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Severe Injury Leads to Plasmin Consumption Below a Critical Threshold Required to Heal Soft Tissue Injury
Emilie Amaro, BS1, Nicholas A. Mignemi, PhD1, Stephanie N. Moore-Lotridge, BS1, Breanne HY Gibson, BS1, Courtney E. Baker, BS1, Gregory D. Hawley, BA1, Rivka C. Ihejirika, MD2, Julia K. Bohannon, PhD1, William K. Oelsner, BS3, Christopher S. Wallace, BS1, LiMing Luang, PhD1, Edward R. Sherwood, MD, PhD1, Jonathan G. Schoenecker, MD, PhD1.
1Vanderbilt University, Nashville, TN, USA, 2New York University, New York, NY, USA, 3Medical University of South Carolina, Charleston, SC, USA.

PURPOSE:
Severe burn injury is associated with delayed or failed repair of skin and soft tissue. Following burn injury, impaired tissue healing occurs both at the site of injury and in tissue concurrently injured with, but anatomically remote from, the injury. Thus, the predominate hypothesis is that severe injury provokes derangements in circulating acute phase reactants necessary for soft tissue repair, contributing to pathologic changes in tissue healing. It has been determined that failure to remove fibrin, the major constituent of the coagulation matrix, impairs healing of all tissues. Plasmin is the principle protease responsible for removing fibrin and is essential for the regeneration and healing of all tissues in genetically modified mouse models. It is unknown whether plasmin levels are consumed following significant injuries or whether changes in plasmin levels below a critical threshold contribute to pathologic healing. The purpose of this study is to determine whether plasmin levels are consumed following burn injury in humans and whether plasmin levels are associated with pathologic tissue healing and regeneration in mouse models following a burn injury. We postulate that a significant burn injury influences plasmin levels contributing to poor healing at both the site of burn injury and in tissue anatomically remote from the injury.
METHODS:
All human and animal studies were approved by Vanderbilt IRB and IACUC respectively. Circulating plasminogen levels were determined using a commercial sandwich ELISA (Molecular Innovations; Novi, MI) from human burn patient plasma samples obtained one and three days following burn injury. All murine burn studies were conducted in 6-week-old male mice. After adequate anesthesia, a full thickness cutaneous burn covering 30% of the total body surface area (TBSA) was induced. To simulate the clinical scenario of superimposed burn and muscle injury, WT mice assigned to the injury cohort were injected with CTX in the lower extremity prior to sustaining a burn injury. Dystrophic calcification at the site of muscle injury was evaluated as a marker of pathologic muscle healing.
RESULTS:
In human patients, significant hypoplasminogenemia occurred following burn injury and persisted through 3-days post burn when compared to controls (p<.05, Image A). The extent of hypoplasminogenemia in these patients correlated with the TBSA (p= 0.0014; Spearman r= -0.70, Image B). Similar to human patients, mice who sustained a 30% TBSA burn were also hypoplasminogenemic 3-days post injury. Combined burn and CTX-injected WT mice showed significant radiographic evidence of heterotopic ossification compared to burn alone (p<0.05, Image C). The incidence and severity of HO in α2APASO-treated mice was significantly decreased compared to controlASO-treated combined burn/muscle injury mice (p<0.001, Image D).

CONCLUSION:
This data provides evidence that significant burn injury leads to derangements in systemic plasmin levels that result in poor tissue healing both at the site of injury and in an anatomically remote site. Pharmacologic intervention to preserve circulating plasmin levels may drastically improve outcomes in patients sustaining significant injuries.


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