Do Transfusion Dependent E-Βeta Thalassemics Behave Differently from Patients with Βeta-Thalassemia Major?

Abstract

Objective

To compare the blood transfusion pattern between children with transfusion dependent Eβ-thalassemia and β-thalassemia major.

Methods

168 children (age 3 months to 12 years) with transfusion dependent Eβ thalassemia and β thalassemia major were admitted to the hospital. 120 children who met our inclusion criteria, were selected and detailed history including various parameters indicating the blood transfusion pattern were recorded.

Results

In this study 72 children (60%) of the patients were transfusion dependent Eβ thalassemia. They started receiving blood transfusion (BT) at a later age(p < 0.0001), they received BT less frequently(p = 0.001), the total number of blood transfusions received up to 5 years of age were less in number(p < 0.0001), the pre-transfusion Hb levels were higher (p < 0.0001) and the peak ferritin level was much lower in them (p < 0.0001). Their transfusion requirement was much less, need for splenectomy was less (p < 0.006), their spleen span and liver span were also less than the children with β-thalassemia major.

Conclusion

Our study clearly depicts that transfusion dependent Eβ thalassemia which is more common in our region shows a wide variation from β thalassemia major patients with respect to various parameters including their transfusion pattern.

Introduction

Thalassemias are a heterogeneous group of genetic disorders resulting from defects in genes producing α or β globin chains. [1]. Clinically important variants prevalent in India are β-thalassemia, Hemoglobin Eβ-thalassemia(Eβ thalassemia), Hemoglobin S (HbS) and Hemoglobin E (HbE) disorders. Eβ-thalassemia comprises 60–70% of the thalassemics registered in different tertiary care hospitals in West Bengal.

Children with β-thalassemia major are clinically of a severe phenotype and are dependent on regular blood transfusion (BT) for their survival from late infancy. On the other hand, patients with Eβ-thalassemia present with a remarkable clinical heterogeneity with respect to the age at onset of 1st BT, frequency of BT, pretransfusion hemoglobin(Hb) levels, spleen size, need for splenectomy, growth and development [2]. Their BT requirements vary from frequent to no BT at all.

The pathophysiology of Hb E/β-thalassemia is related to many factors including reduced β chain synthesis resulting in globin chain imbalance, ineffective erythropoiesis, apoptosis, oxidative damage and shortened red cell survival [3, 4]. The phenotypic variability of E β-thalassemia and the paucity of long-term clinical data, present challenges in providing definitive recommendations for the optimal management of patients [5, 6].

At present, there is no comparative study regarding variable clinical parameters and blood transfusion patterns between β and Eβ thalassemia patients of South Bengal. This study was thus designed to analyze the heterogeneity of the phenotype from the charts of β and E β thalassemia patients to compare mainly their BT pattern, so that early prediction of the natural history of the disease could lead to better planning of resources for comprehensive care.

Materials and Methods

This was a comparative observational study involving transfusion dependent thalassemia patients in the age group of 3 months to 12 years, admitted to our hospital between June 2012 and May 2013 and matched in terms of age and sex. All these children were transfusion dependent and the trigger for a blood transfusion was usually a hemoglobin of less than 6 g/dL due to logistic constraints and demand–supply mismatch, irrespective of the type of Thalassemia. The subjects were chosen by simple random sampling, of which 72 patients had Eβ-thalassemia and 48 patients were homozygous for β-thalassemia on the basis of High-performance liquid chromatography (HPLC, Variant, Biorad). Children with any major congenital anomaly or with life threatening conditions, or those who had fever or any suspicion of chronic infection or severe jaundice were excluded from the study as they could have influenced the results.

With proper approval of Institutional Ethics Committee, the study was initiated. After taking appropriate consent from the parents, the children were enrolled into the study following which clinical case recordings were made in a predesigned and pretested proforma. A detailed history including address, age at presentation of the disease, age of 1^st BT, amount of blood required, vaccination, splenectomy, type of BT etc., were taken, followed by clinical examination including anthropometry, facial changes, icterus, pallor, liver and spleen size.

Blood parameters like Hb levels, RBC indices were measured using SysmexX7-200; ADVIA 2120 auto analyzer followed by manual checking. ABO grouping, Rh typing, HPLC reports, HBsAg, HIV and HPLC reports of family members were also checked. Serum Ferritin level was assessed using Electrochemiluminiscence Immunoassay (ECLIA) (Cobas 6000), Elecsys 2010.

A flowchart depicting the various criteria that were considered to exclude certain cases and to arrive at the final number of the cases is depicted as Fig. 1.

Fig. 1.

A flowchart depicting the various criteria that were considered to exclude certain cases and to arrive at the final number of the cases (study inclusion)

Statistical Analysis

Statistical analysis was done using statistical software SPSS Vs 24.0 with an alpha level of 5%, thus any p value less than 0.05 was significant. Continuous variables were evaluated as Mean ± Standard deviation and comparison across groups was performed using unpaired t test.

Results

In this comparative observational study conducted in the Departments of Pediatrics and Pathology in a tertiary care teaching hospital in Kolkata in the state of West Bengal, 120 patients with transfusion dependent thalassemia on the basis of HPLC reports were included in the study. Among them, 72 patients had E-β thalassemia and 48 were homozygous for β-thalassemia. 55% in the E-β-thalassemia group and 56% of the β thalassemia patients were males.

The various clinical and transfusion parameters of the two groups have been represented in Table 1:

Table 1.

Clinical and transfusion parameters of  Beta and E-β-thalassemia patients

Parameters		E-β Thalassemia	β Thalassemia	P value
Patients	Number	72	48
	Percentage(%)	60	40
Age (in years) (Mean ± SD)		3.6 ± 3.1	4.6 ± 3.1	0.0912
Age of 1st BT (in years) (Mean ± SD)		2.8 ± 2.7	0.4 ± 0.8	< 0.0001
Average interval of BT (in days) (Mean ± SD)		32.4 ± 12.9	25.6 ± 6.1	0.0011
Total number of BT (Mean ± SD)		24.7 ± 24.7	54.8 ± 54.8	< 0.0001
Pre-Transfusion Hb levels (in gm/dl) (Mean ± SD)		6.3 ± 0.5	5.9 ± 0.5	< 0.0001
Peak Ferritin (in ng/ml) (Mean ± SD)		254.8 ± 339.2	1532.4 ± 875.7	< 0.0001
Splenectomy (%)(Mean ± SD)		8.3 ± 0.2	12.5 ± 0.3	0.4603
Spleen span (in cm) (Mean ± SD)		12.2 ± 5.7	12.0 ± 5.5	0.8425
Liver span (in cm) (Mean ± SD)		10.0 ± 3.3	10.7 ± 2.9	0.2183
Transfusion requirement (in ml/kg/yr) (Mean ± SD)		172.7 ± 94.4	218.7 ± 78.3	0.006

In this study there were more E-β thalassemia patients because they comprise 60% of the total transfusion dependent patients in our hospital. Our study clearly revealed that children with E β-thalassemia started receiving BT at a later age, they received BT less frequently and the total number of blood transfusions received upto 5 years of age was less in number. The study further underlines the facts that the pre-transfusion Hb levels were higher and the peak ferritin level was much lower in the transfusion dependent E β-thalassemia patients than the β-thalassemics. Even the transfusion requirement was much less in E β-thalassemics as depicted in Table 1. All these were statistically significant. It was also seen that a smaller number of E β-thalassemia patients had undergone splenectomy, their spleen span and liver span also being less than the children with β thalassemia major, although these were not statistically significant. Even with respect to age and sex, HIV and HBsAg status in the two groups did not show any statistically significant difference.

Discussion

E β-thalassemia is extremely common in the eastern part of India [6]. Study by Mondal et al.[7], has shown that E β-thalassemia is more prevalent than β-thalassemia in West Bengal. Hence, our cohort had more transfusion dependent E β-thalassemics than β-thalassemia major patients in the ratio of 1.5:1.

Study conducted by Sripichai et al. [8], suggested that age at 1st BT was lower for patients with β-thalassemia and variable for those with E β-thalassemia and the average interval between two transfusions was lower for β-thalassemia than those for E β-thalassemia patients. Our study revealed similar data.

A study by Wahidiyat et al. [9], showed that average age at 1st BT for E β-thalassemia patients was 4 years and mean number of BT required was eleven per year which corroborates with our study, where we saw average age at 1^st BT to be 2 years 11 months and mean number of BT to be eleven per year for E β-thalassemia patients. In our study, the patients with β-thalassemia major required the first BT earlier (6 months) and also required more BT (Mean thirteen per year).

Our study showed that the average interval between transfusions was about 5 weeks in patients with Eβ-thalassemia which is similar to the findings by Panigrahi I et al. [10]

With respect to ferritin levels, our study showed that the mean peak ferritin level in case of β-thalassemia patients was about 6 times that of E β-thalassemia patients, which was also earlier seen by Goswami et al. [11]

Although E β-thalassemia is so common, still uniform transfusion guidelines are lacking for these patients [12]. Hence, this study tries to compare the various parameters relating to transfusion patterns in nonchelated β and E β-thalassemia patients to provide a true picture pertaining to the heterogeneity, clinical behavior, transfusion requirements and the need for chelation in both the groups. However, this study suffers from the limitations of being a retrospective chart-based analysis with its inherent shortcomings. The genotypic profile of these children was also not available to comment on the β0 or β + phenotype or the coinheritance of alpha globin mutations.

The modifiers of disease severity in patients with E/β-thalassemia influencing the transfusion requirement include the type of β-thalassemia mutation, co-inheritance of α-thalassemia and determinants that increase HbF production, as well as tertiary modifiers of complications such as the inherited variability in the function of the gene for UDP-glucuronosyltransferase-1 leading to more severe chronic hyperbilirubinemia and an increased incidence of gallstones in some patients [13, 14]. It should also be noted that patients with E/β-thalassemia show different phenotypic severity at particular stages of development. Advancing age has an independent and direct effect on the background level of erythropoietin production in response to anemia [15]. The most notable environmental factor influencing phenotype in patients with E/β-thalassemia is infection with malaria, particularly Plasmodium vivax which is quite prevalent here [16].

Conclusion

Our study shows that even when patients with E β-thalassemia are transfusion dependent, they still require less transfusion, as depicted by various transfusion parameters like later age of onset of BT, less frequent BT, less number of blood transfusions till 5 years of age, higher pre-transfusion Hb levels, lower peak ferritin levels with less number of patients undergoing splenectomy.

Both genotypic and post translational factors may contribute to this distinct phenotype in patients with Eβ-thalassemia. More prospective studies are required to understand the natural history of patients with E β-thalassemia with special reference to the transfusion strategies.