Download PDF
Thromb Haemost 1998; 79(06): 1166-1170
DOI: 10.1055/s-0037-1615035
Rapid Communication
Schattauer GmbH

Activated Protein C Sensitivity, Protein C, Protein S and Coagulation in Normal Pregnancy

P. Clark
1   From the Department of Haematology, Royal Infirmary, Glasgow, UK
,
J. Brennand
2   University Department of Obstetrics and Gynaecology, Royal Infirmary, Glasgow, UK
,
J. A. Conkie
1   From the Department of Haematology, Royal Infirmary, Glasgow, UK
,
F. McCall
1   From the Department of Haematology, Royal Infirmary, Glasgow, UK
,
I. A. Greer
2   University Department of Obstetrics and Gynaecology, Royal Infirmary, Glasgow, UK
,
Isobel D. Walker
1   From the Department of Haematology, Royal Infirmary, Glasgow, UK
› Author Affiliations
Further Information

Publication History

Received 29 July 1997

Accepted after resubmission 26 February 1998

Publication Date:
07 December 2017 (online)

    Permissions and Reprints

Summary

A prospective study of activated protein C sensitivity, protein C, protein S, and other coagulation factors in 239 women during normal pregnancy was carried out. Protein C activity appeared unaffected by gestation, although an elevation of protein C activity was observed in the early puerperium. A fall in total and free protein S with increasing gestation was observed. Activated protein C sensitivity ratio (APC:SR) showed a progressive fall through pregnancy. This fall correlated with changes in factor VIIIc, factor Vc and protein S. 38% of subjects, with no evidence of Factor V Leiden or anticardiolipin antibodies, showed a low APC:SR (APC:SR <2.6) in the third trimester of pregnancy. Aside from a significant reduction in birth weight, no difference in pregnancy outcome was observed between these subjects and those with a normal APC:SR. Activated protein C sensitivity ratio, modified by pre-dilution of patient samples with factor V depleted plasma, showed no consistent trend with gestation.

 

  • References

  • 1 Pabinger I, Kyrle PA, Heistinger M, Eichinger S, Wittmann E, Lechner K. The risk of thromboembolism in asymtomatic patients with protein C and protein S deficiency: a prospective cohort study. Thromb Haemost 1994; 71 (04) 441-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Trauscht Van Horn JJ, Capeless EL, Easterling TR, Bovill EG. Pregnancy loss and thrombosis with protein C deficiency. Am J Obstet Gynecol 1992; 167 4 Pt 1 968-72.
    CrossrefPubMedGoogle Scholar
  • 3 Dekker GA, De Vries JIP, Doelitzsch PM. et al. Underlying disorders associated with severe early-onset pre-eclampsia. Am J Obstet Gynecol 1995; 173 (04) 1042-8.
    CrossrefPubMedGoogle Scholar
  • 4 Cadroy Y, Grandjean H, Pichon J. et al. Evaluation of six markers of haemostatic system in normal pregnancy and pregnancy complicated by hyper-tension or pre-eclampsia. Br J Obstet Gynaecol 1993; 100 (05) 416-20.
    CrossrefPubMedGoogle Scholar
  • 5 Brenner B, Lanir N, Thaler I. HELLP syndrome associated with factor V R 506Q mutation. Br J Haematol 1996; 92 (04) 999-1001.
    CrossrefPubMedGoogle Scholar
  • 6 Preston FE, Rosendaal FR, Walker ID. et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348 9032 913-6.
    CrossrefPubMedGoogle Scholar
  • 7 Rai R, Regan L, Hadley E, Dave M, Cohen H. Second-trimester pregnancy loss is associated with activated protein C resistance. Br J Haematol 1996; 92 (02) 489-90.
    PubMedGoogle Scholar
  • 8 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90 (03) 1004-8.
    CrossrefPubMedGoogle Scholar
  • 9 Koster T, Rosendaal FR, DeRonde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein-C – Leiden Thrombophilia Study. Lancet 1993; 342 8886-7 1503-6.
    CrossrefPubMedGoogle Scholar
  • 10 Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in the majority of thrombophilic patients. Blood 1993; 82: 1989-93.
    PubMedGoogle Scholar
  • 11 Bertina RM, Koeleman BPC, Koster T. et al. Mutation in blood-coagulation factor-V associated with resistance to activated protein-C. Nature 1994; 369 6475 64-7.
    CrossrefPubMedGoogle Scholar
  • 12 Cumming AM, Tait RC, Fildes S, Yoong A, Keeney S, Hay CR. Development of resistance to activated protein C during pregnancy. Br J Haematol 1995; 90 (03) 725-7.
    CrossrefPubMedGoogle Scholar
  • 13 Mathonnet F, De Mazancourt P, Bastenaire B. et al. Activated protein C sensitivity ratio in pregnant women at delivery. Br J Haematol 1996; 92 (01) 244-6.
    CrossrefPubMedGoogle Scholar
  • 14 Jorquera JI, Aznar J, Fernandez MA, Montoro JM, Curats R, Casana P. A modification of the APC resistance test and its application to the study of patients on coumarin therapy. Thromb Res 1996; 82 (03) 217-24.
    CrossrefPubMedGoogle Scholar
  • 15 Stirling Y, Woolf L, North WRS, Seghatchian MJ, Meade TW. Haemostasis in normal pregnancy. Thromb Haemost 1984; 52 (02) 176-82.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 De Ronde H, Bertina RM. Laboratory diagnosis of APC-resistance: A critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost 1994; 72 (06) 880-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Colluci M, Ciavarella N, Giliberti MG, Semeraro N. Resistance to activated protein C (APC): influence of factor V levels. Thromb Haemost 1994; 72: 987-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Freyburger G, Bilhou-Nabera C, Dief S. et al. Technical and biological conditions influencing the functional APC resistance test. Thromb Haemost 1996; 75 (03) 460-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Lefkowitz JB, Clarke AH, Barbour LA. Comparison of protein S functional and antigenic assays in normal pregnancy. Am J Obstet Gynecol 1996; 175 (03) 657-60.
    CrossrefPubMedGoogle Scholar
  • 20 Hellgren M, Blombäck M. Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium. Gynecol Obstet Invest 1981; 12 (03) 141-54.
    CrossrefPubMedGoogle Scholar
  • 21 Bremme K, Ostlund E, Almqvist I, Heinonen K, Blomback M. Enhanced thrombin generation and fibrinolytic activity in normal pregnancy and the puerperium. Obstet Gynecol 1992; 80 (01) 132-7.
    PubMedGoogle Scholar
  • 22 Weenink GH, Treffers PE, Kahle LH, ten Cate JW. Antithrombin III in normal pregnancy. Thromb Res 1982; 26: 281-7.
    CrossrefPubMedGoogle Scholar
  • 23 Weiner CP, Brandt J. Plasma antithrombin III activity in normal pregnancy. Obstet Gynecol 1980; 56 (05) 601-3.
    PubMedGoogle Scholar
  • 24 Mannucci PM, Vigano S, Botasso B. et al. Protein C antigen during pregnancy, delivery and the puerperium. Thromb Haemost 1984; 52: 217.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Gonzalez R, Alberca I, Vicente V. Protein C levels in late pregnancy and in women on oral contraceptives. Thromb Res 1985; 39: 637-40.
    CrossrefPubMedGoogle Scholar
  • 26 Gatti L, Tenconi PM, Guarneri D. et al. Hemostatic parameters and platelet activation by flow cytometry in normal pregnancy: a longitudinal study. Int J Clin Lab Res 1994; 24: 217-9.
    CrossrefPubMedGoogle Scholar
  • 27 Tait RC, Walker ID, Islam SIAM. et al. Protein C activity in healthy volunteers-influence of age, sex, smoking and oral contraceptives. Thromb Haemost 1993; 70: 281-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Vigano S, Mannucci PM, D’Angelo A. et al. Protein C antigen is not an acute phase reactant and is often high in ischaemic heart disease and diabetes. Thromb Haemost 1984; 52 (03) 263-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Grip L, Blombäck M, Schulman S. Hypercoagulable state following warfarin withdrawal in post-myocardial infarction patients. Eur Heart J 1991; 12: 1225-33.
    CrossrefPubMedGoogle Scholar
  • 30 Palaretti G, Legnani G, Guazzaloca M. et al. Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants – A prospective study. Thromb Haemost 1994; 72: 222-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Kluft C, Bertina RM, Preston FE. et al. Protein C an anticoagulant protein is increased in healthy volunteers and surgical patients after treatment with stanozolol. Thromb Res 1984; 33 (03) 297-304.
    CrossrefPubMedGoogle Scholar
  • 32 Sandset PM, Hogevold HE, Lyberg T, Andersson TR, Abildgaard U. Extrinsic pathway inhibitor in elective surgery: a comparison with other coagulation inhibitors. Thromb Haemost 1989; 62 (03) 856-60.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Gibbs NM, Crawford GP, Michalopoulos N. Postoperative changes in coagulant and anticoagulant factors following abdominal aortic surgery. J Cardiothor Vasc Anaesth 1992; 6 (06) 680-5.
    PubMedGoogle Scholar
  • 34 Conlan MG, Folsom AR, Finch A, Davis CE, Sorlie P, Wu KK. Correlation of plasma protein C levels with cardiovascular risk factors in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost 1993; 70 (05) 762-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Woodward M, Lowe GDO, Rumley A. et al. Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey II. Relationships to cardiovascular risk factors and prevalent cardiovascular disease. Br J Haematol 1997; 97: 785-97.
    CrossrefPubMedGoogle Scholar
  • 36 Sattar N, Greer IA, Louden J. et al. Lipoprotein subfraction changes in normal pregnancy: threshold effect of plasma triglyceride on appearance of small dense low density lipoprotein. J Clin Endocrin Metab 1997; 82: 2483-91.
    PubMedGoogle Scholar
  • 37 Faught W, Garner P, Jones G, Ivey B. Changes in protein C and protein S levels in normal pregnancy. Am J Obstet Gynecol 1995; 172 1 Pt 1 147-50.
    CrossrefPubMedGoogle Scholar
  • 38 Malm J, Laurell M, Dahlbäck B. Changes in the plasma levels of vitamin K-dependent proteins C and S and of C4b-binding protein during pregnancy and oral contraception. Br J Haematol 1988; 68: 437-43.
    CrossrefPubMedGoogle Scholar
  • 39 Comp PC, Thurnau GR, Welsh J, Esmon CT. Functional and immunologic protein S levels are decreased during pregnancy. Blood 1986; 68 (04) 881-5.
    PubMedGoogle Scholar
  • 40 Cumming AM, Tait RC, Fildes S, Hay CR. Diagnosis of APC Resistance during pregnancy (letter). Br J Haematol 1996; 92 (04) 1026-9.
    CrossrefPubMedGoogle Scholar
  • 41 Mathonnet F, de Mazancourt P, Denninger M-H, Morot M, Benattar N, Giudicelli Y. Role of factor VIII on activated protein C resistance ratio on inflammatory diseases. Br J Haematol 1996; 95: 423-5.
    CrossrefPubMedGoogle Scholar
  • 42 Henkens CMA, Bom VJJ, van der Meer J. Lowered APC-sensitivity ratio related to increased factor VIII-clotting activity. Thromb Haemost 1995; 74 (04) 1197-207.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Colucci B, Ciavaralla N, Giliberti MG, Semeraro N. Resistance to activated protein C (APC): Influence of factor V levels (letter). Thromb Haemost 1994; 72 (06) 987-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Freyburger G, Bilhou-Nabera C, Dief S. et al. Technical and biological conditions influencing the functional APC resistance test. Thromb Haemost 1996; 75 (03) 460-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Bokarewa MI, Wramsby M, Bremme K, Blomback M. Variability of the response to activated protein during normal pregnancy. Blood Coag Fibrinol 1997; 8: 239-44.
    CrossrefPubMedGoogle Scholar
  • 46 Trossaert M, Conard J, Horellou MH. et al. Modified APC resistance assay for patients on oral anticoagulants. Lancet 1994; 344: 1709.
    PubMedGoogle Scholar
  • 47 Clark P, Brennand J, Conkie J, McCall F, Greer IA, Walker ID. A normal range for activated protein C resistance in the third trimester of pregnancy (abstract). Blood Coag Fibrinol 1997; 8 (07) 481.
    PubMedGoogle Scholar
  • 48 Comeglio P, Fedi S, Liotta AA. et al. Blood clotting activation during normal pregnancy. Thromb Res 1996; 84 (03) 199-202.
    CrossrefPubMedGoogle Scholar
  • 49 Mercilina-Roumans PEAM, Ubachs JMH, van Wersch JMH. Coagulation and fibrinolysis in smoking and non-smoking pregnant women. Br J Obstet Gynaecol 1996; 103: 789-94.
    CrossrefPubMedGoogle Scholar
  • 50 Schlit AF, Col-De BC, Moriau M, Lavenne-Pardonge E. Acquired activated protein C resistance in pregnancy. Thromb Res 1996; 84 (03) 203-6.
    CrossrefPubMedGoogle Scholar
  • 51 Lockwood CJ, Romero R, Feinberg RF, Clyne LP, Coster B, Hobbins JC. The prevalence and biologic significance of lupus anticoagulant and anti-cardiolipin antibodies in a general obstetric population. Am J Obstet Gynecol 1989; 161 (02) 369-73.
    CrossrefPubMedGoogle Scholar
  • 52 Pattison NS, Chamley LW, McKay EJ, Liggins GC, Butler WS. Antiphospholipid antibodies in pregnancy: prevalence and clinical associations. Br J Obstet Gynecol 1993; 100 (10) 909-13.
    CrossrefPubMedGoogle Scholar
  • 53 Bonnar J, Daly L, Sheppard BL. Changes in the fibrinolytic system during pregnancy. Semin Thromb Haemost 1990; 16 (03) 221-9.
    Article in Thieme ConnectPubMedGoogle Scholar