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

Joanne m. Said; Vera Ignjatovic; Paul T. Monagle; Susan P. Walker; John R. Higgins; Shaun P. Brennecke

doi:10.1160/TH09-07-0476

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 103(05): 984-988
DOI: 10.1160/TH09-07-0476

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

Joanne m. Said

¹Department of Perinatal Medicine, The Royal Women’s Hospital, Parkville, Victoria, Australia

²The University of Melbourne, Department of Obstetrics and Gynaecology, Parkville, Victoria, Australia

,

Vera Ignjatovic

³Department of Haematology, The Royal Children’s Hospital, Parkville, Victoria, Australia

⁴Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia

,

Paul T. Monagle

³Department of Haematology, The Royal Children’s Hospital, Parkville, Victoria, Australia

⁴Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia

,

Susan P. Walker

²The University of Melbourne, Department of Obstetrics and Gynaecology, Parkville, Victoria, Australia

⁵Mercy Hospital for Women, Heidelberg, Victoria, Australia

,

John R. Higgins

¹Department of Perinatal Medicine, The Royal Women’s Hospital, Parkville, Victoria, Australia

²The University of Melbourne, Department of Obstetrics and Gynaecology, Parkville, Victoria, Australia

⁶Anu Research Centre, Department of Obstetrics & Gynaecology, University College Cork, Ireland

,

Shaun P. Brennecke

¹Department of Perinatal Medicine, The Royal Women’s Hospital, Parkville, Victoria, Australia

²The University of Melbourne, Department of Obstetrics and Gynaecology, Parkville, Victoria, Australia

› Author Affiliations

Abstract

Summary

Protein S, protein C and antithrombin are important regulators of coagulation. While deficiencies of these proteins have been linked to adverse pregnancy outcomes, testing for these deficiencies during pregnancy is limited by the use of non-pregnant reference ranges and a limited understanding of the changes that occur during pregnancy. Although several small studies have previously reported on the activity of these proteins during pregnancy, potentially important changes have been overlooked by continuing to compare the activity during pregnancy with non-pregnant reference ranges. In the current study, we investigated the activity of protein S, protein C and antithrombin during the first half of pregnancy in 440 otherwise asymptomatic women who went on to have uncomplicated singleton pregnancies. Consistent with previous studies, we found that antithrombin activity remained unchanged, while protein S activity decreased significantly to a mean level of 46%. We did not observe a progressive decrease in protein S during the second trimester as several studies have suggested previously. In contrast, we observed a potentially biologically significant increase in protein C activity throughout the first 22 weeks of pregnancy. Given the physiological role of protein C, we postulate that this increase may play a role in maintaining early pregnancy through both an anticoagulant and an inflammatory regulation pathway.

Keywords

Antithrombin - natural anticoagulants - protein C - protein S - pregnancy - reference ranges - thrombophilia - thrombosis

Full Text

References

References
1 O’Riordan MN, Higgins JR. Haemostasis in normal and abnormal pregnancy. Best Pract Res Clin Obstet Gynaecol 2003; 17: 385-396.
2 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 Repr Biol 1997; 73: 31-36.
3 Clark P, Brennand J, Conkie JA. et al. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998; 79: 1166-1170.
4 Uchikova E, Ledjev II. Changes in haemostasis during normal pregnancy. Eur J Obstet Gynecol Repr Biol 2005; 119: 185-188.
5 Dekker GA, de Vries JI, Doelitzsch PM. et al. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995; 173: 1042-1048.
6 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.
7 Wickstrom K, Edelstam G, Lowbeer CH. et al. Reference intervals for plasma levels of fibronectin, von-Willebrand factor, free protein S, and antithrombin during third-trimester pregnancy. Scand J Clin Lab Invest 2004; 64: 31-40.
8 Bremme K, Ostlund E, Almqvist I. et al. Enhanced thrombin generation and fibrinolytic activity in normal pregnancy and the puerperium. Obstet Gynecol 1992; 80: 132-137.
9 Lefkowitz J, Clarke S, Barbour L. Comparison of protein S functional and antigenic assays in normal pregnancy. Am J Obstet Gynecol 1996; 175: 657-660.
10 Oruc S, Saruc M, Koyuncu FM. et al. Changes in plasma activities of protein C and protein S during pregnancy. Aust N Z J Obstet Gynaecol 2000; 40: 448-450.
11 Tait RC, Walker ID, Islam SI. et al. Influence of demographic factors on anti-thrombin III activity in a healthy population. Br J Haematol 1993; 84: 476-480.
12 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.
13 Faught W, Garner P, Jones G. et al. Changes in protein C and protein S levels in normal pregnancy. Am J Obstet Gynecol 1995; 172: 147-150.
14 Monagle P, Barnes C, Ignjatovic V. et al. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost 2006; 95: 362-372.
15 Tait RC, Walker ID, Islam SI. et al. Protein C activity in healthy volunteers – influence of age, sex, smoking and oral contraceptives. Thromb Haemost 1993; 70: 281-285.
16 Isermann B, Sood R, Pawlinski R. et al. The thrombomodulin-protein C system is essential for the maintenance of pregnancy. Nature Med 2003; 09: 331-337.
17 Weiler H. Mouse models of thrombosis: thrombomodulin. Thromb Haemost 2004; 92: 467-477.
18 Esmon CT. Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Crit Care Med 2001; 29 (Suppl. 07) S48-S52.
19 Toltl LJ, Swystun LL, Pepler L. et al. Protective effects of activated protein C in sepsis. Thromb Haemost 2008; 100: 582-592.
20 Murakami K, Okajima K, Uchiba M. et al. Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am J Physiol Lung Cell Mol Physiol 1997; 272: L197-202.