Targeted deletion of murine coagulation factor XII gene-a model for contact phase activation in vivo

Hans-Ulrich Pauer; Thomas Renné; Bernhard Hemmerlein; Tobias Legler; Saskia Fritzlar; Ibrahim Adham; Werner Müller-Esterl; Guenter Emons; Ulrich Sancken; Wolfgang Engel; Peter Burfeind

doi:10.1160/TH04-04-0250

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(03): 503-508
DOI: 10.1160/TH04-04-0250

Theme Issue Article

Schattauer GmbH

Targeted deletion of murine coagulation factor XII gene-a model for contact phase activation in vivo

Hans-Ulrich Pauer

¹Department of Gynecology and Obstetrics, Medical School, University of Goettingen, Germany

,

Thomas Renné

²Junior Group at the Institute of Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, Germany

,

Bernhard Hemmerlein

³Department of Pathology, Medical School, University of Goettingen, Germany

,

Tobias Legler

⁴Department of Transfusion Medicine, Medical School, University of Goettingen, Germany

,

Saskia Fritzlar

⁵Institute of Human Genetics, University of Goettingen, Germany

,

Ibrahim Adham

⁵Institute of Human Genetics, University of Goettingen, Germany

,

Werner Müller-Esterl

⁶Institute of Biochemistry II, Medical School, University of Frankfurt, Germany

,

Guenter Emons

¹Department of Gynecology and Obstetrics, Medical School, University of Goettingen, Germany

,

Ulrich Sancken

⁵Institute of Human Genetics, University of Goettingen, Germany

,

Wolfgang Engel

⁵Institute of Human Genetics, University of Goettingen, Germany

,

Peter Burfeind

⁵Institute of Human Genetics, University of Goettingen, Germany

› Author Affiliations

Abstract

Summary

To analyze the biological role of factor XII (FXII, Hageman Factor) in vivo, we generated mice deficient for FXII using a gene targeting approach on two distinct genetic backgrounds, i.e. mixed C57Bl/6J X 129X1/SvJ and inbred 129X1/SvJ. Homozygous FXII knockout (FXII-/-) mice showed no FXII plasma activity and had a markedly prolonged activated partial thromboplastin time (aPTT). In contrast, coagulation factors XI, VIII, IX, X,VII,V, II and fibrinogen did not differ between FXII-/- mice and their wild-type littermates. Heterozygous matings segregated according to the Mendelian inheritance indicating that FXII deficiency does not increase fetal loss. Furthermore, matings of FXII-/- males and FXII-/females resulted in normal litter sizes demonstrating that total FXII deficiency in FXII-/females does not affect pregnancy outcome. Also, gross and histological anatomy of FXII-/mice was indistinguishable from that of their wild-type littermates on both genetic backgrounds. Thus it appears that deficiency of murine FXII does not cause thrombophilia or impaired fibrinolysis in vivo. These results indicate that FXII deficiency does not affect hemostasis in vivo and we anticipate that the FXII-/mice will be helpful to elucidate the biological role(s) of FXII in health and disease.

Keywords

Coagulation - factor XII - gene targeting

Full Text

References

References
1 Citarella F, Fedele G, Roem D. et al. The second exon-encoded factor XII region is involved in the interaction of factor XII with factor XI and does not contribute to the binding site for negatively charged surfaces. Blood 1998; 92: 4198-206.
2 Renne T, Gailani D, Meijers JC. et al. Characterization of the H-kininogen-binding site on factor XI: a comparison of factor XI and plasma prekallikrein. J Biol Chem 2002; 277: 4892-9.
3 Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997; 90: 3819-43.
4 Mahdi F, Madar ZS, Figueroa CD. et al. Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 on endothelial cell membranes. Blood 2002; 99: 3585-96.
5 Zeerleder S, Schloesser M, Redondo M. et al. Reevaluation of the incidence of thromboembolic complications in congenital factor XII deficiency—a study on 73 subjects from 14 Swiss families. Thromb Haemost 1999; 82: 1240-6.
6 Girolami A, Simioni P, Scarano L. et al. Symptomatic combined homozygous factor XII deficiency and heterozygous factor V Leiden. J Thromb Thrombolysis 2000; 09: 271-5.
7 Halbmayer WM, Haushofer A, Schon R. et al. The prevalence of moderate and severe FXII (Hageman factor) deficiency among the normal population: evaluation of the incidence of FXII deficiency among 300 healthy blood donors. Thromb Haemost 1994; 71: 68-72.
8 Kohler HP, Futers TS, Grant PJ. FXII (46C–>T) polymorphism and in vivo generation of FXII activity – gene frequencies and relationship in patients with coronary artery disease. Thromb Haemost 1999; 81: 745-7.
9 Kohler HP, Carter AM, Stickland MH. et al. Levels of activated FXII in survivors of myocardial infarction – association with circulating risk factors and extent of coronary artery disease. Thromb Haemost 1998; 79: 14-18.
10 Schloesser M, Zeerleder S, Lutze G. et al. Mutations in the human factor XII gene. Blood 1997; 90: 3967-77.
11 Gris JC, Ripart-Neveu S, Maugard C. et al. Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) Study. Thromb Haemost 1997; 77: 1096-103.
12 Matsuura T, Kobayashi T, Asahina T. et al. Is factor XII deficiency related to recurrent miscarriage?. Semin Thromb Hemost 2001; 27: 115-20.
13 Ogasawara MS, Aoki K, Katano K. et al. Factor XII but not protein C, protein S, antithrombin III, or factor XIII is a predictor of recurrent miscarriage. Fertil Steril 2001; 75: 916-9.
14 Pauer HU, Burfeind P, Köstering H. et al. Factor XII deficiency is strongly associated with primary recurrent abortions. Fertil Steril 2003; 80: 590-4.
15 Rosahl TW, Spillane D, Missler M. et al. Essential functions of synapsins I and II in synaptic vesicle regulation. Nature 1995; 375: 488-93.
16 Wurst W, Joyner AL. Production of targeted embryonic stem cell clones. In: Gene targeting: a practical approach. Joyner AL. IRL Press; Oxford: 1993: 33-61.
17 Furie B, Furie BC. The molecular basis of blood coagulation. Cell 1988; 53: 505-18.
18 Braat EA, Dooijewaard G, Rijken DC. Fibrinolytic properties of activated FXII. Eur J Biochem 1999; 263: 904-11.
19 Cui J, Eitzman DT, Westrick RJ. et al. Spontaneous thrombosis in mice carrying the factor V Leiden mutation. Blood 2000; 96: 4222-6.
20 Ong K, Horsfall W, Conway EM. et al. Early embryonic expression of murine coagulation system components. Thromb Haemost 2000; 84: 1023-30.
21 Soria JM, Almasy L, Souto JC. et al. A quantitative-trait locus in the human factor XII gene influences both plasma factor XII levels and susceptibility to thrombotic disease. Am J Hum Genet 2002; 70: 567-74.
22 Gailani D, Lasky NM, Broze Jr GJ. A murine model of factor XI deficiency. Blood Coagul Fibrinolysis 1997; 08: 134-44.
23 Jiang Y, Doolittle RF. The evolution of vertebrate blood coagulation as viewed from a comparison of puffer fish and sea squirt genomes. Proc Natl Acad Sci 2003; 100: 7527-32.