Blood-based protein biomarkers of sickle cell disease pain: a systematic review and meta-analysis

Pain is a major complication of sickle cell disease (SCD), and persons with SCD experience acute vaso-occlusive pain episodes (VOEs). Many adults with SCD also develop chronic pain (CP). We conducted a systematic review and meta-analysis (PROSPERO CRD42024535776) to evaluate blood-based protein biomarkers of SCD pain in 3 clinical contexts: VOE (objective 1), frequency of VOE (objective 2), and CP (objective 3). We searched 5 electronic databases through November 26, 2024. The search yielded 151 eligible observational studies on 159 biomarkers, including 10,208 persons with SCD. Most biomarkers were evaluated during acute pain and were biomarkers of pain biology, inflammation, immune activation, coagulation, and hemolysis or tissue damage. A meta-analysis was conducted for biomarkers reported in 2 or more studies: 80 biomarkers for objective 1, 7 for objective 2, and 4 for objective 3, respectively. We found 28 biomarkers with higher and 2 with lower levels in VOE compared with steady state. No biomarker was associated with frequency of VOE or with chronic SCD pain. This work summarizes the existing literature to provide quantitative estimates of biomarker effect sizes and offers insights from existing literature on pathways implicated in SCD pain. This work highlights the limitations of current approaches and gaps in the scientific literature and supports the premise of using unbiased proteomic platform-based approaches for biomarker discovery in future studies. We highlight the goals and challenges of identifying biomarkers in SCD pain and propose conceptual and methodological considerations to advance the field of protein biomarker research in SCD.