Kalaska Bartlomiej, Kaminski Kamil, Miklosz Joanna, Yusa Shin-Ichi, Sokolowska Emilia, Blazejczyk Agnieszka, Wietrzyk Joanna, Kasacka Irena, Szczubialka Krzysztof, Pawlak Dariusz, Nowakowska Maria, Mogielnicki Andrzej
Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.
Faculty of Chemistry, Jagiellonian University, Krakow, Poland.
Transl Res. 2016 Nov;177:98-112.e10. doi: 10.1016/j.trsl.2016.06.009. Epub 2016 Jul 5.
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.
胃肠外抗凝剂可能会导致无法控制的、危及生命的出血。鱼精蛋白是唯一注册的肝素解毒剂，对低分子量肝素部分有效，对磺达肝癸钠完全无效，且可能会引起不可接受的毒性。因此，我们旨在研发一种合成化合物，用于安全有效地中和所有胃肠外抗凝剂。我们合成了聚乙二醇化的PMAPTAC嵌段共聚物，然后选择了一种主要的肝素结合共聚物（HBC）。我们通过测量血栓重量、出血时间、活化部分凝血活酶时间、活化凝血时间和抗Xa因子活性，评估了HBC在大鼠颈动脉电诱导动脉血栓形成模型中的有效性。监测了活体组织分布、心肺功能和器官毒性。HBC减弱了普通肝素的抗血栓和抗凝作用。此外，它能止血，并完全逆转依诺肝素或磺达肝癸钠引起的凝血时间延长和抗Xa因子活性增强。我们观察到有轻微的肺充血和细胞浸润，但心肺参数保持不变。我们在尿液中发现了荧光标记的HBC的强烈信号，在肝脏和肾脏中的信号较弱。在血液生化或组织病理学检查中未观察到肝毒性或肾毒性的迹象。我们研发了一种共聚物，能在生物体内有效中和肝素的作用，其疗效/安全性非常有前景，可能有助于处理因抗凝剂注射导致的无法控制的出血。HBC可使接受心脏手术和复杂血管手术的患者安全地用低分子量肝素替代普通肝素。
