PB1051 - Quantitative Tissue Factor Pathway Inhibitor Antigen Release and Functionality After Intravenous Administration of Heparins Sourced from Various Species in Non-human Primates

Background: Tissue factor pathway inhibitor (TFPI) is a multi-domain Kunitz-type inhibitor that plays an important role in regulating TFP through its release upon heparin administration. Currently, heparin is primarily porcine-derived, however, recently it has been re-sourced from bovine and ovine tissues.

Aims: In this context, we compared these heparins’ abilities to release endogenous TFPI following intravenous gravimetric and USP potency-adjusted heparin dosages.

Methods: 10mg/mL solutions of porcine, bovine, and ovine heparins were prepared. Individual groups of non-human primates (n=6) were intravenously injected with 0.5mg/kg and 100U/kg dosages of each heparin type. Blood samples were drawn at 0-, 15-, 30-, 60-, and 120-minutes post-administration. Citrated blood samples were centrifuged to obtain platelet-poor plasma and stored at -80C until analysis. TFPI antigen release and functionality were quantified via sandwich ELISA and a chromogenic, substrate-based method, respectively. All results were calculated in terms of group means ±SD.

Results: Gravimetric porcine and ovine heparin dosages produced comparable TFPI release in both the functional and immunologic assays while bovine heparin demonstrated slightly lower peak TFPI antigen release and slightly higher peak function, as shown in Figure 1a and 1c, respectively. When compared following administration of USP-adjusted 100U/kg dosages, all three heparins consistently demonstrated essentially identical TFPI antigen release and functional profiles, as shown in Figure 1b and 1d, respectively. Overall, any potential differences in the gravimetric dosing regimens were adequately corrected following USP potency adjustment in both TFPI antigen release and functionality, as seen in Figure 1. Furthermore, all three heparins demonstrated comparable pharmacokinetic profiles in both TFPI antigen release and function levels, as shown in Table 1.

Conclusion(s): These results demonstrate heparins from various sources are capable of comparatively releasing TFPI antigen. While the gravimetrically-dosed studies demonstrated less consistent trajectories, potency-based dosages allowed for improved pharmacokinetic homogeneity. These studies underscore the viability of alternative heparin sources as pharmacokinetic equivalents.