APC resistance during the normal menstrual cycle

Summary

Increased serum levels of endogenous as well as exogenous estrogen are regarded to be responsible for acquired activated protein C (APC) resistance. It was the objective of this study to evaluate whether the physiological increase in serum estradiol concentration during the normal menstrual cycle affects the individual’s sensitivity to APC. Seventy-two women with normal menstrual cycles were included in the study. Blood samples for analysis of estradiol (E2), progesterone (P4) and APC resistance were drawn at two time points of the menstrual cycle (day 3–5 and day 22–25). Two methods of measuring APC resistance were used: the activated partial thromboplastin time (aPTT)-based assay and the endogenous thrombin potential (ETP)-based APC resistance test. Independent of the method used, no changes in APC resistance were found, even though the E2 concentration increased significantly between the two menstrual phases. No correlations between E2 levels and APC resistance, P4 levels and APC resistance or changes in E2 concentrations and changes in APC resistance were detected. Ten women were carriers of the factor V_Leiden mutation. Their baseline APC resistance was increased, but their response to elevated E2 during the menstrual cycle did not differ from that of non-carriers. In conclusion, our observations suggest that physiological differences in serum levels of estradiol and progesterone between the early follicular and the luteal phase in a normal menstrual cycle do not have any significant impact on the individual’s sensitivity to APC.

Keywords

Menstrual cycle - APC resistance - ETP-based - aPTT-based - estradiol

• References

• 1 Martinelli I. Thromboembolism in women. Semin Thromb Hemost 2006; 32: 709-715.
• 2 Bottiger LE, Boman G, Eklund G. et al. Oral contraceptives and thromboembolic disease: effects of lowering oestrogen content. Lancet 1980; 110: 97-101.
• 3 Koster T, Rosendahl FR, de Ronde. et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-1506.
• 4 Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522.
• 5 Wu O, Robertson L, Langhorne P. et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost 2005; 94: 17-25.
• 6 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
• 7 Lunghi B, Iacoviello L, Gemmati D. et al. Detection of new polymorphic markers in the factor V gene: association with factor V levels in plasma. Thromb Haemost 1996; 75: 45-48.
• 8 Chan WP, Lee CK, Kwong YL. et al. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood 1998; 91: 1135-1139.
• 9 Williamson D, Brown K, Luddington R. et al. Factor V Cambridge: a new mutation (Arg306-->Thr) associated with resistance to activated protein C. Blood 1998; 91: 1140-1144.
• 10 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.
• 11 Rosing J, Curvers J, Tans G. Oral contraceptives, thrombosis and haemostasis. Eur J Obstet Gynecol Reprod Biol 2001; 95: 193-197.
• 12 Couturaud F, Kearon C, Leroyer C. et al.; Groupe d’Etude de la Thrombose de Bretagne Occidentale (G.E.T.B.O). Incidence of venous thromboembolism in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. Thromb Haemost 2006; 96: 744-749.
• 13 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.
• 14 Rosing J, Middeldorp S, Curvers J. et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999; 354: 2036-2040.
• 15 van Rooijen M, Silveira A, Hamsten A. et al. Sex hormone--binding globulin--a surrogate marker for the prothrombotic effects of combined oral contraceptives. Am J Obstet Gynecol 2004; 190: 332-337.
• 16 Tans G, van Hylckama Vlieg A, Thomassen MC. et al. Activated protein C resistance determined with a thrombin generation-based test predicts for venous thrombosis in men and women. Br J Haematol 2003; 122: 465-470.
• 17 Jick H, Jick SS, Gurewich V. et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589-1593.
• 18 World Health Organization.. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589-1593.
• 19 Alhenc-Gelas M, Plu-Bureau G, Guillonneau S. et al. Impact of progestagens on activated protein C (APC) resistance among users of of oral contraceptives. J Thromb Haemost 2004; 2: 1594-2600.
• 20 Kemmeren JM, Algra A, Meijers JC. et al. Effect of second-and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial. Blood 2004; 103: 927-933.
• 21 Wramsby ML, Bokarewa MI, Blomback M. et al. Response to activated protein C during normal menstrual cycle and ovarian stimulation. Hum Reprod 2000; 15: 795-797.
• 22 Wramsby ML, Bremme K, Blomback M. Measurement of activated protein C resistance during menstrual cycle in women with and without the Leiden mutation. Thromb Haemost 2001; 85: 614-618.
• 23 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.
• 24 Nicolaes GA, Thomassen MC, Tans G. et al. Effect of activated protein C on thrombin generation and on the thrombin potential in normal and APC- resistant individuals. Blood Coagul Fibrinolysis 1997; 8: 28-38.
• 25 Holmberg K, Persson ML, Uhlen M. et al. Pyrosequencing analysis of thrombosis-associated risk markers. Clin Chem 2005; 51: 1549-1552.
• 26 Roger EK. Experimental design: Procedures for the behavioral sciences. Brooks/Cole Publishing Company Pacific Grove; USA: 1995
• 27 Littell RC, Milliken GA, Stroup WW. et al. SAS System for Mixed Models, Cary. NC: SAS Institute Inc.; 1996
• 28 de Visser MC, Roosendaal FR, Bertina RM. A reduced sensitivity for protein C in the absence for Factor V increases the risk of venous thrombosis. Blood 1998; 93: 1271-1276.
• 29 Zoller B, Hillarp A, Berntorp E. et al. Activated protein C resistance due to a common factor V gene mutation is a major risk factor for venous thrombosis. Annu Rev Med 1997; 48: 45-58.
• 30 Meinardi JR, Henkens CM, Heringa MP. et al. Acquired APC resistance related to oral contraceptives and pregnancy and its possible implications for clinical practice. Blood Coagul Fibrinolysis 1997; 8: 152-154.
• 31 Hoibraaten E, Mowinckel MC, de Ronde H. et al. Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, doubleblind, placebo-controlled trial. Br J Haematol 2001; 115: 415-420.
• 32 Olivieri O, Friso S, Manzato F. et al. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol 1995; 91: 465-470.
• 33 Lindberg BS, Johansson ED, Nilsson BA. Plasma levels of nonconjugated oestrone, oestradiol-17beta and oestriol during uncomplicated pregnancy. Acta Obstet Gynecol Scand Suppl 1974; 32: 21-36.
• 34 Bokarewa MI, Wramsby M, Bremme K. et al. Variability of the response to activated protein C during normal pregnancy. Blood Coagul Fibrinolysis 1997; 8: 239-244.
• 35 Cumming AM, Tait RC, Fildes S. et al. Diagnosis of APC Resistance during pregnancy. Br J Haematol 1996; 92: 1026-1029.
• 36 Curvers J, Nap AW, Thomassen MC. et al. Effect of in vitro fertilization treatment and subsequent pregnancy on the protein C pathway. Br J Haematol 2001; 115: 400-407.
• 37 van Rooijen M, Silveira A, Thomassen S. et al. Rapid activation of haemostasis after hormonal emergency contraception. Thromb Haemost 2007; 97: 15-20.