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Updated: Mar 7, 2026
A Precision Medicine Tool for Measurement and Monitoring of Hemoglobin S in Sickle Cell Disease Patients Receiving Transfusion Therapy
A systematic review of the literature for severity predictors in children with sickle cell anemia
Emily Riehm Meier1, Ross M Fasano2, Paul R Levett3
1Indiana Hemophilia and Thrombosis Center, Indianapolis, IN 46260, USA.
Insights
Predicting sickle cell anemia (SCA) severity in children is challenging. While alpha thalassemia and fetal hemoglobin show some protective effects, only transcranial Doppler and reticulocyte count reliably predict complications, highlighting the need for better early indicators.
Area of Science:
- Hematology
- Genetics
- Pediatric Medicine
Background:
- Sickle cell anemia (SCA) presents with variable clinical phenotypes despite a single genetic mutation.
- Predicting SCA severity early in life is difficult, hindering timely therapeutic interventions for high-risk patients.
Purpose of the Study:
- To identify validated predictors of SCA severity in pediatric patients.
- To evaluate the effectiveness of various biomarkers in predicting SCA complications.
Main Methods:
- A systematic literature search was conducted across PubMed, Cochrane Clinical Trials Register, and Scopus.
- Full-text review of 94 articles from 590 references, with 54 ultimately included in the analysis.
Main Results:
- Alpha globin gene number, fetal hemoglobin (HbF), and reticulocyte count were commonly studied predictors.
- Alpha thalassemia trait demonstrated protection against stroke and abnormal transcranial Doppler (TCD), but not painful crises or silent cerebral infarct.
- HbF showed mixed results; while some studies indicated benefits, others found no association with reduced hospitalization or stroke rates.
- Transcranial Doppler (TCD) and absolute reticulocyte count showed the most consistent ability to predict SCA complications.
Conclusions:
- Existing SCA severity predictors in children have limited reliability.
- Transcranial Doppler (TCD) and absolute reticulocyte count are the most promising validated predictors currently available.
- There is an urgent need for more robust and reliable predictors to guide therapeutic decisions in pediatric SCA patients.
Abstract:
All patients with HbSS (SCA) share the same genetic mutation but the clinical phenotype is variable and difficult to predict early in life. A reliable severity predictor would be invaluable toward directing therapeutic decisions in those patients at highest risk of SCA complications. A search of PubMed, Cochrane Clinical Trials Register, and Scopus was performed to determine which SCA severity predictors have been validated in pediatric patients. The full text of 94 of the 590 references identified was reviewed based on the title/abstract. Fifty-four articles were included in the analysis. Alpha globin gene number was the most commonly studied severity predictor, followed by fetal hemoglobin (HbF) and reticulocyte count. Alpha thalassemia trait was protective against overt stroke and abnormal transcranial Doppler (TCD) in all but one study, but not frequency of painful crisis or silent cerebral infarct. Two thirds of the HbF studies reported beneficial effects with increasing HbF levels; however, increased HbF levels were not associated with lower hospitalization or stroke rates in others. The ability to predict SCA complications was mixed for all variables, except TCD and absolute reticulocyte count. More reliable predictors are urgently needed to guide therapeutic decisions in children with SCA.
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