Morbidities in β-thalassemia intermedia across the spectrum of disease severity: A nationwide study in Türkiye

Abstract Introduction Accumulated data show that anemia caused by ineffective erythropoiesis and iron overload is linked to multiple morbidities, significantly reducing quality of life in β-thalassemia intermedia (β-TI). The spectrum of β-TI varies from occasional transfusions to more frequent ones, and phenoconversion to a transfusion-dependent (TD) state. We conducted a retrospective cohort study to evaluate the morbidities of β-TI patients with varying disease severities, using data retrieved from the National Hemoglobinopathy Registry (NHR) of the Turkish Hematology Association in Turkey. Methods The NHR is a voluntary, computerized medical record system that standardizes the collection of clinical, laboratory, and imaging data from thalassemia centers across Turkey, serving as a prospective cohort since 2015. We obtained ethics committee approval and written informed consent from patients at each center for the collection and use of the data. The β-TI patients aged ≥10 years who had not received any red blood cells (RBCs) or had received RBCs occasionally (1-3 times), frequently (4-7 times), or regularly (≥8 times) within the 12 months preceding the last observation were included in the analysis. Patients with an intact spleen and no transfusion during their previous year are classified as having a mild phenotype. Patients who have either been occasionally or frequently transfused or splenectomized, as well as those who have both, are identified as having moderate and severe phenotypes, respectively. Regularly transfused patients were also divided into those with an intact spleen or who had undergone splenectomy. Chelation history, as well as the average hemoglobin (Hb) and serum ferritin (SF) levels, were documented over a 10-year observation period. The risk factors that may influence the occurrence of morbidities were evaluated using age-adjusted logistic regression analysis. Results A total of 330 β-TI patients (57.3% female), aged 10 years or older, were included in this analysis. 112 (34.0%) of patients were transfusion-free, 127 (38.5%) were receiving regular transfusions, while 48 (14.5%) and 43 (13.0%) had received RBC transfusions 1-3 times and 4-7 times a year, respectively. 148 (45%) of patients had undergone splenectomy. Chelation history was present in 90.6% of the population. In the overall group, skeletal complications were the most common (44.2%), followed by endocrine (22.4%) and cardiovascular (16.4%) complications. In contrast, we did not observe hepatic complications, such as chronic liver disease, cirrhosis, and hepatocellular carcinoma; only one patient had a chronic HBV infection. Age was a significant determinant of morbidity development (p < 0.001). The disease severity showed that the mild phenotype had the lowest morbidity rate at 10.5% compared to the moderate (34%) and the severe phenotypes (57.6%), with an odds ratio (OR) of 1.58 (95% CI: 1.36-1.82) (p < 0.001). In the moderate phenotype, non-transfused but splenectomized subjects had a clinically meaningful higher morbidity rate (47.2%) compared to those transfused but had an intact spleen (25.8%) (p=0.057). In patients receiving regular transfusions, those who had undergone splenectomy experienced significantly higher morbidity rates (77.2%) compared to those with an intact spleen (37.5%) (p<0.001). Splenectomy emerged as a significant risk factor for the development of morbidity, with an OR of 4.9 (95% CI: 3.0-8.0) (p< 0.001). On the other hand, the presence of transfusion also significantly increases the risk of morbidity (OR 2.89 -95% CI: 1.70-4.92) (p<0.001), but Hb levels did not significantly impact morbidity (OR 0.90 (95% CI: 0.75 - 1.08 (p=0.245). Similarly, SF levels also showed no significant effect, with an OR of 1.00 (95% CI: 1.00 - 1.00) (p=0.334). This lack of significance may be related to a lower transfusion policy than what is needed for the severity of the disease, as well as relatively well-controlled SF levels across all disease severities. Conclusions Splenectomy and transfusion requirements play a significant role in the development of morbidity in patients with β-TI. Rather than opting for splenectomy, providing adequate transfusion support may help protect against lifelong complications. However, this transfusion support should be tailored to the severity of the disease and accompanied by appropriate chelation therapy. Failing to maintain sufficient transfusions could increase the risk of additional morbidities.