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851 Liver X Receptor (LXR) Is a Novel and Reversible Regulator of Trauma-Induced Coagulopathy

Program: Oral and Poster Abstracts
Session: 321. Blood Coagulation and Fibrinolytic Factors: Poster I
Hematology Disease Topics & Pathways:
Diseases, Bleeding and Clotting, Biological Processes, Thrombosis, Technology and Procedures, Clinically relevant, Thrombotic Disorders, mass cytometry, molecular interactions, pathways, proteomics
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Peter Einersen1*, Sanchayita Mitra1*, Reid Selby2*, Ernest E. Moore, MD3*, Marguerite Kelher4*, Miguel Fragoso5*, Daran Schiller1*, Megan Swope6*, Geoffrey Nunns1*, Navin Vigneshwar1*, James Chandler1*, Arsen Ghasabayan7*, John Desisto8*, Bridget Sanford8*, Monika Dzieciatkowska, PhD5*, Linda Johnson9*, Mitchell J. Cohen10,11*, Angelo D’Alessandro, PhD12*, Erik Peltz13*, Anirban Banerjee, PhD14*, Kirk Hansen15*, Christopher C. Silliman, MD, PhD16 and Kenneth Jones2,8*

1Department of Surgery/Trauma Research Center, University of Colorado School of Medicine, Aurora, CO
2University of Oklahoma Health Sciences Center, Harold Hamm Diabetes Center, Oklahoma City, OK
3Surgery, Denver Health Medical Center, Denver, CO
4Univ of Colorado Denver/Bonfils Blood Center, Denver, CO
5University of Colorado Denver, Aurora, CO
6Ernest E Moore Shock Trauma Center, Denver Health Medical Center, Denver, CO
7Department of Surgery/Trauma Research Center,, University of Colorado School of Medicine, Aurora, CO
8Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
9Department of Pathology, University of Colorado School of Medicine, Aurora, CO
10University of Colorado, Denver, CO
11Denver Health Medical Center/ University of Colorado, Denver, CO
12Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO
13University of Colorado, Aurora, CO
14Surgery, School of Medicine, University of Colorado Denver, Aurora, CO
15UC Denver, Aurora, CO
16Research Laboratory, Bonfils Blood Center, Denver, CO

Trauma-induced coagulopathy (TIC) manifests as a bimodal disruption of normal fibrinolysis, where at the two extremes, fibrinolytic shutdown (TICFS) places the patient at increased risk for thromboembolism and post-injury multiple organ failure, and systemic hyperfibrinolysis (TICHF) results in excessive bleeding. Plasma proteomic profiles for 65 trauma patients were used to identify changes in the patient’s plasma protein profile stratifying them by risk for TIC. A strong correlation was seen between total plasma protein concentration of individual patients and the concentration of coagulation proteins within that patient, suggesting that trauma-induced coagulation may be affected through a mechanism that controls the efflux of many coagulation proteins into the plasma (Figure 1). Pathway analysis, in addition to elucidating changes in the coagulation cascade, identified several proteins that are known to be regulated by the Liver X receptor/Retinoid X receptor (LXR/RXR), suggesting that LXR/RXR-mediated activity may regulate TIC (p=9.03E-26). Validation experiments in a rat model revealed that fibrinolytic response to an LXR antagonist and/or agonist can be observed in less than 60 minutes (Figure 2). Additionally, we show through reciprocal rescue of fibrinolysis that the TIC phenotypes (TICHF and TICFS) are one continuum and are ultimately co-reversible, where the reduced LXR signaling that causes sequestration of blood factors in the liver leading to excess bleeding or induced LXR signaling that causes excess efflux leading to thrombosis can be reversed through administration of the LXR agonist or antagonist, respectively. Thus, as modulation of LXR shows co-reversibility and rapid response, induction/inhibition of the LXR pathway provides a direct and novel therapeutic intervention in severely injured patients at risk for TIC.

Disclosures: No relevant conflicts of interest to declare.

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