Anticoagulation therapy has been a very difficult clinical problem, and warfarin is underutilized in the clinic because of its complicated application and the need for continuous monitoring of prothrombin time. The new specific anticoagulants (e.g., dabigatran, rivaroxaban, etc.) are easy to use but have some drawbacks, such as the lack of reversal drugs, which makes it very problematic for patients to restore coagulation quickly once they bleed or need emergency surgery. However, a new anticoagulant “antidote” has already entered the clinical research stage. PER977 (Perosphere) is a synthetic, water-soluble, cationic small molecule that binds specifically to normal heparin or low molecular weight heparin through non-covalent hydrogen bonds and ion-ion interactions. Similarly, PER977 can be combined with novel oral factor Xa inhibitors (edoxaban/edoxaban/edoxaban, rivaroxaban/rivaroxaban/bactrim, and apixaban/apixaban) or oral thrombin inhibitors (dabigatran/dabigatran). Thromboelastography and rat tail dissection bleeding assays confirmed that PER977 reversed the effects of various novel oral anticoagulants. Non-clinical studies have shown that PER977 does not bind to plasma proteins, including albumin, and does not bind to some common cardiovascular drugs, antiepileptic drugs, and anesthetic drugs. Ansell et al. studied the safety and side effects of PER977 alone, as well as the safety, side effects, and reversal of anticoagulation with the application of 60-mg factor Xa inhibitor edoxaban. This was a double-blind placebo-controlled clinical trial in 80 healthy individuals to study the pharmacokinetics and pharmacodynamics of a single intravenous application of different doses (5 to 300 mg) of PER977, alone or after oral application of 60-mg edoxaban. edoxaban’s anticoagulant effect and the reversal of PER977 were measured using whole- blood clotting time (WHBCT). Clinical trials with PER977 showed low variability in whole-blood clotting time (3.0% inter-examiner variability), high reproducibility (3.6% inter-subject variability), and good correlation with edoxaban plasma concentrations. Mean whole blood clotting time increased by 37% from baseline levels after edoxaban application. After 3 hours of edoxaban application, whole blood clotting time returned to no more than 10% of baseline levels within 10 minutes in patients who received a single intravenous injection of PER977 (100 to 300 mg), compared with approximately 12 to 15 hours in patients who received placebo. After 24 hours of a single injection of PER977, the whole blood clotting time remained at or below 10% of the baseline level. Clots formed during the detection of whole blood clotting time were examined by scanning electron microscopy to determine the mean fibrin fibril diameter by computer analysis. edoxaban anticoagulation significantly reduced the mean fibrin fibril diameter (from approximately 250 nm to approximately 125 nm, P<0.001< span="">). Fibrin fibril diameter returned to normal 30 minutes after PER977 application. d-dimer, prothrombin fragment 1.2, and tissue factor pathway inhibitor tests, as well as whole blood coagulation time tests, demonstrated no procoagulant activity with PER977 application. Possible adverse effects were transient mild periorbital and facial congestion and abnormal taste; one subject had moderate headache. In addition, one subject had moderate muscle cramps and elevated creatine kinase, which may not be related to PER977 application. This study showed that the anticoagulant status returned to baseline clotting status 10 to 30 minutes after application of 100 to 300 mg PER977 and that the effect lasted 24 hours, which was faster and more sustained than the reversal of warfarin by vitamin K application.