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Navigating the complexities of a severe burn injury is a challenging endeavour where the natural course of some patients can be difficult to predict. Straddling both the coagulation and inflammatory cascades that feature strongly in the burns systemic pathophysiology, we propose the pleiotropic protein C (PC) system may produce a viable biomarker to assist traditional evaluation methods for diagnostic and prognostic purposes.We enrolled 86 patients in a prospective observational cohort study. Over three weeks, serial blood samples were taken and measured for PC, activated (A)PC, their receptor endothelial protein C receptor (EPCR), and a panel of inflammatory cytokines including C-reactive protein (CRP), tumour necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, and IL-17. Their temporal trends were analysed alongside clinical factors including burn size, burn depth, presence of inhalational injury, and a composite outcome of requiring increased support.(i) APC increased from a nadir on Day 3 (2.3±2.1ng/mL vs 4.1±2.5ng/mL by Day 18, p0.0005), only becoming appropriately correlated to PC from Day 6 onwards (r=0.412-0.721, p0.05 for all Days 6-21). (ii) This early disturbance in the PC system was amplified in the more severe burns (≥30% total body surface area, predominantly full thickness, or with inhalational injury), which were characterised by a marked fall in PC activation (approximated by APC/PC ratio) and APC levels during Days 0-3 with low unchanged PC levels. Critically low levels of this cytoprotective agent was associated with greater inflammatory burden, as reflected by significantly elevated CRP, IL-6, and IL-8 levels in the more severe compared to less severe burns, and by negative correlations between both PC and APC with most inflammatory cytokines. (iii) Alongside clinical markers of severity at admission (burn size, burn depth, and presence of inhalational injury), only Day 0 APC/PC ratio (OR 1.048 (1.014-1.083), p=0.006), APC (OR 1.364 (1.032-1.803), p=0.029), PC (OR 0.899 (0.849-0.953), p0.0005), and not any inflammatory cytokines were predictive markers of requiring increased support. Uniquely, decreased Day 0 PC was further individually associated with each increased total length of stay, ICU length of stay, intravenous fluid resuscitation, and total surgeries, as well as possibly mortality.An early functional depletion of the cytoprotective PC system provides a physiological link between severe burns and the cytokine storm, likely contributing to worse outcomes. Our findings on the changes in APC, PC and PC activation during this pathological state support APC and PC as early diagnostic and prognostic biomarkers, and provides a basis for their therapeutic potential in severe burn injuries.

Protein C circulates in human plasma to regulate inflammation and coagulation. It has shown a crucial role in wound healing in animals, and low plasma levels predict the presence of a wound in diabetic patients. However, no detailed study has measured protein C levels in patients with severe burns over the course of a hospital admission. A severe burn is associated with dysfunction of inflammation and coagulation as well as a significant risk of morbidity and mortality. The current methods of burn assessment have shortcomings in reliability and have limited prognostic value. The discovery of a biomarker that estimates burn severity and predicts clinical events with greater accuracy than current methods may improve management, resource allocation and patient counseling. This is the first study to assess the potential role of protein C as a biomarker of burn severity. We measured the plasma protein C levels of 86 patients immediately following a severe burn, then every three days over the first three weeks of a hospital admission. We also analysed the relationships between burn characteristics, blood test results including plasma protein C levels and clinical events. We used a primary composite outcome of increased support utilisation defined as: a mean intravenous fluid administration volume of five litres or more per day over the first 72 h of admission, a length of stay in the intensive care unit of more than four days, or greater than four surgical procedures during admission. The hypothesis was that low protein C levels would be negatively associated with increased support utilisation. At presentation to hospital after a severe burn, the mean plasma protein C level was 76 ± 20% with a range of 34–130% compared to the normal range of 70–180%. The initial low can be plausibly explained by impaired synthesis, increased degradation and excessive consumption of protein C following a burn. Levels increased gradually over six days then remained at a steady-state until the end of the inpatient study period, day 21. A multivariable regression model (Nagelkerke’s R2 = 0.83) showed that the plasma protein C level on admission contributed the most to the ability of the model to predict increased support utilisation (OR = 0.825 (95% CI = 0.698-0.977), P = 0.025), followed by burn size (OR = 1.252 (95% CI = 1.025–1.530), P = 0.027), burn depth (partial thickness was used as the reference, full thickness OR = 80.499 (1.569–4129.248), P = 0.029), and neutrophil count on admission (OR = 1.532 (95% CI = 0.950–2.473), P = 0.08). Together, these four variables predicted increased support utilisation with 93.2% accuracy, 83.3% sensitivity and 97.6% specificity. However if protein C values were disregarded, only 49.5% of the variance was explained, with 82% accuracy, 63% sensitivity and 91.5% specificity. Thus, protein C may be a useful biomarker of burn severity and study replication will enable validation of these novel findings.