Download PDF
Thromb Haemost 2015; 114(01): 65-69
DOI: 10.1160/TH14-11-0928
Coagulation and Fibrinolysis
Schattauer GmbH

Low levels of plasma protein S, protein C and coagulation factor XII during early pregnancy and adverse pregnancy outcome

Yasuhiko Ebina
1   Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan
,
Masahiro Ieko
2   Department of Internal Medicine, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
,
Sumiyoshi Naito
3   Department of Clinical Laboratory School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
,
Gen Kobashi
4   Department of Planning and Management, National Institute of Radiological Sciences, Chiba, Japan
,
Masashi Deguchi
1   Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan
,
Hisanori Minakami
5   Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
,
Tatsuya Atsumi
6   Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, Japan
,
Hideto Yamada
1   Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan
› Author Affiliations Financial support: This work was supported in part by a Grant-in-Aid from the Japan Society for the Promotion of Science (Grant No. 26462489, 25462593) and the Ministry of Health, Labour and Welfare of Japan (Grant No. H25-Jisedai-Ippan-005).
Further Information

Publication History

Received: 12 November 2014

Accepted after major revision: 23 February 2015

Publication Date:
22 November 2017 (online)

    Permissions and Reprints

Summary

It was the study objective to evaluate whether low levels of plasma protein S (PS) activity, free PS, protein C (PC) activity and coagulation factor XII (FXII) during early pregnancy are related to adverse pregnancy outcomes. Peripheral blood samples were obtained at 8–14 gestational weeks (GW) from a consecutive series of 1,220 women. The levels of plasma PS activity, free PS, PC activity, and FXII were measured. Cut-off values were defined as < 1st, < 5th, and < 10th percentiles of values obtained from 933 women whose pregnancies ended in normal deliveries without complications. PS activity of < 10th percentile yielded risks of pregnancy-induced hypertension (PIH) and severe PIH, while free PS level of < 5th percentile yielded a risk of preeclampsia. FXII level of < 1st percentile yielded a risk of premature delivery (PD) at < 34 GW. None was associated with PD at < 37 GW, fetal growth restriction or fetal loss. A multivariate analysis demonstrated that PS activity of < 10th percentile (odds ratio 5.9, 95 % confidence interval 1.7–18.1) and body mass index (BMI) ≥ 25 kg/m2 (4.3, 1.1–13.3) were independent risk factors for severe PIH. Similarly, free PS level of < 5th percentile (4.4, 1.0–14.3) and BMI ≥ 25 kg/m2 (4.0, 1.3–10.9) were independent risk factors for pre-eclampsia. In conclusion, women with low levels of plasma PS activity and free PS during early pregnancy might have increased risks of PIH, severe PIH or pre-eclampsia. Women with low FXII level might have an increased risk of PD at < 34 GW.

Keywords

Factor XII - pregnancy - pregnancy-induced hypertension - premature delivery - protein C - protein S
 

  • References

  • 1 Abdel Gader AM, Al-Mishari AA, Awadalla SA. et al. Total and free tissue factor pathway inhibitor in pregnancy hypertension. Int J Gynaecol Obstet 2006; 95: 248-253.
    CrossrefPubMedGoogle Scholar
  • 2 Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review. Eur J Obstet Gynecol Reprod Biol 2002; 101: 6-14.
    CrossrefPubMedGoogle Scholar
  • 3 De Bonis M, Sabatini L, Galeazzi LR. et al. Maternal serum protein S forms in pregnancies complicated by intrauterine growth restriction. Eur J Obstet Gynecol Reprod Biol 2012; 160: 142-146.
    CrossrefPubMedGoogle Scholar
  • 4 Hojo S, Tsukimori K, Kinukawa N. et al. Decreased maternal protein S activity is associated with fetal growth restriction. Thromb Res 2008; 123: 55-59.
    CrossrefPubMedGoogle Scholar
  • 5 Osmanagaoglu MA, Topcuoglu K, Ozeren M. et al. Coagulation inhibitors in preeclamptic pregnant women. Arch Gynecol Obstet 2005; 271: 227-230.
    CrossrefPubMedGoogle Scholar
  • 6 Paidas MJ, Ku DH, Langhoff-Roos J. et al. Inherited thrombophilias and adverse pregnancy outcome: screening and management. Semin Perinatol 2005; 29: 150-163.
    CrossrefPubMedGoogle Scholar
  • 7 Rey E, Kahn SR, David M. et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901-908.
    CrossrefPubMedGoogle Scholar
  • 8 Sayin M, Varol FG, Sayin NC. Evaluation of natural coagulation inhibitor levels in various hypertensive states of pregnancy. Eur J Obstet Gynecol Reprod Biol 2005; 123: 183-187.
    CrossrefPubMedGoogle Scholar
  • 9 Wu O, Robertson L, Twaddle S. et al. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess 2006; 10: 1-110.
    PubMedGoogle Scholar
  • 10 Robertson L, Wu O, Langhorne P, Twaddle S. et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132: 171-196.
    CrossrefPubMedGoogle Scholar
  • 11 Kluft C, Dooijewaard G, Emeis JJ. Role of the contact system in fibrinolysis. Semin Thromb Hemost 1987; 13: 50-68.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Lammle B, Wuillemin WA, Huber I. et al. Thromboembolism and bleeding tendency in congenital factor XII deficiency--a study on 74 subjects from 14 Swiss families. Thromb Haemost 1991; 65: 117-121.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Rodeghiero F, Castaman G, Ruggeri M. et al. Thrombosis in subjects with homozygous and heterozygous factor XII deficiency. Thromb Haemost 1992; 67: 590-591.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol 2009; 114: 1326-1331.
    CrossrefPubMedGoogle Scholar
  • 15 Dykes AC, Walker ID, McMahon AD. et al. A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br J Haematol 2001; 113: 636-641.
    CrossrefPubMedGoogle Scholar
  • 16 Said JM, Ignjatovic V, Monagle PT. et al. Altered reference ranges for protein C and protein S during early pregnancy: Implications for the diagnosis of protein C and protein S deficiency during pregnancy. Thromb Haemost 2010; 103: 984-988.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Cerneca F, Ricci G, Simeone R. et al. Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis. Eur J Obstet Gynecol Reprod Biol 1997; 73: 31-36.
    CrossrefPubMedGoogle Scholar
  • 18 Choi JW, Pai SH. Tissue plasminogen activator levels change with plasma fibrinogen concentrations during pregnancy. Ann Hematol 2002; 81: 611-615.
    CrossrefPubMedGoogle Scholar
  • 19 Yamada H, Atsumi T, Kobashi G. et al. Antiphospholipid antibodies increase the risk of pregnancy-induced hypertension and adverse pregnancy outcomes. J Re-prod Immunol 2009; 79: 188-195.
    CrossrefPubMedGoogle Scholar
  • 20 Gregg JP, Yamane AJ, Grody WW. Prevalence of the factor V-Leiden mutation in four distinct American ethnic populations. Am J Med Genet 1997; 73: 334-336.
    CrossrefPubMedGoogle Scholar
  • 21 Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost 2009; 07 (Suppl. 01) 301-304.
    CrossrefPubMedGoogle Scholar
  • 22 Miyata T, Okada H, Kawasaki T. et al. Genetic risk factors for thrombophilia in Japanese. Jap J Clin Hematol 2009; 50: 381-388.
    PubMedGoogle Scholar
  • 23 Nomura T, Suehisa E, Kawasaki T. et al. Frequency of protein S deficiency in general Japanese population. Thromb Res 2000; 100: 367-371.
    CrossrefPubMedGoogle Scholar
  • 24 Kimura R, Honda S, Kawasaki T. et al. Protein S-K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients. Blood 2006; 107: 1737-1738.
    CrossrefPubMedGoogle Scholar
  • 25 Kujovich JL. Thrombophilia and pregnancy complications. Am J Obstet Gynecol 2004; 191: 412-424.
    CrossrefPubMedGoogle Scholar
  • 26 Kupferminc MJ, Eldor A, Steinman N. et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9-13.
    CrossrefPubMedGoogle Scholar
  • 27 Salafia CM, Pezzullo JC, Lopez-Zeno JA. et al. Placental pathologic features of preterm preeclampsia. Am J Obstet Gynecol 1995; 173: 1097-1105.
    CrossrefPubMedGoogle Scholar
  • 28 Yamada H, Kato EH, Ebina Y. et al. Factor XII deficiency in women with recurrent miscarriage. Gynecol Obstet Invest 2000; 49: 80-83.
    CrossrefPubMedGoogle Scholar
  • 29 Yamada H, Kato EH, Kobashi G. et al. Recurrent pregnancy loss: etiology of thrombophilia. Semin Thromb Hemost 2001; 27: 121-129.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 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: 1096-1103.
    Article in Thieme ConnectPubMedGoogle Scholar