Unfractionated Heparin Resourced from Bovine, Ovine, and Porcine Origin Is Bioequivalent

Introduction: Unfractionated heparin (UFH) in the United States is sourced from porcine mucosa and is mainly supplied from China. This sole dependence on one source can potentially lead to a serious health crisis for this essential medicine if there is a shortage of UFH due to any supply chain disruption. A realistic solution would be to develop bovine and ovine mucosa as alternate sources to porcine mucosa to produce UFH. In this study, the pharmacologic profile of single-sourced bovine, ovine, and porcine heparins were evaluated to demonstrate and validate their bio-equivalence. The immunological effect of these heparins in terms of heparin-induced thrombocytopenia (HIT) was also assessed. Materials: Multiple batches of UFH active pharmaceutical ingredient (API) from KinMaster (Brazil), Ronnsi (China), and Medefil (USA) were included in this study. USP compliant anti-Xa and anti-IIa assays (Aniara Diagnostics, USA) were used. HIT antibody was a pool of sera from clinically diagnosed HIT patients. Methods: Molecular weight profile of each heparin type was determined by HPLC. The anticoagulant effects of gravimetric amounts (µg/mL) of each heparin were evaluated by the anti-Xa, anti-IIa, and aPTT (HemosIL, Werfen) assays, then assessed for neutralization by protamine sulfate (PS) in each assay. The HIT profile was evaluated by the platelet aggregation assay. Results: The heparins, irrespective of their source, demonstrated comparable molecular weight profiles (15,020 Daltons bovine, 14,100 Daltons ovine, 14,500 Daltons porcine). While the anti-Xa and anti-IIa showed similar potency for ovine (191 anti-Xa, 188 U/mL anti-IIa) and porcine UFH (205 U/mL anti-Xa, 195 U/mL anti-IIa), the bovine UFH consistently showed lower potency for both activities (108 U/mL anti-Xa, 110 U/mL anti-IIa). Complete neutralization by PS was observed with all UFHs at all concentrations. The HIT profile, irrespective of heparin origin, exhibited a similar, expected, parabolic curve profile at equivalent heparin concentrations with no enhanced effect observed for either bovine or ovine UFH compared to porcine UFH. Conclusion: These studies support the hypothesis that heparin from bovine and ovine origin exhibit comparable in vitro anticoagulant, neutralization, and immunologic profiles, with an equivalent molecular weight profile, and can be considered for use as an alternative source to porcine heparin. This study suggests that heparin derived from bovine and ovine sources produced under current manufacturing practices are effective and safe alternatives to porcine heparin.

No relevant conflicts of interest to declare.