Download PDF
CC BY 4.0 · TH Open 2019; 03(03): e263-e272
DOI: 10.1055/s-0039-1695709
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Anti-Factor XII Autoantibodies in Patients with Recurrent Pregnancy Loss Recognize the Second Epidermal Growth Factor–Like Domain

Yoshihiro Sato
1   Laboratory for Recurrent Pregnancy Loss, Sugi Women's Clinic, Yokohama, Japan
2   Yoshihiro Women's Clinic, Tokyo, Japan
,
Toshitaka Sugi
1   Laboratory for Recurrent Pregnancy Loss, Sugi Women's Clinic, Yokohama, Japan
,
Rie Sakai
1   Laboratory for Recurrent Pregnancy Loss, Sugi Women's Clinic, Yokohama, Japan
› Author Affiliations Funding This research was supported in part by the Project for Baby and Infant Research of Health and Development to Adolescent and Young Adult from Japan Agency for Medical Research and Development, AMED.
Further Information

Publication History

06 May 2019

04 July 2019

Publication Date:
03 September 2019 (online)

Also available at
   Permissions and Reprints

Summary

Background Factor XII (FXII) deficiency and autoantibodies that bind to FXII (anti-FXII) have been described in patients with adverse pregnancy outcomes, including recurrent pregnancy loss. It has been reported that FXII functions not only as a coagulation protein but also as a growth factor.

Objectives We studied the association between anti-FXII and the epidermal growth factor (EGF) system in patients with recurrent pregnancy loss.

Patients/Methods We used synthetic peptides that span the second EGF-like domain in the heavy chain of FXII (EGF2) in inhibition and direct binding studies to determine if anti-FXII antibodies recognize EGF2. Furthermore, we examined whether anti-FXII antibodies, which recognize EGF2, also recognize recombinant EGF and heparin-binding EGF-like growth factor (HB-EGF).

Results Among 100 patients with recurrent pregnancy loss, the plasma of 23 patients (23.0%) recognized the synthetic peptide ASQ41, which covers EGF2. Among the 23 anti-ASQ41-positive patients, plasma samples from 13 patients (56.5%) recognized the 22-residue segment C-terminal half of ASQ41. Among the 23 anti-ASQ41-positive patients, the plasma of 17 patients (73.9%) recognized recombinant human EGF. Affinity-purified anti-FXII antibodies, which recognize ASQ41, also recognized recombinant EGF family proteins such as EGF and HB-EGF.

Conclusions The autoantibodies in patients with recurrent pregnancy loss recognized the EGF2 domain in FXII and other proteins of the EGF family. Since proteins in the EGF family play an important role in normal pregnancy, autoantibody-associated disruption of the EGF system may cause pregnancy loss.

Keywords

factor XII - pregnancy loss - recurrent pregnancy loss - epidermal growth factor - heparin-binding EGF-like growth factor

Authors' Contributions

Study concept and design: Y. Sato and T. Sugi; acquisition of data: Y. Sato, T. Sugi, and R. Sakai; analysis and interpretation of data: Y. Sato and T. Sugi; patient inclusion and management: Y. Sato and T. Sugi; drafting of the manuscript: Y. Sato and T. Sugi; study supervisor: T. Sugi.


 

  • References

  • 1 Schved JF, Gris JC, Neveu S, Dupaigne D, Mares P. Factor XII congenital deficiency and early spontaneous abortion. Fertil Steril 1989; 52 (02) 335-336
    CrossrefPubMedGoogle Scholar
  • 2 Braulke I, Pruggmayer M, Melloh P, Hinney B, Köstering H, Günther E. Factor XII (Hageman) deficiency in women with habitual abortion: new subpopulation of recurrent aborters?. Fertil Steril 1993; 59 (01) 98-101
    CrossrefPubMedGoogle Scholar
  • 3 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 (06) 1096-1103
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Gallimore MJ, Jones DW, Winter M. Factor XII determinations in the presence and absence of phospholipid antibodies. Thromb Haemost 1998; 79 (01) 87-90
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Jones DW, Gallimore MJ, Harris SL, Winter M. Antibodies to factor XII associated with lupus anticoagulant. Thromb Haemost 1999; 81 (03) 387-390
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Matsuura T, Kobayashi T, Asahina T, Kanayama N, Terao T. Is factor XII deficiency related to recurrent miscarriage?. Semin Thromb Hemost 2001; 27 (02) 115-120
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Pauer HU, Renné T, Hemmerlein B. , et al. Targeted deletion of murine coagulation factor XII gene-a model for contact phase activation in vivo. Thromb Haemost 2004; 92 (03) 503-508
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Iwaki T, Castellino FJ. Plasma levels of bradykinin are suppressed in factor XII-deficient mice. Thromb Haemost 2006; 95 (06) 1003-1010
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Jones DW, Gallimore MJ, MacKie IJ, Harris SL, Winter M. Reduced factor XII levels in patients with the antiphospholipid syndrome are associated with antibodies to factor XII. Br J Haematol 2000; 110 (03) 721-726
    CrossrefPubMedGoogle Scholar
  • 10 Jones DW, MacKie IJ, Gallimore MJ, Winter M. Antibodies to factor XII and recurrent fetal loss in patients with the anti-phospholipid syndrome. Br J Haematol 2001; 113 (02) 550-552
    CrossrefPubMedGoogle Scholar
  • 11 Inomo A, Sugi T, Fujita Y, Matsubayashi H, Izumi S, Mikami M. The antigenic binding sites of autoantibodies to factor XII in patients with recurrent pregnancy losses. Thromb Haemost 2008; 99 (02) 316-323
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Bradford HN, Pixley RA, Colman RW. Human factor XII binding to the glycoprotein Ib-IX-V complex inhibits thrombin-induced platelet aggregation. J Biol Chem 2000; 275 (30) 22756-22763
    CrossrefPubMedGoogle Scholar
  • 13 Clarke BJ, Côté HCF, Cool DE. , et al. Mapping of a putative surface-binding site of human coagulation factor XII. J Biol Chem 1989; 264 (19) 11497-11502
    CrossrefPubMedGoogle Scholar
  • 14 Pixley RA, Stumpo LG, Birkmeyer K, Silver L, Colman RW. A monoclonal antibody recognizing an icosapeptide sequence in the heavy chain of human factor XII inhibits surface-catalyzed activation. J Biol Chem 1987; 262 (21) 10140-10145
    CrossrefPubMedGoogle Scholar
  • 15 Sato Y, Sugi T, Sakai R. Autoantibodies to factor XII and kininogen-dependent antiphosphatidylethanolamine antibodies in patients with recurrent pregnancy loss augment platelet aggregation. Am J Reprod Immunol 2015; 74 (03) 279-289
    PubMedGoogle Scholar
  • 16 Velayuthaprabhu S, Matsubayashi H, Sugi T. , et al. A unique preliminary study on placental apoptosis in mice with passive immunization of anti-phosphatidylethanolamine antibodies and anti-factor XII antibodies. Am J Reprod Immunol 2011; 66 (05) 373-384
    CrossrefPubMedGoogle Scholar
  • 17 Sugi T, McIntyre JA. Autoantibodies to phosphatidylethanolamine (PE) recognize a kininogen-PE complex. Blood 1995; 86 (08) 3083-3089
    CrossrefPubMedGoogle Scholar
  • 18 Sugi T, Mclntyre JA. Phosphatidylethanolamine induces specific conformational changes in the kininogens recognizable by antiphosphatidylethanolamine antibodies. Thromb Haemost 1996; 76 (03) 354-360
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Katsunuma J, Sugi T, Inomo A, Matsubayashi H, Izumi S-I, Makino T. Kininogen domain 3 contains regions recognized by antiphosphatidylethanolamine antibodies. J Thromb Haemost 2003; 1 (01) 132-138
    CrossrefPubMedGoogle Scholar
  • 20 Schmeidler-Sapiro KT, Ratnoff OD, Gordon EM. Mitogenic effects of coagulation factor XII and factor XIIa on HepG2 cells. Proc Natl Acad Sci U S A 1991; 88 (10) 4382-4385
    CrossrefPubMedGoogle Scholar
  • 21 Gordon EM, Venkatesan N, Salazar R. , et al. Factor XII-induced mitogenesis is mediated via a distinct signal transduction pathway that activates a mitogen-activated protein kinase. Proc Natl Acad Sci U S A 1996; 93 (05) 2174-2179
    CrossrefPubMedGoogle Scholar
  • 22 LaRusch GA, Mahdi F, Shariat-Madar Z. , et al. Factor XII stimulates ERK1/2 and Akt through uPAR, integrins, and the EGFR to initiate angiogenesis. Blood 2010; 115 (24) 5111-5120
    CrossrefPubMedGoogle Scholar
  • 23 Payne SG, Brindley DN, Guilbert LJ. Epidermal growth factor inhibits ceramide-induced apoptosis and lowers ceramide levels in primary placental trophoblasts. J Cell Physiol 1999; 180 (02) 263-270
    CrossrefPubMedGoogle Scholar
  • 24 Smith S, Francis R, Guilbert L, Baker PN. Growth factor rescue of cytokine mediated trophoblast apoptosis. Placenta 2002; 23 (04) 322-330
    CrossrefPubMedGoogle Scholar
  • 25 Bass KE, Morrish D, Roth I. , et al. Human cytotrophoblast invasion is up-regulated by epidermal growth factor: evidence that paracrine factors modify this process. Dev Biol 1994; 164 (02) 550-561
    CrossrefPubMedGoogle Scholar
  • 26 Leach RE, Kilburn B, Wang J, Liu Z, Romero R, Armant DR. Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype. Dev Biol 2004; 266 (02) 223-237
    CrossrefPubMedGoogle Scholar
  • 27 Armant DR, Kilburn BA, Petkova A. , et al. Human trophoblast survival at low oxygen concentrations requires metalloproteinase-mediated shedding of heparin-binding EGF-like growth factor. Development 2006; 133 (04) 751-759
    CrossrefPubMedGoogle Scholar
  • 28 Leach RE, Kilburn BA, Petkova A, Romero R, Armant DR. Diminished survival of human cytotrophoblast cells exposed to hypoxia/reoxygenation injury and associated reduction of heparin-binding epidermal growth factor-like growth factor. Am J Obstet Gynecol 2008; 198 (04) 471.e1-471.e7 , discussion 471.e7–471.e8
    CrossrefPubMedGoogle Scholar
  • 29 Sakata T, Okamoto A, Mannami T, Tomoike H, Miyata T. Prevalence of protein S deficiency in the Japanese general population: the Suita Study. J Thromb Haemost 2004; 2 (06) 1012-1013
    CrossrefPubMedGoogle Scholar
  • 30 Ebina Y, Ieko M, Naito S. , et al. Low levels of plasma protein S, protein C and coagulation factor XII during early pregnancy and adverse pregnancy outcome. Thromb Haemost 2015; 114 (01) 65-69
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Suleiman L, Négrier C, Boukerche H. Protein S: a multifunctional anticoagulant vitamin K-dependent protein at the crossroads of coagulation, inflammation, angiogenesis, and cancer. Crit Rev Oncol Hematol 2013; 88 (03) 637-654
    CrossrefPubMedGoogle Scholar
  • 32 Matsumoto M, Tachibana D, Nobeyama H. , et al. Protein S deposition at placenta: a possible role of protein S other than anticoagulation. Blood Coagul Fibrinolysis 2008; 19 (07) 653-656
    CrossrefPubMedGoogle Scholar
  • 33 Sato Y, Sugi T, Sakai R. Antigenic binding sites of anti-protein S autoantibodies in patients with recurrent pregnancy loss. Res Pract Thromb Haemost 2018; 2 (02) 357-365
    CrossrefPubMedGoogle Scholar