38 – Should the dose of LMWH for the prevention of VTE be weight-adjusted?

38 – Should the dose of LMWH for the prevention of VTE be weight-adjusted?

Louis M. Kwong, Hasan Huseyin Ceylan.

Response/Recommendation: Limited data suggests that weight-adjusted dosing of low-molecular-weight heparin (LMWH) may be of benefit in venous thromboembolism (VTE) prophylaxis for very low body weight and obese patients.

Strength of Recommendation: Limited.

Rationale: While the safety and efficacy of LMWH have been studied extensively in prospective, randomized, control clinical trials, those patients of very low body weight, as well as those of high body weight, were excluded from studies with these agents for prophylaxis following major orthopaedic surgery1–3.  Concerns regarding the use of fixed standard dosing include reduced glomerular filtration rate (GFR) and creatinine clearance (CrCL) in patients of low body weight as well as a lower volume distribution (Vd) in these individuals.  Because LMWH are primarily renally excreted, increased exposure to the drug due to accumulation may result in over anti-coagulation and a reduction in safety as manifested by an increased bleeding risk in low body weight patients4,5.  Conversely, in those of extremely high body weight, a larger Vd may diminish the effectiveness of the antithrombotic agent resulting in a decrease in thromboprophylactic efficacy6,7.  Interestingly, obesity is also a risk factor for chronic kidney disease (CKD) and renal insufficiency8.  Should this occur, an obese patient with CKD on standard LMWH dosing may experience reduced renal clearance of the drug, increased exposure due to accumulation, and a resultant potential decrease in safety due to increased bleeding risk.  Additionally, because LMWHs are hydrophilic in nature and not well distributed in adipose tissue, overdosing may be a risk in those patients whose total bodyweight is represented by a larger proportion of adipose tissue as opposed to an increase in lean body mass9,10.

A meta-regression analysis by Zufferey et al., evaluated the possibility of a dose-effect relationship of LMWH in major orthopedic surgery patients.  They reported a correlation between the dose of LMWH administered and the relative risk reduction of asymptomatic total deep venous thrombosis (DVT) observed in each of the dosing studies evaluated11.  A preponderance of scientific studies has used the measurement of anti-Xa levels as a surrogate for both efficacy and safety in support of the use of dose-adjusted LMWH for patients at both extremes of body weight12–17.  The number of studies in support of weight-adjustment of LMWH administration have increased in the bariatric surgery literature since the introduction of the various LMWH, but limited data exist on the management of obese patients in the trauma and orthopaedic arenas.

In orthopaedic surgery, the literature is unclear as to the effectiveness of standard doses of LMWH for prophylaxis in obese patients18,19.  The literature is similarly unclear as to the safety of standard doses of LMWH in patients of very low body weight, although a number of small prospective studies, as well as a trial in healthy volunteers, support a reduction in LMWH dose in patients of low body weight8,20.  A number of studies have focused on different dose regimens in support of patients at the extremes of body-weight instead of adjusted dosing calculated based on weight8,21–26.  Those few prospective clinical studies were underpowered to show differences in the effectiveness of various dosing regimens on VTE events as well as bleeding events12,24,27,28.  While weight-adjustment of LMWH has been demonstrated to be effective in achieving a target anti-Xa level, there is not a consensus on optimum anti-Xa ranges, especially in terms of a clear link between anti-factor Xa levels and bleeding or thrombotic events29.  There is also no strong evidence that anti-Xa levels correlate with a reduction in the incidence of clinically important VTE events in patients undergoing orthopaedic procedures30.  While many studies support the benefits of weight-adjustment of LMWH administration31–34, no level 1 evidence exists to support the safety and efficacy of weight-adjusted dosing of LMWH for prophylaxis against VTE in orthopaedic surgery.  Further trials are needed to confirm the efficacy and safety of weight-adjusted LMWH prophylaxis in orthopaedic surgery for those patients at the extremes of body weight.


1.         Colwell CW, Spiro TE, Trowbridge AA, et al. Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. A clinical trial comparing efficacy and safety. Enoxaparin Clinical Trial Group. J Bone Joint Surg Am. 1994;76(1):3-14. doi:10.2106/00004623-199401000-00002

2.         Eriksson BI, Kälebo P, Anthymyr BA, Wadenvik H, Tengborn L, Risberg B. Prevention of deep-vein thrombosis and pulmonary embolism after total hip replacement. Comparison of low-molecular-weight heparin and unfractionated heparin. J Bone Joint Surg Am. 1991;73(4):484-493.

3.         Colwell CW, Spiro TE, Trowbridge AA, Stephens JW, Gardiner GA, Ritter MA. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep venous thrombosis after elective knee arthroplasty. Enoxaparin Clinical Trial Group. Clin Orthop Relat Res. 1995;(321):19-27.

4.         Buckheit D, Lefemine A, Sobieraj DM, Hobbs L. Venous Thromboembolism Prophylaxis in Underweight Hospitalized Patients. Clin Appl Thromb Hemost. 2021;27:10760296211018752. doi:10.1177/10760296211018752

5.         DailyMed – LOVENOX- enoxaparin sodium injection. Accessed September 7, 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5017a927-2a24-4f27-89f9-27c805bf7d59#S12.3

6.         Frederiksen SG, Hedenbro JL, Norgren L. Enoxaparin effect depends on body-weight and current doses may be inadequate in obese patients. Br J Surg. 2003;90(5):547-548. doi:10.1002/bjs.4068

7.         Schijns W, Deenen MJ, Aarts EO, et al. The Effect of Obesity on Anti-Xa Concentrations in Bariatric Patients. Obes Surg. 2018;28(7):1997-2005. doi:10.1007/s11695-018-3130-2

8.         Kawamoto R, Kohara K, Tabara Y, et al. An association between body mass index and estimated glomerular filtration rate. Hypertens Res. 2008;31(8):1559-1564. doi:10.1291/hypres.31.1559

9.         Fareed J, Hoppensteadt D, Walenga J, et al. Pharmacodynamic and pharmacokinetic properties of enoxaparin : implications for clinical practice. Clin Pharmacokinet. 2003;42(12):1043-1057. doi:10.2165/00003088-200342120-00003

10.       Cheer SM, Dunn CJ, Foster R. Tinzaparin sodium: a review of its pharmacology and clinical use in the prophylaxis and treatment of thromboembolic disease. Drugs. 2004;64(13):1479-1502. doi:10.2165/00003495-200464130-00006

11.       Zufferey P, Laporte S, Quenet S, et al. Optimal low-molecular-weight heparin regimen in major orthopaedic surgery. A meta-analysis of randomised trials. Thromb Haemost. 2003;90(4):654-661. doi:10.1160/TH03-02-0086

12.       Adolf J, Fritsche HM, Haas S, et al. Comparison of 3,000 IU aXa of the low molecular weight heparin certoparin with 5,000 IU aXa in prevention of deep vein thrombosis after total hip replacement. German Thrombosis Study Group. Int Angiol. 1999;18(2):122-126.

13.       Karcutskie CA, Dharmaraja A, Patel J, et al. Relation of antifactor-Xa peak levels and venous thromboembolism after trauma. J Trauma Acute Care Surg. 2017;83(6):1102-1107. doi:10.1097/TA.0000000000001663

14.       Celik F, Huitema ADR, Hooijberg JH, van de Laar AWJM, Brandjes DPM, Gerdes VEA. Fixed-dose enoxaparin after bariatric surgery: the influence of body weight on peak anti-Xa levels. Obes Surg. 2015;25(4):628-634. doi:10.1007/s11695-014-1435-3

15.       Bigos R, Solomon E, Dorfman JD, Ha M. A Weight- and Anti-Xa-Guided Enoxaparin Dosing Protocol for venous thromboembolism Prophylaxis in intensive care unit Trauma Patients. J Surg Res. 2021;265:122-130. doi:10.1016/j.jss.2021.02.034

16.       Freeman A, Horner T, Pendleton RC, Rondina MT. Prospective comparison of three enoxaparin dosing regimens to achieve target anti-factor Xa levels in hospitalized, medically ill patients with extreme obesity. Am J Hematol. 2012;87(7):740-743. doi:10.1002/ajh.23228

17.       Rojas L, Aizman A, Ernst D, et al. Anti-Xa activity after enoxaparin prophylaxis in hospitalized patients weighing less than fifty-five kilograms. Thromb Res. 2013;132(6):761-764. doi:10.1016/j.thromres.2013.10.005

18.       Jones DL, Jones WA, Fleming KI, et al. Underdosing of Prophylactic Enoxaparin Is Common in Orthopaedic Trauma and Predicts 90-Day Venous Thromboembolism. J Orthop Trauma. 2019;33(11):570-576. doi:10.1097/BOT.0000000000001563

19.       Lassen MR, Borris LC, Jensen HP, Poulsen KA, Ejstrud P, Andersen BS. Dose relation in the prevention of proximal vein thrombosis with a low molecular weight heparin (tinzaparin) in elective hip arthroplasty. Clin Appl Thromb Hemost. 2000;6(1):53-57. doi:10.1177/107602960000600109

20.       Fuji T, Ochi T, Niwa S, Fujita S. Prevention of postoperative venous thromboembolism in Japanese patients undergoing total hip or knee arthroplasty: two randomized, double-blind, placebo-controlled studies with three dosage regimens of enoxaparin. J Orthop Sci. 2008;13(5):442-451. doi:10.1007/s00776-008-1264-0

21.       Wang T-F, Milligan PE, Wong CA, Deal EN, Thoelke MS, Gage BF. Efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients. Thromb Haemost. 2014;111(1):88-93. doi:10.1160/TH13-01-0042

22.       Miranda S, Le Cam-Duchez V, Benichou J, et al. Adjusted value of thromboprophylaxis in hospitalized obese patients: A comparative study of two regimens of enoxaparin: The ITOHENOX study. Thromb Res. 2017;155:1-5. doi:10.1016/j.thromres.2017.04.011

23.       INSPIRATION Investigators, Sadeghipour P, Talasaz AH, et al. Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial. JAMA. 2021;325(16):1620-1630. doi:10.1001/jama.2021.4152

24.       Vavken P, Lunzer A, Grohs JG. A prospective cohort study on the effectiveness of 3500 IU versus 5000 IU bemiparin in the prophylaxis of postoperative thrombotic events in obese patients undergoing orthopedic surgery. Wien Klin Wochenschr. 2009;121(13-14):454-458. doi:10.1007/s00508-009-1175-x

25.       Kopelman TR, O’Neill PJ, Pieri PG, et al. Alternative dosing of prophylactic enoxaparin in the trauma patient: is more the answer? Am J Surg. 2013;206(6):911-915; discussion 915-916. doi:10.1016/j.amjsurg.2013.10.005

26.       Mennuni MG, Renda G, Grisafi L, et al. Clinical outcome with different doses of low-molecular-weight heparin in patients hospitalized for COVID-19. J Thromb Thrombolysis. Published online March 1, 2021. doi:10.1007/s11239-021-02401-x

27.       Zwicker JI, Roopkumar J, Puligandla M, et al. Dose-adjusted enoxaparin thromboprophylaxis in hospitalized cancer patients: a randomized, double-blinded multicenter phase 2 trial. Blood Adv. 2020;4(10):2254-2260. doi:10.1182/bloodadvances.2020001804

28.       Haentjens P. Thromboembolic prophylaxis in orthopaedic trauma patients: a comparison between a fixed dose and an individually adjusted dose of a low molecular weight heparin (nadroparin calcium). Injury. 1996;27(6):385-390. doi:10.1016/0020-1383(96)00042-3

29.       Rondina MT, Wheeler M, Rodgers GM, Draper L, Pendleton RC. Weight-based dosing of enoxaparin for VTE prophylaxis in morbidly obese, medically-Ill patients. Thromb Res. 2010;125(3):220-223. doi:10.1016/j.thromres.2009.02.003

30.       Vandiver JW, Ritz LI, Lalama JT. Chemical prophylaxis to prevent venous thromboembolism in morbid obesity: literature review and dosing recommendations. J Thromb Thrombolysis. 2016;41(3):475-481. doi:10.1007/s11239-015-1231-5

31.       Kay AB, Majercik S, Sorensen J, et al. Weight-based enoxaparin dosing and deep vein thrombosis in hospitalized trauma patients: A double-blind, randomized, pilot study. Surgery. Published online April 23, 2018:S0039-6060(18)30094-1. doi:10.1016/j.surg.2018.03.001

32.       Alnatsheh AH, Beckett RD, Waterman S. Comparison of the effectiveness of venous thromboembolism prophylaxis with enoxaparin between obese and non-obese patients. J Oncol Pharm Pract. 2019;25(4):813-817. doi:10.1177/1078155218760159

33.       Sanderink G-J, Le Liboux A, Jariwala N, et al. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers. Clin Pharmacol Ther. 2002;72(3):308-318. doi:10.1067/mcp.2002.127114

34.       Bara L, Planes A, Samama MM. Occurrence of thrombosis and haemorrhage, relationship with anti-Xa, anti-IIa activities, and D-dimer plasma levels in patients receiving a low molecular weight heparin, enoxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery. Br J Haematol. 1999;104(2):230-240. doi:10.1046/j.1365-2141.1999.01153.x

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