Role of protein S and tissue factor pathway inhibitor in the development of activated protein C resistance early in pregnancy in women with a history of preeclampsia

Svetlana N. Tchaikovski; M. Christella L. G. D. Thomassen; Serban-Dan Costa; Louis L. H. Peeters; Jan Rosing

doi:10.1160/TH11-04-0244

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2011; 106(05): 914-921
DOI: 10.1160/TH11-04-0244

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Role of protein S and tissue factor pathway inhibitor in the development of activated protein C resistance early in pregnancy in women with a history of preeclampsia

Authors

Svetlana N. Tchaikovski

¹Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

³University Women's Hospital, Otto-von-Guericke University, Magdeburg, Germany
M. Christella L. G. D. Thomassen

¹Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
Serban-Dan Costa

³University Women's Hospital, Otto-von-Guericke University, Magdeburg, Germany
Louis L. H. Peeters

²Department of Gynaecology, University Hospital Maastricht, Maastricht, The Netherlands
Jan Rosing

¹Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

Abstract

als PDF herunterladen

Summary

Pregnancy increases the risk of venous thromboembolism. Particularly in early pregnancy, the thrombosis risk can be attributed to the changes in coagulation. Elevated thrombin generation and resistance to activated protein C (APC) are likely to contribute to the increased thrombosis risk during pregnancy. We studied changes and the determinants of thrombin generation and APC resistance in the first 16 weeks of gestation in women with history of preeclampsia. Additionally, we investigated the influence of pregnancy-induced haemodilution on the coagulation system. We measured thrombin generation, APC resistance and plasma levels of prothrombin, factor V, factor X, protein S and tissue factor pathway inhibitor (TFPI) in 30 non-pregnant and 21 pregnant women at 8, 12 and 16 weeks of gestation. All participants shared a history of a hypertensive complication in the preceding pregnancy. Thrombin generation and APC resistance were higher at eight weeks of pregnancy than in the non-pregnant state, and progressively increased between eight and 16 weeks of gestation. Changes in the TFPI and protein S levels accounted for ~70% of pregnancy-induced APC resistance. Interestingly, a significant correlation (slope 2.23; 95%CI: 1.56 to 2.91; r= 0.58) was observed between protein S_total or protein S_free levels and haematocrit. In conclusion, pregnancy induces a decrease of TFPI_free and protein S_free levels that attenuates the function of the TFPI and protein C systems and results in elevated thrombin generation and increased APC resistance. Besides, our data suggest that pregnancy-dependent haemodilution may contribute to the decreased peripheral protein S levels.

Keywords

Pregnancy - thrombin generation - APC resistance - protein S - TFPI - haematocrit

PDF (682 kb)

Referenzen

References
1 Pomp ER, Lenselink AM, Rosendaal FR. et al. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008; 6: 632-637.
2 Rabhi Y, Charras-Arthapignet C, Gris JC. et al. Lower limb vein enlargement and spontaneous blood flow echogenicity are normal sonographic findings during pregnancy. J Clin Ultrasound 2000; 28: 407-413.
3 James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the postpartum period. Am J Obstet Gynecol 2005; 193: 216-219.
4 Tchaikovski SN, Rosing J. Mechanisms of estrogen-induced venous thromboembolism. Thromb Res 2010; 126: 5-11.
5 Brenner B. Haemostatic changes in pregnancy. Thromb Res 2004; 114: 409-414.
6 Tchaikovski SN, van Vliet HA, Thomassen MC. et al. Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography. Thromb Haemost 2007; 98: 1350-1356.
7 Rosing J, Tans G, Nicolaes GA. et al. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol 1997; 97: 233-238.
8 Vandenbroucke JP, Helmerhorst FM, Bloemenkamp KW. et al. Third-generation oral contraceptive and deep venous thrombosis: from epidemiologic controversy to new insight in coagulation. Am J Obstet Gynecol 1997; 177: 887-891.
9 Rosenkranz A, Hiden M, Leschnik B. et al. Calibrated automated thrombin generation in normal uncomplicated pregnancy. Thromb Haemost 2008; 99: 331-337.
10 Curvers J, Thomassen MC, Rimmer J. et al. Effects of hereditary and acquired risk factors of venous thrombosis on a thrombin generation-based APC resistance test. Thromb Haemost 2002; 88: 5-11.
11 Rai R, Shlebak A, Cohen H. et al. Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage. Hum Reprod 2001; 16: 961-965.
12 Clark P, Sattar N, Walker ID. et al. The Glasgow Outcome, APCR and Lipid (GOAL) Pregnancy Study: significance of pregnancy associated activated protein C resistance. Thromb Haemost 2001; 85: 30-35.
13 Macey MG, Bevan S, Alam S. et al. Platelet activation and endogenous thrombin potential in pre-eclampsia. Thromb Res 2010; 125: e76-81.
14 Lindqvist PG, Svensson P, Dahlback B. Activated protein C resistance -- in the absence of factor V Leiden -- and pregnancy. J Thromb Haemost 2006; 4: 361-366.
15 Lund CJ, Donovan JC. Blood volume during pregnancy. Significance of plasma and red cell volumes. Am J Obstet Gynecol 1967; 98: 394-403.
16 Sep SJ, Smits LJ, Prins MH. et al. Simple prepregnant prediction rule for recurrent early-onset hypertensive disease in pregnancy. Reprod Sci 2009; 16: 80-87.
17 Koedam JA, Meijers JC, Sixma JJ. et al. Inactivation of human factor VIII by activated protein C. Cofactor activity of protein S and protective effect of von Willebrand factor. J Clin Invest 1988; 82: 1236-1243.
18 Rosing J, Bakker HM, Thomassen MC. et al. Characterization of two forms of human factor Va with different cofactor activities. J Biol Chem 1993; 268: 21130-21136.
19 Schiffman S, Theodor I, Rapaport SI. Separation from Russell's viper venom of one fraction reacting with factor X and another reacting with factor V. Biochemistry 1969; 8: 1397-1405.
20 Curvers J, Thomassen MC, Nicolaes GA. et al. Acquired APC resistance and oral contraceptives: differences between two functional tests. Br J Haematol 1999; 105: 88-94.
21 Koenen RR, Christella M, Thomassen LG. et al. Effect of oral contraceptives on the anticoagulant activity of protein S in plasma. Thromb Haemost 2005; 93: 853-859.
22 Bertina RM, van der Marel-van Nieuwkoop W, Loeliger EA. Spectrophotometric assays of prothrombin in plasma of patients using oral anticoagulants. Thromb Haemost 1979; 42: 1296-1305.
23 Nicolaes GA, Tans G, Thomassen MC. et al. Peptide bond cleavages and loss of functional activity during inactivation of factor Va and factor VaR506Q by activated protein C. J Biol Chem 1995; 270: 21158-211166.
24 Nicolaes GA, Thomassen MC, van Oerle R. et al. A prothrombinase-based assay for detection of resistance to activated protein C. Thromb Haemost 1996; 76: 404-410.
25 Hemker HC, Giesen P, Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
26 Maurissen LF, Castoldi E, Simioni P. et al. Thrombin generation-based assays to measure the activity of the TFPI-protein S pathway in plasma from normal and protein S-deficient individuals. J Thromb Haemost 2010; 8: 750-758.
27 Mayer A, Erez O, Novack L. et al. Chronic hypertension is an independent risk factor for preeclampsia and preterm delivery in women with rheumatologic diseases: a population-based study. Eur J Obstet Gynecol Reprod Biol 2007; 133: 157-163.
28 de Visser MC, van Hylckama Vlieg A, Tans G. et al. Determinants of the APTT- and ETP-based APC sensitivity tests. J Thromb Haemost 2005; 3: 1488-1494.
29 Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol 2003; 16: 153-168.
30 Uchikova EH, Ledjev II. Changes in haemostasis during normal pregnancy. Eur J Obstet Gynecol Reprod Biol 2005; 119: 185-188.
31 Sarig G, Blumenfeld Z, Leiba R. et al. Modulation of systemic hemostatic parameters by enoxaparin during gestation in women with thrombophilia and pregnancy loss. Thromb Haemost 2005; 94: 980-985.
32 Dielis AW, Castoldi E, Spronk HM. et al. Coagulation factors and the protein C system as determinants of thrombin generation in a normal population. J Thromb Haemost 2008; 6: 125-131.
33 Dahm AE, Sandset PM, Rosendaal FR. The association between protein S levels and anticoagulant activity of tissue factor pathway inhibitor type 1. J Thromb Haemost 2008; 6: 393-395.
34 Hackeng TM, Sere KM, Tans G. et al. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci USA 2006; 103: 3106-3111.
35 Dahm AE, Iversen N, Birkenes B. et al. Estrogens, selective estrogen receptor modulators, and a selective estrogen receptor down-regulator inhibit endothelial production of tissue factor pathway inhibitor 1. BMC Cardiovasc Disord 2006; 6: 40.
36 Suzuki A, Sanda N, Miyawaki Y. et al. Down-regulation of PROS1 gene expression by 17{beta}-estradiol via estrogen receptor {alpha} (ER{alpha})/Sp1 interaction recruiting receptor interacting protein 140 and corepressors-HDAC3 complex. J Biol Chem 2010; 285: 13444-13453.
37 Weenink GH, Ten Cate JW, Kahle LH. et al. „Morning after pill“ and antithrombin III. Lancet 1981; 1: 1105.
38 Fortney SM, Turner C, Steinmann L. et al. Blood volume responses of men and women to bed rest. J Clin Pharmacol 1994; 34: 434-439.
39 Spaanderman M, Ekhart T, van Eyck J. et al. Preeclampsia and maladaptation to pregnancy: a role for atrial natriuretic peptide?. Kidney Int 2001; 60: 1397-1406.
40 Whittaker PG, Macphail S, Lind T. Serial hematologic changes and pregnancy outcome. Obstet Gynecol 1996; 88: 33-39.
41 Braekkan SK, Mathiesen EB, Njolstad I. et al. Hematocrit and risk of venous thromboembolism in a general population. The Tromso study. Haematologica 2010; 95: 270-275.