Poster W13 - Development and Evaluation of Site-Localizing Anticoagulant

Saturday, October 26, 2024

10:00 AM - 11:00 AM EST

Location: Exhibit Hall E, F & G

Presenting Author(s)

EL

Emily Lee (she/her/hers)

Graduate student researcher
University of California, Davis
Davis, California, United States

Co-Author(s)

JZ

Junhan Zhou, PhD (she/her/hers)

Postdoctoral research fellow
Stanford University
Menlo Park, California, United States
Phung N. Thai, PhD

Postdoctoral Scholar
University of California, Davis, United States
Nipavan Chiamvimonvat, MD

Professor
University of Arizona
Phoenix, Arizona, United States

Primary Investigator(s)

AL

Angelique Louie, PhD

Professor
University of California, Davis, California, United States

Introduction: Atrial fibrillation (AF) is a heart arrythmia affecting more than 33 million people worldwide. It leads to poor blood clearance out of the atria, especially the left atrial appendage (LAA) due to its dead-end anatomy. This creates a blood stasis region prone to thrombosis, increasing the patient’s stroke risk by 5-fold. Current antithrombic therapy includes oral anticoagulants such as warfarin that freely circulate throughout the body and put patients at heßmorrhage risks. We propose sulfated dextran-coated iron oxide nanoparticles (SDIO) as a novel, safer anticoagulant that will localize to the LAA, reducing the risk of internal bleeding elsewhere in the body. SDIO with macrophage-targeting ability holds high potential to localize to the LAA which is associated with macrophage accumulation. Additionally, SDIO is coated with dextran sulfate, a known anticoagulant. In this work, we evaluated SDIO efficacy to simultaneously localize and inhibit coagulation.

Materials and

Methods: To test SDIO efficacy in vivo, we utilized thoracic aortic constriction (TAC) mouse model, also found to have inflammation and clotting in the LAA. To first confirm SDIO accumulation to the heart, we injected sham and TAC mice 4-weeks and 6-weeks post-surgery with radiolabeled SDIO, then imaged using positron emission tomography (PET) 4 and 24 hours after injection. We then intravenously injected TAC mice with either a control saline or SDIO solution every 10 days starting 3-weeks post-surgery. The LAA was collected at week 8, which was then sectioned and stained with hematoxylin & eosin. For quantitative comparison of thrombosis between the two groups, we measured the fibrin/platelet-rich clot volume of each sample using ImageJ then analyzed for statistical difference of p< 0.05.

Results, Conclusions, and Discussions: PET imaging comparison of sham and TAC mice showed increased SDIO accumulation in TAC mice for both 4-weeks and 6-weeks post-surgery. This shows that SDIO successfully localizes to the heart with inflammation present. In our analysis of thrombosis in the LAA of TAC mice, we observed visible differences between the control and test groups. The LAA lumen of the group that received saline injections were prominently filled more with clots compared to those that received SDIO injections. Quantitative volume comparison of fibrin/platelet-rich clots between the two groups showed significant difference where average clot volume of the test group was smaller than that of the control group. These findings demonstrate SDIO as a successful site-localizing anticoagulant. We showed that SDIO successfully localizes and inhibits coagulation in the LAA of TAC mouse model. Development of such site-localizing anticoagulant could significantly improve the safety of antithrombic therapy for AF patients. Our future work includes improving the efficacy of SDIO by modifying surface conjugation to further improve anticoagulant or LAA-targeting abilities.

Acknowledgements (Optional):