Co-inherited α-Thalassemia and β-Globin Haplotypes as Determinants of Vaso-Occlusive Crisis, Stroke, and Mortality in Sickle Cell Disease: A Systematic Review

Abstract

Background: Clinical severity in sickle cell disease (SCD) varies widely. Co-inherited α-thalassemia and β-globin (HBB) haplotypes are proposed modifiers, but their relationships with vaso-occlusive crisis (VOC), stroke, and mortality remain uncertain.

Objectives: To synthesize evidence on the associations of α-thalassemia and β-globin haplotypes with VOC, cerebrovascular outcomes, and mortality in SCD.

Methods: We conducted a PRISMA-guided systematic review (final search 6 Nov 2025) across MEDLINE, Embase, Web of Science, CENTRAL, Scopus, Google Scholar, and regional/grey sources. Eligible studies enrolled individuals with SCD (any genotype/age) and reported genotyped α-thalassemia and/or β-globin haplotypes alongside ≥1 prespecified outcomes. Two reviewers screened records, extracted data, and appraised risk of bias.

Results: Of 1,964 records, 10 studies met inclusion (predominantly pediatric HbSS; Caribbean, South America, North America, and French Guiana). Across cohorts, α-thalassemia showed a consistent protective signal for cerebrovascular phenotypes: lower odds of overt stroke and fewer abnormal transcranial Doppler velocities. Evidence for VOC was heterogeneous—one prospective cohort reported higher healthcare-attended VOC in homozygous α-thalassemia, whereas adjusted analyses elsewhere were null. Mortality data were scarce; a cross-sectional genetic survey suggested better survival among α-thalassemia carriers. β-globin haplotypes showed weak or inconsistent associations with all outcomes once fetal hemoglobin and treatment era were considered. The principal methodological limitation was residual confounding; outcome measurement for stroke/TCD was robust, while VOC ascertainment varied.

Conclusions: α-thalassemia appears to reduce cerebrovascular risk in SCD, while effects on VOC are context-dependent. β-globin haplotypes add limited independent prognostic value beyond fetal hemoglobin. Contemporary, adjusted, genotype-specific cohorts are needed to refine effect sizes and inform risk-stratified care.