Download PDF
Semin Thromb Hemost 2017; 43(03): 261-269
DOI: 10.1055/s-0036-1581129
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Laboratory Monitoring of Low-Molecular-Weight Heparin and Fondaparinux

Jennifer L. Babin
1   Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake City, Utah
,
Katie L. Traylor
1   Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake City, Utah
,
Daniel M. Witt
1   Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake City, Utah
› Author Affiliations
Further Information

Publication History

Publication Date:
09 June 2016 (online)

    Permissions and Reprints

Abstract

Compared with older agents, low-molecular-weight heparins (LMWH) and fondaparinux offer improved bioavailability and more predictable, dose-independent clearance. While routine monitoring of coagulation parameters is not usually necessary with these agents, certain populations (including pregnant patients, children, obese patients, and patients with renal impairment) may benefit from the monitoring of anti–factor Xa activity, thromboelastography, or other coagulation assays to help guide therapy. The chromogenic anti–factor Xa assay is currently the gold standard for monitoring LMWH and fondaparinux therapy. Thromboelastography has been used to monitor LMWH therapy in special situations but is not needed for routine use.

Keywords

low-molecular-weight heparin - fondaparinux - anti-Xa - thromboelastography
 

  • References

  • 1 Garcia DA, Baglin TP, Weitz JI, Samama MM ; American College of Chest Physicians. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141 (2, Suppl): e24S-e43S
    CrossrefPubMedGoogle Scholar
  • 2 Harris LF, O'Brien A, Castro-López V, O'Donnell JS, Killard AJ. Comparison of the anticoagulant response of a novel fluorogenic anti-FXa assay with two commercial anti-FXa chromogenic assays. Thromb Res 2011; 128 (6) e166-e170
    CrossrefPubMedGoogle Scholar
  • 3 Gehrie E, Laposata M. Test of the month: the chromogenic antifactor Xa assay. Am J Hematol 2012; 87 (2) 194-196
    CrossrefPubMedGoogle Scholar
  • 4 Funk DM. Coagulation assays and anticoagulant monitoring. Hematology (Am Soc Hematol Educ Program) 2012; 2012: 460-465
    PubMedGoogle Scholar
  • 5 Bonar RA, Favaloro EJ, Marsden K. External quality assurance for heparin monitoring. Semin Thromb Hemost 2012; 38 (6) 632-639
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Laposata M, Green D, Van Cott EM, Barrowcliffe TW, Goodnight SH, Sosolik RC. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch Pathol Lab Med 1998; 122 (9) 799-807
    PubMedGoogle Scholar
  • 7 Yentz S, Onwuemene OA, Stein BL, Cull EH, McMahon B. Clinical use of anti-Xa monitoring in malignancy-associated thrombosis. Thrombosis 2015; 2015: 126975
    PubMedGoogle Scholar
  • 8 Duplaga BA, Rivers CW, Nutescu E. Dosing and monitoring of low-molecular-weight heparins in special populations. Pharmacotherapy 2001; 21 (2) 218-234
    CrossrefPubMedGoogle Scholar
  • 9 Favaloro EJ, Lippi G, Adcock DM. Preanalytical and postanalytical variables: the leading causes of diagnostic error in hemostasis?. Semin Thromb Hemost 2008; 34 (7) 612-634
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Houbouyan L, Boutière B, Contant G , et al. Validation protocol of analytical hemostasis systems: measurement of anti-Xa activity of low-molecular-weight heparins. Clin Chem 1996; 42 (8, Pt 1): 1223-1230
    CrossrefPubMedGoogle Scholar
  • 11 Brophy DF, Martin EJ, Best AM, Gehr TW, Carr ME. Antifactor Xa activity correlates to thrombin generation time, platelet contractile force and clot elastic modulus following ex vivo enoxaparin exposure in patients with and without renal dysfunction. J Thromb Haemost 2004; 2 (8) 1299-1304
    CrossrefPubMedGoogle Scholar
  • 12 Brophy DF, Martin EJ, Gehr TW, Best AM, Paul K, Carr Jr ME. Thrombin generation time is a novel parameter for monitoring enoxaparin therapy in patients with end-stage renal disease. J Thromb Haemost 2006; 4 (2) 372-376
    CrossrefPubMedGoogle Scholar
  • 13 Reikvam H, Steien E, Hauge B , et al. Thrombelastography. Transfus Apheresis Sci 2009; 40 (2) 119-123
    CrossrefPubMedGoogle Scholar
  • 14 Yang Y, Yao Z, Dai W, Shi P, Luo L, Zhang C. Changes of thrombelastography in patients undergoing elective primary total knee and total hip replacement with low molecular heparin prophylaxis. J Orthop Surg 2014; 9: 52
    CrossrefPubMedGoogle Scholar
  • 15 Jackson GN, Ashpole KJ, Yentis SM. The TEG vs the ROTEM thromboelastography/thromboelastometry systems. Anaesthesia 2009; 64 (2) 212-215
    CrossrefPubMedGoogle Scholar
  • 16 Klein SM, Slaughter TF, Vail PT , et al. Thromboelastography as a perioperative measure of anticoagulation resulting from low molecular weight heparin: a comparison with anti-Xa concentrations. Anesth Analg 2000; 91 (5) 1091-1095
    CrossrefPubMedGoogle Scholar
  • 17 White H, Sosnowski K, Bird R, Jones M, Solano C. The utility of thromboelastography in monitoring low molecular weight heparin therapy in the coronary care unit. Blood Coagul Fibrinolysis 2012; 23 (4) 304-310
    CrossrefPubMedGoogle Scholar
  • 18 Casey ME, Hodges O, Dunn R, Thomas J. Thromboelastography to monitor the intra-operative effects of low-molecular weight heparin following bridging anticoagulation in a child with normal renal function. Anaesthesia 2013; 68 (1) 91-96
    CrossrefPubMedGoogle Scholar
  • 19 Backe SK, Lyons GR. High-dose tinzaparin in pregnancy and the need for urgent delivery. Br J Anaesth 2002; 89 (2) 331-334
    CrossrefPubMedGoogle Scholar
  • 20 Simons R, Mallett SV. Use of thromboelastography to demonstrate persistent anticoagulation after stopping enoxaparin. Anaesthesia 2007; 62 (11) 1175-1178
    CrossrefPubMedGoogle Scholar
  • 21 Bounameaux H, de Moerloose P. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? No. J Thromb Haemost 2004; 2 (4) 551-554
    CrossrefPubMedGoogle Scholar
  • 22 Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO ; American College of Chest Physicians. 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
  • 23 Knol HM, Schultinge L, Erwich JJ, Meijer K. Fondaparinux as an alternative anticoagulant therapy during pregnancy. J Thromb Haemost 2010; 8 (8) 1876-1879
    CrossrefPubMedGoogle Scholar
  • 24 Kamel H, Navi BB, Sriram N, Hovsepian DA, Devereux RB, Elkind MS. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med 2014; 370 (14) 1307-1315
    CrossrefPubMedGoogle Scholar
  • 25 Monagle P, Chan AK, Goldenberg NA , et al; American College of Chest Physicians. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141 (2, Suppl): e737S-e801S
    CrossrefPubMedGoogle Scholar
  • 26 Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous thromboembolism. Am J Med 2005; 118 (9) 978-980
    CrossrefPubMedGoogle Scholar
  • 27 Thompson D, Brown JB, Nichols GA, Elmer PJ, Oster G. Body mass index and future healthcare costs: a retrospective cohort study. Obes Res 2001; 9 (3) 210-218
    CrossrefPubMedGoogle Scholar
  • 28 Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet 2010; 49 (2) 71-87
    CrossrefPubMedGoogle Scholar
  • 29 Brill MJ, Diepstraten J, van Rongen A, van Kralingen S, van den Anker JN, Knibbe CA. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet 2012; 51 (5) 277-304
    CrossrefPubMedGoogle Scholar
  • 30 Bazinet A, Almanric K, Brunet C , et al. Dosage of enoxaparin among obese and renal impairment patients. Thromb Res 2005; 116 (1) 41-50
    CrossrefPubMedGoogle Scholar
  • 31 Hainer JW, Barrett JS, Assaid CA , et al. Dosing in heavy-weight/obese patients with the LMWH, tinzaparin: a pharmacodynamic study. Thromb Haemost 2002; 87 (5) 817-823
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Wilson SJ, Wilbur K, Burton E, Anderson DR. Effect of patient weight on the anticoagulant response to adjusted therapeutic dosage of low-molecular-weight heparin for the treatment of venous thromboembolism. Haemostasis 2001; 31 (1) 42-48
    CrossrefPubMedGoogle Scholar
  • 33 Rowan BO, Kuhl DA, Lee MD, Tichansky DS, Madan AK. Anti-Xa levels in bariatric surgery patients receiving prophylactic enoxaparin. Obes Surg 2008; 18 (2) 162-166
    CrossrefPubMedGoogle Scholar
  • 34 Simoneau MD, Vachon A, Picard F. Effect of prophylactic dalteparin on anti-factor Xa levels in morbidly obese patients after bariatric surgery. Obes Surg 2010; 20 (4) 487-491
    CrossrefPubMedGoogle Scholar
  • 35 Davidson BL, Büller HR, Decousus H , et al; Matisse Investigators. Effect of obesity on outcomes after fondaparinux, enoxaparin, or heparin treatment for acute venous thromboembolism in the Matisse trials. J Thromb Haemost 2007; 5 (6) 1191-1194
    CrossrefPubMedGoogle Scholar
  • 36 Turpie AG, Bauer KA, Caprini JA, Comp PC, Gent M, Muntz JE ; Apollo Investigators. Fondaparinux combined with intermittent pneumatic compression vs. intermittent pneumatic compression alone for prevention of venous thromboembolism after abdominal surgery: a randomized, double-blind comparison. J Thromb Haemost 2007; 5 (9) 1854-1861
    CrossrefPubMedGoogle Scholar
  • 37 Agnelli G, Bergqvist D, Cohen AT, Gallus AS, Gent M ; PEGASUS investigators. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg 2005; 92 (10) 1212-1220
    CrossrefPubMedGoogle Scholar
  • 38 Martinez L, Burnett A, Borrego M, Streeter JC, Townsend K, Garcia D. Effect of fondaparinux prophylaxis on anti-factor Xa concentrations in patients with morbid obesity. Am J Health Syst Pharm 2011; 68 (18) 1716-1722
    CrossrefPubMedGoogle Scholar
  • 39 Lee YR, Vega JA, Duong HN, Ballew A. Monitoring enoxaparin with antifactor Xa levels in obese patients. Pharmacotherapy 2015; 35 (11) 1007-1015
    CrossrefPubMedGoogle Scholar
  • 40 Taura P, Rivas E, Martinez-Palli G , et al. Clinical markers of the hypercoagulable state by rotational thrombelastometry in obese patients submitted to bariatric surgery. Surg Endosc 2014; 28 (2) 543-551
    CrossrefPubMedGoogle Scholar
  • 41 Forfori F, Ferro B, Mancini B , et al. Role of thrombolestagrophy in monitoring perioperative coagulation status and effect of thromboprophylaxis in bariatric surgery. Obes Surg 2012; 22 (1) 113-118
    CrossrefPubMedGoogle Scholar
  • 42 Lim W, Dentali F, Eikelboom JW, Crowther MA. Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med 2006; 144 (9) 673-684
    CrossrefPubMedGoogle Scholar
  • 43 Lachish T, Rudensky B, Slotki I, Zevin S. Enoxaparin dosage adjustment in patients with severe renal failure: antifactor xa concentrations and safety. Pharmacotherapy 2007; 27 (10) 1347-1352
    CrossrefPubMedGoogle Scholar
  • 44 Hoffmann P, Keller F. Increased major bleeding risk in patients with kidney dysfunction receiving enoxaparin: a meta-analysis. Eur J Clin Pharmacol 2012; 68 (5) 757-765
    CrossrefPubMedGoogle Scholar
  • 45 Sanofi-Aventis. Lovenox prescribing information. 2015. Available at: http://products.sanofi.us/lovenox/lovenox.html . Accessed August 30, 2015
    PubMedGoogle Scholar
  • 46 Siguret V, Gouin-Thibault I, Pautas E, Leizorovicz A. No accumulation of the peak anti-factor Xa activity of tinzaparin in elderly patients with moderate-to-severe renal impairment: the IRIS substudy. J Thromb Haemost 2011; 9 (10) 1966-1972
    CrossrefPubMedGoogle Scholar
  • 47 Harder S. Renal profiles of anticoagulants. J Clin Pharmacol 2012; 52 (7) 964-975
    CrossrefPubMedGoogle Scholar
  • 48 Aspri Pharma. Arixtra prescribing information. 2015 . Available at: http://www.aspripharma.com/pdf/Arixtra%20PM_EN.pdf . Accessed March 18, 2016.
    PubMedGoogle Scholar
  • 49 Scotté F, Rey JB, Launay-Vacher V. Thrombosis, cancer and renal insufficiency: low molecular weight heparin at the crossroads. Support Care Cancer 2012; 20 (12) 3033-3042
    CrossrefPubMedGoogle Scholar
  • 50 Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer 2011; 117 (7) 1334-1349
    CrossrefPubMedGoogle Scholar
  • 51 Lee AY, Levine MN, Baker RI , et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349 (2) 146-153
    CrossrefPubMedGoogle Scholar
  • 52 Kearon C, Akl EA, Comerota AJ , et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141 (2, Suppl): e419S-e494S
    CrossrefPubMedGoogle Scholar
  • 53 Streiff MB, Holmstrom B, Ashrani A , et al. Cancer-associated venous thromboembolic disease, version 1.2015. J Natl Compr Canc Netw 2015; 13 (9) 1079-1095
    CrossrefPubMedGoogle Scholar
  • 54 Mandalà M, Falanga A, Roila F ; ESMO Guidelines Working Group. Management of venous thromboembolism (VTE) in cancer patients: ESMO clinical practice guidelines. Ann Oncol 2011; 22 (Suppl. 06) vi85-vi92
    CrossrefPubMedGoogle Scholar
  • 55 PfizerLabs. Fragmin prescribing information. 2015. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=2293 . Accessed September 1, 2015
    PubMedGoogle Scholar
  • 56 Aspen Phrama. Fraxiparine prescribing information. 2015. Available at: http://www.aspripharma.com/pdf/Fraxiparine%20&%20Forte%20PM_EN.pdf . Accessed March 18, 2016.
    PubMedGoogle Scholar
  • 57 LEOPharmaceuticalProducts. Innohep prescribing information. 2016 . Available at: http://www.leo-pharma.us/Files/Billeder/LEO_local_images/LEO-Pharma.US/Innohep Packaging Insert 9-29.pdf. Accessed February 18, 2016
    PubMedGoogle Scholar
  • 58 Scholten DJ, Hoedema RM, Scholten SE. A comparison of two different prophylactic dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg 2002; 12 (1) 19-24
    CrossrefPubMedGoogle Scholar
  • 59 Nutescu EA, Spinler SA, Wittkowsky A, Dager WE. Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother 2009; 43 (6) 1064-1083
    CrossrefPubMedGoogle Scholar