The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs. Any treatment regimen, particularly one involving medication, involves inherent risk that must be weighed on a case-by-case basis against the benefits anticipated. The reader is cautioned that the purpose of this resource is to inform and enlighten; the information contained herein is not intended as, and should not be employed as, a substitute for individual diagnosis and treatment.
Interest in low molecular weight heparin (LMWH) was stimulated by two observations reported in the 1980s. The first was that LMWH preparations have reduced antifactor IIa activity relative to antifactor Xa activity.1,2 The second was that, compared with heparin, LMWH showed less bleeding in animal studies for an equivalent antithrombotic effect.3,4 LMWHs were also shown to have superior pharmacokinetic properties to those of heparin.5–11
The mechanism for the higher of antifactor Xa of LMWH, relative to its antifactor IIa activity,was elucidated by a number of investigators.12–17
References:
1. Harenberg J. Pharmacology of low molecular weight heparins. Sem Thromb Hemost 1990;16:12–8.
2. Johnson EA, Kirkwood TB, Stirling Y, et al. Four heparin preparations: anti-Xa potentiating effect of heparin after subcutaneous injection.Thromb Haemost 1976;35:586–91.
3. Carter CJ, Kelton JG, Hirsh J, et al.The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparins in rabbits. Blood 1982;59:1239–45.
4. Bergqvist D, Nilsson B, Hedner U, et al. The effects of heparin fragments of different molecular weight in experimental thrombosis and haemostasis.Thromb Res 1985;38:589–601.
5. Frydman A, Bara L, Leroux Y, et al.The antithrombotic activity and pharmacokinetics of Enoxaparin, a low molecular weight heparin, in man given single subcutaneous doses of 20 up to 80 mg. J Clin Pharmacol 1988;28:609–18. 45Hirsch_fondaparinux_2 5/2/07 10:34 PM Page 45
6. Briant L, Caranobe C, Saivin S, et al. Unfractionated heparin and CY216. Pharmacokinetics and bioavailabilities of the anti-factor Xa and IIa. Effects of intravenous and subcutaneous injection in rabbits.Thromb Haemost 1989;61:348–53.
7. Bratt G,Tornebohm E,Widlund L, et al. Low molecular weight heparin (KABI 2165, FRAGMIN):
pharmacokinetics after intravenous and subcutaneous administration in human volunteers.Thromb Res 1986;42:613–20.
8. Matzsch T, Bergqvist D, Hedner U, et al. Effect of an enzymatically depolymerized heparin as compared with conventional heparin in healthy volunteers.Thromb Haemost 1987;57:97–101.
9. Bara L, Samama MM. Pharmacokinetics of low molecular weight heparins. Acta Chir Scand 1988;543:65–72.
10. Bradbrook ID, Magnani HN, Moelker HC, et al. ORG 10172: a low molecular weight heparinoid anticoagulant with a long half life in man. Br J Clin Pharmacol 1987;23:667–75.
11. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688–98.
12. Jordan RE, Oosta GM, Gardner WT, et al.The kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin. J Biol Chem 1980;255:10081–90.
13. Holmer E,Kurachi K, Soderstrom G.The molecular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and kallikrein by antithrombin. Biochem J 1981;193:395–400.
14. Holmer E, Soderberg K, Bergqvist D, et al. Heparin and its low molecular weight derivatives: anticoagulant and antithrombotic properties. Haemostasis 1986;16(Suppl 2):1–7.
15. Griffith MJ. Heparin-catalyzed inhibitor/protease reactions: kinetic evidence for a common mechanism of action of heparin. Proc Natl Acad Sci USA 1983;80:5460–4.
16. Pletcher CH, Nelsestuen GL. Two-substrate reaction models for the heparin-catalyzed bovine antithrombin/protease reaction. J Biol Chem 1983;258:1086–91.
17. Danielsson A, Raub E, Lindahl U, et al. Role of ternary complexes, in which heparin binds both antithrombin and proteinase, in the acceleration of the reactions between antithrombin and thrombin or factor Xa. J Biol Chem 1986;261:15467–73.