Sickle cell disease (SCD) is associated with severe systemic complications and increased mortality risk. Predicting SCD severity is currently difficult because of a lack of biomarkers. Here, we measured 5411 plasma proteins in 376 patients with SCD and 103 participants without SCD to find new predictors of SCD mortality. We used protein signatures of mortality that were developed in non-SCD populations to calculate predicted mortality risk scores in our SCD data set. The mortality scores were higher in patients with SCD than in individuals without SCD (P = 3.7 × 10˗10) and were associated with increased mortality in patients with SCD (risk factor–adjusted hazard ratio, 2.2; 95% confidence interval, 1.3-3.6; P = .0032). The mortality scores correlated with several clinical variables (eg, white blood cell count and hemoglobin concentration) and complications (eg, leg ulcers and stroke) that are clinically relevant yet insufficient individually to predict SCD mortality. In addition to the protein signatures, we found 499 plasma proteins that associate with mortality in patients with SCD (false discovery rate of ≤5%), including many proteins involved in inflammatory responses, such as the interleukin-18 signaling cascade. Finally, we estimated biological age in patients with SCD and individuals without SCD using the plasma proteome data. We confirmed that SCD patients age prematurely (+6.0 ± 5.4 years older than their chronological age) and found that brain biological age positively associates with past occurrences of stroke. Altogether, our results support the use of the plasma proteome to monitor and predict clinical severity in SCD.
