Thromb Haemost 1994; 72(03): 330-334
DOI: 10.1055/s-0038-1648866
Review Article
Schattauer GmbH Stuttgart

Low Molecular Weight Heparin Therapy: Is Monitoring Needed?

B Boneu
Laboratoire de Recherche sur I’Hemostase et la Thrombose, Toulouse, France
› Author Affiliations
Further Information

Publication History

Received 26 November 1993

Accepted after resubmission 18 March 1994

Publication Date:
25 July 2018 (online)

Summary

Recent meta-analyses indicate that low molecular weight heparins (LMWH) are more effective than unfractionated heparin (UH) in preventing and treating deep vein thrombosis. This article presents the arguments for and against the need for laboratory monitoring. At the present time, the only tests currently available for monitoring LMWH therapy are those which measure the anti Xa activity in the plasma. Due to lower binding to plasma proteins and to cell surfaces,the plasma anti Xa activity generated by a given dose of LMWH is more predictable than for UH.

Some clinical trials suggest that LMWH delivered at the recommended dose expose the patient to less bleeding risk than UH. Several . meta-analyses indicate comparable risk while any overdose unaccept-ably increases the haemorrhagic risk. The lowest dose of LMWH still effective in treating established DVT is presently unknown; some reports indicate that inadequate doses of LMWH are associated with a lack of efficacy for prevention. An overview of the published clinical trials indicates that the LMWH dose has never been monitored for prevention of DVT. In the treatment of established DVT, several trials have been performed without any monitoring, while in others the dose was adapted to target a given anti Xa activity. These considerations suggest that in prevention of DVT, monitoring the dose is not required. In the treatment of established DVT, considering the haemorrhagic risk of LMWH, the risk of undertreating the patient and the absence of large clinical trials comparing the advantages of monitoring the dose or not, it might be useful to check anti Xa activity at least once at the beginning of the treatment but the need for this initial check remains to be established. Because a large proportion of patients will be in the desired range, dose adjustments will be far less frequent than for UH.

 
  • References

  • 1 Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. N Engl J Med 1988; 318: 1162-1173
  • 2 Poller L, Tabemer DA, Sandilands DG, Galasko CS. An evaluation of APTT monitoring of low-dose heparine dosage in hip surgery. Thromb Haemost 1982; 47: 50-53
  • 3 Leyvraz PF, Richard J, Bachmann F, Van Melle G, Treyvand J, Livio J. Adjusted versus fixed doses subcutaneous heparin in the preventionof deep vein thrombosis after totalhip replacement. N Engl J Med 1983; 309: 954-958
  • 4 Taberner DA, Poller L, Thomson J. A randomized study of adjusted dose heparin versus fixed low dose heparin in the prophylaxis of deep vein thrombosis in hip surgery. Br J Surg 1989; 76: 933-935
  • 5 Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972; 287: 325-327
  • 6 Hull R, Raskob G, Hirsh J, Jay RM, Leclerc JR, Geerts WH, Rosenbloom D, Sackett DL, Anderson C, Harisson L, Gent M. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis. N Engl J Med 1986; 315: 1109-1114
  • 7 Levine MN, Hirsh J, Landefeld S, Raskob G. Hemorrhagic complications of anticoagulant treatment. Chest 1992; 102: 353s-363s
  • 8 Chiu HM, Hirsh J, Yung WL, Regoeczi E, Gent M. Relationship between the anticoagulant and antithrombotic effects of heparin in experimental venous thrombosis. Blood 1977; 49: 171-184
  • 9 Hyers TM, Hull DR, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest 1992; 102: 408s-425s
  • 10 Nurmohamed MT, Rosendal FR, Buller HR, Dekker E, Hommes DW, Vanderbranke J, Briet E. Low molecular weight heparin ingeneral and orthopedic surgery, a meta-analysis. Lancet 1992; 640: 152-156
  • 11 Leizorovicz A, Hough M, Chapuis F, Samama M, Boissel JD. Low molecular weight heparin inprevention of post-operative thrombosis. Br Med J 1992; 305: 913-920
  • 12 Jorgensen LN, Wille-Jorgensen P, Hauch O. Prophylaxis of post-operative thromboembolism with low molecular weight heparins. Br J Surg 1993; 80: 689-704
  • 13 Anderson DR, O’Brien BJ, Levine MN, Roberts R, Wells PS, Hirsh J. Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. Ann Intern Med 1993; 119: 1105-1112
  • 14 Leizorovicz A, Simmonneau G, Decousus H. Comparison of low molecular weight heparin and unfractionated heparin in the treatment of DVT: a metaanalysis. Thromb Haemost 1993; 69-647 abstr
  • 15 Hirsh J, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1992; 102: 337s-351s
  • 16 Alhenc-Gelas M, Jestin-Le GuernicC, Vitoux JF, Kher A, Aiach M, Fiessinger JN. Adjusted versus fixed doses of the low molecular weight heparin Fragmin in the treatment of deep veinthrombosis. Thromb Haemost 1994; 71: 698-702
  • 17 Boneu B, Faruel-Bille V, Pierrejean D, Gabaig AM. Limitations of the chronometricassays to determine plasma antifactor Xa activity during low molecularweight heparin therapy. Nouv Rev Fr Hematol 1991; 33: 287-291
  • 18 Walker FJ, Esmon CT. The effects of phosphilipids and factor V on the inhibition of factor Xa by antithrombin III. BiochemBiophys Res Commun 1979; 90: 641-647
  • 19 Briant L, Caranobe C, Saivin S, Sie P, Bayrou B, Houin G, Boneu B. Unfractionated heparin and CY216: pharmacokinetics and bioavailabilities of the antifactor Xa and Ilaeffects after intravenous and subcutaneous injection in the rabbit. Thromb Haemost 1989; 61: 348-353
  • 20 Hemker H, Beguin S, Bendetowicz A, Wielders S. The determination of the levelsof unfractionated heparin and low molecular weight heparins in plasma.Their effect on thrombin mediated feedback reactions in vivo. Preliminary results on samplesafter subcutaneous injection. Haemost 1991 21. 258-272
  • 21 Bendetowciz A, Beguin S, Caplain H, Hemker HC. Pharmacokinetics and pharmacodynamics of a low molecular weight heparin (Enoxaparin) after subcutaneous injection, comparison with unfractionated heparin. A three way crossover study inhuman volunteers. Thromb Haemost 1994 71. 305-313
  • 22 Bara L, Billaud E, Gramond G, Kher A, Samama M. Comparative pharmacokinetics ofa low molecular weight heparin (PK 10169) and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 1985; 39: 631-636
  • 23 Hemker HC, Wielders S, Kessels H, Beguin S. Continuous registration of thrombin generation in plasma, its use for the determination of the thrombin potential. Thromb Haemost 1993; 70: 617-624
  • 24 Barrowcliffe TW, Curtis A, Johnson E, Thomas DP. An international standard for low molecular weight heparin. Thromb Haemost 1988; 1-60
  • 25 Sie P, Aillaud MF, de Prost D, Droulle C, Forestier F, Guedj P, Juhan-Vague I, Polack B, Potron G, Roncato M, Roussi J, Sampol J, Aiach M. Measurement of low molecular weight heparin ex vivo activities in clinical laboratories using variousanti Xa assays: interlaboratory variability and requirement of an agreed low molecular weight heparin standard. Thromb Haemost 1987; 58: 879-883
  • 26 Dignac M, Gabaig AM, Cambus JP, Boneu B. A new chronometric assay to determine plasma antifactor Xa activity which is insensitive to the antithrombin activity of low molecular weight heparins. Nouv Rev Hematol 1993; 35: 545-549
  • 27 Hirsh H, Van Aken WG, Gallus AS, Dollery CT, Cade JF, Yung WL. heparin kinetics in venous thrombosis and pulmonary embolism. Circulation 1976; 53: 691-695
  • 28 Benchekroun S, Eychenne B, Mericq O, Colombani A, Doust-Blazy P, Barret A, Sie P, Boneu B. Heparin half-life and sensitivity in normal subjects and in patients affected by deep vein thrombosis. Eur J Clin Invest 1986; 16: 536-539
  • 29 Bratt G, Aberg W, Johansson M, Tornebohm E, Granqvist S, Lockner D. Two daily subcutaneous injections of Fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis (DVT). Thromb Haemost 1990; 64: 506-510
  • 30 Handeland GF, Abildgaard U, Holm HA, Arnesen KE. Dose adjusted heparin treatmentof deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin. Eur J Clin Pharmacol 1990; 39: 107-112
  • 31 Aiach M, Fiessinger JN, Vitoux JF, Derlon A, Grollier G, Le Querrec A, Gouault-Heilmann M, Huet Y, Franco A, Polack B, Pouzol P, Dubois A, Schved JF, Boneu B, Guittard J, Sie P, Heilmann JJ, Kher A, Haye I. Traitement des thromboses veineuses profondes constitutes. Etude comparative d’un fragment d’heparine de bas poids moleculaire (Fragmine®)administreepar voie sous-cutanee etde l’heparine standard administree parvoie intraveineuse continue. Etude multicentrique. Rev Med Interne 1989 10. 375-81
  • 32 Young E, Prins M, Levine MN, Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparin resistance. Thromb Haemost 1992; 67: 639-643
  • 33 Young E, Cosmi B, Weitz J, Hirsh J. Comparison of the non-specific binding of unfractionated heparin and low molecular weight heparin (Enoxaparin) to plasma proteins. Thromb Haemost 1993; 70: 625-630
  • 34 Barzu T, van Rijn JL, Petitou M, Molho-Sabatier P, Tobelem G, Caen JP. Endothelial binding sites for heparin. Specificity and role in heparin neutralization. Biochem J 1986 238. 847-854
  • 35 van Rijn JL, Trillou M, Mardiguian J, Tobelem G, Caen J. Selective binding of heparins to human endothelial cells. Implications for pharmacokinetics. Thromb Res 1987 45. 211-222
  • 36 Boneu B, Caranobe C, Saivin S, Dol F, Sie P. Pharmacokinetics of heparin andof dermatan sulfate: clinical implications. Adv Exp Med Biol 1992; 313: 237-247
  • 37 De Swart CAM, Nijmeyer B, Roelofs JMM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood 1982; 60: 1251-1258
  • 38 Carter CJ, Kelton JG, Hirsh J, Cerskus A, Santos AV, Gent M. The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits. Blood 1982; 59: 1239-1245
  • 39 Palm M, Mattsson C, Magnus Svahn C, Weber M. Bleeding times in rats treated with heparin, heparin fragments of high and low anticoagulant activityand chemically modified heparin fragments of low anticoagulant activity. Thromb Haemost 1990; 64: 127-132
  • 40 Schmitz-Huebner U, Bunte H, Freise G, Reers B, Ruschmeyer C, Scherer R, Schulte H, Van de Loo J. Clinical efficacy of low molecular weight heparin in post-operative thrombosis prophylaxis. Klin Wochenschr 1984; 62: 349-353
  • 41 Koller M, Schoch U, Buchmann P, Largiader F, Von Felten A, Frieck PG. Low molecular weight heparin (Kabi 2165) as thromboprophylaxis in elective visceral surgery. A randomized, double-blind study versus unfractionated heparin. Thromb Haemost 1986 56. 243-246
  • 42 Bergqvist D, Burmark US, Frisell J, Lindblad B, Risberg B, Tomgren S, Walling G. Low molecular weight heparin once daily compared with conventionallow-dose heparin twice daily. A prospective double-blind multicentre trial on prevention of postoperative thrombosis. Br J Surg 1986 73. 204-208
  • 43 Samama M, Bernard P, Bonnardot JP, Combe-Tamzali S, Lanson Y, Tissot E. Low molecular weight heparin compared with unfractionated heparin in prevention of postoperative thrombosis. Br J Surg 1988; 75: 128-131
  • 44 Bratt G, Tornebohm E, Grnaqvist S, Aberq W, Lockner D. A comparison between low molecular weight heparin (Kabi 2165) and standard heparin in the intravenoustreatment of deep venous thrombosis. Thromb Haemost 1989; 59: 813-817
  • 45 Thery C, Simonneau G, Meyer G, Helenon O, Bridey F, Armagnac C, d’Azemar P, Coquart JP. Randomized trial of subcutaneous low molecular weight heparin, CY216 (Fraxiparine) compared with intravenous unfractionated heparin in the curative treatment of submassivepulmonary embolism: a dose ranging study. Circulation 1992; 85: 1380-1389
  • 46 Prandoni P, Lensing A. Comparison of subcutaneous low molecular weight heparin with intravenous standard in proximal deep vein thrombosis. Lancet 1992; 339: 441-445
  • 47 Hull R, Raskob GE, Pineo GF, Green D, Trowbridge AA, Elliott CG, Lemer RG, Hall J, Sparling T, Brettell HR, Norton J, Carter CJ, George R, Merli G, Ward J, Mayo W, Rosenbloom D, Brant R. Subcutaneous low-molecular weight heparin compared with continuousintravenous heparin in the treatment of proximal vein thrombosis. N Engl J Med 1992; 326: 975-82
  • 48 Kakkar VV, Cohen AT, Edmonson RA, Phillips MJ, Cooper DJ, Das SK, Maher KT, Sanderson RM, Ward VP, Kakkar S. Low molecular weight versus standard heparin for prevention of venous thromboembolism after major abdominal surgery. Lancet 1993; 341: 259-265
  • 49 Levine MN, Planes A, Hirsh J, Goodyear M, Vochelle N, Gent M. The relationship between antifactor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost 1989; 62: 940-944
  • 50 Bara L, Leizorovicz A, Picolet H, Samama M. Correlation between anti Xa andoccurrence of thrombosis and haemorrhage in post-surgical patients treated with either logiparin® (LMWH) or unfractionated heparin. Thromb Res 1992; 65: 641-650
  • 51 Albada J, Nieuwenhuis HK, Sixma JJ. Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin). Results of a double-bind randomized study. Circulation 1989 80. 935-940
  • 52 Nieuwenhuis HK, Albada J, Banga JD, Sixma JJ. Identification of risk factors for bleeding during treatment of acute venous thromboembolism with heparin or low molecular weight heparin. Blood 1991; 78: 2337-2343
  • 53 Kakkar VV, Boneu B, Cohen AT, Sujata M. A prospective, randomized, double-blind trial comparing a new low molecular weight heparin (LMWH, LU U7311-Clivarine) and unfractionatedheparin (UFH) in prevention of deepvein thrombosis after major abdominal surgery. Thromb Haemost 1993; 69-651 abstr
  • 54 Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled clinical trial. Lancet 1960; 1: 1309-1312
  • 55 Holmstrom MC, Berglund S, Granquist S, Bratt G, Tornebohm E, Lockner D. Fragmin once or twice daily subcutaneously in the treatment of deep venous thrombosis of the leg. Thromb Res 1992; 67: 49-55
  • 56 Leizorovicz A, Picolet H, Peyreyx JC, Boissel JP and HBPM group. Prevention of perioperative deep vein thrombosis in general surgery: a multicentre double-blind studycomparing two doses of Logiparin and Standard Heparin. Br J Surg 1991; 78: 412-416
  • 57 Spiro TE. and the Enoxaparin Clinical Trial Group A randomized, trial of Enoxaparin administered post-operatively for the prevention of deep vein thrombosis following elective hip replacement surgery. Thromb Haemost 1991; 65-927 abstr
  • 58 Leyvraz PF, Bachmann F, Hoek J, Buller HR, Postel M, Samama M, Vandenbroek MD. Prevention of deep vein thrombosis after hip replacement: randomised comparison between unfractionated heparin and low molecular weight heparin. Br Med J 1991; 303: 543-548
  • 59 Duroux P. A randomised trial of subcutaneous low molecular weight heparin (CY216) compared with intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1991; 65: 251-256
  • 60 Simonneau G, Charbonnier B, Decousus H, Planchon B, Ninet J, Sie P, Silsiguen M, Combe S. Subcutaneous low molecular weight heparin compared with continuousintravenous unfractionated heparin in the initial treatment of proximal vein thrombosis. A multicenter randomized trial: DVTENOX study. Arch Int Med 1993 153. 1541-1546
  • 61 Cadroy Y, Pourrat J, Baladre MF, Saivin S, Houin G, Montastruc JL, Vernier I, Boneu B. Delayed elimination of enoxaparine in patients with chronic renal insufficiency. Thromb Res 1991; 63: 385-390
  • 62 Goudable C, Saivin S, Houin G, Sie P, Boneu B, Tonthat H, Sue JM. Pharmacokinetics of a low molecular weight heparin (Fraxiparine®) in various stages of chronic renal failure. Nephron 1991; 59: 543-545
  • 63 Aiach M, Boneu B, Potron G. on behalf of Groupe d’Etudes sur l’Hemostase et la Thrombose. Utilisation des heparines en pratique medi-cale courante. STY 1991 3. Suppl 4-11