Abstract Number: OC 36.3
Meeting: ISTH 2022 Congress
Background: In human plasma, TFPIα is the most effective anticoagulant TFPI form. TFPIα plasma levels appear to be determined by plasma levels of FVshort, which functions as a carrier protein diminishing renal filtration. TFPIα anticoagulant function is appreciably augmented by its cofactor, protein S. In vivo characterisation of the TFPIα – protein S pathway in mice is confounded by the embryonic lethality of TFPI-deficiency in mice, the apparent lack of both TFPIα and FVshort in murine plasma, and uncertainty as to whether murine TFPIα is augmented by protein S.
Aims: To model/interrogate the TFPIα–protein S anticoagulant pathway in vivo.
Methods: FXa inhibition/CAT assays were used to measure enhancement of human/murine TFPIα function by human/murine protein S. Mice were injected with recombinant human TFPIα (±an in-house non-inhibitory anti-TFPIα mAb), and its clearance monitored by ELISA. The influence of human TFPIα on laser-induced thrombus formation was measured.
Results: Unlike human TFPIα, murine TFPIα was not enhanced by murine/human protein S, due to amino acid differences in the murine TFPI K3 domain. Injected human TFPIα was cleared rapidly (minutes) from circulation in mice, likely due to the absence of FVshort. However, formation of a complex between TFPIα and a non-inhibitory mouse anti-human TFPI K3 mAb appreciably extended the plasma half-life of human TFPIα enabling its persistence in circulation. In the laser-induced thrombosis model, we measured reduced fibrin deposition in the presence of human TFPIα demonstrating its anticoagulant function in vivo.
Conclusion(s): Using human TFPIα in complex with a non-inhibitory mAb enables interrogation of the TFPIα – protein S anticoagulant pathway in vivo (as murine TFPIα is not enhanced by protein S). This also provides a novel means of augmenting endogenous TFPIα levels through the use of non-inhibitory anti-TFPI mAbs to reduce renal filtration, which may represent a potential new anticoagulant strategy.
To cite this abstract in AMA style:Petri A, Sasikumar P, Badia Folgado P, Jones D, Ahnström J, Salles-Crawley I, Crawley J. Analysis of TFPI-protein S anticoagulant function in vivo. [abstract]. https://abstracts.isth.org/abstract/analysis-of-tfpi-protein-s-anticoagulant-function-in-vivo/. Accessed February 28, 2024.
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