Matthew F Whelihan1, Brian Cooley2, Yongmei Xu3, Rafal Pawlinski1, Jian Liu3, Nigel S Key4. 1. Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. 2. Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. 3. Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, NC, United States. 4. Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Electronic address: Nigel_key@med.unc.edu.
Abstract
BACKGROUND: The global supply of unfractionated heparin (UFH) and all commercially available low molecular weight heparins (LMWH) remain dependent on animal sources, such as porcine intestine or bovine lung. Recent experience has shown that contamination of the supply chain (with over-sulfated chondroitin sulfates) can result in lethal toxicity. Fondaparinux is currently the only commercially available synthetic analog of heparin. We recently described a new class of chemoenzymatically synthesized heparin analogs. One of these compounds (S12-mer) is a dodecasaccharide consisting of an antithrombin-binding moiety with repeating units of IdoA2S-GlcNS6S and two 3-O-sulfate groups that confer the ability to bind protamine. OBJECTIVE/ METHODS: We sought to further characterize this new compound in vitro using biochemical and global coagulation assays and in vivo using thrombosis and hemostasis assays. RESULTS: The anticoagulant activities of the Super 12-mer (S12-mer) and Enoxaparin in anti-factor Xa and plasma-based thrombin generation assays were roughly equivalent with a 50% reduction in peak thrombin generation occurring at approximately 325nM. When protamine was titrated against a fixed concentration of S12-mer in plasma or blood, the S12-mer displayed a significant restitution of thrombin generation and clot formation. In vivo, S12-mer inhibited venous thrombosis to a similar extent as Enoxaparin, with similar bleeding profiles. CONCLUSIONS: These data show that the S12-mer has almost identical efficacy to Enoxaparin in terms of FXa inhibition, while displaying significant reversibility with protamine. Taken together with the ability to ensure purity and homogeneity from batch to batch, the S12-mer is a promising new synthetic heparin analog with a potentially enhanced safety profile.
BACKGROUND: The global supply of unfractionated heparin (UFH) and all commercially available low molecular weight heparins (LMWH) remain dependent on animal sources, such as porcine intestine or bovine lung. Recent experience has shown that contamination of the supply chain (with over-sulfated chondroitin sulfates) can result in lethal toxicity. Fondaparinux is currently the only commercially available synthetic analog of heparin. We recently described a new class of chemoenzymatically synthesized heparin analogs. One of these compounds (S12-mer) is a dodecasaccharide consisting of an antithrombin-binding moiety with repeating units of IdoA2S-GlcNS6S and two 3-O-sulfate groups that confer the ability to bind protamine. OBJECTIVE/ METHODS: We sought to further characterize this new compound in vitro using biochemical and global coagulation assays and in vivo using thrombosis and hemostasis assays. RESULTS: The anticoagulant activities of the Super 12-mer (S12-mer) and Enoxaparin in anti-factor Xa and plasma-based thrombin generation assays were roughly equivalent with a 50% reduction in peak thrombin generation occurring at approximately 325nM. When protamine was titrated against a fixed concentration of S12-mer in plasma or blood, the S12-mer displayed a significant restitution of thrombin generation and clot formation. In vivo, S12-mer inhibited venous thrombosis to a similar extent as Enoxaparin, with similar bleeding profiles. CONCLUSIONS: These data show that the S12-mer has almost identical efficacy to Enoxaparin in terms of FXa inhibition, while displaying significant reversibility with protamine. Taken together with the ability to ensure purity and homogeneity from batch to batch, the S12-mer is a promising new synthetic heparin analog with a potentially enhanced safety profile.
Authors: J Holst; B Lindblad; D Bergqvist; K Garre; H Nielsen; U Hedner; P B Ostergaard Journal: Blood Coagul Fibrinolysis Date: 1994-10 Impact factor: 1.276
Authors: Colton M Miller; Yongmei Xu; Katrina M Kudrna; Blake E Hass; Brianna M Kellar; Andrew W Egger; Jian Liu; Edward N Harris Journal: Thromb Res Date: 2018-05-17 Impact factor: 3.944
Authors: Gabrielly M D Chiarantin; Lina M Delgado-Garcia; Laura N Zamproni; Marcelo A Lima; Helena B Nader; Ivarne L S Tersariol; Marimélia Porcionatto Journal: Glycoconj J Date: 2021-01-07 Impact factor: 2.916