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2668 Loss of 12-Lipoxygenase Improves the Post-Transfusion Function of Stored Platelets

Program: Oral and Poster Abstracts
Session: 401. Blood Transfusion: Poster II
Hematology Disease Topics & Pathways:
Fundamental Science, Research, Translational Research
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Hannah Larsen1*, Daire Byrne2,3*, Hasan Tahsin Ozpolat, MD4*, Aastha Chauhan3*, Shawn Bailey, BS5*, Nicole Rhoads6*, Franklin Reed6*, Massiel Chavez Stolla, PhD7, Raymond Adili, MD6, Michael Holinstat, PhD8, Xiaoyun Fu, PhD6 and Moritz Stolla, MD9,10

1Bloodworks NW Research Institute, Seattle
2Research Institute, Bloodworks Northwest, Seattle, WA
3Bloodworks NW Research Institute, Seattle, WA
4Department of Medicine, University of Arizona, Tucson, AZ
5Bloodworks NW, Seattle, WA
6Bloodworks Research Institute, Seattle, WA
7Department of Medicine, University of Washington, Seattle, WA
8Pharmacology, University of Michigan, Ann Arbor, MI
9Bloodworks Northwest Research Institute, Seattle, WA
10Department of Medicine, Division of Hematology, University of Washington, Seattle, WA

Objective Platelets for transfusion are stored for 5-7 days. During storage, platelets undergo numerous detrimental functional changes. Previous studies have shown that HETE levels in the storage bag negatively correlate with platelet performance in vivo, suggesting that the dysregulation of bioactive lipid mediators may contribute to the storage lesion. In the current study, we sought to understand how genetic deletion and pharmacologic inhibition of 12–lipoxygenase (12-LOX) affects platelets during storage and after transfusion.

Approach and Results Platelets from 12-LOX+/+ (wild-type [WT]) and 12-LOX-/- mice were stored for 24 and 48 hours and profiled using LC-MS/MS-MRM. Polyunsaturated fatty acids increased significantly in stored platelets from 12-LOX-/- mice, while oxylipin concentrations were significantly higher in WT platelets. Baseline αIIbβ3 integrin activation was significantly lower before and after 24 hours of storage in 12-LOX-/- platelets than in WT platelets. Surprisingly, after transfusion to thrombocytopenic mice, we observed significantly more baseline αIIbβ3 integrin activation in 12-LOX-/- platelets than in WT platelets. Stored platelets from 12-LOX-/- mice occluded vessels significantly faster than stored WT platelets in thrombocytopenic recipients challenged with a FeCl3-induced carotid artery injury. In hemostasis models, significantly more stored 12-LOX-/- than WT platelets accumulated at the site of venous injury leading to reduced blood loss. Inhibition of cyclooxygenase-1 (COX-1) with acetylsalicylic acid abrogated both increased integrin activation and thromboxane generation in stored 12-LOX-/- platelets, highlighting a critical role of this pathway for improved post-transfusion function.

Consistent with our mouse studies, human platelets stored with the 12-LOX inhibitor, VLX-1005, showed increased integrin activation compared to vehicle-treated platelets upon transfusion in NOD/SCID mice.

Conclusion Deleting 12-LOX improves the post-transfusion function of stored murine and human platelets by increasing thromboxane generation through a COX-1-dependent mechanism. Future studies should determine the feasibility and safety of 12-LOX-inhibited platelets transfused to humans.

Disclosures: Holinstat: Veralox Therapeutics: Consultancy, Current equity holder in private company; Cereno Scientific: Consultancy, Current equity holder in publicly-traded company, Research Funding.

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