Download PDF
Hamostaseologie 2014; 34(02): 160-166
DOI: 10.5482/HAMO-13-08-0046
Review
Schattauer GmbH

Coagulation factor XIII deficiency

Diagnosis, prevalence and management of inherited and acquired formsFaktor-XIII-MangelerkrankungenDiagnose, Vorkommen, Behandlung erblicher und erworbener Formen
A. Biswas
1   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany
,
V. Ivaskevicius
1   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany
,
A. Thomas
1   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany
,
J. Oldenburg
1   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany
› Author Affiliations
Further Information

Publication History

received: 23 August 2013

accepted in revised form: 28 January 2014

Publication Date:
28 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

The plasma circulating zymogenic coagulation factor XIII (FXIII) is a protransglutaminase, which upon activation by thrombin and calcium cross-links preformed fibrin clots/fibrinolytic inhibitors making them mechanically stable and less susceptible to fibrinolysis. The zymogenic plasma FXIII molecule is a heterotetramer composed of two catalytic FXIII-A and two protective FXIII-B subunits. Factor XIII deficiency resulting from inherited or acquired causes can result in pathological bleeding episodes. A diverse spectrum of mutations have been reported in the F13A1 and F13B genes which cause inherited severe FXIII deficiency. The inherited severe FXIII deficiency, which is a rare coagulation disorder with a prevalence of 1 in 4 million has been the prime focus of clinical and genetic investigations owing to the severity of the bleeding phenotype associated with it. Recently however, with a growing understanding into the pleiotropic roles of FXIII, the fairly frequent milder form of FXIII deficiency caused by heterozygous mutations has become one of the subjects of investigative research. The acquired form of FXIII deficiency is usually caused by generation of autoantibodies or hyperconsumption in other disease states such as disseminated intravascular coagulation. Here, we update the knowledge about the pathophysiology of factor XIII deficiency and its therapeutic options.

Zusammenfassung

Der plasmatische Blutgerinnungsfaktor XIII (FXIII) ist eine Protransglutaminase, die nach Aktivierung durch Thrombin und Kalzium nicht kovalent vernetzte Fibrindimere verknüpft und zusätzlich durch Einfügen von Fibrinolyse-Inhibitoren dem Blutgerinnsel eine bessere mechanische Stabilität sowie Schutz vor vorzeitiger Fibrinolyse verleiht. Plasma -FXIII ist ein Heterotetramer aus 2 katalytischen FXIII-A- und 2 schützenden FXIII-B-Untereinheiten. Ein angeborener oder erworbener Faktor-XIII-Mangel kann zu Blutungskomplikationen führen. Für einen schweren angeborenen FXIII-Mangel konnte ein breites Mutationspektrum im F13A1- und F13B-Gen ermittelt werden. Trotz der Seltenheit (Prävalenz: 1 in 4 Millionen) stand er vererbbare FXIII-Mangel wegen des Schweregrades an Blutungserscheinungen im Fokus klinischer und genetischer Studien. Mit steigendem Verständnis der pleiotrophen Rolle von FXIII gewinnt der mildere, durch heterozygote Mutationen verursachte FXIII-Mangel zunehmend an Bedeutung in der Forschung. Der erworbene FXIII-Mangel entsteht häufig durch Auto-antikörper oder tritt aufgrund der Verbrauchskoagulation bei anderen Grunder-krankungen (z. B. disseminierte intravasale Koagulopathie) auf.

Diese Übersicht soll aktuelles Wissen zur Pathophysiologie des Faktor-XIII-Mangels und den therapeutischen Optionen vermitteln.

Keywords

Factor XIII - transglutaminase - heterozygous deficiency - heterotetramer

Schlüsselwörter

Blutgerinnungsfaktor XIII - FXIII - Protrans -glutaminase - heterozygote Mutationen
 

  • References

  • 1 Lorand L, Losowsky MS, Miloszewski KJ. Human factor XIII: fibrin-stabilizing factor. Prog Hemost Thromb 1980; 05: 245-290.
    PubMedGoogle Scholar
  • 2 Schwartz ML, Pizzo SV, Hill RL, McKee PA. Human Factor XIII from plasma and platelets. Molecular weights, subunit structures, proteolytic activation, and cross-linking of fibrinogen and fibrin. J Biol Chem 1973; 248: 1395-1407.
    PubMedGoogle Scholar
  • 3 Muszbek L, Ariens RA, Ichinose A. Isth Ssc Subcommittee On Factor X. Factor XIII: recommended terms and abbreviations. J Thromb Haemost 2007; 05: 181-183.
    CrossrefPubMedGoogle Scholar
  • 4 Weiss MS, Metzner HJ, Hilgenfeld R. Two nonproline cis peptide bonds may be important for factor XIII function. FEBS Lett 1998; 423: 291-296.
    CrossrefPubMedGoogle Scholar
  • 5 Yee VC, Pedersen LC, Le Trong I. et al. Three-dimensional structure of a transglutaminase: human blood coagulation factor XIII. Proc Natl Acad Sci USA 1994; 91: 7296-7300.
    CrossrefPubMedGoogle Scholar
  • 6 Yee VC, Le Trong I, Bishop PD. et al. Structure and function studies of factor XIIIa by x-ray crystallography. Semin Thromb Hemost 1996; 22: 377-384.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Kloczko J, Wereszczynska U, Wojtukiewicz M. et al. Fibrin stabilization, factor XIII transamidase activity and subunits “A” and “B” concentration in plasma of patients with liver cirrhosis. Folia Haematol Int Mag Klin Morphol Blutforsch 1986; 113: 539-544.
    PubMedGoogle Scholar
  • 8 Bottenus RE, Ichinose A, Davie EW. Nucleotide sequence of the gene for the b subunit of human factor XIII. Biochemistry 1990; 29: 11195-11209.
    CrossrefPubMedGoogle Scholar
  • 9 Ichinose A, McMullen BA, Fujikawa K, Davie EW. Amino acid sequence of the b subunit of human factor XIII, a protein composed of ten repetitive segments. Biochemistry 1986; 25: 4633-4638.
    CrossrefPubMedGoogle Scholar
  • 10 Souri M, Kaetsu H, Ichinose A. Sushi domains in the B subunit of factor XIII responsible for oligomer assembly. Biochemistry 2008; 47: 8656-8664.
    CrossrefPubMedGoogle Scholar
  • 11 Souri M, Koseki-Kuno S, Takeda N. et al. Administration of factor XIII B subunit increased plasma factor XIII A subunit levels in factor XIII B subunit knock-out mice. Int J Hematol 2008; 87: 60-68.
    CrossrefPubMedGoogle Scholar
  • 12 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Komaromi I, Bagoly Z, Muszbek L. Factor XIII: novel structural and functional aspects. J Thromb Haemost 2011; 09: 9-20.
    CrossrefPubMedGoogle Scholar
  • 14 Kohler HP. Interaction between FXIII and fibrinogen. Blood 2013; 121: 1934.
    CrossrefPubMedGoogle Scholar
  • 15 Smith KA, Adamson PJ, Pease RJ. et al. Interactions between factor XIII and the alphaC region of fibrinogen. Blood 2011; 117: 3460-3468.
    CrossrefPubMedGoogle Scholar
  • 16 Smith KA, Pease RJ, Avery CA. et al. The activation peptide cleft exposed by thrombin cleavage of FXIII-A(2) contains a recognition site for the fibrinogen alpha chain. Blood 2013; 121: 2117-2126.
    CrossrefPubMedGoogle Scholar
  • 17 Doolittle RF, Hong S, Wilcox D. Evolution of the fibrinogen gamma’ chain: implications for the binding of factor XIII, thrombin and platelets. J Thromb Haemost 2009; 07: 1431-1433.
    CrossrefPubMedGoogle Scholar
  • 18 Fraser SR, Booth NA, Mutch NJ. The antifibrinolytic function of factor XIII is exclusively expressed through alpha(2)-antiplasmin cross-linking. Blood 2011; 117: 6371-6374.
    CrossrefPubMedGoogle Scholar
  • 19 Van Giezen JJ, Minkema J, Bouma BN, Jansen JW. Cross-linking of alpha 2-antiplasmin to fibrin is a key factor in regulating blood clot lysis: species differences. Blood Coagul Fibrinolysis 1993; 04: 869-875.
    CrossrefPubMedGoogle Scholar
  • 20 Richardson VR, Cordell P, Standeven KF, Carter AM. Substrates of Factor XIII-A: roles in thrombosis and wound healing. Clin Sci (Lond) 2013; 124: 123-137.
    CrossrefPubMedGoogle Scholar
  • 21 Ichinose A, Davie EW. Characterization of the gene for the a subunit of human factor XIII (plasma transglutaminase), a blood coagulation factor. Proc Natl Acad Sci USA 1988; 85: 5829-5833.
    CrossrefPubMedGoogle Scholar
  • 22 Ichinose A, Davie EW. Primary structure of human coagulation factor XIII. Adv Exp Med Biol 1988; 231: 15-27.
    PubMedGoogle Scholar
  • 23 Webb GC, Coggan M, Ichinose A, Board PG. Localization of the coagulation factor XIII B subunit gene (F13B) to chromosome bands 1q31–32.1 and restriction fragment length polymorphism at the locus. Hum Genet 1989; 81: 157-160.
    CrossrefPubMedGoogle Scholar
  • 24 Anwar R, Gallivan L, Edmonds SD, Markham AF. Genotype/phenotype correlations for coagulation factor XIII: specific normal polymorphisms are associated with high or low factor XIII specific activity. Blood 1999; 93: 897-905.
    PubMedGoogle Scholar
  • 25 De Lange M, Andrew T, Snieder H. et al. Joint linkage and association of six single-nucleotide polymorphisms in the factor XIII-A subunit gene point to V34L as the main functional locus. Arterioscler Thromb Vasc Biol 2006; 26: 1914-1919.
    CrossrefPubMedGoogle Scholar
  • 26 Biswas A, Ivaskevicius V, Seitz R. et al. An update of the mutation profile of factor 13 A and B genes. Blood Rev 2011; 25: 193-204.
    CrossrefPubMedGoogle Scholar
  • 27 Ariens RA, Philippou H, Nagaswami C. et al. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 2000; 96: 988-995.
    PubMedGoogle Scholar
  • 28 Mikkola H, Syrjala 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
  • 29 Li B, Zhang L, Yin Y. et al. Lack of evidence for association between factor XIII-A Val34Leu polymorphism and ischemic stroke: a meta-analysis of 8,800 subjects. Thromb Res 2012; 130: 654-660.
    CrossrefPubMedGoogle Scholar
  • 30 Kohler HP, Schroder V. Role of coagulation factor XIII in cardioand cerebrovascular diseases. Hämostaseologie 2002; 22: 53-58.
    PubMedGoogle Scholar
  • 31 Wang W, Huang L, Ma Q. et al. Homozygous intronic mutation leading to inefficient transcription combined with a novel frameshift mutation in F13A1 gene causes Factor XIII deficiency. J Hum Genet 2011; 56: 460-463.
    CrossrefPubMedGoogle Scholar
  • 32 Ivaskevicius V, Biswas A, Thomas A. et al. A common F13A1 intron 1 variant IVS1+12(A) is associated with mild Factor XIII deficiency in Caucasian population. Ann Hematol 2013; 92: 975-979.
    CrossrefPubMedGoogle Scholar
  • 33 Board PG. Genetic polymorphism of the B subunit of human coagulation factor XIII. Am J Hum Genet 1980; 32: 348-353.
    PubMedGoogle Scholar
  • 34 Board PG. Genetic heterogeneity of the B subunit of coagulation factor XIII: resolution of type 2. Ann Hum Genet 1984; 48: 223-228.
    CrossrefPubMedGoogle Scholar
  • 35 Kamboh MI, Ferrell RE. Genetic studies of low abundance human plasma proteins. II. Population genetics of coagulation factor XIIIB. Am J Hum Genet 1986; 39: 817-825.
    PubMedGoogle Scholar
  • 36 Iwata H, Kitano T, Umetsu K. et al. Distinct C-terminus of the B subunit of factor XIII in a population-associated major phenotype: the first case of complete allele-specific alternative splicing products in the coagulation and fibrinolytic systems. J Thromb Haemost 2009; 07: 1084-1091.
    CrossrefPubMedGoogle Scholar
  • 37 Nakamura S, Ohue O, Abe K. Genetic polymorphism of coagulation factor XIII B subunit in the Japanese population: description of three new rare alleles. Hum Genet 1986; 73: 183-185.
    CrossrefPubMedGoogle Scholar
  • 38 Komanasin N, Catto AJ, Futers TS. et al. A novel polymorphism in the factor XIII B-subunit (His95Arg): relationship to subunit dissociation and venous thrombosis. J Thromb Haemost 2005; 03: 2487-2496.
    CrossrefPubMedGoogle Scholar
  • 39 Ryan AW, Hughes DA, Tang K. et al. Natural selection and the molecular basis of electrophoretic variation at the coagulation F13B locus. Eur J Hum Genet 2009; 17: 219-227.
    CrossrefPubMedGoogle Scholar
  • 40 Duckert F, Jung E, Shmerling DH. A hitherto undescribed congenital haemorrhagic diathesis probably due to fibrin stabilizing factor deficiency. Thromb Diath Haemorrh 1960; 05: 179-186.
    PubMedGoogle Scholar
  • 41 Muszbek L, Bereczky Z, Bagoly Z. et al. Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev 2011; 91: 931-972.
    CrossrefPubMedGoogle Scholar
  • 42 Ivaskevicius V, Seitz R, Kohler HP. 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
  • 43 Lak M, Peyvandi F, Ali ASharifian. et al. Pattern of symptoms in 93 Iranian patients with severe factor XIII deficiency. J Thromb Haemost 2003; 01: 1852-1853.
    CrossrefPubMedGoogle Scholar
  • 44 Miloszewski KJA, Losowsky MS. Fibrin stabilisation and factor XIII deficiency. In Francis L. ed Fibrinogen, Fibrin Stabilisation and Fibrinolysis. Chichester: Ellis Horwood; 1988: 175-202.
    Google Scholar
  • 45 Ivaskevicius V, van der Ven K, van der Ven H. et al. Successful in vitro fertilization under FXIII concentrate substitution in female with inherited FXIII-A subunit deficiency. Hämostaseologie. 2008 28. P-02C-06.
    PubMedGoogle Scholar
  • 46 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: 415-418.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Egbring R, Seitz R, Gürten GV. et al. Bleeding complications in heterozygotes with congenital Factor XIII deficiency. In Fibrinogen 3. Biochemistry, biological functions, gene regulation and expression. Mosesson MW. (Hrsg) et al. Amsterdam: Elsevier; 1988: 341-346.
    Google Scholar
  • 48 Ivaskevicius V, Biswas A, Bevans C. et al. Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function. Haematologica 2010; 95: 956-962.
    CrossrefPubMedGoogle Scholar
  • 49 Ivaskevicius V, Biswas A, Loreth R. et al. Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: results of a genetic study in 14 families with factor XIII B deficiency. Haemophilia 2010; 16: 675-682.
    CrossrefPubMedGoogle Scholar
  • 50 Peyvandi F, Di Michele D, Bolton-Maggs PH. et al. Classification of rare bleeding disorders (RBDs) based on the association between coagulant factor activity and clinical bleeding severity. J Thromb Haemost 2012; 10: 1938-1943.
    CrossrefPubMedGoogle Scholar
  • 51 Ichinose A. Hemorrhagic acquired factor XIII (13) deficiency and acquired hemorrhaphilia 13 revisited. Semin Thromb Hemost 2011; 37: 382-388.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Lorenz R, Born P, Classen M. Substitution of factor XIII concentrate in treatment refractory ulcerative colitis. A prospective pilot study. Med Klin (Munich) 1994; 89: 534-537.
    PubMedGoogle Scholar
  • 53 Luo YY, Zhang GS. Acquired factor XIII inhibitor: clinical features, treatment, fibrin structure and epitope determination. Haemophilia 2011; 17: 393-398.
    CrossrefPubMedGoogle Scholar
  • 54 Lorand L. Fibrinoligase: the fibrin-stabilizing factor system of blood plasma. Ann NY Acad Sci 1972; 202: 6-30.
    CrossrefPubMedGoogle Scholar
  • 55 Lorand L. Hemorrhagic disorders of fibrin stabilization. In Ogston D, Bennett B. eds Hemostasis: Biochemistry, Physiology and Pathology. London: John Wiley & Sons Ltd; 1977: 405-423.
    Google Scholar
  • 56 Fukue H, Anderson K, McPhedran P. et al. A unique factor XIII inhibitor to a fibrin-binding site on factor XIIIA. Blood 1992; 79: 65-74.
    PubMedGoogle Scholar
  • 57 Lorand L, Velasco PT, Hill JM. et al. Intracranial hemorrhage in systemic lupus erythematosus associated with an autoantibody against actor XIII. Thromb Haemost 2002; 88: 919-923.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 58 Ajzner E, Schlammadinger A, Kerenyi 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
  • 59 Wada H, Souri M, Matsumoto R. et al. Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency. Thromb Haemost 2013; 109: 661-668.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 Ichinose A, Souri M. Japanese collaborative research group on “Acquired haemorrha-philia due to factor Xd. As many as 12 cases with haemorrhagic acquired factor XIII deficiency due to its inhibitors were recently found in Japan. Thromb Haemost 2011; 105: 925-927.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 61 Ichinose A, Souri M. Reduced difference of á(2)plasmin inhibitor levels between plasma and serum in patients with severe factor XIII deficiency, including autoimmune haemorrhaphilia due to anti-factor XIII antibodies. Int J Hematol 2012; 95: 47-50.
    CrossrefPubMedGoogle Scholar
  • 62 Franchini M, Frattini F, Crestani S, Bonfanti C. Acquired FXIII inhibitors: a systematic review. J Thromb Thrombolysis 2013; 36: 109-114.
    CrossrefPubMedGoogle Scholar
  • 63 Kessel R, Hu C, Shore-Lesserson L. et al. A child with acquired factor XIII deficiency: case report and literature review. Haemophilia 2013; 19: 814-826.
    CrossrefPubMedGoogle Scholar
  • 64 Miesbach W. Rituximab in the treatment of factor XIII inhibitor possibly caused by Ciprofloxacin. Thromb Haemost 2005; 93: 1001-1003.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 65 Anwar R, Miloszewski KJ. Factor XIII deficiency. Br J Haematol 1999; 107: 468-484.
    CrossrefPubMedGoogle Scholar
  • 66 Katona E, Penzes K, Molnar E, Muszbek L. Measurement of factor XIII activity in plasma. Clin Chem Lab Med 2012; 50: 119402.
    PubMedGoogle Scholar
  • 67 Ariens RA, Kohler HP, Mansfield MW, Grant PJ. Subunit antigen and activity levels of blood coagulation factor XIII in healthy individuals. Relation to sex, age, smoking, and hypertension. Arterioscler Thromb Vasc Biol 1999; 19: 2012-2016.
    CrossrefPubMedGoogle Scholar
  • 68 Karpati L, Penke B, Katona E. et al. A modified, optimized kinetic photometric assay for the determination of blood coagulation factor XIII activity in plasma. Clin Chem 2000; 46: 1946-1955.
    CrossrefPubMedGoogle Scholar
  • 69 Kohler HP, Ichinose A, Seitz R, Ariens RA, Muszbek L, Factor X. et al. Diagnosis and classification of factor XIII deficiencies. J Thromb Haemost 2011; 09: 1404-1406.
    CrossrefPubMedGoogle Scholar
  • 70 Fadoo Z, Merchant Q, Rehman KA. New developments in the management of congenital factor XIII deficiency. J Blood Med 2013; 04: 65-73.
    PubMedGoogle Scholar
  • 71 Inbal A, Oldenburg J, Carcao M. et al. Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency. Blood 2012; 119: 5111-5117.
    CrossrefPubMedGoogle Scholar
  • 72 Lovejoy AE, Reynolds TC, Visich JE. 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
  • 73 Williams M, Will A, Stenmo C. et al. Pharmacokinetics of recombinant factor XIII in young children with congenital factor XIII deficiency and comparison with older patients. Haemophilia 2013; 20: 99-105.
    PubMedGoogle Scholar
  • 74 Bishop PD, Morton KM. Safety, pharmacokinetics, and immunogenicity of single-doserFXIII administration to healthy volunteers. J Thromb Haemost 2005; 03: 922-928.
    CrossrefPubMedGoogle Scholar
  • 75 Dirkmann D, Gorlinger K, Gisbertz C. et al. Factor XIII and tranexamic acid but not recombinant factor VIIa attenuate tissue plasminogen activator-induced hyperfibrinolysis in human whole blood. Anesth Analg 2012; 114: 1182-1188.
    CrossrefPubMedGoogle Scholar