LAUSR

Background Sepsis, the dysregulated host response to infection, triggers abnormal pro-coagulant and pro-inflammatory host responses. Limitations in early disease intervention highlight the need for effective diagnostic and prognostic biomarkers. Protein C’s role as an anticoagulant and anti-inflammatory molecule makes it an appealing target for sepsis biomarker studies. This meta-analysis aims to assess the diagnostic and prognostic value of protein C (PC) as a biomarker for adult sepsis. Methods We searched MEDLINE, PubMed, EMBASE, CINAHL and Cochrane Library from database inception to September 12, 2021. We included prospective observational studies of (1) adult patients (> 17) with sepsis or suspicion of sepsis that; (2) measured PC levels with 24 h of study admission with; and (3) the goal of examining PC as a diagnostic or prognostic biomarker. Two authors screened articles and conducted risk of bias (RoB) assessment, using the Quality in Prognosis Studies (QUIPS) and the Quality Assessment in Diagnostic Studies-2 (QUADAS-2) tools. If sufficient data were available, meta-analysis was conducted to estimate the standardized mean difference (SMD) between patient populations. Results Twelve studies were included, and 8 were synthesized for meta-analysis. Pooled analysis demonstrated moderate certainty of evidence that PC levels were less reduced in sepsis survivors compared to non-survivors (6 studies, 741 patients, SMD = 0.52, 95% CI 0.24–0.81, p  = 0.0003, I 2  = 55%), and low certainty of evidence that PC levels were less reduced in septic patients without disseminated intravascular coagulation (DIC) compared to those with DIC (3 studies, 644 patients, SMD = 0.97, 95% CI 0.62–1.32, p  < 0.00001, I 2  = 67%). PC could not be evaluated as a diagnostic tool due to heterogeneous control populations between studies. Conclusion and relevance Our review demonstrates that PC levels were significantly higher in sepsis survivors compared to non-survivors and patients with sepsis but not disseminated intravascular coagulation (DIC). Our evaluation is limited by high RoB in included studies and poor reporting of the sensitivity and specificity of PC as a sepsis biomarker. Future studies are needed to determine the sensitivity and specificity of PC to identify its clinical significance as a biomarker for early sepsis recognition. Trial Registration PROSPERO registration number: CRD42021229786. The study protocol was published in BMJ Open.