Heparin-binding copolymer reverses effects of unfractionated heparin, enoxaparin, and fondaparinux in rats and mice

摘要

The parenteral anticoagulants may cause uncontrolled and life-threatening bleeding. Protamine, the only registered heparin antidote, is partially effective against low-molecular weight heparins, completely ineffective against fondaparinux and may cause unacceptable toxicity. Therefore, we aimed to develop a synthetic compound for safe and efficient neutralization of all parenteral anticoagulants. We synthesized pegylated PMAPTAC block copolymers, and then, we selected a lead heparin-binding copolymer (HBC). We assessed the effectiveness of HBC in the model of arterial thrombosis electrically induced in the carotid artery of rats by measuring thrombus weight, bleeding time, activated partial thromboplastin time, activated clotting time, and anti-factor Xa activity. The intravital tissue distribution, the cardiorespiratory, and organ toxicity were monitored. HBC diminished antithrombotic and anticoagulant effects of unfractionated heparin. Moreover, it stopped bleeding and completely reversed the enhancement of clotting times and anti factor Xa activity caused by enoxaparin or fondaparinux. We observed slight pulmonary congestion and cell infiltration, but the cardiorespiratory parameters remained unchanged. We found a strong signal of fluorescently-labeled HBC in the urine, and a weaker in the liver and in the kidney. No signs of hepatic or nephrotoxicity were observed in the blood biochemistry or histopathologic examination. We developed a copolymer efficiently neutralizing effects of heparins in the living organism, which shows a very promising efficacy/safety profile and may help in the management of uncontrolled bleeding resulting from an anticoagulant injection. HBC could enable the safe replacement of unfractionated heparin with low-molecular weight heparins in patients undergoing cardiac surgery and complex vascular procedures.