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.
Heparin was isolated from a dog’s liver by McLean in 19161 and shown to have anticoagulant properties. In 1939 Brinkhous and associates2 demonstrated that heparin required a plasma cofactor to produce an anticoagulant effect, a property that led to its classification as an indirect anticoagulant. This heparin cofactor was subsequently named antithrombin III (ATIII) by Abildgaard in 1968,3 and now is referred to simply as antithrombin (AT). In a series of elegant experiments in the 1970s, Rosenberg’s group and Lindahl’s group elucidated the mechanism of the heparin–AT interaction.4–6 Heparin binds to lysine sites on AT, producing a conformational change at the arginine reactive center, which converts AT from a slow, progressive thrombin inhibitor to a very rapid inhibitor.The arginine reactive center on the AT molecule binds covalently to the active center serine of thrombin and other coagulation enzymes, thereby irreversibly inhibiting their procoagulant activity.4 Heparin then dissociates from the ternary complex and is reutilized.4 Subsequently it was discovered that heparin binds to AT through a unique glucosamine unit7 contained within a pentasaccharide sequence.8 In the 1980s, results of studies with low–molecular-weight fractions of heparin showed that the inactivation of thrombin and other activated coagulation factors by heparin molecules is chain-length–dependent, whereas the inactivation of factor Xa only requires the presence of the high-affinity pentasaccharide. This high-affinity pentasaccharide has been synthesized, modified, and developed into the synthetic pentasaccharide, fondaparinux.9–13
References:
1. McLean J.The thromboplastic action of cephalin.Am J Physiol 1916;41:250–7.
2. Brinkhous KM, Smith HP,Warner ED, et al.The inhibition of blood clotting: an unidentified substance which acts in conjunction with heparin to prevent the conversion of prothrombin into thrombin. Am J Physiol 1939;125:683–7.
3. Abildgaard U. Highly purified antithrombin III with heparin cofactor activity prepared by disc electrophoresis. Scand J Clin Lab Invest 1968;21:89–91.
4. Rosenberg RD, Bauer KA.The heparin-antithrombin system: a natural anticoagulant mechanism. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, editors. Hemostasis and thrombosis: basic principles and clinical practice. 3rd ed. Philadelphia: JB Lippincott Co.; 1994. p. 837–60.
5. Rosenberg RD, Lam L. Correlation between structure and function of heparin. Proc Natl Acad Sci USA 1979;76:1218–22.
6. Lindahl U, Backstrom G, Hook M, et al. Structure of the antithrombin-binding site of heparin. Proc Natl Acad Sci USA 1979;76:3198–202.
7. Casu B, Oreste P,Torri G, et al.The structure of heparin oligosaccharide fragments with high anti- (factor Xa) activity containing the minimal antithrombin III-binding sequence. Biochem J 1981;97:599–609.
8. Choay J, Lormeau JC, Petitou M, et al. Structural studies on a biologically active hexasaccharide obtained from heparin.Ann NY Acad Sci 1981;370:644–9.
9. Vuillemenot A, Schiele F, Meneveau N, et al. Efficacy of a synthetic pentasaccharide, a pure factor Xa inhibitor, as an antithrombotic agent—a pilot study in the setting of coronary angioplasty.Thromb Haemost 1999;81:214–20.
10. Herbert JM, Herault JP, Bernat A, et al. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide. Blood 1998;91:4197–205.
11. Eriksson BI, Bauer KA, Lassen MR, et al, for the Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001;345:1298–304.
12. Bauer KA, Eriksson BI, Lassen MR, et al., for the Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345:1305–10.
13. Turpie AGG, Bauer KA, Eriksson BI, et al, for the PENTATHLON 2000 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for the prevention of venous thromboembolism after elective hip-replacement surgery: a randomized double-blind trial. Lancet 2002;359:1721–6.