PB0566 - Prediction and validation of the effects of targeting either coagulation FXI activation or activity on thrombin generation

Monday, June 26, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Si Han Wang, PhD (she/her/hers)

Postdoctoral fellow
Oregon Health & Science University
Portland, Oregon, United States

Co-Author(s)

Hari Lakshmanan, MS, PhD

PhD
Oregon Health & Science University
portland, Oregon, United States
MF

Meghan E. Fallon

PhD Candidate
Oregon Health & Science University
Portland, Oregon, United States
HV

Helen H. Vu

Research Assistant I
Oregon Health & Science University
Portland, Oregon, United States

Co-Author(s)

JS

Joseph J. Shatzel

Assistant Professor
Oregon Health & Science University
Portland, Oregon, United States

Co-Author(s)

Cristina Puy, PhD

Research Assistant Professor
Oregon Health & Science University
Portland, Oregon, United States
David Gailani, MD

Professor
Vanderbilt University Medical Center
Nashville, Tennessee, United States
ET

Erik I. Tucker

Chief Executive Officer
Aronora, Inc.
Portland, Oregon, United States
CL

Christina U. Lorentz

Director of Clinical Operations
Aronora, Inc
Portland, Oregon, United States
Owen J.T McCarty, PhD, FAHA

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

Background: The coagulation factor (F) XI circulates as a zymogen and is converted to the active enzyme, FXIa, by coagulation factors including thrombin. FXIa cleaves FIX, resulting in thrombin generation. While FXI has been championed as a druggable target to reduce thrombin generation, it is unclear whether superior or equivalent efficacy will be observed for pharmacological inhibition of FXI activation or inhibition of the enzymatic activity of FXIa itself.

Aims: Model the effects of targeting the activation of FXI or activity of FXIa on thrombin generation.

Methods: We developed a computational model incorporating FXI, feedback activation of FXI by thrombin, and kinetic constants for conversation of FXI to FXIa and FXIa activation of FIX. We validated the model using plasma thrombin generation assays with FXI inhibitors.

Results: Our in silico model predicted that 0.125pM tissues factor generated a peak estimated thrombin potential (ETP) of 2550nM*min/L, a peak of thrombin of 153nM at 37min with a lag time of 25min. These predictions were validated using in vitro thrombin generation assays. Our model predicted that the rate of thrombin generation was sensitive to either inhibition of FXI activation or activity, with an increased efficacy for inhibiting the activity of FXIa as compared to inhibition of FXI conversion to FXIa. Dual inhibition of FXI activation and activity was predicted to be more sensitive than targeted FXIa alone; this prediction was validated in vitro with 1A6, which blocks FXIa activation of FIX, compared to 12F5, which blocks FXIa activity.

Conclusion(s): Our systems biology and experiment validation approach suggest that thrombin generation is reduced by inhibition of FXI activation or activity; a saturable effect was observed for targeting FXIa activity, while thrombin generation was sensitive to inhibition of FXI activation or dual inhibition of FXI activation and activity.