The lysis of TF-induced plasma clot containing UHRA or PS exposed to exogenous tissue plasminogen activator (t-PA) was studied by turbidimetric assay. The influence of UHRA on fibrin clot architecture was evaluated by scanning electron microscopy (SEM).The anticoagulant neutralization (heparins) by UHRA was studied by fluorogenic thrombin generation assay (TGA) in human platelet-rich plasma (PRP). The interaction of UHRA on fibrinogen was investigated by fibrinogen aggregation assay, fibrin polymerization assay and by spectroscopic analysis (fluorescence and circular dichroism (CD)). Recalcification and tissue factor (TF) initiated turbidimetric plasma clotting assays was performed to understand the impact of UHRA on coagulation system.
UHRA was developed by incorporating tertiary amine based heparin binding groups on a dendritic hyperbranched polyglycerol scaffold and capping it with methoxy polyethylene glycol chains. This study aims to demonstrate the nontoxic nature of UHRA by assessing its influence on fibrinogen, fibrin clot architecture, plasma clotting and clot lysis. In vivo studies revealed that UHRA completely reverse the activity of all clinical available parenteral anticoagulants and is nontoxic.
Recently, we developed a synthetic universal heparin reversal agent (UHRA) with high binding affinity to heparins. However, PS interacts with coagulation proteins such as fibrinogen to form aggregates which leads to cardiovascular adverse effects. Inability of PS to completely reverse low molecular weight heparins and fondaparinux is due to its low binding affinity to these drugs. PS has toxic side effects and limitations. To date, protamine sulphate (PS), a cationic polypeptide is the only clinically approved antidote for unfractionated heparin. Antidotes are administered to counteract anticoagulation and to restore normal hemostasis. Haemorrhage in surgical patients receiving anticoagulants is a major concern.
Anticoagulants play a pivotal role in the treatment of thromboembolic disorders.
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