Thromb Haemost 2009; 102(02): 309-313
DOI: 10.1160/TH09-02-0123
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Haplotype M2 in the annexin A5 (ANXA5) gene and the occurrence of obstetric complications

Giovanni Tiscia
1   Atherosclerosis and Thrombosis Unit, I.R.C.C.S. Casa Sollievo della Sofferenza, S. Giovanni R. (FG), University of Foggia, Foggia, Italy
,
Donatella Colaizzo
1   Atherosclerosis and Thrombosis Unit, I.R.C.C.S. Casa Sollievo della Sofferenza, S. Giovanni R. (FG), University of Foggia, Foggia, Italy
,
Elena Chinni
1   Atherosclerosis and Thrombosis Unit, I.R.C.C.S. Casa Sollievo della Sofferenza, S. Giovanni R. (FG), University of Foggia, Foggia, Italy
,
Daniela Pisanelli
1   Atherosclerosis and Thrombosis Unit, I.R.C.C.S. Casa Sollievo della Sofferenza, S. Giovanni R. (FG), University of Foggia, Foggia, Italy
,
Natale Sciannamè
2   Obstetrics and Gynaecology, I.R.C.C.S. Casa Sollievo della Sofferenza, S. Giovanni R. (FG), University of Foggia, Foggia, Italy
,
Giovanni Favuzzi
1   Atherosclerosis and Thrombosis Unit, I.R.C.C.S. Casa Sollievo della Sofferenza, S. Giovanni R. (FG), University of Foggia, Foggia, Italy
,
Maurizio Margaglione
1   Atherosclerosis and Thrombosis Unit, I.R.C.C.S. Casa Sollievo della Sofferenza, S. Giovanni R. (FG), University of Foggia, Foggia, Italy
3   Medical Genetics, University of Foggia, Foggia, Italy
,
Elvira Grandone
1   Atherosclerosis and Thrombosis Unit, I.R.C.C.S. Casa Sollievo della Sofferenza, S. Giovanni R. (FG), University of Foggia, Foggia, Italy
› Author Affiliations
Further Information

Publication History

Received: 26 February 2009

Accepted after major revision: 01 May 2009

Publication Date:
22 November 2017 (online)

Summary

Inherited or acquired thrombophilias have been largely explored as a cause of pregnancy complications. However, pathogenesis of obstetric complications, as fetal loss and pregnancyrelated hypertensive disorders is still partly unexplained. Recently, a common haplotype (M2) within the annexin A5 (ANXA5) gene has been described as a risk factor in recurrent fetal losses (RFL). It has been demonstrated to reduce the promoter activity of the ANXA5 promoter in luciferase reporter assays. Aim of this study was to investigate the prevalence of M2 haplotype in three different settings of women with previous obstetric complications: RFL, intra-uterine fetal death (IUFD) and pregnancy-related hypertension (gestational hypertension [GH] and pre-eclampsia [PE]). One hundred three patients with previous RFL, 54 with IUFD, 158 with hypertensive disease (67 GH, 91 PE) were investigated. As controls,195 women from the same ethnic background with uneventful pregnancies were enrolled. Logistic regression, correcting for age, gravidity and parity showed that the ANXA5 haplotype is significantly and independently associated with the occurrence of RFL (3.1; 95%CI: 1.1–9.5; p=0.047) and pregnancy-related hypertensive disorders (2.1; 95%CI: 1.2–3.5; p=0.008).The M2 haplotype might be a new and relevant risk factor for obstetric complications.

 
  • References

  • 1 Younis JS, Samueloff A. Gestational vascular complications. Best Pract Res Clin Haematol 2003; 16: 135-151.
  • 2 Grandone E, Margaglione M. Inherited thrombophilia and gestational vascular complications. Best Pract Res Clin Haematol 2003; 16: 321-332.
  • 3 Rey E, Kahn SR, David M. et al. Thrombophilic disorders and fetal loss: a metaanalysis. Lancet 2003; 361: 901-908.
  • 4 Chunilal SD, Bates SM. Venous thromboembolism in pregnancy: diagnosis, management and prevention. Thromb Haemost 2009; 101: 428-434.
  • 5 Kovalevsky G, Gracia CR, Berlin JA. et al. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a metaanalysis. Arch Intern Med 2004; 164: 558-563.
  • 6 Sarig G, Younis JS, Hoffman R. et al. Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 2002; 77: 342-347.
  • 7 Grandone E, Margaglione M, Colaizzo D. et al. Factor V Leiden, C > T MTHFR polymorphism and genetic susceptibility to preeclampsia. Thromb Haemost 1997; 77: 1052-1054.
  • 8 Grandone E, De Stefano V, Rossi E. et al. Antithrombotic prophylaxis during pregnancy in women with deficiency of natural anticoagulants. Blood Coagul Fibrinolysis 2008; 19: 226-230.
  • 9 Brenner B, Aharon A. Thrombophilia and adverse pregnancy outcome. Clin Perinatol 2007; 34: 527-541.
  • 10 Martinelli P, Grandone E, Colaizzo D. et al. Familial thrombophilia and the occurrence of fetal growth restriction. Haematologica 2001; 86: 428-431.
  • 11 Morrison ER, Miedzybrodzka ZH, Campbell DM. et al. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review. Thromb Haemost 2002; 87: 779-785.
  • 12 Robertson L, Wu O, Langhorne P. et al. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Br J Haematol 2006; 132: 171-196.
  • 13 Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis. Thromb Haemost 2004; 91: 700-711.
  • 14 Greer IA. Thrombophilia: implications for pregnancy outcome. Thromb Res 2003; 109: 73-81.
  • 15 Bates SM, Greer IA, Pabinger I. et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. Chest 2008; 133: 844S-886S.
  • 16 Kist WJ, Janssen NG, Kalk JJ. et al. Thrombophilias and adverse outcome - A confounded problem!. Thromb Haemost 2008; 99: 77-85.
  • 17 Funakoshi T, Hendrickson LE, McMullen BA. et al. Primary structure of human placental anticoagulant protein. Biochemistry 1987; 26: 8087-8092.
  • 18 Gerke V, Creutz CE, Moss SE. Annexins: linking Ca2+ signalling to membrane dynamics. Nat Rev Mol Cell Biol 2005; 06: 449-461.
  • 19 Rand JH, Wu XX. Antibody-mediated disruption of the annexin-V antithrombotic shield: a new mechanism for thrombosis in the antiphospholipid syndrome. Thromb Haemost 1999; 82: 649-655.
  • 20 Rand JH, Arslan AA, Wu XX. et al. Reduction of circulating annexin A5 levels and resistance to annexin A5 anticoagulant activity in women with recurrent spontaneous pregnancy losses. Am J Obstet Gynecol 2006; 194: 182-188.
  • 21 Rand JH, Wu XX, Guller S. et al. Reduction of annexin-V (placental anticoagulant protein-I) on placental villi of women with antiphospholipid antibodies and recurrent spontaneous abortion. Am J Obstet Gynecol 1994; 171: 1566-1572.
  • 22 Thiagarajan P, Tait JF. Binding of annexin V/placental anticoagulant protein I to platelets Evidence for phosphatidylserine exposure in the procoagulant response of activated platelets. J Biol Chem 1990; 265: 17420-17423.
  • 23 Ravassa S, Bennaghmouch A, Kenis H. et al. Annexin A5 down-regulates surface expression of tissue factor: a novel mechanism of regulating the membrane receptor repertoire. J Biol Chem 2005; 280: 6028-6035.
  • 24 Cookson BT, Engelhardt S, Smith C. et al. Organization of the human annexin V (ANX5). Genomics 1994; 20: 463-467.
  • 25 Carcedo MT, Iglesias JM, Bances P. et al. Functional analysis of the human annexin A5 gene promoter: a downstream DNA element and an upstream long terminal repeat regulate transcription. Biochem J 2001; 356: 571-579.
  • 26 Bogdanova N, Horst J, Chlystun M. et al. A common haplotype of the annexin A5 (ANXA5) gene promoter is associated with recurrent pregnancy loss. Hum Mol Genet 2007; 16: 573-578.
  • 27 Chinni E, Tiscia GL, Colaizzo D. et al. Annexin V expression in human placenta is influenced by the carriership of the common haplotype M2. Fertil Steril 2009; 91: 940-942.
  • 28 Grandone E, Margaglione M, Colaizzo D. et al. Factor V Leiden is associated with repeated and recurren unexplained fetal losses. Thromb Haemost 1997; 77: 822-824.
  • 29 Paladini D, Rustico M, Viora E. et al. Fetal size charts for the Italian population. Normative curves of head, abdomen and long bones. Prenat Diagn 2005; 25: 456-464.
  • 30 Poort SR, Rosendal FR, Reitsma PH. et al. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-3703.
  • 31 Grandone E, Colaizzo D, Vergura P. et al. Age and homocysteine plasma levels are risk factors for thrombotic complications after ovarian stimulation. Hum Reprod 2004; 19: 1796-1799.
  • 32 Getahun D, Ananth CV, Kinzler WL. Risk factors for antepartum and intrapartum stillbirth: a populationbased study. Am J Obstet Gynecol 2007; 196: 499-507.
  • 33 Wang X, Campos B, Kaetzel MA. et al. Annexin V is critical in the maintenance of murine placental integrity. Am J Obstet Gynecol 1999; 180: 1008-1016.
  • 34 Shu F, Sugimura M, Kanayama N. et al. Immunohistochemical study of annexin V expression in placentae of preeclampsia. Gynecol Obstet Invest 2000; 49: 17-23.
  • 35 Sugimura M, Kobayashi T, Shu F. et al. Annexin V inhibits phosphatidylserine-induced intrauterine growth restriction in mice. Placenta 1999; 20: 555-560.
  • 36 Khong TY, De Wolf F, Robertson WB. et al. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for gestational age infants. Br J Obstet Gynaecol 1986; 93: 1049-1059.