title: Ultrasonic-assisted preparation of a low molecular weight heparin (LMWH) with anticoagulant activity.
abstract: Low molecular weight heparin (LMWH) is currently used as an anticoagulant agent and constitutes an alternative to unfractionated heparin, which is the cause of serious adverse drug reaction such as heparin-induced thrombocytopenia (HIT). Commercially available LMWH is produced by enzymatic depolymerization that is costly or by chemical methods that are generally carried out under conditions that could imply side reactions that reduce final product efficiency and yields. In this work, we present the use of a physicochemical method for the production of LMWH. This method consists in the use of hydrogen peroxide-catalyzed radical hydrolysis assisted by ultrasonic waves. LMWH that are produced using this physicochemical method have an average molecular weight and anticoagulant properties (Anti-Xa and Anti-IIa) that are comparable to some of commercial LMWH that are currently used. Ultrasonic-assisted radical depolymerization of heparin leads to products with a remarkably low polydispersity index. Moreover, in comparison to other LMWH such as those produced by enzymatic β-elimination, this physicochemical depolymerization of heparin induces fewer oligosaccharides with less than five monosaccharide units. This contributes to the better preservation of the ATIII pentasaccharide binding sequence, which results in a high Anti-Xa/Anti-IIa ratio (1.86). However, LMWH obtained using this physicochemical method have a lower degree of sulfation than other LMWH, which seems to be the cause of a lower Anti-Xa and Anti-IIa activity (143.62±5.42 and 77.07±4.4, respectively).
authors.affiliation: Université de La Rochelle, UMR CNRS 7266, LIENSs, Equipe Approches Moléculaires Environnement-Santé, Département de Biotechnologies, Avenue Michel Crépeau, 17042 La Rochelle, France.
authors.forename: Oussama
authors.initials: O
authors.lastname: Achour
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bridiau
authors.forename: Azza
authors.initials: A
authors.lastname: Godhbani
authors.forename: Florian
authors.initials: F
authors.lastname: Le Joubioux
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bordenave Juchereau
authors.forename: Fredéric
authors.initials: F
authors.lastname: Sannier
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Piot
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fruitier Arnaudin
authors.forename: Thierry
authors.initials: T
authors.lastname: Maugard
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis*; D002384:Catalysis / Q000187:drug effects; D005591:Chemical Fractionation; D002850:Chromatography, Gel; D015951:Factor Xa / Q000378:metabolism; D006495:Heparin, Low-Molecular-Weight / Q000138:chemical synthesis* / Q000494:pharmacology; D006868:Hydrolysis / Q000187:drug effects; D008970:Molecular Weight; D058105:Polymerization / Q000187:drug effects; D011516:Prothrombin / Q000378:metabolism; D034421:Sus scrofa; D014465:Ultrasonics
chemical_list: D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D011516:Prothrombin; C025337:Factor IIa; D015951:Factor Xa
keywords: Anti-IIa; Anti-Xa; DP; Depolymerization; GAGs; HIT; Heparin; I; LMWH; M(n); M(w); MW(avg); SEC; UFH; ULMWH; Ultrasonic waves; average molecular weight; degree of polymerization; glycosaminoglycans; heparin-induced thrombocytopenia; low molecular weight heparin; number-averaged molecular weight; polydispersity index; size exclusion chromatography; ultra-low-molecular-weight heparin; unfractionated heparin; weight-averaged molecular weight