Trauma-Derived Extracellular Vesicles Are Sufficient to Induce Endothelial Dysfunction and Coagulopathy

BACKGROUND: Cryoprecipitate (CP) can augment hemostasis after hemorrhagic shock (HS). Similar to fresh frozen plasma (FFP), CP may provide short-term endothelial protection. We tested a new 5-day postthaw CP (5-day pathogen-reduced cryoprecipitate [5PRC]) and lyophilized pathogen-reduced cryoprecipitate (LPRC) to overcome challenges of early administration and hypothesized that 5PRC and LPRC would provide lasting organ protection in a rodent model of HS. METHODS:Mice underwent trauma/HS (laparotomy then HS), mean arterial pressure (MAP) 35 Â 90 minutes, and then 6 hours of hypotensive resuscitation (MAP, 55-60 mm Hg) with lactated Ringer's solution (LR), FFP, CP, 5PRC, or LPRC and compared with shams. Animals were followed for 72 hours. Organs and blood were collected. Data are presented as mean ± SD and analysis of variance with Bonferroni post hoc. RESULTS:Mean arterial pressure was comparable between experimental groups at baseline, preresuscitation, and 6 hours per protocol. However, volume needed to resuscitate to target MAP over 6 hours was less than half for CP, 5PRC, LPRC, and FFP compared with LR, suggesting that CP products can serve as effective resuscitative agents. Mean arterial pressure at 72 hours was also significantly higher in the CP, 5PRC, and FFP groups compared with LR. Resuscitation with CP, 5PRC, and LPRC provided lasting protection from gut injury and enhanced syndecan immunostaining comparable with FFP, while LR mice demonstrated persistent organ dysfunction. Sustained endothelial protection was demonstrated by lessened lung permeability, while cystatin C was an indicator of kidney function, and liver aspartate aminotransferase and alanine transaminase returned to sham levels in all groups. CONCLUSION: Cryoprecipitate products can provide lasting organ protection comparable with FFP in a sustained rodent model of trauma/HS and hypotensive resuscitation. The availability of 5PRC and LPRC will allow for investigation into the immediate use of cryoprecipitate for severely injured patients. As lyophilized products such as cryoprecipitate become available clinically, their use has important implications for prehospital, rural, and battlefield usage.

Section: Methodsmentioning

confidence: 99%

“…Total protein in the BAL fluid was measured with the BCA Protein Assay (Thermo Fisher Scientific, Waltham, MA) as an indicator of permeability. 21…”

Section: Lung Permeabilitymentioning

confidence: 99%

Immediate use cryoprecipitate products provide lasting organ protection in a rodent model of trauma/hemorrhagic shock and prolonged hypotensive resuscitation

Zeineddin

Cao

et al. 2023

“…When EVs were isolated from severely injured patients and injected into naive mice, EC injury, as demonstrated by syndecan-1 shedding; coagulopathy; and organ injury were all significantly increased as compared with mice receiving EVs from minimally injured patients. 84 Similarly, Dyer et al 85 found that platelet EVs released after trauma were prohemostatic but also prothrombotic and contributed to enhanced venous thrombosis.…”

Section: Targeting Adamts-13 and Vwfmentioning

confidence: 98%

Injury-induced endotheliopathy: What you need to know

Cardenas

Dong

Kozar

2023

“…92,93 Activated endothelial cells also release EVs in response to various stimuli, including injury. 94 These EVs carry bioactive molecules such as TF, microribonucleic acids, and cytokines, which can contribute to coagulation and inflammation by further enhancing platelet activation, promoting leukocyte adhesion, and modulating immune cell function. 95 The net effect of inflammation and trauma-induced EV release on the coagulation status of the patient and their potential as a therapeutic to treat TIC is not fully understood and remains an area of ongoing investigation.…”

Section: Role Of Extracellular Vesicles In Mediating Sirsmentioning

confidence: 99%

The intersection of coagulation activation and inflammation after injury: What you need to know

Costantini,

Kornblith,

Pritts

et al. 2023

The systemic inflammatory response syndrome (SIRS) after severe injury can lead to distant organ injury, multi-organ failure, and complications during recovery. Post-injury SIRS is driven by the activation of innate immune cells and release of pro-inflammatory cytokines that drives this inflammation response. In addition, the coagulation cascade and complement system is altered, resulting in a widespread inflammatory response. Importantly, these different components of SIRS are interrelated and propagate further alterations in thrombosis and inflammation. Efforts to mitigate the acute changes in coagulation and inflammation and its complex interactions following injury could provide novel strategies for resuscitation and management of complications of trauma-induced coagulopathy, SIRS, and multiple organ failure. In this review, we review the pathophysiology of post-traumatic SIRS and highlight current approaches to mitigate innate immune cell activation, thromboinflammation, and associated clinical complications. Level of Evidence IV, Review article