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Thromb Haemost 2001; 85(01): 30-35
DOI: 10.1055/s-0037-1612659
Review Article
Schattauer GmbH

The Glasgow Outcome, APCR and Lipid (GOAL) Pregnancy Study: Significance of Pregnancy Associated Activated Protein C Resistance

Peter Clark
1   Department of Haematology and University Departments of Biochemistry, Royal Infirmary, Glasgow, UK
,
Naveed Sattar
1   Department of Haematology and University Departments of Biochemistry, Royal Infirmary, Glasgow, UK
,
Isobel D. Walker
2   Department of Haematology and University Departments of Obstetrics and Gynaecology, Royal Infirmary, Glasgow, UK
,
Ian A. Greer
2   Department of Haematology and University Departments of Obstetrics and Gynaecology, Royal Infirmary, Glasgow, UK
› Author Affiliations
Further Information

Publication History

Received 18 November 1999

Accepted after resubmission 16 August 2000

Publication Date:
08 December 2017 (online)

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Summary

Activated protein C (APC) resistance secondary to Factor V Leiden (FVL) is associated with pregnancy failure and pre-eclampsia (PET). In non-pregnant subjects, the degree of resistance to APC relates to venous thrombosis risk. In pregnancy, resistance to APC occurs in the absence of FVL. We investigated, in an unselected prospective longitudinal study of 1671 pregnant, non-FVL subjects, the relationship of the APC sensitivity ratio (APC:SR) with demographic variables and pregnancy outcome.

Lower APC:SR values at 7-16 weeks gestation were observed in subjects who subsequently developed PET (median APC:SR 2.55, IQR 2.29-2.70 vs 2.69, IQR 2.48-2.93, Mann-Whitney U-test p = 0.003) in the current pregnancy. An APC:SR < the median (2.69) at 7-16 weeks was associated with a 2.95-fold increased risk (CI95 1.2-7.4) of PET in the current pregnancy. No relationship between the APC:SR, at any gestation, and fetal loss was observed. An inverse correlation between the APC:SR and birth weight was noted. Higher APC:SRs were observed in blood group O subjects and smokers. An inverse relationship of the APC:SR with age, diastolic blood pressure and total serum cholesterol was observed.

Keywords

APC resistance - pregnancy - pre-eclampsia
 

  • References

  • 1 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
  • 2 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
  • 3 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85 (06) 1504-8.
    PubMedGoogle Scholar
  • 4 Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332 (14) 912-7.
    CrossrefPubMedGoogle Scholar
  • 5 Clark P, Brennand J, Conkie JA, McCall F, Greer IA, Walker ID. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998; 79 (06) 1166-70.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 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 (01) 233-8.
    CrossrefPubMedGoogle Scholar
  • 7 de Visser MCH, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93 (04) 1271-6.
    PubMedGoogle Scholar
  • 8 Tosetto AM, E. Gatto E., Rodeghiero F. The VITA project: phenotypic resistance to activated protein C and Factor V Leiden mutation in the general population. Vicenza Thrombophilia and Atherosclerosis. Thromb Haemost 1997; 78 (02) 859-63.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Clark P, Walker ID, Greer I. Acquired activated protein C resistance in pregnancy and association with increased thrombin generation and fetal weight. Lancet 1999; 353 9149 292-3.
    PubMedGoogle Scholar
  • 10 Reinthaller A, Mursch-Edlmayar G, Tatra G. Thrombin-antithrombin III complex levels in normal pregnancy, with hypertensive disorders and after delivery. Br J Obstet Gynaecol 1990; 97: 506-10.
    CrossrefPubMedGoogle Scholar
  • 11 Halligan A, Bonnar J, Sheppard B, Darling M, Walshe J. Haemostatic, fibrinolytic and endothelial variables in normal pregnancies and preeclampsia. Br J Obstet Gynaecol 1994; 101: 488-92.
    CrossrefPubMedGoogle Scholar
  • 12 Lindoff C, Ingemarsson I, Martinsson G, Segelmark M, Thysell H, Astedt B. Preeclampsia is associated with a reduced response to activated protein C. Am J Obstet Gynecol 1997; 176 (02) 457-60.
    CrossrefPubMedGoogle Scholar
  • 13 Grandone E, Margaglione M, Colaizzo D. et al. Factor V Leiden, C>T MTHFR polymorphism and genetic susceptibility to pre-eclampsia. Thromb Haemost 1997; 77: 1052-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Preston FE, Rosendaal FR, Walker ID. et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348 9032 913-6.
    CrossrefPubMedGoogle Scholar
  • 15 Grandone E, Margaglione M, Colaizzo D. et al. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 1997; 77 (05) 822-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 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
  • 17 Svensson PJ, Zoller B, Dahlbäck B. Evaluation of original and modified APC resistance tests in unselected outpatients with clinically suspected thrombosis and in healthy controls. Thromb Haemost 1997; 77: 332-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Cumming AM, Tait RC, Fildes S, Hay CR. Diagnosis of APC resistance during pregnancy. Br J Haematol 1996; 92 (04) 1026-9.
    CrossrefPubMedGoogle Scholar
  • 19 Lindqvist PG, Svensson PJ, Dahlback B, Marsal K. Factor V Q506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss – a possible evolutionary selection mechanism. Thromb Haemost 1998; 79 (01) 69-73.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Lipid Research Clinics Program. Manual of Laboratory Operations. Lipid and Lipoprotein Analysis. National Institute of Health. Bethseda, MD: DHEW Publications (NIH); 1975: 75.
    Google Scholar
  • 21 Roberts JM, Redman CWG. Pre-eclampsia: More than pregnancy-induced hypertension. Lancet 1993; 341: 1447-51.
    CrossrefPubMedGoogle Scholar
  • 22 Altman DG, Coles EC. Normograms for precise determination of birth weight for dates. Br J Obstet Gynaecol 1980; 87 (02) 81-6.
    CrossrefPubMedGoogle Scholar
  • 23 Khong TY, de Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by preeclampsia and by small-for-gestation-age infants. Br J Obstet Gynaecol 1986; 93: 1049-59.
    CrossrefPubMedGoogle Scholar
  • 24 Zeek PM, Assali NS. Vascular changes with eclamptogenic toxaemia of pregnancy. Am J Obstet Gynecol 1950; 20: 1099-109.
    PubMedGoogle Scholar
  • 25 Labarrere CA. Acute atherosis. A histopathological hallmark of immune aggression. Placenta 1988; 9: 95-108.
    CrossrefPubMedGoogle Scholar
  • 26 Kobayashi T, Terao T. Pre-eclampsia as chronic intravascular coagulation. Gynecol Obstet Invest 1987; 24: 170-8.
    CrossrefPubMedGoogle Scholar
  • 27 Saleh AA, Bottoms SF, Ali AM, Mariona FG, Mammen EF. Pre-eclampsia, delivery and the hemostatic system. Am J Obstet Gynecol 1987; 157: 331-6.
    CrossrefPubMedGoogle Scholar
  • 28 Kiechl S, Muigg A, Snater P. et al. Poor response to activated protein C as a prominent risk predictor of advanced atherosclerosis and arterial disease. Circul 1999; 99 (05) 614-9.
    CrossrefPubMedGoogle Scholar
  • 29 Rifae N, Merrill JR, Holly RG. Postprandial effect of a high fat meal on plasma lipid, lipoprotein cholesterol and apolipoprotein measurements. Ann Clin Biochem 1990; 27 (05) 489-93.
    CrossrefPubMedGoogle Scholar
  • 30 Bokarewa MI, Wramsby M, Bremme K, Blomback M. Variability of the response to activated protein C during normal pregnancy. Blood Coag Fibrinol 1997; 8 (04) 239-44.
    CrossrefPubMedGoogle Scholar
  • 31 Meade TW, Cooper JA, Stirling Y, Howarth DJ, Ruddock V, Miller GJ. Factor VIII, ABO blood group and the incidence of ischaemic heart disease. Br J Haematol 1994; 88: 601-7.
    CrossrefPubMedGoogle Scholar
  • 32 Woodward M, Lowe GDO, Rumley A. et al. Epedemiology 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
  • 33 Kawasaki T, Kambayashi J, Sakon M. Hyperlipidemia: a novel etiologic factor in deep vein thrombosis. Thromb Res 1995; 79 (02) 147-51.
    CrossrefPubMedGoogle Scholar
  • 34 Kawasaki T, Kambayashi JI, Ariyoshi H, Sakon M, Suehisa E, Monden M. Hypercholesterolemia as a risk factor for deep-vein thrombosis. Thromb Res 1997; 88 (01) 67-73.
    CrossrefPubMedGoogle Scholar
  • 35 Conlan MG, Folsom AR, Finch A. et al. Associations of factor VIII and von-Willebrand factor with age, race, sex and risk factors for atherosclerosis. Thromb Haemost 1993; 70: 380-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 van der Velde WJ, Treffers PE. Smoking in pregnancy: the influence on percentile birth weight, mean birth weight, placental weight, menstrual age, perinatal mortality and maternal diastolic blood pressure. Gynecol Obstet Invest 1985; 19 (02) 57-63.
    CrossrefPubMedGoogle Scholar
  • 37 Klonoff-Cohen H, Edelstein S, Savitz D. Cigarette smoking and preeclampsia. Obstet Gynecol 1993; 81 (04) 541-14.
    PubMedGoogle Scholar
  • 38 Cnattingius S, Mills JL. et al. The paradoxical effect of smoking in preeclamptic pregnancies: smoking reduces the incidence but increases the rates of perinatal mortality, abruptio placentae, and intrauterine growth restriction. Am J Obstet Gynecol 1997; 177 (01) 156-61.
    CrossrefPubMedGoogle Scholar
  • 39 Dizon-Townson DS, Meline L, Nelson LM, Varner M, Ward K. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol 1997; 177 (02) 402-5.
    CrossrefPubMedGoogle Scholar
  • 40 Cavedon G, Figa-Talamanca I. Correlates of early fetal death among women working in industry. Am J Indust Med 1987; 11 (05) 497-504.
    CrossrefPubMedGoogle Scholar
  • 41 Ahlborg GJ, Bodin L. Tobacco smoke exposure and pregnancy outcome among working women. A prospective study at prenatal care centers in Orebro County, Sweden. Am J Epidemiol 1991; 133 (04) 338-47.
    CrossrefPubMedGoogle Scholar
  • 42 Jensen OH, Foss OP. Smoking in pregnancy. Effects on the birth weight and on thiocyanate concentration in mother and baby. Acta Obstet Gynecol Scand 1981; 60 (02) 177-81.
    PubMedGoogle Scholar
  • 43 Petridou E, Panagiotopoulou K, Katsouyanni K, Spanos E, Trichopoulos D. Tobacco smoking, pregnancy estrogens, and birth weight. Epidemiology 1990; 1 (03) 247-50.
    CrossrefPubMedGoogle Scholar