Plasma levels of bradykinin are suppressed in factor XII-deficient mice

Summary

A genetically-transmissible factor (F) XII-inactivated allele has been produced in mice by targeted replacement of exons 3–8 of the FXII gene with the neomycin resistance gene. Interbreeding of these mice provided offspring homozygous for two inactivated FXII alleles (FXII^−/−). Male and female FXII-deficient mice bred normally in all genotypic combinations of the heterozygous and homozygous states, and the offspring survived to adulthood, suggesting that a total FXII deficiency does not affect embryonic development and survival. Neither FXII transcripts nor FXII antigen was found in various tissues of adult FXII^−/−mice. No obvious unchallenged coagulopathies were present in FXII^−/−adult mice, despite greatly prolonged activated partial thromboplastin times in this mouse cohort. FXII^−/−mice were then used to assess the in vivo importance of the plasma FXII/prekallikrein/kininogen pathway in provision of resting plasma bradykinin (BK) levels and in generation of plasma BK stimulated by contact with an artificial surface, using a new and greatly improved plasma BK assay developed during these studies. It was found that approximately 50% of resting BK, and all of the contact-stimulated plasma BK, was provided by this FXII-dependent pathway, without a requirement for FXI. These results provide clear evidence that surface-stimulated BK production, in mice, is dependent on the activation of FXII.

Keywords

FXII deficiency - targeted gene replacement - bradykinin generation - vasoactivity - reproduction - intrinsic coagulation pathway - contact activation

• References

• 1 Kluft C. et al. Role of the contact system in fibrinolysis. Sem Thromb Haemost 1987; 13: 50-68.
• 2 Cool DE. et al. Characterization of human blood coagulation factor XII cDNA. Prediction of the primary structure of factor XII and the tertiary structure of beta-factor XIIa. J Biol Chem 1985; 260: 13666-76.
• 3 Kaplan AP, Austen KF. A prealbumin activator of prekallikrein. II. Derivation of activators of prekallikrein from active Hageman factor by digestion with plasmin. J Exp Med 1971; 133: 696-712.
• 4 Forbes CD. et al. Inhibition of activated Hageman factor and activated plasma thromboplastin antecedent by purified serum C1 inactivator. J Lab Clin Med 1970; 76: 809-15.
• 5 Hojima Y. et al. Hageman factor fragment inhibitor in corn seeds: purification and characterization. Thromb Res 1980; 20: 149-62.
• 6 Cool DE, MacGillivray RT. Characterization of the human blood coagulation factor XII gene. Intron/exon gene organization and analysis of the 5’-flanking region. J Biol Chem 1987; 262: 13662-73.
• 7 Royle NJ. et al. Structural gene encoding human factor XII is located at 5q33-qter. Somat Cell Mol Genet 1988; 14: 217-21.
• 8 Ratnoff OD, Colopy JE. A familial hemorrhagic trait associated with a clot-promoting fraction of plasma. J Clin Invest 1955; 34: 602.
• 9 Bernardi F. et al. A frequent factor XII gene mutation in Hageman trait. Hum Genet 1988; 80: 149-51.
• 10 Miyata T. et al. Coagulation factor XII (Hageman factor) Washington DC: inactive factor XIIa results from Cys-571-->Ser substitution. Proc Natl Acad Sci USA 1989; 86: 8319-22.
• 11 Hovinga JK. et al. Coagulation factor XII Locarno: the functional defect is caused by the amino acid substitution Arg 353-->Pro leading to loss of a kallikrein cleavage site. Blood 1994; 84: 1173-81.
• 12 Schloesser M. et al. Mutations in the human factor XII gene. Blood 1997; 90: 3967-77.
• 13 Kondo S. et al. Factor XII Tenri, a novel cross-reacting material negative factor XII deficiency, occurs through a proteasome-mediated degradation. Blood 1999; 93: 4300-8.
• 14 Kanaji T. et al. Identification and characterization of two novel mutations (Q421 K and R123P) in congenital factor XII deficiency. Thromb Haemost 2001; 86: 1409-15.
• 15 Kempter B. et al. The genetics of factor XII deficiency. Beitr Infusionsther 1993; 31: 174-8.
• 16 Schloesser M. et al. The novel acceptor splice site mutation 11396(G-->A) in the factor XII gene causes a truncated transcript in cross-reacting material negative patients. Hum Mol Genet 1995; 04: 1235-7.
• 17 Kanaji T. et al. A common genetic polymorphism (46C to T substitution) in the 5’-untranslated region of the coagulation factor XII gene is associated with low translation efficiency and decrease in plasma factor XII level. Blood 1998; 91: 2010-4.
• 18 Hofferbert S. et al. A novel 5’-upstream mutation in the factor XII gene is associated witha TaqI restriction site in an Alu repeat in factor XII-deficient patients. Hum Genet 1996; 97: 838-41.
• 19 Turi DC, Peerschke EI. Sensitivity of three activated partial thromboplastin time reagents to coagulation factor deficiencies. Am J Clin Pathol 1986; 85: 43-9.
• 20 Pauer HU. et al. Targeted deletion of murine coagulation factor XII gene-a model for contact phase activation in vivo . Thromb Haemost 2004; 92: 503-8.
• 21 McDonough RJ, Nelson CL. Clinical implications of factor XII deficiency. Oral Surg Oral Med Oral Pathol 1989; 68: 264-6.
• 22 Dyerberg J, Stoffersen E. Recurrent thrombosis in a patient with factor XII deficiency. Acta Haematol 1980; 63: 278-82.
• 23 Lammle B. et al. Thromboembolism and bleeding tendency in congenital factor XII deficiency--a study on 74 subjects from 14 Swiss families. Thromb Haemost 1991; 65: 117-21.
• 24 Halbmayer WM. et al. The prevalence of factor XII deficiency in 103 orally anticoagulated outpatients suffering from recurrent venous and/or arterial thromboembolism. Thromb Haemost 1992; 68: 285-90.
• 25 Castaman G. et al. Thrombosis in patients with heterozygous and homozygous factor XII deficiency is not explained by the associated presence of factor V Leiden. Thromb Haemost 1996; 76: 275.
• 26 Zito F. et al. Association of the factor XII 46C-->T polymorphism with risk of coronary heart disease (CHD) in the WOSCOPS study. Atherosclerosis 2002; 165: 153-8.
• 27 von Kanel R. et al. Factor XII clotting activity and antigen levels in patients with thromboembolic disease. Blood Coagul Fibrinolysis 1992; 03: 555-61.
• 28 Zeerleder S. 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.
• 29 Oguchi S. et al. Genotype distribution of the 46C/T polymorphism of coagulation factor XII in the Japanese population: absence of its association with ischemic cerebrovascular disease. Thromb Haemost 2000; 83: 178-9.
• 30 Renne T. et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202: 271-81.
• 31 Davie EW. et al. The role of serine proteases in the blood coagulation cascade. Adv Enzymol Relat Areas Mol Biol 1979; 48: 277-318.
• 32 Cochrane CG. et al. Activation of Hageman factor in solid and fluid phases. A critical role of kallikrein. J Exp Med 1973; 138: 1564-83.
• 33 Braat EAM, Rijken DC. The inactivation of singlechain urokinase-type plasminogen activator by thrombin may provide an additional explanation for the antifibrinolytic effect of factor XI. Thromb Haemost 1999; 81: 657.
• 34 Ichinose A. et al. The activation of pro-urokinase by plasma kallikrein and its inactivation by thrombin. J Biol Chem 1986; 261: 3486-9.
• 35 Schousboe I. Factor XIIa activation of plasminogen is enhanced by contact activating surfaces and Zn2+. Blood Coagul Fibrinolysis 1997; 08: 97-104.
• 36 Yamamoto T. et al. The Hageman factor-dependent system in the vascular permeability reaction. Biochim Biophys Acta 1988; 966: 196-206.
• 37 Ghebrehiwet B. et al. Mechanisms of activation of the classical pathway of complement by Hageman factor fragment. J Clin Invest 1983; 71: 1450-6.
• 38 Toossi Z. et al. Induction of expression of monocyte interleukin1 by Hageman factor (factor XII). Proc Natl Acad Sci USA 1992; 89: 11969-72.
• 39 Jones DW. et al. Antibodies to factor XII: a possible predictive marker for recurrent foetal loss. Immunobiology 2003; 207: 43-6.
• 40 Braulke I. et al. Factor XII (Hageman) deficiency in women with habitual abortion: new subpopulation of recurrent aborters?. Fertil Steril 1993; 59: 98-101.
• 41 Yamada H. et al. Factor XII deficiency in women with recurrent miscarriage. Gynecol Obstet Invest 2000; 49: 80-3.
• 42 Iinuma Y. et al. Coagulation factor XII activity, but not an associated common genetic polymorphism (46C/T),is linked to recurrent miscarriage. Fertil Steril 2002; 77: 353-6.
• 43 Matsuura T. et al. Is factor XII deficiency related to recurrent miscarriage?. Semin Thromb Hemost 2001; 27: 115-20.
• 44 Girolami A. et al. Symptomatic combined homozygous factor XII deficiency and heterozygous factor V Leiden. J Thromb Thrombolysis 2000; 09: 271-5.
• 45 Matsushita T. et al. A female hemophilia A combined with hereditary coagulation factor XII deficiency: a case report. AmJ Hematol 1992; 39: 137-41.
• 46 Maurin N. et al. Thrombophilia witha combination of antithrombin III and factor XII deficiency. Thromb Haemost 1988; 60: 127.
• 47 Zeitler P. et al. Combination of von Willebrand disease type 1 and partial factor XII deficiency in children: clinical evidence for a diminished bleeding tendency. Acta Paediat 1999; 88: 1233-7.
• 48 Bux-Gewehr I. et al. Combined von Willebrand factor deficiency and factor XII deficiency. Thromb Haemost 2000; 84: 514-5.
• 49 Rosen E. et al. Mice lacking Factor VII develop normally but suffer fatal perinatal bleeding. Nature 1997; 390: 290-4.
• 50 Jalbert LR. et al. Inactivation of the gene for anticoagulant Protein C causes lethal perinatal consumptive coagulopathy in mice. J Clin Invest 1998; 102: 1481-8.
• 51 Ploplis VA. et al. A total fibrinogen deficiency is compatible with the development of pulmonary fibrosis in mice. Am J Pathol 2000; 157: 703-8.
• 52 Mullen CA. et al. Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: a negative selection system. Proc Natl Acad Sci USA 1992; 89: 33-7.
• 53 Ogasawara MS. 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.
• 54 Pauer HU. et al. Factor XII deficiency is strongly associated with primary recurrent abortions. Fertility and Sterility 2003; 80: 590-4.
• 55 Yamada H. et al. Recurrent pregnancy loss: etiology of thrombophilia. Semin Thromb Hemost 2001; 27: 121-9.
• 56 Shariat-Madar Z. et al. Overexpression of prolylcarboxypeptidase enhances plasma prekallikrein activation on Chinese hamster ovary cells. Am J Physiol Heart Circ Physiol 2005; 289: H2697-H703.
• 57 Joseph K. et al. Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII. Proc Natl Acad Sci USA 2002; 99: 896-900.
• 58 Joseph K, Kaplan AP. Formation of bradykinin: a major contributor to the innate inflammatory response. Adv Immunol 2005; 86: 159-208.