Porous dynamic covalent polymers as promising reversal agents for heparin anticoagulants

Zong, Yang; Xu, Yanyan; Wu, Yan; Liu, Yamin; Li, Qian; Lin, Furong; Yu, Shang‐Bo; Wang, Hui; Zhou, Wei; Sun, Xing‐Wen; Zhang, Dan‐Wei; Li, Zhan‐Ting

doi:10.1039/d2tb00174h

Cited by 5 publications

(2 citation statements)

References 71 publications

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“…Multivalency has been established as an efficient strategy for this aim, as demonstrated by protamine, whose guanidine groups in the side chains multivalently form electrostatic binding with the anionic groups of heparins. We previously reported that polymeric frameworks formed by tri- and tetracationic precursors can adsorb both UFH and LMWHs to neutralize their anticoagulant action. , We thus designed and prepared a library of caltrop-like multicationic molecules TP-1–8 , TI-1 , TI-2 , and TQ-1 (Figure ), which consisted of pyridinium, imidazolium, or isoquinoline-2-ium units and discrete side chains bearing a peripheral amino group, to test their potential as small-molecule antidotes for heparin neutralization. All the compounds displayed good solubility in water.…”

Section: Resultsmentioning

confidence: 99%

Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo

Zong,

Lei,

et al. 2024

J. Med. Chem.

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Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) are widely applied for surgical procedures and extracorporeal therapies, which, however, suffer bleeding risk. Protamine, the only clinically approved antidote, can completely neutralize UFH, but only partially neutralizes LMWHs, and also has a number of safety drawbacks. Here, we show that caltrop-like multicationic small molecules can completely neutralize both UFH and LMWHs. In vitro and ex vivo assays with plasma and whole blood and in vivo assays with mice and rats support that the lead compound is not only superior to protamine by displaying higher neutralization activity and broader therapeutic windows but also biocompatible. The effective neutralization dose and the maximum tolerated dose of the lead compound are determined to be 0.4 and 25 mg/kg in mice, respectively, suggesting good promise for further preclinical studies.

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Section: Resultsmentioning

confidence: 99%

Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo

Zong,

Lei,

et al. 2024

J. Med. Chem.

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“…There are also cationic polymers such as universal heparin reversal agent, dynamic covalent polymers, and others described by Bromfield et al, which could be useful as neutralizers in diagnostic tests, although further research is needed to check if their efficacy profile could be better than protamine [121][122][123].…”

Section: Other Cationic Polymersmentioning

confidence: 99%

The methods for removal of direct oral anticoagulants and heparins to improve the monitoring of hemostasis: a narrative literature review

et al. 2023

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The assessment of hemostasis is necessary to make suitable decisions on the management of patients with thrombotic disorders. In some clinical situations, for example, during thrombophilia screening, the presence of anticoagulants in sample makes diagnosis impossible. Various elimination methods may overcome anticoagulant interference. DOAC-Stop, DOAC-Remove and DOAC Filter are available methods to remove direct oral anticoagulants in diagnostic tests, although there are still reports on their incomplete efficacy in several assays. The new antidotes for direct oral anticoagulants – idarucizumab and andexanet alfa – could be potentially useful, but have their drawbacks. The necessity to remove heparins is also arising as heparin contamination from central venous catheter or therapy with heparin disturbs the appropriate hemostasis assessment. Heparinase and polybrene are already present in commercial reagents but a fully-effective neutralizer is still a challenge for researchers, thus promising candidates remain in the research phase.

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Supramolecular systems for bioapplications: recent research progress in China

Liu,

Yu,

Pan

et al. 2024

Sci. China Chem.

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Porous dynamic covalent polymers as promising reversal agents for heparin anticoagulants

Abstract: Heparins are natural and partially degraded polyelectrolytes that consist of sulfated polysaccharide backbones. However, as clinically used anticoagulants, heparins are associated clinical bleeding risks and thus require rapid neutralization. Protamine...

Cited by 5 publications

References 71 publications

Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo

Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo

The methods for removal of direct oral anticoagulants and heparins to improve the monitoring of hemostasis: a narrative literature review

Supramolecular systems for bioapplications: recent research progress in China

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