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Thromb Haemost 2007; 98(01): 163-171
DOI: 10.1160/TH06-10-0574
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

The effect of dalteparin on coagulation activation during pregnancy in women with thrombophilia

A randomized trial
Karim Abou-Nassar
1   Hematology, Ottawa Hospital, Ottawa, Ontario, Canada
,
Michael J. Kovacs
2   Hematology, Victoria Hospital, London, Ontario, Canada
,
Susan R. Kahn
3   Department of Medicine and Center for Clinical Epidemiology and Community Studies, Jewish General Hospital, Montreal, Quebec, Canada
,
Philip Wells
1   Hematology, Ottawa Hospital, Ottawa, Ontario, Canada
,
Steve Doucette
1   Hematology, Ottawa Hospital, Ottawa, Ontario, Canada
,
Tim Ramsay
1   Hematology, Ottawa Hospital, Ottawa, Ontario, Canada
,
Anne Marie Clement
1   Hematology, Ottawa Hospital, Ottawa, Ontario, Canada
,
Rshmi Khurana
4   Medicine, Royal Alexandra Hospital, Edmonton, Alberta, Canada
,
Karen MacKinnon
1   Hematology, Ottawa Hospital, Ottawa, Ontario, Canada
,
Mark Blostein
5   Hematology, S.M.B.D. Jewish General Hospital, Montreal, Quebec, Canada
,
Susan Solymoss
6   Hematology, St Mary‘s Hospital Center, Montreal, Quebec, Canada
,
John Kingdom
7   Department of Obstetrics, Mount Sinai Hospital, Toronto, Ontario, Canada
,
Matthew Sermer
7   Department of Obstetrics, Mount Sinai Hospital, Toronto, Ontario, Canada
,
Evelyne Rey
8   Medicine, Hopital Saint Justine, Montreal, Quebec, Canada
,
Marc Rodger
1   Hematology, Ottawa Hospital, Ottawa, Ontario, Canada
,
the TIPPS investigators › Author AffiliationsDisclosure: The TIPPS study was partially funded by Pharmacia (now Pfizer) in the form of an unrestricted grant. This support was withdrawn when Pfizer acquired Pharmacia in 2004. Pfizer was not involved in the design, analysis or interpretation of the study that is the subject of this manuscript. Doctors Rodger, Wells, Kahn, Kovacs and Solymoss have participated on Pfizer Advisory Boards and received compensation for this participation. Doctors Rodger, Wells, Solymoss, Kovacs and Kahn have received honoraria for lectures. Doctors Rodger, Wells, Kovacs and Rey have received grant funding from Pfizer. Pfizer is the current manufacturer of dalteparin.
Further Information

Publication History

Received 10 October 2006

Accepted after resubmission 03 April 2007

Publication Date:
29 November 2017 (online)

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Summary

Low-molecular-weight heparin (LMWH) is increasingly being used for prophylaxis of venous thromboembolism (VTE) and prevention of pregnancy associated morbidity in pregnant women with thrombophilia. We sought to determine if the administration of prophylactic doses of LMWH downregulates coagulation activation in high risk pregnant women with thrombophilia. This sub-study was planned as part of a randomized open label controlled trial (Thrombophilia in Pregnancy Prophylaxis Study[TIPPS])in which patients at high risk of pregnancy complications with confirmed thrombophilia are randomized to receive either dalteparin (5,000 units/day until 20 weeks then 5,000 units q12h until 37 weeks or onset of labor) or no treatment. Blood samples were collected at baseline, day 7–9 (after starting study drug), week 20 (before increasing study drug), week 36 (prior to stopping study drug) and at the time of admission to the labor and delivery unit. Samples were not drawn at fixed times in relation to drug injection. These samples were analyzed for levels of thrombin-antithrombin complexes (TAT), prothrombin fragments 1+2 (F1.2), D-dimer and anti-Xa activity. Generalized linear mixed models were used for statistical analysis and model results were controlled for age, smoking status, type of thrombophilia and predisposing risk factors. The effect of dalteparin onTAT levels was defined as the primary outcome. Of 198 patients eligible, 114 were enrolled in TIPPS. Ninety-one were eligible for the TIPPS coagulation activation sub-study and randomized. Thirty-nine patients were analyzed in the treatment group (dalteparin) and 46 patients in the control group (no intervention). Levels of coagulation activation factors F1.2, TAT and D-dimer increased significantly throughout pregnancy in both groups (p<0.0001). Dalteparin prophylaxis resulted in a significant increase in anti-Xa activity through pregnancy (p<0.0001) compared to controls. Dalteparin had no significant effects on the levels of TAT, F1.2 and D-dimer throughout pregnancy in thrombophilic women.A post-hoc Monte Carlo power analysis revealed that our study had 100% and 88% power to detect reductions in TAT values on treatment of 50% and 25%, respectively. Prophylaxis with dalteparin at doses used in this study did not reduce coagulation activation in high risk thrombophilic women during pregnancy.

Keywords

Low-molecular-weight heparin - pregnancy - thrombophilia - coagulation activation
 

  • References

  • 1 Cerneca F, Ricci G, Simeone R. et al. Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis. Eur J Obstet Gynecol Reprod Biol 1997; 73: 31-36.
    CrossrefPubMedGoogle Scholar
  • 2 Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost 2003; 29: 125-130.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Eichinger S, Weltermann A, Philipp K. et al. Prospective evaluation of hemostatic system activation and thrombin potential in healthy pregnant women with and without factor V Leiden. Thromb Haemost 1999; 82: 1232-1236.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 McColl M, Ramsay JE, Tait RC. et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 8: 1183-1188.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Lin J, August P. Genetic thrombophilias and preeclampsia: a meta-analysis. Obstet Gynecol 2005; 105: 182-192.
    CrossrefPubMedGoogle Scholar
  • 6 Alferivic Z, Roberts D, Martlew V. How strong is the association between maternal thrombophilia and adverse pregnancy outcome. Eur J Obstet Gyencol Reprod Biol 2002; 101: 6-14.
    PubMedGoogle Scholar
  • 7 Howley HE, Walker M, Rodger MA. A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction. Am J Obstet Gynecol 2005; 192: 694-708.
    CrossrefPubMedGoogle Scholar
  • 8 Rey E, Kahn SR, David M. et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901-908.
    CrossrefPubMedGoogle Scholar
  • 9 Kujovich JL. Thrombophilia and pregnancy complications. Am J Obstet Gynecol 2004; 191: 412-424.
    CrossrefPubMedGoogle Scholar
  • 10 Weiner Z, Younis JS, Blumenfeld Z. et al. Assessment of uterine placental circulation in thrombophilic women. Semin Thromb Hemost 2003; 29: 213-218.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Arias F, Romero R, Joist H. et al. Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta. J Mat Fet Med 1998; 7: 277-286.
    PubMedGoogle Scholar
  • 12 Greer IA, De Swiet M. Thrombosis prophylaxis in obstetrics and gynaecology. Br J Obstet Gynaecol 1993; 100: 37-40.
    CrossrefPubMedGoogle Scholar
  • 13 Dolovich L, Ginsberg JS, Douketis JD. et al. A meta-analysis comparing low molecular weight heparins to unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000; 160: 181-188.
    CrossrefPubMedGoogle Scholar
  • 14 Gould MK, Dembitzer AD, Doyle RL. et al. Low molecular weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130: 800-809.
    CrossrefPubMedGoogle Scholar
  • 15 Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005; 106: 401-407.
    CrossrefPubMedGoogle Scholar
  • 16 Bates SM, Greer IA, Hirsh J. et al. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl. 03) 627S-644S.
    CrossrefPubMedGoogle Scholar
  • 17 Schambeck CM, Eberl E, Geisen U. et al. The impact of dalteparin (Fragmin) on thrombin generation in pregnant women with venous thromboembolism: significance of the factor V Leiden mutation. Thromb Haemost 2001; 85: 782-786.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Hoke M, Kyrle PA, Philipp K. et al. Prospective evaluation of coagulation activation in pregnant women receiving low-molecular weight heparin. Thromb Haemost 2004; 91: 935-940.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Gris JC, Mercier E, Quéré I. et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 2004; 103: 3695-3699.
    CrossrefPubMedGoogle Scholar
  • 20 Brenner B, Hoffman R, Carp H. et al. LIVE-ENOX Investigators.. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the LIVE-ENOX study. J Thromb Haemost 2005; 3: 227-229.
    CrossrefPubMedGoogle Scholar
  • 21 Wells PS, Rodger MA. Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications. J Thromb Haemost 2004; 2: 1188-1190.
    CrossrefPubMedGoogle Scholar
  • 22 Lopez Y, Paloma J, Rifon J. et al. Measurement of prethrombotic markers in the assassement of acquired hypercoagulable states. Thromb Res 1999; 93: 71-78.
    CrossrefPubMedGoogle Scholar
  • 23 Hunt BJ, Doughty HA, Majumdar G. et al. Thromboprophylaxis with LMWH (fragmin) in high risk pregnancies. Thromb Haemost 1997; 77: 39-43.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Sephton V, Farquharson RG, Topping J. et al. A longitudinal study of maternal dose response to low molecular weight heparin in pregnancy. Obstet Gynecol 2003; 101: 1307-1311.
    PubMedGoogle Scholar
  • 25 Norris LA, Bonnar J, Smith MP, Steer PJ. et al. Low molecular weight heparin (tinzaparin) therapy for moderate risk thromboprophylaxis during pregnancy. A pharmacokinetic study. Thromb Haemost 2004; 92: 791-796.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Yoneda M, Brosnan JF, Norris LA. et al. The effect of LMWH (tinzaparin) on coagulation and fibrinolytic activation in pregnant women at risk of thrombosis. Thromb Res 2006; 117: 283-290.
    CrossrefPubMedGoogle Scholar
  • 27 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Bombeli T, Raddatz Mueller P, Fehr J. Evaluation of an optimal dose of low molecular-weight heparin for thromboprophylaxis in pregnant women at risk of thrombosis using coagulation activation markers. Haemostasis 2001; 31: 90-98.
    PubMedGoogle Scholar
  • 29 Cofrancesco E, Cortellaro M, Corradi A. et al. Coagulation activation markers in prediction of venous thrombosis after elective hip surgery. Thromb Haemost 1997; 77: 267-269.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Ginsberg JS, Brill-Edwards P, Panju A. et al. Preoperative plasma levels of hrombin-antothrombin III complexes correlate with the development of venous thrombosis after major hip or knee surgery. Thromb Haemost 1995; 74: 602-605.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Cadroy Y, Grandjean H, Pichon J. et al. Evaluation of six markers of haemostatic system in normal pregnancy and pregnancy complicated by hypertension or pre-eclampsia. Br J Obstet Gynaecol 1993; 100: 416-420.
    CrossrefPubMedGoogle Scholar
  • 32 Antovic A, Blomback M, Bremme K. et al. The assay of overall haemostasis potential used to monitor the low molecular mass (weight) heparin, dalteparin, treatment in pregnant women with previous thromboembolism. Blood Coagul Fibrinolysis 2002; 13: 181-186.
    CrossrefPubMedGoogle Scholar
  • 33 Isermann B, Sood R, Pawlinski R. et al. Thrombomodulin-protein C system is essential for the maintenance of pregnancy. Nat Med 2003; 9: 258-260.
    CrossrefPubMedGoogle Scholar
  • 34 Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004; 10: 1222-1226.
    CrossrefPubMedGoogle Scholar