Cell-Free Hemoglobin: A New Therapeutic Target in Sepsis?

Abstract

Sepsis is a heterogeneous clinical syndrome that has defied all attempts to identify effective pharmacologic therapies. A growing body of evidence suggests that an elevated level of circulating cell-free hemoglobin is a feature of some, but not all patients with sepsis. Cell-free hemoglobin can cause tissue injury and organ dysfunction through a variety of injurious mechanisms including scavenging of nitric oxide, pro-inflammatory signaling, and oxidative injury. The kidney and lung appear to be particularly vulnerable to cell-free hemoglobin-mediated injury. A number of potential therapies to target cell-free hemoglobin in sepsis have been identified including haptoglobin, hemopexin, and acetaminophen. Early phase clinical trials suggest that acetaminophen may have beneficial effects on lipid peroxidation and kidney function in patients with sepsis. Measurement of cell-free hemoglobin levels at the bedside has the potential to facilitate predictive enrichment for future therapeutic trials of cell-free hemoglobin-targeted therapeutics in sepsis such that only patients with elevated cell-free hemoglobin who would be most likely to benefit would be enrolled. However, rapid, accurate bedside tests for plasma cell-free hemoglobin will need to be developed in order for such trials to move forward.