Leading article New anticoagulants and thromboprophylaxis Marnix R. Hoppener and Harry R. B ¨ uller Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands(e-mail: M.R.Hoppener@AMC.UVA.nl) Published online in Wiley InterScience (www.bjs.co.uk). DOI: 10.1002/bjs.4899 In 1915 McLean and colleagues dis- covered heparin 1 . About 60 years later the efficacy and safety of heparin thromboprophylaxis was convincingly demonstrated in the surgical setting, with low dose heparin shown to be superior to placebo 2 . The next impor- tant development was the introduc- tion of low molecular weight hep- arins (LMWHs) and, in the 1980s, clinical studies demonstrated their modest superiority over conventional, unfractionated heparin. LMWHs also had the advantage of a once daily mode of administration. Over a simi- lar time frame vitamin K antagonists came to prominence in the prevention of venous thromboembolism (VTE), particularly in the out of hospital set- ting. This leading article focuses on the efficacy and safety of a new gen- eration of antithrombotic agents that may soon replace both LMWHs and vitamin K antagonists. Currently available antithrombotic agents have several disadvantages, including insufficient efficacy (partic- ularly in some high risk patients), a cumbersome mode of administration (multiple subcutaneous injections) and, in the case of vitamin K antag- onists, the need for repeated con- trol of intensity and dose-adjustment. Clearly there is ample motivation to search for new agents with higher efficacy, improved safety and simpler administration. The new generation of antithrombotics, some of which have become available recently, can be categorized according to the level at which they interfere in the coagu- lation cascade (Figure 1) 3 . Tissue factor/factor VIIa inhibitors There are several agents under inves- tigation that can block tissue factor or the complex of tissue factor and factor VIIa. The rationale for this approach is that the initiation of thrombus for- mation occurs when tissue factor is exposed within a damaged blood ves- sel; it rapidly complexes with factor VIIa. The compound at the most advanced stage of study is recombi- nant nematode anticoagulant protein C2 (r-NAPc2), which is based on a substance present in the saliva of the hookworm. This potent inhibitor of the tissue factor/factor VIIa complex has been shown in a dose finding study to be effective in the prevention of VTE after total knee replacement 4 , but further studies are required to confirm its general efficacy and safety. r-NAPc2 is administered by subcuta- neous injection every other day. Factor Xa inhibitors Factor Xa inhibitors can be subclassi- fied into direct or indirect inhibitors. New indirect inhibitors are synthetic analogues of the five key sugars (pen- tasaccharides) present in heparin that specifically bind to the natural anti- coagulant anti-thrombin, and subse- quently block factor Xa, a key enzyme in the acceleration of coagulation acti- vation. Two pentasaccharides, both administered subcutaneously, are now available and their principal distinc- tion is in terms of elimination half life. Fondaparinux has a half life of 15 to 20 h (which makes it suitable for once a day administration), whereas idra- parinux has a half life of about 130 h (and so can be administered once a week). The clinical efficacy of fonda- parinux started 6 to 8h after operation has been investigated in four randomized, double-blind stud- ies in patients undergoing major orthopaedic surgery 5 . The combined data suggest that fondaparinux pro- phylaxis produces a reduction of about 50 per cent in postoperative VTE, with a similar risk of bleeding as that experienced with LMWH. A recent clinical trial in patients undergoing high-risk abdominal surgery com- pared fondaparinux with LMWH and found no significant differences in the rates of VTE and bleeding between the two groups 6 . The long acting pentasaccharide, idraparinux, has not so far been assessed in the surgical setting; a potential problem with pen- tasaccharides, especially long acting ones, is that no antidote is available should serious bleeding occur. Several direct, usually orally admin- istered factor Xa inhibitors are in development, and early dose find- ing studies suggest that they are at least as effective and safe as LWMH 7 . Their main advantage is that they can be initiated after surgery and contin- ued with ease after discharge from hospital, should prophylaxis remain indicated. Thrombin inhibitors The prototype of thrombin inhibitors is recombinant hirudin, which is based on the anticoagulant produced by leeches. The main difference between hirudin and heparin is that the for- mer can block thrombin indepen- dent of antithrombin; it is a direct Copyright  2005 British Journal of Surgery Society Ltd British Journal of Surgery 2005; 92: 259–261 Published by John Wiley & Sons Ltd