Inactivation of heparin by cationically modified chitosan.

Barbara Lorkowska-Zawicka,Jacek Jawień,Krzysztof Okoń,Dariusz Adamek,Magdalena Białas,Ryszard Korbut,Krzysztof Szczubiałka,Kamil Kamiński,Justyna Ciejka,Rafał Olszanecki,Maria Nowakowska

doi:10.3390/md12073953

Barbara Lorkowska-Zawicka, Jacek Jawień + Show 9 more

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https://doi.org/10.3390/md12073953

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Journal: Marine Drugs	Publication Date: Jun 30, 2014
Citations: 57	License type: CC BY 4.0

Affiliation: Jagiellonian University

Abstract

This study was performed to evaluate the ability of N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC), the cationically modified chitosan, to form biologically inactive complexes with unfractionated heparin and thereby blocking its anticoagulant activity. Experiments were carried out in rats in vivo and in vitro using the activated partial thromboplastin time (APTT) and prothrombin time (PT) tests for evaluation of heparin anticoagulant activity. For the first time we have found that HTCC effectively neutralizes anticoagulant action of heparin in rat blood in vitro as well as in rats in vivo. The effect of HTCC on suppression of heparin activity is dose-dependent and its efficacy can be comparable to that of protamine-the only agent used in clinic for heparin neutralization. HTCC administered i.v. alone had no direct effect on any of the coagulation tests used. The potential adverse effects of HTCC were further explored using rat experimental model of acute toxicity. When administered i.p. at high doses (250 and 500 mg/kg body weight), HTCC induced some significant dose-dependent structural abnormalities in the liver. However, when HTCC was administered at low doses, comparable to those used for neutralization of anticoagulant effect of heparin, no histopathological abnormalities in liver were observed.

Highlights

Heparin, usually used in cardiovascular surgery to prevent thromboembolism, often leads to a high incidence of bleeding complications
On the basis of these results, we chose a dose of 3 IU of heparin/mL of blood to study the effect of HTCC on hemostatic parameters
HTCC caused a dose-dependent decrease in activated partial thromboplastin time (APTT) level of heparinized rat blood (Figure 2)

Summary

Introduction

Usually used in cardiovascular surgery to prevent thromboembolism, often leads to a high incidence of bleeding complications. Protamine consists of a group of heterogeneous cationic peptides obtained from fish and its antiheparin activity results from the attractive electrostatic interaction with anionic heparin [1]. It is a relatively safe drug; its administration is occasionally associated with severe, life-threatening reactions, including significant systemic hypotension, severe pulmonary hypertension, anaphylactic shock, fatal cardiac arrest as well as thrombocytopenia [2]. As a cationic polysaccharide, can interact with negatively charged (macro)molecules. This feature was essential for our concept that chitosan can interact with heparin. Other beneficial properties such as antitumor, hypocholesterolemic, weight lowering, antioxidant, neuroprotective, and antimicrobial presented it to nutritional health supplements [7,8,9]

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Conclusion