Subscribe to RSS
DOI: 10.1055/s-0037-1622012
Der Faktor XIII des Menschen: eine Übersicht
Factor XIII in man: a reviewPublication History
Publication Date:
29 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00034925/200201/lookinside/thumbnails/10-1055-s-0037-1622012_de-1.jpg)
Zusammenfassung
Der durch Kalziumionen und Thrombin aktivierte Faktor XIII (FXIIIa) vernetzt Fibrin und erhöht dadurch die Stabilität des Fibringerinnsels. Durch Vernetzung weiterer Proteine wie α2-Plasmininhibitor, Fibronektin und Kollagen erfüllt FXIIIa hämostatische und reparative Funktionen. Der Val34Leu-Polymorphismus ist für die Athero- und Thrombogenese von Bedeutung. FXIII-Mangel wird autosomal rezessiv vererbt. Das Kardinalsymptom ist die prolongierte Blutung aus der Nabelschnur in den ersten Tagen nach der Geburt. Die Verdachtsdiagnose wird durch die Löslichkeitsprobe in Harnstoff (5 mol/l) bestätigt und mit einem Inkorporationstest oder immunelektrophoretisch weiter differenziert. Die Blutungsneigung beginnt typischerweise bei Aktivitäten >1-2% des Referenzwerts. Gerade bei Heterozygoten treten aber auch schwere Blutungen bei Aktivitäten um 30-50% auf. Die zum Teil lebensbedrohliche Blutungstendenz lässt sich mit Faktor-XIII-Konzentraten behandeln. Erworbener FXIII-Mangel kann bei verschiedenen internistischen Erkrankungen und nach Operation auftreten. Die klinische Relevanz ist noch nicht vollständig geklärt. Als Bestandteil von Fibrinkleber wird der Faktor XIII auch lokal angewandt.
Summary
Activated by calcium and thrombin, factor XIII (FXIIIa) cross-links fibrin, thus increasing the stability of the fibrin clot. Furthermore, the hemostatic and reparative function of factor XIIIa is mediated by cross-linking other proteins like α2-plasmin-inhibitor, fibronectin, and collagen. The FXIII Val34Leu polymorphism plays a role in athero- and thrombogenesis. FXIII deficiency is an autosomal recessive disorder. The most common symptom is the bleeding tendency of the umbilical cord some days after birth. The diagnosis is confirmed by a solubility clot test in urea (5 mol/l) and then differentiated with an incorporation assay and immunoelectrophoresis. The bleeding tendency typically becomes obvious when FXIIIa activity is <1-2%. Severe bleeding episodes, however, may even occur with FXIIIa activities of 30-50%, especially in heterozygous persons. The sometimes life-threatening bleeding tendency of the inherited FXIII deficiency can be treated with FXIII concentrates. Acquired FXIII deficiency occurs in several internal diseases and after major surgery. The clinical significance is not completely clear. Moreover, FXIII is applied locally as a component of fibrin glues.
-
Literatur
- 1 Adany R. Antal M. Three different cell types scan synthesize factor XIII subunit A in the human liver. Thromb Haemost 1996; 76: 74-9.
- 2 Adany R. Intracellular factor XIII: cellular distribution of factor XIII subunit a in humans. Semin Thromb Hemost 1996; 22: 399-408.
- 3 Anwar R. Stewart AD. Miloszewski K. et al Molecular basis of inherited factor XIII deficiency: identification of multiple mutations provides insights into protein function. Br J Haematol 1995; 91: 728-35.
- 4 Anwar R. Gallivan L. Miloszewski KJ. et al Splicing and missense mutations in the human FXIIIA gene causing FXIII deficiency: effects of these mutations on FXIIIA RNA processing and protein structure. Br J Haematol 1998; 103: 425-8.
- 5 Anwar R. Miloszewski KJA. Markham AF. 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: 149-53.
- 6 Anwar R. Miloszewski KJA. Markham FA. New splicing mutations in the human factor XIIIA gene, each producing multiple mutant transcripts of varying abundance. Thromb Haemost 1998; 79: 1151-6.
- 7 Anwar R. Gallivan L. Edmonds SD. et al Genotype/phenotype correlations for coagulation factor XIII: specific normal polymor phismsare associated with high or low factor XIII specific activity. Blood 1999; 93: 897-905.
- 8 Aslam S. Poon MC. Yee VC. et al Factor XIIIACalgary: a candidate missense mutation (Leu667Pro) in the beta barrel 2 domain of the factor XIIIA subunit. Br J Haematol 1995; 91: 452-7.
- 9 Aslam S. Bowen DJ. Mandalaki T. et al Factor XIIIA subunit deficiency due to a homozygous 13-base pair deletion in exon 3 of the A subunit gene. Am J Hematol 1996; 53: 77-80.
- 10 Aslam S. Yee VC. Narayanan S. et al Structural analysis of a missense mutation (Val414Phe) in the catalytic core domain of the factor XIIIA subunit. Br J Haematol 1997; 98: 346-52.
- 11 Aslam S. Standen GR. Bruce LJ. et al A novel insertion mutation (1286insC) in exon 9 of the factor XIII-A sub-unit gene. Blood Coagul Fibrinolysis 1998; 9: 441-3.
- 12 Bernstein CN. Shanahan F. Factor XIII: is it a factor in Crohn‛s disease?. Gastroenterology 1993; 105: 605-7.
- 13 Board PG. Coggan M. Molecular genetic analysis of factor XIII deficiency. In: McDonagh J. Seitz R. Egbring R. (Hrsg). Factor XIII. Second international conference, Marburg 1991 Stuttgart: Schattauer; 1993: 146-51.
- 14 Board PG. Losowsky MS. Miloszewski JA. Factor XIII: Inherited and acquired deficiency. Blood Rev 1993; 7: 229-42.
- 15 Catto AJ. Kohler HP. Bannan S. et al Factor XIII Val 34 Leu: a novel association with primary intracerebral hemorrhage. Stroke 1998; 29: 813-6.
- 16 Catto AJ. Kohler HP. Coore J. et al Association of a common polymorphism in the factor XIII gene with venous thrombosis. Blood 1999; 93: 906-8.
- 17 Chiarantini E. Valanzano R. Liotta AA. et al Persistence of hemostatic alterations in patients affected by Crohn‛s disease after bowel surgery. Thromb Res 1997; 87: 539-46.
- 18 Dempfle CE. Hochreuter K. Helmchen G. et al Microtiter assay for factor XIII activity. In: McDonagh J. Seitz R. Egbring R. (Hrsg). Faktor XIII. Second international conference, Marburg 1991 Stuttgart: Schattauer; 1993: 112-21.
- 19 Dempfle CE. Magez J. Röckel A. et al Acquired factor XIII-deficiency and substitution of factor XIII in exacerbated ulcerative colitis and Crohn‛s disease. In: McDonagh J. Seitz R. Egbring R. (Hrsg). Faktor XIII. Second international conference, Marburg 1991 Stuttgart: Schattauer; 1993: 181-92.
- 20 Devine DV. Bishop PD. Platelet- associated factor XIII in platelet activation, adhesion, andclot stabilization. Semin Thromb Hemost 1996; 22: 409-13.
- 21 Duckert F. Jung E. Shmerling DH. A hitherto undescribed congenital haemorrhagic diathesis probably due to fibrin stabilizing factor deficiency. Thromb Diath Haemorrh 1960; 5: 179-86.
- 22 Dufner G. Der Faktor XIII des Menschen. Inauguraldissertation; Universität Basel: 1998
- 23 Egbring R. Kailing A. Kehl HG. et al Disorders with severe acquired factor XIII deficiency; lack of synthesis or increased consumption (DIC). Efficacy of factor XIII replacement in bleeding complications. In: McDonagh J. Seitz R. Egbring R. (Hrsg). Faktor XIII. Second international conference, Marburg 1991 Stuttgart, New York: Schattauer; 1993: 216-40.
- 24 Egbring R. Kröninger A. Seitz R. Factor XIII deficiency: pathogenic mechanisms and clinical significance. Semin Thromb Hemost 1996; 22: 419-25.
- 25 Elbaz E. Poirier O. Canaple S. et al on behalf of the GENIC investigators The association between the Val34Leu polymorphism in the factor XIII gene and brain infarction. Blood 2000; 95: 586-91.
- 26 Fickenscher K. Berichrom FXIII: test procedure and the biochemical basis of this kinetic assay. In McDonagh J. Seitz R. Egbring R. (Hrsg). Faktor XIII. Second international conference, Marburg 1991 Stuttgart: Schattauer; 1993: S. 122-7.
- 27 Fox BA. Yee VC. Pedersen LC. et al Identification of the calcium binding site and a novel ytterbium site in blood coagulation factor XIII by x-ray crystallography. J Biol Chem 1999; 274 (08) 4917-23.
- 28 Franco RF. Pazin-Filho A. Tavella MH. et al Factor XIII val34leu and the risk of myocardial infarction. Haematologica 2000; 85: 67-71.
- 29 Franco RF. Reitsma PH. Lourenço D. et al Factor XIII Val34Leu is a genetic factor involved in the aetiology of venous thrombosis. Thromb Haemost 1999; 81: 676-9.
- 30 Gibran NS. Nickoloff BJ. Holbrook KA. Ontogeny and characterization of factor XIIIa+ cells in developing human skin. Anat Embryol(Berl) 1999; 193: 35-41.
- 31 Girolami A. Burul A. Fabris F. et al A tentative classification of factor XIII deficiency in two groups. Acta Haematol 1977; 58: 318-20.
- 32 Gödje O. Haushofer M. Lamm P. et al The effect of factor XIII on bleeding in coronary surgery. Thorac Cardiovasc Surg 1998; 46: 263-7.
- 33 Gootenberg JE. Factor concentrates for thetreatment of factor XIII deficiency. Curr Opin Hematol 1998; 5: 372-5.
- 34 Hashiguchi T. Saito M. Morishita E. et al Two genetic defects in a patient with complete deficiencyof the b subunit for factor XIII. Blood 1993; 82: 145-50.
- 35 Hashiguchi T. Ichinose A. Molecular and cellularbasis of deficiency of the b subunit for factor XIII secondary to a Cys430-Phe mutation in the seventh sushi domain. J Clin Invest 1995; 95: 1002-8.
- 36 Heliö T. Wartiovaara U. Turunen UM. et al Arg506Gln factor V mutation and Val34Leu factor XIII polymorphism in Finnish patients with inflammatory bowel disease. Scan J Gastroenterol 1999; 34: 170-4.
- 37 Henry M. Morange PE. Canavy I. et al Rapid detection of factor XIII Val34Leu by allele specific PCR. Thromb Haemost 1999; 81: 463.
- 38 Ichinose A. McMullen BA. Fujikawa K. et al Amino acid sequence of the b subunit ofhuman factor XIII, a protein composed of tenrepetitive segments. Biochemistry 1986; 25: 4633-8.
- 39 Ichinose A. Kaetsu H. Molecular approach to the structure-function relationship of human coagulation factor XIII. Methods Enzymol 1993; 222: 36-51.
- 40 Ichinose A. Tsukamoto H. Izumi T. et al Arg260-Cys mutation in severe factor XIII deficiency: conformational change of the A subunitis predicted by molecular modelling and mechanics. Br J Haematol 1998; 101: 264-72.
- 41 Inbal A. Yee VC. Kornbrot N. et al Factor XIII deficiency due to a Leu660Pro mutation in the factor XIII subunit-a gene in three unrelated Palestinian Arab families. Thromb Haemost 1997; 77: 1062-7.
- 42 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: 2769-74.
- 43 Izumi T. Nagaoka U. Saito T. et al 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: 479-85.
- 44 Kangsadalampai S. Farges-Berth A. Caglayan SH. et al New mutations causing the premature termination of translation in the A subunit gene of coagulation factor XIII. Thromb Haemost 1996; 76: 139-42.
- 45 Kangsadalampai S. Chelvanayagam G. Baker RT. 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: 481-7.
- 46 Kangsadalampai S. Chelvanayagam G. Baker R. et al Identification and characterisation of two missense mutations causing factor XIIIA deficiency. Br J Haematol 1999; 104: 37-43.
- 47 Karges H. Metzner HJ. Therapeutic factor XIII preparations and perspectives for recombinant factor XIII. Semin Thromb Hemost 1996; 22: 427-36.
- 48 Kohler HP. Grant PJ. The role of factor XIIIVal34Leu in cardiovascular disease. QJM 1999; 92: 67-72.
- 49 Kohler HP. Stickland MH. Ossel-Gerning N. etal Association of a common polymorphism in the factor XIII gene with myocardial infarction. Thromb Haemost 1998; 79: 8-13.
- 50 Kradin RL. Lynch GW. Kurnick JT. et al Factor XIII A is synthesized and expressed on the surface of U937 cells and alveolar macrophages. Blood 1987; 69: 778-85.
- 51 Laurell CB. Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies. Analyt Biochem 1966; 15: 45-52.
- 52 Lorand L. Velasco PT. Murthy SNP. et al Autoimmune antibody in a hemorrhagic patient interacts with thrombin-activated factor XIII in a unique manner. Blood 1999; 93: 909-17.
- 53 Lorenz R. Olbert P. Born P. Factor XIII in chronic inflammatory bowel diseases. Semin Thromb Hemost 1996; 225: 451-5.
- 54 Mary A. Achyuthan KE. Greenberg CS. b-chains prevent the proteolytic inactivation of the a-chains of plasma factor XIII. Biochim Biophys Acta 1988; 966: 328-35.
- 55 McDonagh J. Structure and function of factor XIII. In Colman RW. Hirsh J. Marder VJ. Salzman EW. (Hrsg). Hemostasis and Thrombosis: Basic principles and clinical practice. Philadelphia: Lippincott; 1994: 301-13.
- 56 McDonagh J. Biochemistry of factor XIII and fibrin stabilization. Blood Coagul Fibrinolysis 1995; 6: 334.
- 57 McDonagh J. Fukue H. Determinants of substratespecificity for factor XIII. Semin Thromb Hemost 1996; 22: 369-76.
- 58 Mikkola H. Yee VC. Syrjälä M. et al Four novel mutations in deficiency of coagulation factor XIII: consequences to expression and structure of the A-subunit. Blood 1996; 87: 141-51.
- 59 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: 1279-87.
- 60 Mikkola H. Muszbek L. Haramura G. et al Molecular mechanisms of mutation in factor XIII A-subunit deficiency: in vitro expression in COS-cells demonstrates intracellular degradation of the mutant proteins. Thromb Haemost 1997; 77: 1068-72.
- 61 Miloszewski KJA. Losowsky MS. Safety of long-term prophylaxis in inherited factor XIII deficiency. In McDonagh J. Seitz R. Egbring R. (Hrsg). Factor XIII. Second international conference, Marburg 1991 Stuttgart, New York: Schattauer; 1993: 155-60.
- 62 Muszbek L. Yee VC. Hevessy Z. Blood coagulation factor XIII: Structure and function. Thromb Res 1999; 94: 271-305.
- 63 Nussbaum M. Morse BS. Plasma fibrin stabilizing factor activity in various diseases. Blood 1964; 23: 669-77.
- 64 Poon MC. Russell JA. Low S. et al Hemopoietic origin of factor XIII A subunits in platelets, monocytes, and plasma. Evidence from bone marrow transplantation studies. J Clin Invest 1989; 84: 787-92.
- 65 Radosevich M. Goubran HA. Burnouf T. Fibrin sealant: scientific rationale, production methods, properties, and current clinical use. Vox Sang 1997; 72: 133-43.
- 66 Romanic AM. Arleth AJ. Willette RN. et al Factor XIIIa cross-links lipoprotein (a) with fibrinogen and is present in human atherosclerotic lesions. Circ Res 1998; 83: 264-9.
- 67 Saito M. Asakura H. Yoshida T. et al A familial factor XIII subunit B deficiency. Br J Haematol 1990; 74: 290-4.
- 68 Saito H. Fukushima R. Kobori O. et al Marked and prolonged depression of factor XIII after esophageal resection. Jap J Surg 1992; 22: 201-6.
- 69 Samokhin GP. Lorand L. Contact with the N termini in the central E domain enhances the reactivities of the distal D domains of fibrin to factor XIIIa. J Biol Chem 1995; 270: 21827-32.
- 70 Schwartz ML. Pizzo SV. Hill RL. et al Human factor XIII from plasma and platelets: Molecular weights, subunit structure, proteolytic activation and cross-linking of fibrinogen and fibrin. J Biol Chem 1973; 248: 1395-407.
- 71 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: 415-8.
- 72 Siebenlist KR. Mosesson MW. Progressive cross-linking of fibrin γ chains increases resistance to fibrinolysis. J Biol Chem 1994; 269: 28414-9.
- 73 Siebenlist KR. Meh DA. Mosesson MW. Plasma factor XIII binds specifically to fibrinogen molecules containing gamma chains. Biochemistry 1996; 35: 10448-53.
- 74 Souri M. Izumi T. Higashi Y. et al A foundereffect is proposed for factor XIII B subunitdeficiency caused by the insertion of tripletAAC in exon III encoding the second Sushidomain. Thromb Haemost 1998; 80: 211-3.
- 75 Suzuki K. Henke J. Iwata M. et al Novel polymorphisms and haplotypes in the human coagulation factor XIIIA-subunit gene. Hum Genet 1996; 98: 393-5.
- 76 Takahashi N. Tsukamoto H. Umeyama H. et al 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: 2830-8.
- 77 Vreken P. Niessen RWLM. Peters M. et al A point mutation in an invariant splice acceptor site results in a decreased mRNA level in a patient with severe coagulation factor XIII sub-unit A deficiency. Thromb Haemost 1995; 74: 584-9.
- 78 Wartiovaara U. Perola M. Mikkola H. et al Associationof FXIII Val34Leu with decrease drisk of myocardial infarction in Finnish males. Atherosclerosis 1999; 142: 295-300.
- 79 Wölpl A. Lattke H. Board PG. et al Coagulation factor XIII A and B subunits in bone marrow and liver transplantation. Transplantation 1987; 43: 151-3.
- 80 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: 377-84.
- 81 Yoshida H. Kamiya A. A quicker preparation method for autologous fibrin glue. Biol Pharm Bull 1998; 21: 1367-70.