D11-a - In-Vitro and Computational Assessment of Factor XIa Inhibition in Hemostasis

Saturday, October 11, 2025

10:00 AM - 12:00 PM PDT

Location: Exhibit Hall F, G & H

Presenting Author(s)

Ocean Punsalan

Intern/Student
Oregon Health & Science University
Lake Oswego, Oregon, United States

Co-Author(s)

Ethan Oseas, MS

Graduate Student
Oregon Health and Science University
Portland, Oregon, United States

Primary Investigator(s)

Owen McCarty, PhD

Professor and Chair of Biomedical Engineering
Oregon Health & Science University, Oregon, United States

Introduction: : Hemostasis is a tightly regulated process that prevents excessive bleeding by forming stable blood clots at sites of vascular injury. Disruption of hemostasis can lead to life-threatening outcomes: hemorrhage accounts for up to 30% of injury-related deaths and 27% of maternal deaths, while thrombosis is responsible for one in four deaths worldwide. Hemophilia, a genetic disorder caused by a deficiency in Factor VIII (Hemophilia A) or Factor IX (Hemophilia B), puts individuals at high risk of uncontrolled bleeding during surgery. These patients are typically treated with clotting factor concentrates, but in severe cases, excessive thrombin generation can lead to thrombosis, often managed with FXa inhibitors. The use of such FXa inhibitors carries a heightened bleeding risk, underscoring the need for safer, targeted approaches.This study aims to explore FXIa as potentially safer antithrombotic target.

Materials and

Methods: : We used an extended Hockin–Mann (ext.HM) systems biology model of coagulation to investigate the effects of Factor XIa (FXIa) and Factor Xa (FXa) inhibition under conditions of reduced clotting factor concentrations. The original HM model, which describes the extrinsic pathway, was expanded to include thrombin-mediated activation of FXI, enabling the simulation of FXI’s role in thrombin generation.
The ext.HM model is formulated as a system of ordinary differential equations (ODEs) describing the time-dependent interactions between coagulation factors. Model inputs include enzyme–substrate affinities and plasma concentrations of each coagulation factor. Outputs consist of thrombin concentration profiles over time, from which peak thrombin, lag time, and endogenous thrombin potential (ETP) are derived.
Simulations were performed under three inhibitory conditions: FXa inhibition, FXIa inhibition, tissue factor pathway inhibitor (TFPI), and no inhibition, to compare their effects on thrombin generation. Additionally, tissue factor (TF) concentrations of 0.125 pM and 1 pM were used to model different bleeding severities.

Results, Conclusions, and Discussions:: Thrombin generation was reduced by decreased tissue factor (TF) and increased tissue factor pathway inhibitor (TFPI) in simulated hemophilia A, B, and C. In hemophilia A and B models, simulated FXa inhibition reduced thrombin generation in a TF-dependent manner. Increasing the FXIa generation rate restored thrombin generation in hemophilia A and B, even in the presence of an FXa inhibitor. Simulated FXIa inhibition reduced thrombin generation less than FXa inhibition under FVIII- or FIX-deficient conditions. These findings suggest that FXIa inhibitors may represent a safer anticoagulant strategy for patients with hemophilia A or B. Model predictions indicate that the kinetics of FXIa generation by thrombin (FIIa) constitute an important feedback loop in thrombin generation in hemophilia, particularly in the presence of biomolecules such as platelet polyphosphate that enhance FXIa generation.
Collectively, the results provide rationale for further preclinical studies exploring FXIa inhibitors as a safer, targeted therapeutic strategy for patients with hemophilia. The next steps for this project involve experimental validation of these computational findings using in-vitro thrombin generation assays.

Acknowledgements and/or References (Optional): : Revised model of the tissue factor pathway of thrombin
generation: Role of the feedback activation of FXI