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Blood coagulation is the process of changing the blood from the flowing state to the gel state. It is an important part of the hemostatic function. Coagulation is a process by which a series of coagulation factors are sequentially activated, and finally thrombin is formed to form fibrin clot. Direct thrombin inhibitors are important anticoagulant drug. These drugs can selectively bind to the active site of thrombin, inhibit thrombin activity, have strong action and high specificity, and have important significance in the clinical treatment of thrombus diseases. Some of them come from natural products of animals or plants, and many of them have been applied in the clinic. The other part is derived from the design, synthesis and activity studies of small molecule inhibitors. This review discusses the progress of direct thrombin inhibitors in recent years.