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Open AccessArticle

Crude Heparin Preparations Unveil the Presence of Structurally Diverse Oversulfated Contaminants

1
Departamento de Bioquímica, Instituto de Farmacologia e Biologia Molecular, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Três de Maio, 100 – São Paulo, SP 04044-020, Brazil
2
Departamento de Ciências Farmacêuticas, Campus Diadema, Universidade Federal de São Paulo, Rua Três de Maio, 100 – São Paulo, SP 04044-020, Brazil
3
Departamento de Bioquímica, Setor de Ciências Biológicas, Centro Politécnico, Universidade Federal do Paraná, Avenida Coronel Francisco H. dos Santos, 100, Caixa Postal 19031, Curitiba, PR 81531-980, Brazil
4
Department of Molecular Pharmacology & Therapeutics, Hemostasis & Thrombosis Research Laboratories, Loyola University Medical Center, 2160 S. First Avenue Maywood, IL 60153, USA
5
Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(16), 2988; https://doi.org/10.3390/molecules24162988
Received: 25 June 2019 / Revised: 1 August 2019 / Accepted: 10 August 2019 / Published: 17 August 2019
(This article belongs to the Special Issue Emerging Frontiers in Glycosaminoglycans and Mimetics)
Nowadays, pharmaceutical heparin is purified from porcine and bovine intestinal mucosa. In the past decade there has been an ongoing concern about the safety of heparin, since in 2008, adverse effects associated with the presence of an oversulfated chondroitin sulfate (OSCS) were observed in preparations of pharmaceutical porcine heparin, which led to the death of patients, causing a global public health crisis. However, it has not been clarified whether OSCS has been added to the purified heparin preparation, or whether it has already been introduced during the production of the raw heparin. Using a combination of different analytical methods, we investigate both crude and final heparin products and we are able to demonstrate that the sulfated contaminants are intentionally introduced in the initial steps of heparin preparation. Furthermore, the results show that the oversulfated compounds are not structurally homogeneous. In addition, we show that these contaminants are able to bind to cells in using well known heparin binding sites. Together, the data highlights the importance of heparin quality control even at the initial stages of its production. View Full-Text
Keywords: oversulfated chondroitin sulfate; heparin and oversulfated chondroitin sulfate anticoagulant activities; 1H NMR and COSY; FACE; heparinases oversulfated chondroitin sulfate; heparin and oversulfated chondroitin sulfate anticoagulant activities; 1H NMR and COSY; FACE; heparinases
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MDPI and ACS Style

Mendes, A.; Meneghetti, M.C.Z.; Palladino, M.V.; Justo, G.Z.; Sassaki, G.L.; Fareed, J.; Lima, M.A.; Nader, H.B. Crude Heparin Preparations Unveil the Presence of Structurally Diverse Oversulfated Contaminants. Molecules 2019, 24, 2988.

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