REVIEW: New Antithrombotics for Atrial Fibrillation

Atrial fibrillation (AF) is the most commonly occurring arrhythmia, and is a condition of both significant clinical and economic importance. An antithrombotic agent is considered mandatory as part of the management in most patients with AF. It has been conclusively demonstrated that long‐term anticoagulation therapy can significantly reduce the risk of stroke in patients with nonvalvular AF. While vitamin K antagonists (VKAs) such as warfarin are highly effective, they possess numerous limitations that curtail their use, or make their use challenging for clinicians and patients. A new generation of anticoagulants are being investigated in phase III clinical trials in patients with AF. One or more of these agents have the potential to either replace or act as alternatives to VKA therapy in AF. This group includes the direct thrombin inhibitor, dabigatran, the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, and finally, the vitamin K analogue, tecarfarin. Additional agents are being developed in phase I or II clinical trials. The direct thrombin and factor Xa inhibitors are generally small, synthetic molecules with predictable pharmacokinetics, a predictable pharmacodynamic effect, few drug interactions and do not require routine therapeutic drug monitoring. These new anticoagulants may well represent a new era in anticoagulation. However, they do possess their own limitations and will present new challenges for clinicians.     

Co-ordinated expression of MMP-2 and its putative activator, MT1-MMP, in human placentation

The spatial expression of mRNA for matrix metalloproteinase 2 (MMP-2), its putative activator, the membrane-type 1 matrix metalloproteinase (MT1-MMP), and the MMP-2 substrate type IV collagen was investigated in human placentas of both normal and tubal ectopic pregnancies and in cyclic endometrium using in-situ hybridization. Cytokeratin staining applied to adjacent sections was used to identify epithelial and trophoblast cells. In both normal and tubal pregnancies MT1-MMP, MMP-2 and type IV collagen mRNA were highly expressed and co-localized in the extravillous cytotrophoblasts of anchoring villi, in cytotrophoblasts that had penatrated into the placental bed and in cytotrophoblastic cell islands. In addition, the decidual cells of normal pregnancies in some areas co-expressed MT1-MMP and MMP-2 mRNA, with moderate signals for both components. Fibroblast-like stromal cells in tubal pregnancies were positive for MMP-2 mRNA but generally negative for MT1-MMP mRNA. The consistent co-localization of MT1-MMP with MMP-2 and type IV collagen in the same subset of cytotrophoblasts strongly suggests that all three components co-operate in the tightly regulated fetal invasion process. The co-expression of MT1-MMP and MMP-2 mRNA in some of the decidual cells indicates that these cells are also actively involved in the placentation process.