Abstract Number: PB0406
Meeting: ISTH 2020 Congress
Background: Factor V Leiden (FVL) is the most common inherited risk factor for venous thromboembolism by significantly decreasing Factor Va inactivation by activated protein C (APC), thus demonstrating a critical role for APC as an endogenous antithrombotic. Protein C is activated by thrombin in complex with thrombomodulin on the surface of endothelial cells. However, recent studies show that during hemostasis in large vessels, thrombin activity is confined to the extraluminal compartment, raising questions about the role of APC-mediated thrombin inhibition in these settings.
Aims: Thus, we hypothesized that the contribution of the protein C pathway to hemostasis may depend on local conditions.
Methods: Homozygous FVL mice and a monoclonal mouse APC blocking antibody were used to examine the role of APC during hemostasis in vivo in both the micro- and macro-circulation. Anatomically correct computational models were developed to simulate thrombin generation in the presence and absence of the protein C system in small and large vessels.
Results: We found significantly greater platelet accumulation, activation, and fibrin formation following vascular injury in the microcirculation of FVL mice, and an even more dramatic pro-thrombotic phenotype utilizing the APC blocking antibody, suggesting enhanced thrombin generation compared to wild-type controls. Conversely, in a jugular vein puncture injury model, platelet accumulation, activation and fibrin deposition in FVL and APC blocking antibody infused mice were similar to controls. To reconcile these differences, we simulated thrombin generation following injuries in the micro- and macro-circulation. We found that in the microcirculation thrombin generation/activity can occur both intraluminally and extravascularly. Intraluminal thrombin generation results in APC generation. In contrast, simulations of macrovascular injuries showed that the combined action of flow extravasation and platelet deposition confines thrombin generation/activity to the extravascular space, resulting in negligible Protein C activation.
Conclusions: APC-mediated inhibition of thrombin generation depends on the vascular context and local hemostatic conditions.
To cite this abstract in AMA style:Marar TT, Nettey L, Matzko C, Poventud-Fuentes I, Esmon CT, Sinno TR, Brass LF, Stalker TJ, Tomaiuolo M. The Role of the Protein C Pathway in Hemostasis: The Importance of Physiological Context [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/the-role-of-the-protein-c-pathway-in-hemostasis-the-importance-of-physiological-context/. Accessed October 1, 2023.
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