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Semin Thromb Hemost 2021; 47(07): 824-842
DOI: 10.1055/s-0041-1726374
Review Article

Anti-Xa Monitoring of Low-Molecular-Weight Heparin during Pregnancy: A Systematic Review

Amalie Baun Kjaergaard 
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
,
Jens Fuglsang 
2   Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
,
Anne-Mette Hvas 
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
› Institutsangaben Funding None.
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Abstract

Low-molecular-weight heparin (LMWH) is commonly used for preventing or treating venous thromboembolic disease (VTE) during pregnancy. The physiological changes in maternal metabolism have led to discussions on optimal LMWH dosing strategy and possible need for monitoring. The aim of this systematic review is to summarize and discuss whether LMWH dose adjustment according to anti-Xa provides superior effectiveness and safety compared with weight adjusted or fixed dosed LMWH in pregnant women. A systematic literature search was performed in PubMed, Embase, and Scopus on September 26, 2020. The study is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Effectiveness was defined as episodes of thrombosis and safety as bleeding episodes. In total, 33 studies were included: 4 randomized controlled studies and 29 cohort studies. Prophylactic dosing strategies employing weight dosed, fixed dosed, or anti-Xa adjusted LMWH dosing performed equal in effectiveness and safety. In pregnant women with VTE or high thromboembolic risk, therapeutic weight–adjusted LMWH and weight plus anti-Xa-adjusted LMWH provided equal results in terms of effectiveness and safety. Pregnant women with mechanical heart valves (MHVs) received therapeutic anti-Xa-adjusted LMWH with four out of seven studies presenting mean peak anti-Xa within target ranges. Still, pregnant women with MHV experienced both thrombosis and bleeding with anti-Xa in target. Based on the results of this systematic review, current evidence does not support the need for anti-Xa monitoring when using LMWH as thromboprophylaxis or treatment during pregnancy. Nonetheless, the need for anti-Xa monitoring in pregnant women with MHV may need further scrutiny.

Keywords

low-molecular heparin - anti-Xa - pregnancy - mechanical heart valve - thromboprophylaxis

Supplementary Material



Publikationsverlauf

Artikel online veröffentlicht:
15. Juni 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Sultan AA, West J, Tata LJ, Fleming KM, Nelson-Piercy C, Grainge MJ. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol 2012; 156 (03) 366-373
    CrossrefPubMedGoogle Scholar
  • 2 Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol 2003; 16 (02) 153-168
    CrossrefPubMedGoogle Scholar
  • 3 Lamont MC, McDermott C, Thomson AJ, Greer IA. United Kingdom recommendations for obstetric venous thromboembolism prophylaxis: evidence and rationale. Semin Perinatol 2019; 43 (04) 222-228
    CrossrefPubMedGoogle Scholar
  • 4 Royal College of Obstetricians and Gynaecologists Green-top Guideline No. 37a. Reducing the Risk of Thrombosis and Embolism During Pregnancy and the Puerperium. 2015 . Accessed December 3, 2020 at: https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg37a/?_t_id=1B2M2Y8AsgTpgAmY7PhCfg%3d%3d&_t_q=green+top+guideline+37b&_t_tags=language%3aen%2csiteid%3a39338ee9-cb61-4e10-a686-8f4a5e1b76d7&_t_ip=213.32.242.177&_t_hit.id=EPiServer_Templates_RCOG_Models_Pages_GuidelinesDetailsType/_31d00406-d57c-48b7-9131-d7eda4fc2de9_en&_t_hit.pos=2
    Google Scholar
  • 5 van Hagen IM, Roos-Hesselink JW, Ruys TP. et al; ROPAC Investigators and the EURObservational Research Programme (EORP) Team*. Pregnancy in women with a mechanical heart valve: data of the European Society of Cardiology Registry of Pregnancy and Cardiac Disease (ROPAC). Circulation 2015; 132 (02) 132-142
    CrossrefPubMedGoogle Scholar
  • 6 Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e691S-e736S
    CrossrefPubMedGoogle Scholar
  • 7 Hirsh J, Warkentin TE, Shaughnessy SG. et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119 (1, Suppl): 64s-94s
    CrossrefPubMedGoogle Scholar
  • 8 de Haas S, Ghossein-Doha C, van Kuijk SM, van Drongelen J, Spaanderman ME. Physiological adaptation of maternal plasma volume during pregnancy: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2017; 49 (02) 177-187
    CrossrefPubMedGoogle Scholar
  • 9 Pariente G, Leibson T, Carls A, Adams-Webber T, Ito S, Koren G. Pregnancy-associated changes in pharmacokinetics: a systematic review. PLoS Med 2016; 13 (11) e1002160
    CrossrefPubMedGoogle Scholar
  • 10 Babin JL, Traylor KL, Witt DM. Laboratory monitoring of low-molecular-weight heparin and fondaparinux. Semin Thromb Hemost 2017; 43 (03) 261-269
    PubMedGoogle Scholar
  • 11 Practical-Haemostasis. A Practical Guide to Haemostasis; Anti-Xa Assays. Accessed December 3, 2020 at: https://www.practical-haemostasis.com/Miscellaneous/anti_xa_assays.html
    Google Scholar
  • 12 Newall F. Anti-factor Xa (anti-Xa) assay. Methods Mol Biol 2013; 992: 265-272
    CrossrefPubMedGoogle Scholar
  • 13 Kovacs MJ, Keeney M, MacKinnon K, Boyle E. Three different chromogenic methods do not give equivalent anti-Xa levels for patients on therapeutic low molecular weight heparin (dalteparin) or unfractionated heparin. Clin Lab Haematol 1999; 21 (01) 55-60
    CrossrefPubMedGoogle Scholar
  • 14 Croles FN, Lukens MV, Mulder R, de Maat MPM, Mulder AB, Meijer K. Monitoring of heparins in antithrombin-deficient patients. Thromb Res 2019; 175: 8-12
    CrossrefPubMedGoogle Scholar
  • 15 Kitchen S, Iampietro R, Woolley AM, Preston FE. Anti Xa monitoring during treatment with low molecular weight heparin or danaparoid: inter-assay variability. Thromb Haemost 1999; 82 (04) 1289-1293
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 16 Bounameaux H, de Moerloose P. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? No. J Thromb Haemost 2004; 2 (04) 551-554
    CrossrefPubMedGoogle Scholar
  • 17 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 (02) 401-407
    CrossrefPubMedGoogle Scholar
  • 18 Baglin T, Barrowcliffe TW, Cohen A, Greaves M. British Committee for Standards in Haematology. Guidelines on the use and monitoring of heparin. Br J Haematol 2006; 133 (01) 19-34
    CrossrefPubMedGoogle Scholar
  • 19 Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J. et al; ESC Scientific Document Group. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J 2018; 39 (34) 3165-3241
    CrossrefPubMedGoogle Scholar
  • 20 Bates SM, Rajasekhar A, Middeldorp S. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv 2018; 2 (22) 3317-3359
    CrossrefPubMedGoogle Scholar
  • 21 Harenberg J. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? Yes. J Thromb Haemost 2004; 2 (04) 547-550
    CrossrefPubMedGoogle Scholar
  • 22 Fogerty AE. Challenges of anticoagulation therapy in pregnancy. Curr Treat Options Cardiovasc Med 2017; 19 (10) 76
    CrossrefPubMedGoogle Scholar
  • 23 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6 (07) e1000097
    CrossrefPubMedGoogle Scholar
  • 24 Salim R, Nachum Z, Gavish I, Romano S, Braverman M, Garmi G. Adjusting enoxaparin dosage according to anti-FXa levels and pregnancy outcome in thrombophilic women. A randomised controlled trial. Thromb Haemost 2016; 116 (04) 687-695
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 25 Abou-Nassar K, Kovacs MJ, Kahn SR. et al; TIPPS Investigators. The effect of dalteparin on coagulation activation during pregnancy in women with thrombophilia. A randomized trial. Thromb Haemost 2007; 98 (01) 163-171
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 26 Ensom MHH, Stephenson MD. Pharmacokinetics of low molecular weight heparin and unfractionated heparin in pregnancy. J Soc Gynecol Investig 2004; 11 (06) 377-383
    CrossrefPubMedGoogle Scholar
  • 27 Pettilä V, Kaaja R, Leinonen P, Ekblad U, Kataja M, Ikkala E. Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Thromb Res 1999; 96 (04) 275-282
    CrossrefPubMedGoogle Scholar
  • 28 Simeone R, Giacomello R, Bruno G. et al. Thrombogenesis in thrombophilic pregnancy: evaluation of low-molecular-weight heparin prophylaxis. Acta Haematol 2017; 137 (04) 201-206
    CrossrefPubMedGoogle Scholar
  • 29 Selmeczi A, Roach REJ, Móré C. et al. Thrombin generation and low-molecular-weight heparin prophylaxis in pregnant women with thrombophilia. Thromb Haemost 2015; 113 (02) 283-289
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 30 Sarig G, Blumenfeld Z, Leiba R, Lanir N, Brenner B. Modulation of systemic hemostatic parameters by enoxaparin during gestation in women with thrombophilia and pregnancy loss. Thromb Haemost 2005; 94 (05) 980-985
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 31 O'Connell MP, O'Leary M, MacKeogh L, Murphy K, Keane DP. Is the monitoring of anti-Xa activity necessary in pregnant women undergoing thromboprophylaxis?. Eur J Obstet Gynecol Reprod Biol 2004; 114 (01) 12-14
    CrossrefPubMedGoogle Scholar
  • 32 Norris LA, Bonnar J, Smith MP, Steer PJ, Savidge G. Low molecular weight heparin (tinzaparin) therapy for moderate risk thromboprophylaxis during pregnancy. A pharmacokinetic study. Thromb Haemost 2004; 92 (04) 791-796
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 33 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 (06) 1307-1311
    PubMedGoogle Scholar
  • 34 Casele HL, Laifer SA, Woelkers DA, Venkataramanan R. Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol 1999; 181 (5, Pt 1): 1113-1117
    CrossrefPubMedGoogle Scholar
  • 35 Blombäck M, Bremme K, Hellgren M, Siegbahn A, Lindberg H. Thromboprophylaxis with low molecular mass heparin, ‘Fragmin’ (dalteparin), during pregnancy--a longitudinal safety study. Blood Coagul Fibrinolysis 1998; 9 (01) 1-9
    PubMedGoogle Scholar
  • 36 Patel JP, Green B, Patel RK, Marsh MS, Davies JG, Arya R. Population pharmacokinetics of enoxaparin during the antenatal period. Circulation 2013; 128 (13) 1462-1469
    CrossrefPubMedGoogle Scholar
  • 37 Shapiro NL, Kominiarek MA, Nutescu EA, Chevalier AB, Hibbard JU. Dosing and monitoring of low-molecular-weight heparin in high-risk pregnancy: single-center experience. Pharmacotherapy 2011; 31 (07) 678-685
    CrossrefPubMedGoogle Scholar
  • 38 Lebaudy C, Hulot JS, Amoura Z. et al. Changes in enoxaparin pharmacokinetics during pregnancy and implications for antithrombotic therapeutic strategy. Clin Pharmacol Ther 2008; 84 (03) 370-377
    CrossrefPubMedGoogle Scholar
  • 39 Smith MP, Norris LA, Steer PJ, Savidge GF, Bonnar J. Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol 2004; 190 (02) 495-501
    CrossrefPubMedGoogle Scholar
  • 40 Rowan JA, McLintock C, Taylor RS, North RA. Prophylactic and therapeutic enoxaparin during pregnancy: indications, outcomes and monitoring. Aust N Z J Obstet Gynaecol 2003; 43 (02) 123-128
    CrossrefPubMedGoogle Scholar
  • 41 Rey E, Rivard GE. Prophylaxis and treatment of thromboembolic diseases during pregnancy with dalteparin. Int J Gynaecol Obstet 2000; 71 (01) 19-24
    CrossrefPubMedGoogle Scholar
  • 42 Ellison J, Walker ID, Greer IA. Antenatal use of enoxaparin for prevention and treatment of thromboembolism in pregnancy. BJOG 2000; 107 (09) 1116-1121
    CrossrefPubMedGoogle Scholar
  • 43 Hunt BJ, Doughty HA, Majumdar G. et al. Thromboprophylaxis with low molecular weight heparin (Fragmin) in high risk pregnancies. Thromb Haemost 1997; 77 (01) 39-43
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 44 Aleidan FAS, Aljarba GA, Aldakhil AA. et al. A prospective cohort study comparing achieved anti-factor Xa peak levels in pregnant and non-pregnant patients receiving therapeutic-dose low-molecular-weight heparin. Int J Hematol 2020; 112 (01) 1-7
    CrossrefPubMedGoogle Scholar
  • 45 Petrie S, Barras M, Lust K, Fagermo N, Allen J, Martin JH. Evaluation of therapeutic enoxaparin in a pregnant population at a tertiary hospital. Intern Med J 2016; 46 (07) 826-833
    CrossrefPubMedGoogle Scholar
  • 46 Gibson PS, Newell K, Sam DX. et al. Weight-adjusted dosing of tinzaparin in pregnancy. Thromb Res 2013; 131 (02) e71-e75
    CrossrefPubMedGoogle Scholar
  • 47 Lykke JA, Grønlykke T, Langhoff-Roos J. Treatment of deep venous thrombosis in pregnant women. Acta Obstet Gynecol Scand 2008; 87 (11) 1248-1251
    CrossrefPubMedGoogle Scholar
  • 48 Barbour LA, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol 2004; 191 (03) 1024-1029
    CrossrefPubMedGoogle Scholar
  • 49 Jacobsen AF, Qvigstad E, Sandset PM. Low molecular weight heparin (dalteparin) for the treatment of venous thromboembolism in pregnancy. BJOG 2003; 110 (02) 139-144
    CrossrefPubMedGoogle Scholar
  • 50 Vause S, Clarke B, Tower CL, Hay C, Knight M. on behalf of UKOSS. Pregnancy outcomes in women with mechanical prosthetic heart valves: a prospective descriptive population based study using the United Kingdom Obstetric Surveillance System (UKOSS) data collection system. BJOG 2017; 124 (09) 1411-1419
    CrossrefPubMedGoogle Scholar
  • 51 Saeed CR, Jacobson BF, Pravin M, Aziz RH, Serasheini M, Dominique TG. A prospective trial showing the safety of adjusted-dose enoxaparin for thromboprophylaxis of pregnant women with mechanical prosthetic heart valves. Clin Appl Thromb Hemost 2011; 17 (04) 313-319
    CrossrefPubMedGoogle Scholar
  • 52 Abildgaard U, Sandset PM, Hammerstrøm J, Gjestvang FT, Tveit A. Management of pregnant women with mechanical heart valve prosthesis: thromboprophylaxis with low molecular weight heparin. Thromb Res 2009; 124 (03) 262-267
    CrossrefPubMedGoogle Scholar
  • 53 McLintock C, McCowan LME, North RA. Maternal complications and pregnancy outcome in women with mechanical prosthetic heart valves treated with enoxaparin. BJOG 2009; 116 (12) 1585-1592
    CrossrefPubMedGoogle Scholar
  • 54 Quinn J, Von Klemperer K, Brooks R, Peebles D, Walker F, Cohen H. Use of high intensity adjusted dose low molecular weight heparin in women with mechanical heart valves during pregnancy: a single-center experience. Haematologica 2009; 94 (11) 1608-1612
    CrossrefPubMedGoogle Scholar
  • 55 Yinon Y, Siu SC, Warshafsky C. et al. Use of low molecular weight heparin in pregnant women with mechanical heart valves. Am J Cardiol 2009; 104 (09) 1259-1263
    CrossrefPubMedGoogle Scholar
  • 56 Rowan JA, McCowan LME, Raudkivi PJ, North RA. Enoxaparin treatment in women with mechanical heart valves during pregnancy. Am J Obstet Gynecol 2001; 185 (03) 633-637
    CrossrefPubMedGoogle Scholar
  • 57 Brenner B, Hoffman R, Carp H, Dulitsky M, Younis J. 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 (02) 227-229
    CrossrefPubMedGoogle Scholar
  • 58 Wu T, Xia X, Chen W, Fu J, Zhang J. The effect of anti-Xa monitoring on the safety and efficacy of low-molecular-weight heparin anticoagulation therapy: a systematic review and meta-analysis. J Clin Pharm Ther 2020; 45 (04) 602-608
    CrossrefPubMedGoogle Scholar
  • 59 Chan WS, Rey E, Kent NE. et al; VTE in Pregnancy Guideline Working Group, Society of Obstetricians and Gynecologists of Canada. Venous thromboembolism and antithrombotic therapy in pregnancy. J Obstet Gynaecol Can 2014; 36 (06) 527-553
    CrossrefPubMedGoogle Scholar
  • 60 Royal College of Obstetricians and Gynaecologists Green-top Guideline No. 37b. Thromboembolic Disease in Pregnancy and the Puerperium: Acute Management. 2015 . Accessed December 3, 2020 at: https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg37b/?_t_id=1B2M2Y8AsgTpgAmY7PhCfg%3d%3d&_t_q=green+top+guideline+37b&_t_tags=language%3aen%2csiteid%3a39338ee9-cb61-4e10-a686-8f4a5e1b76d7&_t_ip=213.32.242.177&_t_hit.id=EPiServer_Templates_RCOG_Models_Pages_GuidelinesDetailsType/_7cdde998-17c3-4abc-920a-12f39722c715_en&_t_hit.pos=1
    Google Scholar