OBJECTIVE: Markedly elevated serum ferritin serves as a laboratory marker of macrophage activation syndrome and is associated with increased mortality in sepsis, where hyperinflammation, coagulopathy, and immune dysregulation interplay. Although laboratory studies suggest a relationship between hyperferritinemia and coagulopathy in sepsis, clinical evidence remains limited. This study aims to assess mortality risk and the interplay between hyperferritinemia (ferritin ≥ 500 ng/mL) and thrombocytopenia in two sequential cohorts of adult patients with sepsis. PATIENTS: Patients with sepsis (≥18 years old) admitted to adult ICUs at Beth Israel Deaconess Medical Center between 2001 and 2008, and 2008 to 2019, with at least one ferritin value recorded within a 48-h window preceding or following the initial ICU admission. RESULTS: Among 2339 eligible patients with hyperferritinemic sepsis, 921(39.4%) were categorized into the high ferritin (HF) group (ferritin ≥ 500 ng/mL). Multivariate logistic regression analysis revealed a significant association between the HF group and increased in-hospital mortality (p <
.01). Survival analysis revealed significantly lower survival probabilities at 28 and 90 days in the HF group compared to the low ferritin group. The interaction between the HF group and thrombocytopenia revealed a statistically significant association with in-hospital mortality. Furthermore, causal mediation analysis showed that platelet count mediated 12.6% (95% CI: 0.063-0.27
p <
.001) of the effect of elevated ferritin levels on in-hospital mortality. CONCLUSIONS: Hyperferritinemia is associated with an increased mortality risk in adult septic patients. Thrombocytopenia not only interacts with hyperferritinemia but also serves as a mediating factor in its impact on mortality.