Thalassemia is one of the most common hemoglobinopathies, with around 5% of the world's population expected to have some degree and type of thalassemia. Beta thalassemia (BT) occurs due to a deficient production of the beta-globin chain of hemoglobin. Extramedullary hematopoiesis (EMH) is one of the complications of BT, mainly observed in minor/intermedia subtypes. EMH is the production of blood cells outside the marrow as a compensatory response to longstanding hypoxia. Due to chronic transfusions, it is not expected in patients with beta-thalassemia major (BTM). However, there are increasingly reported cases of EMH in BTM. The incidence of EMH in BTM is thought to be <1%. However, it seems that the true incidence is much higher than expected. This review aims to pool the available data and provide cumulative evidence on the occurrence of EMH in BTM patients.

We aim to conduct a systematic review via searching multiple electronic databases (PubMed, Scopus, Google Scholar) to identify eligible articles from any date up to December 2020. Eligible studies should report extramedullary hematopoiesis in beta-thalassemia major. Case reports, case series, observational studies with cross-sectional or prospective research design, case-control studies, and experimental studies will be included if found relevant. Two reviewers (FA and ES) will individually analyze the study quality using the statistical methodology and categories guided by the Cochrane Collaboration Handbook, PRISMA guidelines, and Joanna Briggs Institute checklist for case reports and series.

Data from 253 cases of EMH in BTM patients were extracted with mean age of 35.3 +/- 0.5 years. Mean hemoglobin at presentation with EMH was 8.2 +/- 2.1 mg/dL. Lower limb weakness was the most common presenting feature (N=23) (paraspinal EMH). Magnetic resonance imaging (MRI) was the most widely used diagnostic modality (N=226). Overall, blood transfusion was the commonest reported treatment (N=30), followed by radiotherapy (N=20), surgery (N=15), hydroxyurea (N=12), steroids (N=6), and exchange transfusion (N=2). An outcome was reported in 20% of patients, all recovered, with no reported mortality.

EMH is considered a rare phenomenon in BTM patients. It can occur in any organ system with varied clinical features. MRI can effectively diagnose EMH, and conservative management has similar results compared to invasive treatments. Larger studies, focusing on outcomes may enhance guidelines on preventive and therapeutic strategies for managing EMH in BTM.