Thalassemia is a genetic hemoglobinopathy and is considered to be among the global public health issues (1–4). Mutations in the globin gene result in abnormal globin chain synthesis, ultimately leading to chronic hemolytic anemia. Thalassemia has alpha (α) and beta (β) forms, and the disease severity is categorized based on the transfusion dependency and complications. Moreover, it can be classified based on its clinical severity and the degree of anemia. The standard phenotype-based classification that is widely applied is transfusion-dependent thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT). Furthermore, while thalassemia major manifests as severe anemia in the neonatal period, some patients with thalassemia intermedia only have asymptomatic anemia (5). The severity of thalassemia is determined by the number of mutated genes—four in α-thalassemia and two in β-thalassemia (6). In Thailand, while approximately 40% of the Thai population carries either α- or β-thalassemia (7, 8), only 1% of patients with thalassemia have TDT (7).

Patients with TDT suffer from chronic anemia, which leads to short life expectancy. Furthermore, although life expectancy can be improved by regular blood transfusions, multiple side effects occur both during (allergic reaction) or after transfusion (such as iron overload or hemochromatosis). In hemochromatosis, iron deposits in the visceral organs (the myocardium, liver, and endocrine glands) lead to organ dysfunction (e.g., congestive heart failure, cirrhosis, and endocrinopathies associated with diabetes mellitus) (9). Thus, novel treatment strategies for thalassemia have been developed to balance the necessary blood transfusion and iron accumulation to increase the survival rate (7, 8). Numerous studies have demonstrated that an optimization of the blood transfusions/iron chelation protocols induces a high survival rate that is close to the life expectancy of the general population (8–12). However, the survival rate of thalassemia is also dependent on several other factors, including disease severity, adequate blood transfusion, blood quality, and preventive iron deposition. The prevalence of cardiopulmonary and bone deformities remains high among western thalassemia patients with high ferritin levels, whereas among eastern TDT patients, infection is the main cause of complications (8, 12–15). It has been hypothesized that different clinical outcomes are the results of the interaction between the α- and β-thalassemia genotypes, which can compensate to yield a normal lifespan in patients with minimal complications (8, 16). The co-inheritance of the α- with β-thalassemia genotypes can affect genotype-based categorization, similar to that observed in other hemoglobinopathy combinations, such as α-thalassemia and sickle cell anemia-sickle hemoglobin (HbS) (17). However, only a few studies have investigated the survival and predictive factors that can influence the outcomes during the clinical course of the α- and β-thalassemia genotypes. Thus, the present study aimed to identify the clinical factors that determine the survival rate in patients with α- and β-thalassemia and in those with co-inheritance of the α- and β-thalassemia genotypes.

This retrospective cohort study aimed to identify the clinical predictors of death and survival rates in Thai patients with thalassemia and to compare the results of this study with those of other studies (8, 9, 14). It is interesting to note that our cohort comprised predominately older women (aged >40 years), similar to another study (14), and that only 19% of the patients underwent splenectomy. This indicates that the availability of blood transfusion has reduced the need for splenectomy. Severe anemia was observed in about half of the cohort, both initially and during follow-up, a finding similar to that of other Thai studies (8, 9). A balance between blood transfusion and iron depletion has been proposed to increase the survival rates among patients with thalassemia (12, 21).

We demonstrated seven clinical factors that were significantly associated with death rate, namely, male sex, low BMI, thalassemia type, comorbidities, low hemoglobin level, high ferritin level, and requirement of regular blood transfusion. These findings are in agreement with those of multiple studies of clinical factors associated with survival rates in thalassemia (22–25). The greater risk due to male sex may be explained by the fact that thalassemia in women might be associated with lower oxidative stress, which in turn affects the cardiac function and incidence of infections (24). This effect is similar to that observed in hemochromatosis, which may also require regular blood transfusion and is associated with greater incidence of cardiac dysfunction and infection. In addition, several studies have demonstrated that high ferritin levels (>2,500 ng/mL) are associated with short-term survival in patients with thalassemia (13, 26). A low BMI typically reflects nutritional deficiencies among patients with thalassemia, and malnutrition can lead to anemia that requires regular blood transfusion (22). Thus, malnutrition is associated with TDT and is thereby related to iron overload, cardiac dysfunction, and increased infection rate. However, it should be noted that most published studies have been conducted on patients with thalassemia major, and it is possible that the type of thalassemia is significantly associated with complications and death. We demonstrated that thalassemia major (β-thalassemia) had a more severe clinical course than α-thalassemia. As blood transfusions are needed to treat anemia, high ferritin levels can be commonly observed among TDT patients (8, 12, 15). This observation potentially reflects the association between transfusion dependence and more severe thalassemia conditions. The difference in the survival rates among various studies may be attributed to sample size disparities or the methods used for calculating the survival rate, which are based on the thalassemia major or thalassemia intermedia types. Similarly, the higher overall survival rate observed in our cohort may be attributed to the thalassemia type, which has also been reported by other studies (27, 28). Patients with thalassemia major are at a higher risk of mortality than those with other types of thalassemia, and the underlying etiology is the need for regular blood transfusions and consequent iron accumulation, leading to organ dysfunction (29). Other factors that may influence the survival of patients with thalassemia include time to diagnosis, availability of healthcare services, regular monitoring, proper treatment, and early iron chelation therapy. Contrary to the results presented here, a study from Great Britain found that 50% of patients with thalassemia intermedia died at a young age (<35 years) (6). Limitations in the study design and data analysis may have influenced the non-significant finding for age of complication onset.

There were hypotheses of the deletion of the α-globin gene with the β-thalassemia genotype affecting the hyperunstable globin variant, leading to easy hemolytic condition (30–32). The pathophysiology of co-inheritance is not clear to explain this phenomenon related to the survival rate. Interestingly, our data showed support that the co-inheritance of the α- and β-thalassemia genotypes with TDT reduced the survival rate. This combined hemoglobinopathy (α- and β-thalassemia) is contradictory to that of another study in patients with co-inheritance of α-thalassemia and other hemoglobinopathy types (HbS), especially with respect to improving the survival rate (17). Some studies have mentioned other clinical factors that might be related to the prognosis of α-thalassemia (10, 33, 34). Similarly to β-thalassemia leading to anemia that needs regular blood transfusions, complications might develop earlier among patients with co-inheritance of the α- and β-thalassemia types. It has been known that co-inheritance of the α- and β-thalassemia genotypes is relatively common in Southeast Asia (35). Blood transfusion with concordant iron chelation therapy was prescribed for the patients in our study. Iron overload due to long-term blood transfusion among patients with thalassemia is the major cause of complications, such as cardiac dysfunction, and 92 patients experienced complications (e.g., liver dysfunction, endocrinopathies, and cardiac disease). In our cohort, more than half were categorized as TDT, and iron chelation therapy, given twice in a 3-month interval, was advised when high serum ferritin levels were >1,000 ng/mL (14). While a few patients used deferasirox owing to its low cost, most patients (77%) received deferiprone and did not develop cardiac problems. This can be explained by the cardioprotective effect of deferiprone, which exhibits greater iron mobilization. This increases the heart signal and improves heart function in patients with iron overload (36). Surprisingly, we found a high incidence of infection (50% of the study population). This observation is different from the results of a previous study (27). In another study, it was demonstrated that thalassemia patients with iron overload predominantly suffered from cardiac complications, including heart failure and arrhythmia (29). We hypothesized that the high ferritin levels in our cohort have rendered the patients susceptible to bacterial infection, with the underlying mechanism involving impaired phagocytic function of macrophages and neutrophils, alternated T lymphocytes, lower numbers and function of natural killer cells, increased numbers and function of B lymphocytes, impaired secretion of immunoglobulin, and suppression of the complement system function (11). In support of this hypothesis, Teawtrakul et al. have demonstrated that a high ferritin level is a significant risk factor to bacterial infection in patients with TDT (15). The strength of this study lies in our observational study supporting the hypothesis of co-inherited thalassemia patients having low survival rates. The limitations of this study include its retrospective design and the fact that the cohort was recruited from a tertiary care center with a small sample size for subgroup analysis. Although we demonstrated poor survival among patients with co-inheritance of the α- and β-thalassemia genotypes and TDT, future studies on a larger population are required to validate the results of the present study. A case–control study may be needed to make conclusions on clinical parameters for use in the global medical fraternity, including exploring potential differences in the efficacy and compliance between the various iron chelators used in clinical practice.

The overall survival rate among patients with thalassemia was 93.7%, and it was higher in those with α-thalassemia-TDT. However, the co-inheritance of the α- and β-thalassemia genotypes with TDT led to poor survival, and it was found that the most common cause of death was infection. Our results suggest the usefulness of clinical parameters in estimating the survival rates among patients with thalassemia.

Available data and materials upon request, please directly contact correspondence author for data request according to the regulation of the Ethical Committees. Requests to access the datasets should be directed to Supat.cha@mahidol.ac.th.

The studies involving humans were approved by The Ethics Committee of the Rajavithi Hospital-Number 050/2562 (Rajavithi Hospital). The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because all patient data were decoded and this was a retrospective study, written informed consent was not required.

KI-a: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing. SC: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. TS: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Resources, Writing – review & editing. PT: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Resources, Writing – review & editing. SF: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Validation, Visualization, Writing – review & editing.