In the case of major bleeding, the antidote for anticoagulants should be administered intravenously for immediate reaction.
For the treatment of venous thromboembolism and acute coronary syndrome in humans, the recommended subcutaneous dose is 30 mg/day or 1 mg/kg/day.
To reflect the clinical scenario of bleeding, we used ENX in the supratherapeutic dose of 5 mg/kg to enhance the anticoagulant effect in mice. Despite high effectiveness, bleeding complications after ENX treatment occur. Īnticoagulant therapy pursues optimal therapeutic effect while minimizing the adverse reactions of the treatment at the same time. Furthermore, besides mild and occasional clinical signs of toxicity and gross necropsy findings, its single therapeutic dose of 20 mg/kg was well tolerated by rats. We have developed a new synthetic compound, heparin-binding copolymer (HBC), that efficaciously binds and completely neutralizes unfractionated heparin (UFH) and LMWHs both in vitro and in vivo. The development of many alternative antidotes such as hexadimethrine bromide (polybrene), low molecular weight protamine, chemically modified inactive antithrombin, or delparantag (PMX-60056) was suspended because of unacceptable side effects. Andexanet alfa, ciraparantag (PER977), and universal heparin reversal agent (UHRA) are currently in the preclinical or clinical trials. Many studies were undertaken to obtain PS substitutes. Protamine sulfate (PS), the only specific antidote for reversal of heparin activities, is partially effective against LMWHs and may cause life-threatening hypersensitivity reactions. HBC administered in an appropriate dose might be an efficient substitute for PS to reverse significantly increased anticoagulant activity that may be connected with major bleeding in patients receiving ENX subcutaneously. Histopathological analysis showed changes in the liver, lungs, and spleen of mice treated with HBC and in the lungs and heart of mice treated with PS. PS did not reverse antifactor Xa activity and partially reversed antifactor IIa activity. Both doses of HBC completely reversed the effect of ENX on antifactor IIa activity. HBC at the lower dose reversed the effect of ENX on antifactor Xa activity for 10 min after antidote administration, whereas at the higher dose, HBC reversed the effect on antifactor Xa activity throughout the course of the experiment. The main organs were collected for histological analysis. The activities of antifactors Xa and IIa and biochemical parameters were measured. The blood was collected after 3, 10, 60, 120, 360, and 600 min after vehicle, HBC, or PS administration. After 110 min, vehicle, HBC (6.25 and 12.5 mg/kg), or PS (5 and 10 mg/kg) were administered into the tail vein. BALB/c mice were subcutaneously injected with ENX at the dose of 5 mg/kg. Here, we focused on the HBC inhibitory activity against subcutaneously administered ENX in healthy mice. We developed a diblock copolymer, heparin-binding copolymer (HBC), that reverses intravenously administered heparins. The only registered antidote for ENX, protamine sulfate (PS), has 60% efficacy and can cause severe adverse side effects. Uncontrolled bleeding after enoxaparin (ENX) is rare but may be life-threatening.