Thrombosis Knowledge Centre
Pharmacological Options: Antithrombotics
Anti Xa Inhibitor
Proposition for the introduction page on Anti Xa inhibitor:
The main characteristics of the natural high-affinity pentasaccharide responsible for the anticoagulant activity of heparin have been elucidated over 25 years. The first critical observation was made by Lindahl and associates in 1979,1 when they isolated heparin fragments with high affinity to antithrombin. Soon after, Choay and associates2 demonstrated that the minimum sequence for binding to antithrombin was confined within six residues. Choay and associates and Thunberg and associates3 then demonstrated that the minimum sequence required for high-affinity binding to antithrombin was contained in the pentasaccharide. On the basis of these observations, in 1983 Jean Choay and associates4,5 synthesized the natural pentasaccharide6 responsible for high-affinity binding of heparin to antithrombin. They demonstrated that this high-affinity pentasaccharide formed an equimolar complex that enhanced the antithrombin-mediated inhibition of factor Xa, and that the pentasaccharide had antithrombotic activity in vivo.
Figure 1: Structure of Fondaparinux
After demonstrating that a 3-0-sulfate group on one of its glucosamine units of the natural pentasaccharide was a requirement for high affinity, analogs of the natural pentasaccharide were synthesized. A pentasaccharide analog lacking this 3-0-sulfate group and two different tetrasaccharides, each part of the high-affinity pentasaccharide sequence, all had markedly reduced anti-factor Xa activity compared with the high-affinity pentasaccharide.These seminal observations established that the anticoagulant activity of heparin (and LMWH) resides largely in a high-affinity, five-sugar unit of the polysaccharide.
In 1987,Attha and associates7 reported that both the 3-O- and 6-O-sulfated glucosamine residues are critical for the ability of a synthetic pentasaccharide to induce the conformational change in antithrombin required to markedly enhance the rate of inhibition of factor Xa by AT. On the basis of these fundamental observations, the modified synthetic pentasaccharide, fondaparinux, was developed as an anticoagulant for clinical use.The pattern of sulfation of fondaparinux differs from that of the natural pentasaccharide, thereby endowing the factor Xa inhibitor with a much higher binding affinity to antithrombin.8
Figure 2: Fondaparinux (Arixtra®)
Mechanism of action
References:
1. Lindahl U, Backstrom G, Hook M, et al. Structure of the antithrombin-binding site of heparin. Proc Natl Acad Sci USA 1979;76:3198.
2. 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.
3. Thunberg L, Backstrom G, Lindahl U. Further characterization of the antithrombin-binding sequence in heparin. Carbohydrate Res 1982;100:393–410.
4. Choay J, Petitou M, Lormeau JC, et al. Structure–activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin and eliciting high anti-factor Xa activity. Biochem Biophys Res Comm 1983;116:492–9.
5. Choay J. Biologic studies on chemically synthesized pentasaccharide and tetrasaccharide fragments. Semin Thromb Hemost 1985;11:81–5.
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.Attha DH, Lormeau JC, Petitou M, et al. Contribution of 3–O– and 6–O–sulfated glucosamine
residues in the heparin–induced conformational change in antithrombin III. Biochemistry 1987; 6;26(20):6454–61.
8. Turpie AGG, Eriksson BI, Bauer KA, Lassen MR. Fondaparinux. J Am Acad Orthop Surg 2004;12:371–5.