Analysis of Heparins Derived From Bovine Tissues and Comparison to Porcine Intestinal Heparins

Ange, Kalib St.; Ōnishi, Akira; Fu, Li; Sun, Xiaojun; Lei, Lin; Mori, Daisuke; Zhang, Fuming; Dordick, Jonathan S.; Fareed, Jawed; Hoppensteadt, Debra; Jeske, Walter; Linhardt, Robert J.

doi:10.1177/1076029616643822

Cited by 41 publications

(49 citation statements)

References 11 publications

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“…Differences among heparins obtained from different animal sources were recently reported elsewhere 21 22 23 .The results obtained via NMR spectroscopy presented in these articles also suggest that heparins from porcine and bovine intestine have dissimilar structures. However, none of these works thoroughly correlate the molecular weight and disaccharide composition of those different heparins with their anticoagulant and antithrombotic potencies, as reported here.…”

Section: Discussionsupporting

confidence: 59%

Structural and haemostatic features of pharmaceutical heparins from different animal sources: challenges to define thresholds separating distinct drugs

Tovar

Santos

Capillé

et al. 2016

Sci Rep

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Heparins extracted from different animal sources have been conventionally considered effective anticoagulant and antithrombotic agents despite of their pharmacological dissimilarities. We performed herein a systematic analysis on the physicochemical properties, disaccharide composition, in vitro anticoagulant potency and in vivo antithrombotic and bleeding effects of several batches of pharmaceutical grade heparins obtained from porcine intestine, bovine intestine and bovine lung. Each of these three heparin types unambiguously presented differences in their chemical structures, physicochemical properties and/or haemostatic effects. We also prepared derivatives of these heparins with similar molecular weight differing exclusively in their disaccharide composition. The derivatives from porcine intestinal and bovine lung heparins were structurally more similar with each other and hence presented close anticoagulant activities whereas the derivative from bovine intestinal heparin had a higher proportion of 6-desulfated α-glucosamine units and about half anticoagulant activity. Our findings reasonably indicate that pharmaceutical preparations of heparin from different animal sources constitute distinct drugs, thus requiring specific regulatory rules and therapeutic evaluations.

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Section: Discussionsupporting

confidence: 59%

Structural and haemostatic features of pharmaceutical heparins from different animal sources: challenges to define thresholds separating distinct drugs

Tovar

Santos

Capillé

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Similar differences, between porcine intestinal, bovine lung, and bovine intestinal heparins, had been previously reported by our laboratory. 17,18 Three independent batches of LMWHs were prepared from a single lot of both bovine lung and bovine intestinal heparin using a chemical b-eliminative process modeled on that thought to be used for the preparation of Lovenox ( Figure 1). The molecular weight and activity properties of these 6 batches of LMWH were examined ( Table 2).…”

Section: Resultsmentioning

confidence: 99%

Comparison of Low-Molecular-Weight Heparins Prepared From Bovine Heparins With Enoxaparin

Ange

Fareed

Hoppensteadt

et al. 2017

Clin Appl Thromb Hemost

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Heparin and its low-molecular-weight heparin (LMWH) derivatives are widely used clinical anticoagulants. These drugs are critical for the practice of medicine in applications including kidney dialysis, cardiopulmonary bypass, and in the management of venous thromboembolism. Currently, these drugs are derived from livestock, primarily porcine intestine. The worldwide dependence on a single animal species has made the supply chain for this critical drug quite fragile, leading to the search for other sources of these drugs, including bovine tissues such as bovine intestine or lung. A number of laboratories are currently examining the similarities and differences between heparins prepared from porcine and bovine tissues. The current study is designed to compare LMWH prepared from bovine heparins through chemical β-elimination, a process currently used to prepare the LMWH, enoxaparin, from porcine heparin. Using top-down, bottom-up, compositional analysis and bioassays, LMWHs, derived from bovine lung and intestine, are shown to closely resemble enoxaparin.

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“…14 The major source of heparin today is porcine intestinal mucosa, but in the past, heparin has been prepared from bovine lung and bovine intestinal mucosa. 15 Moreover, there is current interest in the chemoenzymatic synthesis of non–animal-sourced heparins. 16 In 2007, pharmaceutical heparin was contaminated with a toxic semisynthetic glycosaminoglycan, oversulfated chondroitin sulfate.…”

Section: Introductionmentioning

confidence: 99%

Structural Analysis of Heparin-Derived 3- O -Sulfated Tetrasaccharides: Antithrombin Binding Site Variants

Chen

Lei

Agyekum

et al. 2017

Journal of Pharmaceutical Sciences

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Heparin is a polysaccharide that is widely used as an anticoagulant drug. The mechanism for heparin’s anticoagulant activity is primarily through its interaction with a serine protease inhibitor, antithrombin III (AT), that enhances its ability to inactivate blood coagulation serine proteases, including thrombin (factor IIa) and factor Xa. The AT-binding site in the heparin is one of the most well-studied carbohydrate-protein binding sites and its structure is the basis for the synthesis of the heparin pentasaccharide drug, fondaparinux. Despite our understanding of the structural requirements for the heparin pentasaccharide AT-binding site, there is a lack of data on the natural variability of these binding sites in heparins extracted from animal tissues. The present work provides a detailed study on the structural variants of the tetrasaccharide fragments of this binding site afforded following treatment of a heparin with heparin lyase II. The 5 most commonly observed tetrasaccharide fragments of the AT-binding site are fully characterized, and a method for their quantification in heparin and low-molecular-weight heparin products is described.

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Analysis of Heparins Derived From Bovine Tissues and Comparison to Porcine Intestinal Heparins

Cited by 41 publications

References 11 publications

Structural and haemostatic features of pharmaceutical heparins from different animal sources: challenges to define thresholds separating distinct drugs

Structural and haemostatic features of pharmaceutical heparins from different animal sources: challenges to define thresholds separating distinct drugs

Comparison of Low-Molecular-Weight Heparins Prepared From Bovine Heparins With Enoxaparin

Structural Analysis of Heparin-Derived 3- O -Sulfated Tetrasaccharides: Antithrombin Binding Site Variants

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