Converting the Distinct Heparins Sourced from Bovine or Porcine Mucosa into a Single Anticoagulant Drug

Abstract

Unfractionated heparin (UFH) and their low-molecular-weight derivatives are sourced almost exclusively from porcine mucosa (HPI); however, a worldwide introduction of UFH from bovine mucosa (HBI) has been recommended to reinforce the currently unsteady supply chain of heparin products. Although HBI has different chemical composition and about half of the anticoagulant potency of HPI (∼100 and ∼180 international unit [IU]/mg, respectively), they have been employed as interchangeable UFHs in some countries since the 1990s. However, their use as a single drug provoked several bleeding incidents in Brazil, which precipitated the publication of the first monographs exclusive for HBI and HPI by the Brazilian Pharmacopoeia. Nevertheless, we succeed in producing with high-resolution anion-exchange chromatography a novel HBI derivative with anticoagulant potency (200 IU/mg), disaccharide composition (enriched in N,6-disulfated α-glucosamine) and safety profile (bleeding and heparin-induced thrombocytopaenia potentials and protamine neutralization) similar to those seen in the gold standard HPI. Therefore, we show that it is possible to equalize the composition and pharmacological characteristics of these distinct UFHs by employing an easily implementable improvement in the HBI manufacturing.

Non-Anticoagulant Heparan Sulfate from the Ascidian Phallusia nigra Prevents Colon Carcinoma Metastasis in Mice by Disrupting Platelet-Tumor Cell Interaction

“…The anticoagulant activity of UFH is due to the AT/HCII-mediated inactivation of several coagulation system enzymes, especially FIIa, and FXa [37]. Our in vitro assays revealed that PNH exerts a negligible anticoagulant activity, mostly mediated by HCII.…”

“…Our in vitro assays revealed that PNH exerts a negligible anticoagulant activity, mostly mediated by HCII. This reduced AT-mediated anticoagulant potency may occur due to the absence of the specific pentasaccharide sequence present in UFH, which promotes the conformational change responsible for potentiating AT [37,38]. Despite presenting mostly a serpin-independent anticoagulant activity, the FucCS from H. grisea also activates HCII; nevertheless, its activity (~50 IU/mg) is far higher than that obtained with PNH [15].…”

Pharmacokinetic, Hemostatic, and Anticancer Properties of a Low-Anticoagulant Bovine Heparin

“…Nevertheless, our research group demonstrated that pharmaceutical HBI is actually composed of a mixture of two types of heparin chains bearing different chemical compositions and anticoagulant activities, which in turn can be separated through a single ion-exchange chromatography step (Fig. 1), named as Highanticoagulant Bovine Heparin (HABH) and Low-anticoagulant Bovine Heparin (LABH) 18,19 . While HABH has chemical composition (enriched in N,6-disulfated αglucosamine) and anticoagulant activity (~200 IU/mg) similar to HPI, LABH has diminished potency (~25 IU/mg) due to the preponderance of disaccharides containing N-sulfated but not 6-sulfated α-glucosamine (Fig.…”

“…1). Different from HBI, HPI and pharmaceutical preparations sourced from bovine lung contain diminished amounts of low-anticoagulant heparin chains such as those component of LABH 18 .…”

Manufacturing Heparin with Equivalent Chemical Composition from Different Animal Sources

“…In the current article by Tovar et al, 4 a straightforward application of bovine heparin fractionation with anion exchange chromatography to produce a heparin with similar chemical composition, potency and safety profile to porcine heparin is demonstrated. If such a porcine-like heparin product could be made commercially from a bovine source and obtain approval from regulators, a single heparin drug from different animal sources with different geographical distribution with consistent quality could improve supply chain stability for this important drug.…”