Download PDF
Thromb Haemost 2002; 88(06): 967-974
DOI: 10.1055/s-0037-1613342
Involvement of Thrombin Receptors in the Subject-dependent Variability in Ca2+ Signal Generation
Schattauer GmbH

Targeted Inactivation of the Mouse Locus Encoding Coagulation Factor XIII-A: Hemostatic Abnormalities in Mutant Mice and Characterization of the Coagulation Deficit

Peter Lauer
1   Aventis Behring GmbH, Marburg, Germany
,
Hubert J. Metzner
1   Aventis Behring GmbH, Marburg, Germany
,
Gerd Zettlmeißl
3   Chiron-Behring, Marburg, Germany
,
Meng Li
2   Centre for Genome Research, University of Edinburgh, King’s Buildings, Edinburgh, UK
,
Austin G. Smith
2   Centre for Genome Research, University of Edinburgh, King’s Buildings, Edinburgh, UK
,
Richard Lathe
2   Centre for Genome Research, University of Edinburgh, King’s Buildings, Edinburgh, UK
,
Gerhard Dickneite
1   Aventis Behring GmbH, Marburg, Germany
› Author Affiliations
Further Information

Publication History

Received 21 January 2002

Accepted after revision 28 August 2002

Publication Date:
09 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Blood coagulation factor XIII (FXIII) promotes cross-linking of fibrin during blood coagulation; impaired clot stabilization in human genetic deficiency is associated with marked pathologies of major clinical impact, including bleeding symptoms and deficient wound healing. To investigate the role of FXIII we employed homologous recombination to generate a targeted deletion of the inferred exon 7 of the FXIII-A gene. FXIII transglutaminase activity in plasma was reduced to about 50% in mice heterozygous for the mutant allele, and was abolished in homozygous null mice. Plasma fibrin γ-dimerization was also indetectable in the homozygous deficient animals, confirming the absence of activatable FXIII. Homozygous mutant mice were fertile, although reproduction was impaired. Bleeding episodes, hematothorax, hematoperitoneum and subcutaneous hemorrhage in mutant mice were associated with reduced survival. Arrest of tail-tip bleeding in FXIII-A deficient mice was markedly and significantly delayed; replacement of mutant mice with human plasma FXIII (Fibrogammin® P) restored bleeding time to within the normal range. Thrombelastography (TEG) experiments demonstrated impaired clot stabilization in FXIII-A mutant mice, replacement with human FXIII led to dose-dependent TEG normalization. The mutant mice thus reiterate some key features of the human genetic disorder: they will be valuable in assessing the role of FXIII in other associated pathologies and the development of new therapies.

Keywords

Inactivation of FXIII gene - bleeding disorder - thrombelastography - factor XIII substitution - fibrin γ-dimerisation
 

  • References

  • 1 McDonagh J. Structure and Function of Factor XIII. Hemostasis and Thrombosis. In: Basic Principles and Clinical Practice. Colman RW, Hirsh J, Marder VJ, Salzman EW. eds. Philadelphia: J.B. Lippincott; 1994: 301-13.
    Google Scholar
  • 2 Ichinose A. Physiopathology and regulation of factor XIII. Thromb Haemost 2001; 86: 57-65.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Muszbek L, Yee VC, Hevessy Z. Blood coagulation factor XIII: Structure and function. Thromb Res 1999; 94: 271-305.
    CrossrefPubMedGoogle Scholar
  • 4 Curtis CG, Brown KL, Credo RB, Domanik RA, Gray A, Stenberg P, Lorand L. Calcium-depended unmasking of active center cysteine during activation of fibrin stabilizing factor. Biochem 1974; 13: 3774-80.
    CrossrefPubMedGoogle Scholar
  • 5 Grundmann U, Amann E, Zettlmeissl G, Kupper HA. Characterization of cDNA coding for human factor XIIIa. Proc Natl Acad Sci USA 1986; 83: 8024-8.
    CrossrefPubMedGoogle Scholar
  • 6 Ichinose A, Hendrickson LE, Fujikawa K, Davie EW. Amino acid sequence of the a subunit of human factor XIII. Biochemistry 1986; 25: 6900-6.
    CrossrefPubMedGoogle Scholar
  • 7 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: 5829-33.
    CrossrefPubMedGoogle Scholar
  • 8 Sakata Y, Aoki N. Cross-linking of a2-plasmin inhibitor to fibrin by fibrinstabilizing factor. J Clin Invest 1980; 65: 290-7.
    CrossrefPubMedGoogle Scholar
  • 9 Tamaki T, Aoki N. Cross-linking of a2-plasmin inhibitor to fibrin catalyzed by activated fibrin-stabilizing factor. J Biol Chem 1982; 257: 14767-72.
    PubMedGoogle Scholar
  • 10 Sakata Y, Aoki N. Significance of cross-linking of a2-plasmin inhibitor to fibrin in inhibition of fibrinolysis and in hemostasis. J Clin Invest 1982; 69: 536-42.
    CrossrefPubMedGoogle Scholar
  • 11 Mosher DF, Schad PE. Cross-linking of fibronectin to collagen by blood coagulation factor XIIIa. J Clin Invest 1979; 64: 781-7.
    CrossrefPubMedGoogle Scholar
  • 12 Ueyama M, Urayama T. The role of factor XIII in fibroblast proliferation. Jpn J Exp Med 1978; 48: 135-42.
    PubMedGoogle Scholar
  • 13 Knox P, Crooks S, Rimmer CS. Role of fibronectin in the migration of fibroblasts into plasma clots. J Cell Biol 1986; 102: 2318-23.
    CrossrefPubMedGoogle Scholar
  • 14 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: 1395-407.
    PubMedGoogle Scholar
  • 15 Muszbek L, Adany R, Szegedi G, Polgar J, Kavai M. Factor XIII of blood coagulation in human monocytes. Thromb Res 1985; 37: 401-10.
    CrossrefPubMedGoogle Scholar
  • 16 Henriksson P, Becker S, Lynch G, McDonagh J. Identification of intracellular factor XIII in human monocytes and macrophages. J Clin Invest 1985; 76: 528-34.
    CrossrefPubMedGoogle Scholar
  • 17 Wilhem B, Meinhardt A, Seitz J. Transglutaminase: purification and activity assays. J Chromatogr B Biomed 1996; 20 684 (1-2): 163-77.
    PubMedGoogle Scholar
  • 18 Ichinose A, Izumi T, Hashiguchi T. The normal and abnormal genes of the a and b subunits in coagulation factor XIII. Semin Thromb Haemost 1996; 22: 385-91.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Mikkola H, Palotie A. Gene defects in congenital factor XIII deficiency. Semin Thromb Haemost 1996; 22: 393-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Board PG, Webb GC, McKee J, Ichinose A. Localization of the coagulation factor XIII A subunit gene (F13A) to chromosome bands 6p24 – p25. Cytogenet Cell Genet 1988; 48: 25-7.
    CrossrefPubMedGoogle Scholar
  • 21 Duckert F. Documentation of the plasma factor XIII deficiency in man. Ann NY Acad Sci 1972; 202: 190-9.
    CrossrefPubMedGoogle Scholar
  • 22 Seitz R, Duckert F, Lopaciuk S, Muszbek L, Rodeghiero F, Seligsohn U. ETRO working party on factor XIII questionnaire on congenital factor XIII deficiency in Europe: status and perspectives. Study Group. Semin Thromb Hemost 1996; 22: 415-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 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
  • 24 Hooper ML, Hardy K, Handyside A, Hunter S, Monk M. HPRT-deficient (Lesch-Nyhan) mouse embryos derived from germline colonization by cultured cells. Nature 1987; 326: 292-5.
    CrossrefPubMedGoogle Scholar
  • 25 Smith A G. Culture and differentiation of embryonic stem cells. J Tiss Cult Meth 1991; 13: 89-94.
    CrossrefPubMedGoogle Scholar
  • 26 Ure J, Fiering S, Smith AG. A rapid and efficient method for freezing and recovering clones of embryonic stem cells. Trends Genet 1992; 08: 6.
    PubMedGoogle Scholar
  • 27 Schwartzberg PJ, Goff SP, Robertson EJ. Germ-line transmission of a c-abl mutation produced by targeted gene disruption in ES cells. Science 1989; 246: 799-803.
    CrossrefPubMedGoogle Scholar
  • 28 HE Karges. Blood Coagulation Factor XIII: Determination by Clot Stability Assays. In: Bergmeyer: Methods of Enzymatic Analysis, Volume V. Bergmeyer J, Grassl M. eds. Verlag Chemie: Weinheim; 1984: 400-10.
    Google Scholar
  • 29 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-5.
    CrossrefPubMedGoogle Scholar
  • 30 Burnette WN. “Western blotting”: Electrophoretic transfer of proteins from sodium dodectyl-polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radionated protein A. Anal Biochem 1981; 112: 195-203.
    CrossrefPubMedGoogle Scholar
  • 31 Lóránd L, Losowsky MS, Miloszewski KJ. Human factor XIII: fibrinstabilizing factor. Prog Hemost Thromb 1980; 05: 245-90.
    PubMedGoogle Scholar
  • 32 Miloszewski KJA, Losowsky MS. Fibrin Stabilization and Factor XIII Deficiency. In: Francis JL. ed. Fibrinogen, Fibrin Stabilisation and Fibrinolysis. Chichester: Ellis Horwood; 1988: 175-202.
    Google Scholar
  • 33 Ádány R, Glukhova MA, Kabakov AY, Muszbek L. Characterization of connective tissue cells containing factor XIII subunit a. J Clin Pathol 1988; 41: 49-56.
    CrossrefPubMedGoogle Scholar
  • 34 Ádány R, Muszbek L. Immunohistochemical detection of factor XIII subunit a in hystiocytes of human uterus. Histochemistry 1989; 91: 169-74.
    CrossrefPubMedGoogle Scholar
  • 35 Muszbek L, Adany R, Kavai M, Boda Z, Lopaciuk S. Monocytes of patients congenitally deficient in plasma factor XIII lack factor XIII subunit a antigen and transglutaminase activity. Thromb Haemost 1998; Apr 8; 59 (02) 231-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Rodeghiero F, Castaman GC, Di Bona E, Ruggeri M, Dini E. Successful pregnancy in a woman with congenital factor XIII deficiency treated with substitutive therapy. Blut 1987; 55: 45-8.
    CrossrefPubMedGoogle Scholar
  • 37 Snyder RO, Miao C, Meuse L, Tubb J, Donahue BA, Lin HF, Stafford DW, Patel S, Thompson AR, Nichols T, Read MS, Bellinger DA, Brinkhous KM, Kay MA. Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors. Nat Med Jan 1999; 05: 64-70.
    PubMedGoogle Scholar
  • 38 Balagué C, Zhou J, Dai Y, Alemany R, Josephs SF, Andreason G, Hariharan M, Sethi E, Prokopenko E, Hsing-yi J, Jan HY, Lou YC, Hubert-Leslie D, Ruiz L, Zhang WW. Sustained high-level expression of full-length human factor VIII and restoration of clotting activity in hemophilic mice using a minimal adenovirus vector. Blood 2000; 95: 820-8.
    PubMedGoogle Scholar
  • 39 Hellerer O, Bruckner WL, Frey KW, Westerburg KW, Klessinger U. Fracture healing under factor XIII medication. Arch Orthop Trauma Surg 1980; 97: 157-9.
    CrossrefPubMedGoogle Scholar
  • 40 Marktl W, Rundas B. The effect of factor XIII on wound granulation in the rat. Thromb Diath Haemorrh 1974; 32: 578-81.
    PubMedGoogle Scholar
  • 41 Claes L, Burri C, Gergross H. Bone healing stimulated by plasma FXIII. Acta Orthop Scand 1985; 56: 57-62.
    CrossrefPubMedGoogle Scholar
  • 42 Isogai N, Ueda Y, Kurozumi N, Kamiishi H. Wound healing at the site of microvascular anastomosis: Fibrin-stabilizing factor XIII administration and its effects. Microsurgery 1990; 11: 40-6.
    CrossrefPubMedGoogle Scholar
  • 43 Ogawa T, Morioka Y, Inoue T, Takano M, Tsuda S. Involvement of blood coagulation factor XIII in burn healing in the carbon tetrachloride-induced hepatic injury model in rats. Inflamm Res 1995; 44: 264-8.
    CrossrefPubMedGoogle Scholar
  • 44 Gierhake FW, Papastavrou N, Zimmermann K, Bohn H, Schwick HG. Prophylaxis of postoperative disturbances of wound healing with factor XIII substitution (result of a double-blind study). Dtsch Med Wochenschr 1974; 99: 1004-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Mishima Y, Nagao F, Ishibiki K, Matsuda M, Nakamura N. Factor XIII in the treatment of postoperative refractory wound-healing disorders. Results of a controlled study. Chirurg 1984; 55: 803-8.
    PubMedGoogle Scholar
  • 46 Ueyama M, Urayama T. The role of factor XIII in fibroblast proliferation. Japan J Exp Med 1978; 48: 135-42.
    PubMedGoogle Scholar