96 2479-2486
    PubMedGoogle Scholar
  • 46 Raut S, Merton R E, Rigsby P ISTH/SSC Factor XIII Subcommittee and the Factor XIII Standardization Working Party et al. A collaborative study to establish the 1st International Standard for factor XIII plasma.  J Thromb Haemost. 2007;  5 1923-1929
    CrossrefPubMedGoogle Scholar
  • 47 Katona É, Haramura G, Kárpáti L, Fachet J, Muszbek L. A simple, quick one-step ELISA assay for the determination of complex plasma factor XIII (A2B2).  Thromb Haemost. 2000;  83 268-273
    PubMedGoogle Scholar
  • 48 Katona E E, Ajzner É, Tóth K, Kárpáti L, Muszbek L. Enzyme-linked immunosorbent assay for the determination of blood coagulation factor XIII A-subunit in plasma and in cell lysates.  J Immunol Methods. 2001;  258 127-135
    CrossrefPubMedGoogle Scholar
  • 49 Peyvandi F, Tagliabue L, Menegatti M et al.. Phenotype-genotype characterization of 10 families with severe a subunit factor XIII deficiency.  Hum Mutat. 2004;  23 98
    PubMedGoogle Scholar
  • 50 Ichinose A. Physiopathology and regulation of factor XIII.  Thromb Haemost. 2001;  86 57-65
    PubMedGoogle Scholar
  • 51 Anwar R, Stewart A D, Miloszewski K J, Losowsky M S, Markham A F. Molecular basis of inherited factor XIII deficiency: identification of multiple mutations provides insights into protein function.  Br J Haematol. 1995;  91 728-735
    CrossrefPubMedGoogle Scholar
  • 52 Vysokovsky A, Saxena R, Landau M et al.. Seven novel mutations in the factor XIII A-subunit gene causing hereditary factor XIII deficiency in 10 unrelated families.  J Thromb Haemost. 2004;  2 1790-1797
    CrossrefPubMedGoogle Scholar
  • 53 Vysokovsky A, Rosenberg N, Dardik R, Seligsohn U, Inbal A. Effect of four missense mutations in the factor XIII A-subunit gene on protein stability: studies with recombinant proteins.  Blood Coagul Fibrinolysis. 2006;  17 125-130
    CrossrefPubMedGoogle Scholar
  • 54 Schroeder V, Meili E, Cung T, Schmutz P, Kohler H P. Characterisation of six novel A-subunit mutations leading to congenital factor XIII deficiency and molecular analysis of the first diagnosed patient with this rare bleeding disorder.  Thromb Haemost. 2006;  95 77-84
    PubMedGoogle Scholar
  • 55 Takahashi N, Tsukamoto H, Umeyama H, Castaman G, Rodeghiero F, Ichinose A. Molecular mechanisms of type II factor XIII deficiency: novel Gly562-Arg mutation and C-terminal truncation of the A subunit cause factor XIII deficiency as characterized in a mammalian expression system.  Blood. 1998;  91 2830-2838
    PubMedGoogle Scholar
  • 56 Mikkola H, Muszbek L, Laiho E et al.. Molecular mechanism of a mild phenotype in coagulation factor XIII (FXIII) deficiency: a splicing mutation permitting partial correct splicing of FXIII A-subunit mRNA.  Blood. 1997;  89 1279-1287
    PubMedGoogle Scholar
  • 57 Kangsadalampai S, Chelvanayagam G, Baker R T et al.. A novel Asn344 deletion in the core domain of coagulation factor XIII A subunit: its effects on protein structure and function.  Blood. 1998;  92 481-487
    PubMedGoogle Scholar
  • 58 Aslam S, Standen G R, Bruce L J, Gialeraki R, Mandalaki T. A novel insertion mutation (1286insC) in exon 9 of the factor XIII-A subunit gene.  Blood Coagul Fibrinolysis. 1998;  9 441-443
    CrossrefPubMedGoogle Scholar
  • 59 Izumi T, Nagaoka U, Saito T, Takamatsu J, Saito H, Ichinose A. Novel deletion and insertion mutations cause splicing defects, leading to severe reduction in mRNA levels of the A subunit in severe factor XIII deficiency.  Thromb Haemost. 1998;  79 479-485
    PubMedGoogle Scholar
  • 60 Niiya T, Osawa H, Bando S et al.. A complete deficiency of coagulation factor XIII A-subunit due to a novel compound heterozygote of Ser 413 Leu missense and an nt 389 (ins G) frameshift mutation.  Br J Haematol. 1999;  107 772-775
    CrossrefPubMedGoogle Scholar
  • 61 Anwar R, Miloszewski K J, Markham A F. Identification of a large deletion, spanning exons 4 to 11 of the human factor XIIIA gene, in a factor XIII-deficient family.  Blood. 1998;  91 149-153
    PubMedGoogle Scholar
  • 62 Mikkola H, Syrjälä M, Rasi V et al.. Deficiency in the A-subunit of coagulation factor XIII: two novel point mutations demonstrate different effects on transcript levels.  Blood. 1994;  84 517-525
    PubMedGoogle Scholar
  • 63 Kangsadalampai S, Coggan M, Caglayan S H, Aktuglu G, Board P G. Application of HUMF13A01 (AAAG)n STR polymorphism to the genetic diagnosis of coagulation factor XIII deficiency.  Thromb Haemost. 1996;  76 879-882
    PubMedGoogle Scholar
  • 64 Killick C J, Barton C J, Aslam S, Standen G. Prenatal diagnosis in factor XIII-A deficiency.  Arch Dis Child Fetal Neonatal Ed. 1999;  80 F238-F239
    CrossrefPubMedGoogle Scholar
  • 65 Peyvandi F, Jayandharan G, Chandy M et al.. Genetic diagnosis of haemophilia and other inherited bleeding disorders.  Haemophilia. 2006;  12(Suppl 3) 82-89
    PubMedGoogle Scholar
  • 66 Gootenberg J E. Factor concentrates for the treatment of factor XIII deficiency.  Curr Opin Hematol. 1998;  5 372-375
    PubMedGoogle Scholar
  • 67 Peyvandi F, Duga S, Akhavan S, Mannucci P M. Rare coagulation deficiencies.  Haemophilia. 2002;  8 308-321
    CrossrefPubMedGoogle Scholar
  • 68 Lovejoy A E, Reynolds T C, Visich J E et al.. Safety and pharmacokinetics of recombinant factor XIII-A2 administration in patients with congenital factor XIII deficiency.  Blood. 2006;  108 57-62
    CrossrefPubMedGoogle Scholar
  • 69 Egbring R, Seitz R, Gürten G V et al.. Bleeding complications in heterozygotes with congenital factor XIII deficiency. In: Mosesson MW, Amrani DI, Siebenlist KR, Diorio JP FIbrinogen 3. Biochemistry, Biological Functions, Gene Regulation and Expression. Amsterdam, The Netherlands; Elsevier 1988: 341-346
    Google Scholar
  • 70 Egbring R, Kröniger A, Seitz R. Factor XIII deficiency: pathogenic mechanisms and clinical significance.  Semin Thromb Hemost. 1996;  22 419-425
    Article in Thieme ConnectPubMedGoogle Scholar
  • 71 Castaman G. Prophylaxis of bleeding episodes and surgical interventions in patients with rare inherited coagulation disorders.  Blood Transfus. 2008;  6(Suppl 2) s39-s44
    PubMedGoogle Scholar
  • 72 Dreyfus M, Arnuti B, Beurrier P, Borg J Y, Clayssens S, Girardel J M. Safety and efficacy of Fibrogammin P for the treatment of patients with severe FXIII deficiency.  J Thromb Haemost. 2003;  (Suppl 1) P0299 (Abst)
    PubMedGoogle Scholar
  • 73 Nugent D J. Prophylaxis in rare coagulation disorders—factor XIII deficiency.  Thromb Res. 2006;  118(Suppl 1) S23-S28
    CrossrefPubMedGoogle Scholar
  • 74 Lorand L, Maldonado N, Fradera J, Atencio A C, Robertson B, Urayama T. Haemorrhagic syndrome of autoimmune origin with a specific inhibitor against fibrin stabilizing factor (factor XIII).  Br J Haematol. 1972;  23 17-27
    PubMedGoogle Scholar
  • 75 Lopaciuk S, Bykowska K, McDonagh J M et al.. Difference between type I autoimmune inhibitors of fibrin stabilization in two patients with severe hemorrhagic disorder.  J Clin Invest. 1978;  61 1196-1203
    CrossrefPubMedGoogle Scholar
  • 76 Lorand L, Velasco P T, Rinne J R, Amare M, Miller L K, Zucker M L. Autoimmune antibody (IgG Kansas) against the fibrin stabilizing factor (factor XIII) system.  Proc Natl Acad Sci U S A. 1988;  85 232-236
    CrossrefPubMedGoogle Scholar
  • 77 Fukue H, Anderson K, McPhedran P, Clyne L, McDonagh J. A unique factor XIII inhibitor to a fibrin-binding site on factor XIIIA.  Blood. 1992;  79 65-74
    PubMedGoogle Scholar
  • 78 Tosetto A, Rodeghiero F, Gatto E, Manotti C, Poli T. An acquired hemorrhagic disorder of fibrin crosslinking due to IgG antibodies to FXIII, successfully treated with FXIII replacement and cyclophosphamide.  Am J Hematol. 1995;  48 34-39
    CrossrefPubMedGoogle Scholar
  • 79 Nijenhuis A V, van Bergeijk L, Huijgens P C, Zweegman S. Acquired factor XIII deficiency due to an inhibitor: a case report and review of the literature.  Haematologica. 2004;  89 ECR14
    PubMedGoogle Scholar
  • 80 Ahmad F, Solymoss S, Poon M C, Berube C, Sullivan A K. Characterization of an acquired IgG inhibitor of coagulation factor XIII in a patient with systemic lupus erythematosus.  Br J Haematol. 1996;  93 700-703
    CrossrefPubMedGoogle Scholar
  • 81 Otis P T, Feinstein D I, Rapaport S I, Patch M J. An acquired inhibitor of fibrin stabilization associated with isoniazid therapy: clinical and biochemical observations.  Blood. 1974;  44 771-781
    PubMedGoogle Scholar
  • 82 McDevitt N B, McDonagh J, Taylor H L, Roberts F R. An acquired inhibitor to factor XIII.  Arch Intern Med. 1972;  130 772-777
    CrossrefPubMedGoogle Scholar
  • 83 Ajzner É, Schlammadinger Á, Kerényi A et al.. Severe bleeding complications caused by an autoantibody against the B subunit of plasma factor XIII: a novel form of acquired factor XIII deficiency.  Blood. 2009;  113 723-725
    CrossrefPubMedGoogle Scholar

Mehran KarimiM.D. 

Professor of Pediatric Hematology-Oncology, Hematology Research Center

Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

Email: Karimim@sums.ac.ir