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Thromb Haemost 1999; 82(04): 1232-1236
DOI: 10.1055/s-0037-1614366
Review Article
Schattauer GmbH

Prospective Evaluation of Hemostatic System Activation and Thrombin Potential in Healthy Pregnant Women with and without Factor V Leiden

Sabine Eichinger
1   From the Departments of Internal Medicine I, Division of Hematology and Hemostaseology, University Vienna, Department of Gynecology and Obstetrics and Department of Laboratory Medicine, Donauspital, Vienna, Institute of Biometrics, University Vienna, Department of Laboratory Medicine, University Vienna, Austria
,
Ansgar Weltermann
1   From the Departments of Internal Medicine I, Division of Hematology and Hemostaseology, University Vienna, Department of Gynecology and Obstetrics and Department of Laboratory Medicine, Donauspital, Vienna, Institute of Biometrics, University Vienna, Department of Laboratory Medicine, University Vienna, Austria
,
Karl Philipp
1   From the Departments of Internal Medicine I, Division of Hematology and Hemostaseology, University Vienna, Department of Gynecology and Obstetrics and Department of Laboratory Medicine, Donauspital, Vienna, Institute of Biometrics, University Vienna, Department of Laboratory Medicine, University Vienna, Austria
,
Erich Hafner
1   From the Departments of Internal Medicine I, Division of Hematology and Hemostaseology, University Vienna, Department of Gynecology and Obstetrics and Department of Laboratory Medicine, Donauspital, Vienna, Institute of Biometrics, University Vienna, Department of Laboratory Medicine, University Vienna, Austria
,
Alexandra Kaider
1   From the Departments of Internal Medicine I, Division of Hematology and Hemostaseology, University Vienna, Department of Gynecology and Obstetrics and Department of Laboratory Medicine, Donauspital, Vienna, Institute of Biometrics, University Vienna, Department of Laboratory Medicine, University Vienna, Austria
,
Eva-Maria Kittl
1   From the Departments of Internal Medicine I, Division of Hematology and Hemostaseology, University Vienna, Department of Gynecology and Obstetrics and Department of Laboratory Medicine, Donauspital, Vienna, Institute of Biometrics, University Vienna, Department of Laboratory Medicine, University Vienna, Austria
,
Brigitte Brenner
1   From the Departments of Internal Medicine I, Division of Hematology and Hemostaseology, University Vienna, Department of Gynecology and Obstetrics and Department of Laboratory Medicine, Donauspital, Vienna, Institute of Biometrics, University Vienna, Department of Laboratory Medicine, University Vienna, Austria
,
Christine Mannhalter
1   From the Departments of Internal Medicine I, Division of Hematology and Hemostaseology, University Vienna, Department of Gynecology and Obstetrics and Department of Laboratory Medicine, Donauspital, Vienna, Institute of Biometrics, University Vienna, Department of Laboratory Medicine, University Vienna, Austria
,
Klaus Lechner
1   From the Departments of Internal Medicine I, Division of Hematology and Hemostaseology, University Vienna, Department of Gynecology and Obstetrics and Department of Laboratory Medicine, Donauspital, Vienna, Institute of Biometrics, University Vienna, Department of Laboratory Medicine, University Vienna, Austria
,
Paul A. Kyrle
1   From the Departments of Internal Medicine I, Division of Hematology and Hemostaseology, University Vienna, Department of Gynecology and Obstetrics and Department of Laboratory Medicine, Donauspital, Vienna, Institute of Biometrics, University Vienna, Department of Laboratory Medicine, University Vienna, Austria
› Author Affiliations
Further Information

Publication History

Received 09 December 1998

Accepted after resubmission 10 May 1999

Publication Date:
08 December 2017 (online)

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Summary

Normal pregnancy is associated with alterations of the hemostatic system towards a hypercoagulable state and an increased risk of venous thromboembolism. The risk of venous thrombosis is higher in pregnant women with factor V Leiden (FVL) than in those with wildtype factor V. Routine laboratory assays are not useful to detect hypercoagulable conditions. A prospective and systematic evaluation of hemostatic system activation in women with and without FVL during an uncomplicated pregnancy employing more sensitive markers of hypercoagulability, such as prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), D-Dimer, or the endogenous thrombin potential (ETP), an indicator of the plasma’s potential to generate thrombin, has not been performed. We prospectively followed 113 pregnant women with (n = 11) and without (n = 102) FVL and measured F1+2, TAT, D-Dimer and the ETP at the 12th, 22nd and 34th gestational week as well as 3 months after delivery (baseline) in each subject. None of the women developed clinical signs of venous thromboembolism during pregnancy or postpartum. Pregnant women with and without FVL exhibited substantial activation of the coagulation and fibrinolytic system as indicated by a gradual increase of F1+2, TAT and D-Dimer throughout uncomplicated pregnancy up to levels similar to those found in acute thromboembolic events (p < 0.0001 by analysis of variance for each parameters). Levels of F1+2 and TAT were comparable between women with and without FVL, but levels of D-Dimer were significantly higher in women with FVL than in those without the mutation (p = 0.0005). The ETP remained unchanged in both women with and without FVL at all timepoints. Our data demonstrate a substantial coagulation and fibrinolytic system activation in healthy women with and without FVL during uncomplicated pregnancy. An elevated F1+2, TAT or D-Dimer level during pregnancy is not necessarily indicative for an acute thromboembolic event. The normal ETP in both women with and without FVL suggests that the capacity of the plasma to generate thrombin after in vitro activation of the clotting system is not affected by pregnancy. Higher levels of D-Dimer in women with FVL than in women with wildtype factor V at baseline as well as during pregnancy indicate increased fibrinolytic system activation in carriers of the mutation.

 

  • References

  • 1 Hellgren M, Blombäck M. Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium. Gynecol Obstet Invest 1981; 12: 141-54.
    CrossrefPubMedSearch in Google Scholar
  • 2 Stirling Y, Woolf L, North WRS, Seghatchian MJ, Meade TW. Haemostasis in normal pregnancy. Thromb Haemost 1984; 52: 176-82.
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 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.
    CrossrefPubMedSearch in Google Scholar
  • 4 McColl MD, Ramsay JE, Tait RC, Walker ID, McCall F, Conkie JA, Carty MJ, Greer IA. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 78: 1183-8.
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Bauer KA. Laboratory markers of coagulation activation. Arch Pathol Lab Med 1993; 117: 71-7.
    PubMedSearch in Google Scholar
  • 6 Mannucci PM. Mechanisms, markers and management of coagulation activation. Br Med Bull 1994; 50: 851-70.
    CrossrefPubMedSearch in Google Scholar
  • 7 de Boer K, ten Cate JW, Sturk A, Borm JJJ, Treffers PE. Enhanced thrombin generation in normal and hypertensive pregnancy. Am J Obstet Gynecol 1989; 160: 95-100.
    CrossrefPubMedSearch in Google Scholar
  • 8 Reinthaller A, Mursch-Edlmayr 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.
    CrossrefPubMedSearch in Google Scholar
  • 9 Cadroy Y, Grandjean H, Pichon J, Desprats R, Berrebi A, Fournie A, Boneu B. Evaluation of six markers of haemostatic system in normal pregnancy and pregnancy complicated by hypertension or pre-eclampsia. Br J Obstet Gynaecol 1993; 100: 416-20.
    CrossrefPubMedSearch in Google Scholar
  • 10 Halligan A, Bonnar J, Sheppard B, Darling M, Walshe J. Haemostatic, fibrinolytic and endothelial variables in normal pregnancy and pre-eclampsia. Br J Obstet Gynaecol 1994; 101: 488-92.
    CrossrefPubMedSearch in Google Scholar
  • 11 Zangari M, Lockwood CJ, Scher J, Rand JH. Prothrombin activation fragment (F1.2) is increased in pregnant patients with antiphospholipid antibodies. Thromb Res 1997; 85: 177-83.
    CrossrefPubMedSearch in Google Scholar
  • 12 van Wersch JWJ, Ubachs JMH. Blood coagulation and fibrinolysis during normal pregnancy. Eur J Clin Chem Clin Biochem 1991; 29: 45-50.
    PubMedSearch in Google Scholar
  • 13 Hemker HC, Bèguin S. Thrombin generation in plasma: its assessment via the endogenous thrombin potential. Thromb Haemost 1995; 74: 134-8.
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Wielders S, Mukherjee M, Michiels J, Rijkers DTS, Cambus JP, Knebel RWC, Kakkar V, Hemker HC, Bèguin S. The routine determination of the endogenous thrombin potential, first results in different forms of hyper- and hypocoagulability. Thromb Haemost 1997; 77: 629-36.
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
    CrossrefPubMedSearch in Google Scholar
  • 16 Dahlbäck B. Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 1995; 85: 607-14.
    PubMedSearch in Google Scholar
  • 17 Hellgren M, Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives. Am J Obst Gynecol 1995; 173: 210-3.
    CrossrefPubMedSearch in Google Scholar
  • 18 Martinelli I, Bottasso B, Duca F, Faioni E, Mannucci PM. Heightened thrombin generation in individuals with resistance to activated protein C. Thromb Haemost 1996; 75: 703-5.
    Thieme ConnectPubMedSearch in Google Scholar
  • 19 Zoeller B, Holm J, Svensson P, Dahlbäck B. Elevated levels of prothrombin activation fragment 1+2 in plasma from patients with heterozygous Arg506 to Gln mutation in the factor V gene (APC-resistance) and/or inherited protein S deficiency. Thromb Haemost 1996; 75: 270-4.
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Simioni P, Scarano L, Gavasso S, Sardella C, Girolami B, Scudeller A, Girolami A. Prothrombin fragment 1+2 and thrombin-antithrombin complex levels in patients with inherited APC resistance due to factor V Leiden mutation. Br J Haematol 1996; 92: 435-41.
    CrossrefPubMedSearch in Google Scholar
  • 21 Kyrle PA, Eichinger S, Pabinger I, Stümpflen A, Hirschl M, Bialonczyk C, Schneider B, Mannhalter C, Melichart M, Traxler G, Weltermann A, Speiser W, Lechner K. Prothrombin fragment F1+2 is not predictive for recurrent venous thromboembolism. Thromb Haemost 1997; 77: 829-33.
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Nicolaes GAF, Thomassen MCLGD, Tans G, Rosing J, Hemker HC. Effect of activated protein C on thrombin generation and on the thrombin potential in plasma of normal and APC-resistant individuals. Blood Coagul Fibrin 1997; 8: 28-38.
    CrossrefPubMedSearch in Google Scholar
  • 23 Elashoff JD. nQuery Advisor. Los Angeles, CA: Dixon Associates; 1995
    Search in Google Scholar
  • 24 Crowder MJ, Hand DJ. Analysis of repeated measures. Chapman and Hall; London, UK: 1990
    Search in Google Scholar
  • 25 Boneu B, Bes G, Pelzer H, Sie P, Boccalon H. D-dimers, thrombin antithrombin III complexes and prothrombin fragments 1+2: diagnostic value in clinically suspected deep vein thrombosis. Thromb Haemost 1991; 65: 28-31.
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 Yamada N, Wada H, Nakase T, Minamikawa K, Nagaya S, Nakamura M, Hiraoka N, Fuzioka H, Hayashi T, Suzuki K. et al. Hemostatic abnormalities in patients with pulmonary embolism compared with that in deep vein thrombosis. Blood Coagul Fibrinolysis 1995; 6: 627-33.
    CrossrefPubMedSearch in Google Scholar
  • 27 Merlini PA, Bauer KA, Oltrona L, Ardissino D, Cattaneo M, Belli C, Mannucci PM, Rosenberg RD. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90: 61-8.
    CrossrefPubMedSearch in Google Scholar
  • 28 Nowak-Göttl U, Schneppenheim R, Vielhaber H. APC resistance in childhood thromboembolism: diagnosis and clinical aspects. Semin Thromb Hemost 1997; 23: 253-8.
    Thieme ConnectPubMedSearch in Google Scholar