Oral Thromboprophylaxis Following Total Hip or Knee Replacement: Review and Multicentre Experience with Dabigatran Etexilate

The risk of venous thromboembolism (VTE) in patients undergoing total knee or hip replacement surgery is high. As a result, thromboprophylaxis is highly recommended. While current thromboprophylactic agents, such as low molecular weight heparins (LMWH) and vitamin K antagonists, are safe and effective their use can be problematic. Therefore, there is a need for alternative anticoagulants that are as safe and effective as conventional agents, but are more convenient and easier to use. Dabigatran etexilate, a direct thrombin inhibitor, is one such anticoagulant. For VTE prevention following major orthopaedic surgery, dabigatran etexilate shows similar efficacy and safety to the LMWH enoxaparin, and is approved for use in more than 75 countries, including Europe and Canada. Here, we summarize and discuss the experiences of four German clinics that have recently introduced dabigatran etexilate into clinical practice. Overall, dabigatran etexilate was well received by patients, surgeons and nurses, and compared favourably with enoxaparin. Staff appreciated the oral, single-dose administration of dabigatran etexilate. Patient satisfaction was high, especially in those individuals who had previously used LMWHs. In this review, we also address a number of questions that were asked by patients or staff; this will be of relevance to orthopaedic surgeons and nurses. We conclude that, in these four German clinics, dabigatran etexilate offered an effective oral alternative to existing thromboprophylactic agents in patients undergoing major orthopaedic surgery

Rational Design and Characterization of D-Phe-Pro-D-Arg-Derived Direct Thrombin Inhibitors

The tremendous social and economic impact of thrombotic disorders, together with the considerable risks associated to the currently available therapies, prompt for the development of more efficient and safer anticoagulants. Novel peptide-based thrombin inhibitors were identified using in silico structure-based design and further validated in vitro. The best candidate compounds contained both l- and d-amino acids, with the general sequence d-Phe(P3)-Pro(P2)-d-Arg(P1)-P1′-CONH2. The P1′ position was scanned with l- and d-isomers of natural or unnatural amino acids, covering the major chemical classes. The most potent non-covalent and proteolysis-resistant inhibitors contain small hydrophobic or polar amino acids (Gly, Ala, Ser, Cys, Thr) at the P1′ position. The lead tetrapeptide, d-Phe-Pro-d-Arg-d-Thr-CONH2, competitively inhibits α-thrombin's cleavage of the S2238 chromogenic substrate with a Ki of 0.92 µM. In order to understand the molecular details of their inhibitory action, the three-dimensional structure of three peptides (with P1′ l-isoleucine (fPrI), l-cysteine (fPrC) or d-threonine (fPrt)) in complex with human α-thrombin were determined by X-ray crystallography. All the inhibitors bind in a substrate-like orientation to the active site of the enzyme. The contacts established between the d-Arg residue in position P1 and thrombin are similar to those observed for the l-isomer in other substrates and inhibitors. However, fPrC and fPrt disrupt the active site His57-Ser195 hydrogen bond, while the combination of a P1 d-Arg and a bulkier P1′ residue in fPrI induce an unfavorable geometry for the nucleophilic attack of the scissile bond by the catalytic serine. The experimental models explain the observed relative potency of the inhibitors, as well as their stability to proteolysis. Moreover, the newly identified direct thrombin inhibitors provide a novel pharmacophore platform for developing antithrombotic agents by exploring the conformational constrains imposed by the d-stereochemistry of the residues at positions P1 and P1′