Leg Ulcers in Thalassaemia: A Comparative Retrospective Review of Transfusion‐Dependent and Non‐Transfusion‐Dependent Patients

ABSTRACT

To compare clinical and laboratory characteristics of transfusion‐dependent and non‐transfusion‐dependent beta thalassaemia patients with leg ulcers, and to identify contributing and protective factors We retrospectively reviewed 12 patients with beta thalassaemia and leg ulcers (seven transfusion‐dependent and five non‐transfusion‐dependent) at a tertiary centre. We analysed demographics, haemoglobin levels, ferritin, foetal haemoglobin, transfusion status, comorbidities, and ulcer characteristics. Transfusion‐dependent patients were predominantly younger males (mean age: 31.9 years), while non‐transfusion‐dependent patients were older (mean age: 44.0 years). Ulcers were larger in transfusion‐dependent patients (mean area: 3.1 cm²) but more frequent in non‐transfusion‐dependent patients (mean episodes: 2.2). Splenectomy was performed in all transfusion‐dependent patients and most non‐transfusion‐dependent patients. Transfusion‐dependent patients had higher ferritin levels, while non‐transfusion‐dependent patients had higher foetal haemoglobin and slightly better ulcer resolution rates (80% vs. 71%). Major exacerbating factors included chronic anaemia, iron overload, trauma, and hypercoagulability. Protective factors included higher foetal haemoglobin levels, hydroxyurea use, occasional transfusions, and early conservative wound care. Although more commonly reported in non‐transfusion‐dependent patients, leg ulcers were also clinically significant in transfusion‐dependent patients, where they were associated with larger ulcer size, higher iron burden, and incomplete healing despite regular transfusion and chelation. These findings highlight the need for heightened recognition and tailored preventive strategies for leg ulcers in transfusion‐dependent thalassaemia.

Key Points

• In this small, single‐centre retrospective series of 12 patients with β‐thalassaemia and leg ulcers, ulcers occurred in both transfusion‐dependent and non‐transfusion‐dependent patients, indicating they are not confined to the non‐transfusion‐dependent group.

• Transfusion‐dependent patients tended to have larger ulcers, higher serum ferritin and more severe anaemia, whereas non‐transfusion‐dependent patients had more frequent ulcer episodes, higher foetal haemoglobin and slightly better ulcer resolution.

• These descriptive, hypothesis‐generating observations suggest that iron burden and anaemia, rather than transfusion status alone, may contribute to leg‐ulcer risk in thalassaemia; larger prospective studies are needed to confirm these associations.

1. Introduction

Thalassaemia is a group of monogenetic hematologic diseases that is common worldwide but mostly seen in the Mediterranean, North Africa, and South Asia, though its prevalence is now increasing in other regions due to immigration [1, 2]. The pathology of Thalassaemia involves a defect in the synthesis of beta‐globin chains, resulting in an imbalance between α and β chains of haemoglobin [3, 4]. There is a wide spectrum of Thalassaemia phenotypes, which include Beta Thalassaemia Major (TM), necessitating chronic transfusion on one end, and Beta Thalassaemia minor presenting with mild asymptomatic anaemia on the other end. Thalassaemia Intermedia (TI) lies between these extremes, with milder symptoms than TM but more pronounced than Minor [5].

Thalassaemia can also be grouped into transfusion‐dependent thalassaemia (TDT) patients, whose haemoglobin production is insufficient to maintain survival without transfusions, previously known as TM, as opposed to individuals with non‐transfusion‐dependent thalassaemia (NTDT) [6, 7]. Even though NTDT patients do not usually necessitate regular blood transfusions, they may still require blood transfusion in certain stressful conditions like infection, pregnancy, and surgery, among others [8]. NTDT includes those with thalassaemia intermedia or some milder haemoglobin H disease [9]. Distinct treatment practices, such as limited transfusions, minimal chelation, and frequent splenectomies, help explain the divergent comorbidity profiles of TDT and NTDT [10, 11, 12]. These complications were described in the OPTIMAL CARE study, which compared comorbidities in thalassaemia intermedia and major [13]. The hallmark triad of ineffective erythropoiesis, chronic anaemia, and iron overload underpins many complications, including elevated pulmonary artery pressure, thrombosis, and venous thromboembolism [5, 14, 15, 16].

Leg ulceration is also a disabling complication that significantly affects patients' mobility and quality of life. Leg ulcers have been reported in about 8% of patients with thalassaemia intermedia [13] and in up to 22% of patients with haemoglobin E β‐thalassaemia [17]. While leg ulcers in NTDT patients have been well documented, particularly among thalassaemia intermedia cohorts, data on such complications in TDT patients remain limited. Most studies overlook this subgroup, assuming that regular transfusion and chelation reduce ulcer risk. We therefore reviewed 12 adults with β‐thalassaemia and leg ulcers at a tertiary reference centre (seven TDT and five NTDT) to compare their clinical and laboratory characteristics directly and to describe factors associated with ulceration and healing in each group.

2. Materials and Methods

2.1. Study Design and Setting

This single‐centre retrospective study was conducted at a tertiary reference centre and combined review of electronic medical records with a structured patient telephone interview. The study was approved by the institutional review board of the participating institution and was conducted in accordance with the Declaration of Helsinki. A waiver of consent was granted for the retrospective review of existing medical records; oral informed consent was obtained and documented at the time of the telephone interview.

2.2. Study Population

We screened the records of approximately 500 patients with β‐thalassaemia followed at the centre between January 2022 and March 2025 and identified 12 with leg ulcers. The proportion of patients with leg ulcers identified in this cohort reflects an institutional case frequency rather than a population‐based prevalence estimate.

2.3. Inclusion and Exclusion Criteria

Eligible patients were adults (> 18 years) with β‐thalassaemia and a documented leg ulcer. Patients with α‐thalassaemia or sickle cell disease and those younger than 18 years were excluded.

2.4. Transfusion‐Dependency Classification

Patients were classified as transfusion‐dependent (TDT) if they required regular, lifelong transfusions to maintain adequate haemoglobin and survival, and as non‐transfusion‐dependent (NTDT) if they did not require regular transfusions, receiving them only intermittently for specific indications. Classification followed the Thalassaemia International Federation (TIF) guidelines. For NTDT, this generally means patients who maintain a haemoglobin level of 7–10 g/dL without a regular transfusion regimen [18].

2.5. Data Collection

Data were collected by trained clinical researchers from electronic medical records and a structured telephone interview using a predefined set of variables. Collected variables included demographics, comorbidities, age at splenectomy, history of trauma, foetal haemoglobin (HbF), iron‐chelation type and dose, hydroxyurea use, haemoglobin and ferritin before and during the ulcer episode, number of ulcer episodes, ulcer dimensions, ulcer treatment, and resolution status. Hydroxyurea use was recorded when applicable and was not uniformly prescribed across the cohort. Ulcer dimensions were taken from routine clinical measurements documented by the treating physician during patient visits. Patients with documented comorbidities were receiving standard‐of‐care treatment for those conditions at the time of ulcer assessment, and concomitant medications remained stable during the ulcer episode.

2.6. Phone Interview and Clinical Assessment

The telephone interview supplemented the chart data for variables not consistently captured in the record, using the same predefined variable list for every patient. A formally validated questionnaire was not used.

2.7. Outcome Definitions

Ulcer resolution was defined clinically as complete epithelialisation with no active drainage and no requirement for ongoing wound‐directed therapy, as documented in follow‐up clinical assessments.

2.8. Statistical Analysis

Continuous variables were reported as median (range), except age, which was reported as mean ± standard deviation. Categorical associations between thalassaemia subtype (TDT vs. NTDT) and trauma history, ulcer resolution, ferritin category < 1000 ng/mL versus ≥ 1000 ng/mL, and HbF category < 50% versus ≥ 50% were assessed with Fisher's exact test. Given the small sample size and descriptive design, no multivariable adjustment was performed. Analyses used IBM SPSS Statistics v29.0.2.0; a two‐sided p < 0.05 was considered significant.

3. Results

This study analysed 12 beta‐thalassaemia patients who developed leg ulcers, of whom seven patients were TDT and five were NTDT. Patient and ulcer characteristics are summarised in Tables 1 and 2, respectively.

TABLE 1.

Baseline demographic, clinical, and laboratory characteristics of transfusion‐dependent and non‐transfusion‐dependent β‐thalassaemia patients with leg ulcers (N = 12).

Patient	Group	Age (years)	Sex	Trauma	Comorbidities	Splenectomy age (years)	HbF (%)	Chelation	Hb before (g/dL)	Hb during (g/dL)	Ferritin before (ng/mL)	Ferritin during (ng/mL)
1	TDT	32	Male	Yes	None	17	91.2	DFO 500 mg, 6 tabs daily	7.0	7.0	1939	2136
2	TDT	26	Male	Yes	None	16	61.2	DFO 360 mg, 4 tabs daily	9.1	9.1	1107	899
3	TDT	36	Male	No	None	16	16.3	DFO 360 mg, 4 tabs daily	7.0	7.0	1450	1226
4	TDT	28	Male	No	DM	13	52.1	DFO 500 mg, 4 tabs daily	—	8.2	947	951
5	TDT	24	Male	Yes	None	7	89.0	DFO 500 mg, 4 tabs daily	8.5	11.0	2803	3891
6	TDT	25	Male	Yes	None	1	29.6	DFO 360 mg, 6 tabs daily	8.0	8.3	690	1740
7	TDT	52	Female	No	DM, osteoporosis, atrial fibrillation	11	98.0	DFX	8.1	8.5	1759	2003
TDT—Median (range)/n (%)		28 (24–52)	86% male	57% yes	Common: DM	13	61.2 (16.3–98.0)	Mostly DFO 360–500 mg daily	8.0 (7.0–9.1)	8.3 (7.0–11.0)	1450 (690–2803)	1740 (899–3891)
TDT—Mean ± SD (age)		31.9 ± 9.8
8	NTDT	48	Male	No	Pulmonary hypertension, cardiomegaly	7	16.3	DFO 500 mg, 7 tabs daily	7.0	7.3	719	955
9	NTDT	46	Female	No	Osteoporosis, hyperuricemia	7	70.8	DFO 500 mg, 4 tabs daily	7.0	6.2	619	811
10	NTDT	49	Male	Yes	N/A	N/A	98.8	N/A	9.0	8.0	745	553
11	NTDT	30	Male	No	N/A	23	28.9	N/A	—	7.7	245	686
12	NTDT	47	Male	No	DM	9	84.1	DFO 1250 mg every 4 months	10.0	10.3	1237	1436
NTDT—Median (range)/n (%)		47 (30–49)	80% male	20% yes	Common: osteoporosis, cardiomegaly	7	70.8 (16.3–98.8)	Occasional DFO or none	8.0 (7.0–10.0)	7.7 (6.2–10.3)	719 (245–1237)	811 (553–1436)
NTDT—Mean ± SD (age)		44.0 ± 7.9

Note: Age denotes current age at assessment (years) and is summarised as both median (range) and mean ± SD; all other continuous variables are median (range). Sex is shown as number of male patients (%). Haemoglobin (Hb) and ferritin are shown before and during the ulcer episode. Missing data are indicated by “—”.

Abbreviations: TDT, transfusion‐dependent thalassaemia; NTDT, non‐transfusion‐dependent thalassaemia; HbF, foetal haemoglobin; DM, diabetes mellitus; DFO, deferoxamine; DFX, deferasirox; N/A, not applicable (patient not splenectomised/not chelated).

TABLE 2.

Ulcer episodes, dimensions, treatments, and healing outcomes in transfusion‐dependent and non‐transfusion‐dependent β‐thalassaemia patients (N = 12).

Patient	Ulcer episodes (n)	Ulcer size (cm, length × width)	Treatment	Healed
1	1	8.0 × 0.5	Transfusion, topical antibiotics, honey‐based ointment	Yes
2	3	3.0 × 1.0	Skin graft, synthetic skin replacement, antibiotics	Yes
3	1	1.0 × 1.0	Surgical procedure, antibiotics	Yes
4	3	1.5 × 1.0	Honey‐based ointment, biopsy, transfusion	No
5	1	2.5 × 1.0	Transfusion, oral antibiotics	Yes
6	1	4.0 × 0.5	Topical antibiotics, honey‐based ointment	No
7	2	4.0 × 2.0	Transfusion, ointments, topical antibiotics	Yes
TDT—Median (range)/n (%)	1.0 (1–3)	Area 2.5 (1.0–8.0) cm 2	Most common: transfusion, topical antibiotics, honey‐based ointment	5/7 (71.4%)
TDT—Mean ± SD	1.7 ± 1.0	Area 3.1 ± 2.4 cm 2
8	2	5.0 × 0.3	Diosmin/hesperidin tablets, topical zinc oxide	Yes
9	1	1.5 × 0.7	Transfusion, leg elevation, oral antibiotics	Yes
10	2	1.8 × 0.6	Diosmin/hesperidin tablets, antibiotics	Yes
11	3	2.0 × 1.57	Topical silver gel, oral antibiotics	Yes
12	3	1.0 × 0.5	IV antibiotics, transfusion, honey‐based ointment	No
NTDT—Median (range)/n (%)	2.0 (1–3)	area 1.08 (0.50–3.14) cm 2	Most common: transfusion, oral/topical antibiotics	4/5 (80.0%)
NTDT—Mean ± SD	2.2 ± 0.8	area 1.45 ± 1.01 cm 2

Note: Ulcer size is shown for each patient as length × width (cm) from clinically documented measurements; ulcer area was calculated as length × width (cm²) and is summarised per group as median (range) and mean ± SD. Episode counts are median (range) and mean ± SD. Healing is the number of patients healed/total (%).

Abbreviations: IV, intravenous; NTDT, non‐transfusion‐dependent thalassaemia; TDT, transfusion‐dependent thalassaemia.

3.1. For TDT Patients

Eighty‐six percent of TDT patients were male. The mean age at assessment was 31.9 ± 9.8 years (range: 24–52). All patients had undergone splenectomy. A traumatic event preceded ulcer development in 4 of 7 patients (57%). Comorbidities included diabetes mellitus, osteoporosis, and atrial fibrillation.

Median haemoglobin was 8.0 g/dL (range: 7.0–9.1) before the ulcer episode and 8.3 g/dL (range: 7.0–11.0) during. Ferritin levels increased from a median of 1450 ng/mL (range: 690–2803) to 1740 ng/mL (range: 899–3891). HbF levels were highly variable, with a median of 61.2% (range: 16.3–98.0).

The number of ulcer episodes ranged from 1 to 3, with a median of 1.0 episode and a mean of 1.7 ± 1.0. Median ulcer area was 2.5 cm² (range: 1.0–8.0); mean: 3.1 ± 2.4 cm². Treatments most commonly included transfusion (TX), topical antibiotics (Abx), and honey‐based ointments, with less frequent use of oral antibiotics, biopsy, and surgical interventions. Healing was achieved in 5 of 7 patients (71.4%).

3.2. For NTDT Patients

Eighty percent of NTDT patients were male. The mean age at assessment was 44.0 ± 7.9 years (range: 30–49). Four patients (80%) had undergone splenectomy. A traumatic trigger was reported in one patient (20%). Comorbidities included osteoporosis, pulmonary hypertension, and cardiomegaly.

HbF levels ranged from 16.3% to 98.8%, with a median of 70.8% and a mean of 59.8% ± 32.4%. Median haemoglobin was 8.0 g/dL (range: 7.0–10.0) before the ulcer episode and 7.7 g/dL (range: 6.2–10.3) during. Ferritin increased from a median of 719 ng/mL (range: 245–1237) to 811 ng/mL (range: 553–1436).

The number of ulcer episodes ranged from 1 to 3, with a median of 2 episodes and a mean of 2.2 ± 0.8. The median ulcer area was 1.08 cm² (range: 0.50–3.14); mean: 1.45 ± 1.01 cm². Treatments included transfusion, oral and topical antibiotics, diosmin/hesperidin, topical zinc oxide, topical silver gel, and honey‐based ointments. Healing was achieved in 4 out of 5 patients (80%).

Statistical analysis using Fisher's exact test showed no significant associations between thalassaemia subtype (TDT vs. NTDT) and key clinical features including ulcer healing status (p = 1.000), history of trauma (p = 0.524), HbF category (p = 1.000), and ferritin category (p = 0.524). While not statistically significant due to the small sample size, these comparisons helped highlight trends explored in the discussion.

4. Literature Review and Discussion

In this series, leg ulcers were not confined to NTDT patients: seven of 12 patients were transfusion‐dependent, and their ulcers tended to be larger, associated with higher ferritin and more severe anaemia, and less likely to heal completely than those in NTDT patients, who developed ulcers later in life and had more frequent but generally smaller lesions. These differences are consistent with the interplay of transfusion dependency, iron overload, chronic haemolysis, a hypercoagulable state, and genetic modifiers [19], and suggest that ulcer risk is not limited to the traditionally recognised NTDT phenotype. Because the groups differ across several correlated features and the sample is small, these observations are descriptive and hypothesis‐generating. NTDT patients developed ulcers later in life, reported more frequent episodes, and showed a slightly higher healing rate despite receiving fewer transfusions. In contrast, TDT patients demonstrated deeper ulcers, more severe anaemia, higher iron overload, and greater need for multimodal wound care. These observations suggest differing underlying mechanisms and clinical trajectories between the two groups that may warrant tailored therapeutic strategies.

4.1. Exacerbating Factors for Leg Ulcers in Thalassaemia

4.1.1. Age and Trauma

In our cohort, transfusion‐dependent patients were younger than non‐transfusion‐dependent patients, consistent with prior reports that leg ulcers in non‐transfusion‐dependent disease tend to be a later complication, driven by chronic anaemia and long‐standing microvascular damage [20, 21]. This susceptibility likely reflects age‐related decline in skin and vascular integrity together with chronic anaemia‐induced tissue hypoxia. Reduced oxygen delivery compromises the cutaneous barrier, allowing ulcers to develop in response to minimal trauma [18]. A preceding traumatic event was reported more often in TDT patients. This may be attributable to the combination of younger age, increased activity, and a more ischemic, transfusion‐dependent skin environment. These observations support the need for tailored preventive strategies, including patient education and close skin surveillance based on the thalassaemia subtype.

4.1.2. Chronic Anaemia and Hypoxia

This low level of haemoglobin influences tissue oxygenation and wound healing, with lower levels possibly contributing to slower healing in TDT compared to NTDT. This hypoxic microenvironment weakens the skin barrier and delays ulcer healing despite regular transfusions. While NTDT patients typically have relatively higher haemoglobin levels, their red blood cell mass remains functionally inadequate due to ineffective erythropoiesis, resulting in ongoing tissue hypoxia and oxidative stress. Notably, a haemoglobin level above 10 g/dL has been identified as a protective factor against leg ulcer development in untreated NTDT patients, with those maintaining lower haemoglobin levels facing a significantly higher risk of complications, including leg ulceration, compared to individuals with higher baseline haemoglobin levels [22, 23]. These mechanisms highlight the importance of both absolute haemoglobin levels and red cell functionality in maintaining skin integrity and promoting wound repair.

4.1.3. Irregular Blood Transfusions

It is important to note that in our region, TDT patients often experience persistently low haemoglobin levels due to irregular transfusion schedules. These inconsistencies, driven by blood shortages, limited access, and supply issues, mean that transfusions are administered based on availability rather than on guidelines. In chronically transfused thalassaemia, alloimmunisation is a recognised complication and may further contribute to transfusion delays and difficulty maintaining target haemoglobin levels. Alloimmunisation was not systematically captured in this retrospective cohort, and its association with ulcer risk could not be evaluated. All TDT patients were on daily chelation, yet iron levels were still elevated, which suggests suboptimal chelation efficacy or compliance. This practice may exacerbate anaemia‐driven tissue damage and iron accumulation, creating a cycle of ulcer persistence. Therefore, chronic under‐transfusion and noncompliance exacerbate anaemia, compromises tissue oxygenation, and increases the risk of leg ulcer development.

4.1.4. Iron Overload

Iron overload is also relevant to leg ulcer development. One important study suggested that iron overload has a role in the pathophysiology of ulcers through the production of oxidative stress, as well as a factor exacerbating the chronicity of the ulcer [19]. Chronic transfusions in TDT patients exhibited severe iron overload while NTDT patients had a milder iron burden. Interestingly, both groups experienced higher ferritin levels during ulcer episodes, confirming the role of iron overload. Iron toxicity is clinically relevant at the organ level, particularly in the liver and heart, and is best assessed using MRI‐based techniques (e.g., hepatic and cardiac T2), as serum ferritin may not reliably reflect tissue iron. MRI‐derived organ iron measurements were not consistently available in our cohort and therefore could not be incorporated into the analysis.

A plausible mechanism links iron burden to impaired healing. Excess labile iron can catalyse the generation of reactive oxygen species through Fenton‐type reactions, and sustained oxidative stress has been implicated in tissue damage and in the failure of chronic wounds to progress beyond a prolonged inflammatory phase [24]. Iron accumulation and anaemia have also been associated with delayed healing in chronic leg ulcers of other aetiologies [25]. Because we characterised iron burden using serum ferritin and did not measure tissue iron within the wound or organ iron by MRI, these mechanisms are offered as biological context for the higher ferritin observed in the transfusion‐dependent group rather than as a demonstrated cause of the ulcers in our patients.

4.1.5. Splenectomy and Hypercoagulability

Additionally, splenectomy was prevalent in both groups. Splenectomised thalassaemia patients are known to be in a hypercoagulable state, increasing the risk for microvascular thrombosis and ulcer development [26, 27]. Mechanistically, this may stem from elevated platelet counts and reduced natural anticoagulants such as protein C and protein S [26, 28]. Although splenectomy preceded ulcer onset by several years in our cohort, splenectomy is thought to confer a sustained prothrombotic and vasculopathic milieu that may contribute to microvascular complications over time. Given our retrospective design and small sample size, we cannot infer a temporal or causal relationship between splenectomy timing and ulcer onset.

4.1.6. Endothelial Dysfunction

Chronic haemolysis in thalassaemia releases cell‐free haemoglobin, which scavenges nitric oxide (NO), a critical vasodilator and endothelial protector. The resultant NO depletion exacerbates endothelial dysfunction, microvascular ischemia, and ulcer persistence, particularly in TDT patients with lower baseline haemoglobin [29] This mechanism aligns with our observation of larger, deeper ulcers in TDT. NO dysregulation has also been described in thalassaemia syndromes, with evidence supporting reduced NO bioavailability and haemolysis‐related NO scavenging as contributors to endothelial dysfunction and vascular complications. Emerging mechanistic work further supports impaired endothelial NO signalling in splenectomised β‐thalassaemia cohorts [30].

4.1.7. Comorbidities

While comorbidities such as diabetes mellitus, osteoporosis, pulmonary hypertension, and cardiomegaly were seen in both groups, each potentially impacting wound healing, NTDT patients experienced a slightly higher recurrence of ulcers. Increased venous pressure is also an impeding factor for ulcer development. Patients who underwent splenectomy have high pulmonary pressure, which can lead to right‐sided heart failure. Consequently, lower limb oedema and venous stasis develop [31]. However, one should not confuse venous ulcers and leg ulcers due to thalassaemia, as these present with distinct characteristic features and presentation. It is important to differentiate leg ulcers occurring in the setting of beta Thalassaemia from other aetiologies of chronic leg ulcers, including venous, arterial, and neuropathic ulcers, among others, given their distinct clinical features and pathogenesis [19].

4.2. Protective Factors and Management of Leg Ulcers in Thalassaemia

HbF levels emerged as a potential protective factor, with NTDT patients showing higher median HbF. Elevated HbF may mitigate haemolysis and oxidative stress, offsetting the risks of chronic anaemia in NTDT [8, 13]. In one important study, a bivariate correlation between HbF level and the presence of leg ulcers showed a statistically significant association (p = 0.002) [32]. The protective effect of HbF reinforces its potential as a therapeutic target. NTDT patients achieved better resolution rates (80%), potentially attributable to reduced iron toxicity and higher HbF levels.

Other, protective factors have been noted. Hydroxyurea therapy, which increases HbF and improves microvascular function, has demonstrated benefit in NTDT patients with chronic ulcers unresponsive to standard care [13, 32, 33]. Regular transfusions also offer a protective effect by improving haemoglobin levels and tissue oxygenation, although standardised protocols for ulcer prevention are lacking [21]. Additionally, platelet‐rich plasma (PRP) therapy has shown promise in isolated cases, promoting ulcer healing through growth factor delivery [34]. Supportive measures, including topical antimicrobial therapy, wound dressings selected according to exudate level to maintain moisture balance and avoid periwound maceration, and leg elevation, have also been reported to aid healing [19]. Ulcers requiring more advanced management were treated with surgical procedures or topical silver gel consistent with use in more severe or refractory cases. These findings highlight the potential effectiveness of early, accessible treatments and the need for individualised care based on ulcer severity and patient‐specific factors. Figure 1 summarises the key pathogenic contributors, shared risk factors, and protective strategies for leg ulcers in TDT and NTDT patients as observed in our cohort.

FIGURE 1.

Conceptual summary of factors associated with leg ulcers in β‐thalassaemia, as observed in this cohort and reported in the literature. Left: Features more prominent in non‐transfusion‐dependent (NTDT) patients (older age, vascular comorbidities, chronic anaemia, more frequent recurrence). Right: Features more prominent in transfusion‐dependent (TDT) patients (younger age, preceding trauma, more severe anaemia, higher iron burden). Center: Factors shared by both groups (splenectomy, chronic haemolysis, iron overload, hypercoagulable state). Bottom: Supportive and potentially protective measures (higher foetal haemoglobin [HbF], hydroxyurea, regular transfusion, and local wound care). The figure is a conceptual synthesis, not a quantitative result. TDT, transfusion‐dependent thalassaemia; NTDT, non‐transfusion‐dependent thalassaemia; HbF, foetal haemoglobin.

The observed differences between transfusion‐dependent and non‐transfusion‐dependent patients should be interpreted within the context of transfusion dependency as a composite clinical phenotype rather than a single variable. Transfusion status encompasses multiple interrelated factors, including anaemia severity, iron overload, splenectomy status, age, and vascular dysfunction, all of which are relevant to leg ulcer development. Given the small sample size and descriptive design, formal adjustment for confounders was not performed, and findings should be considered hypothesis‐generating.

Taken together, these observations suggest a stratified management approach: TDT patients, with higher iron burden and more severe ulcer dimensions, may benefit from intensified chelation and HbF‐enhancing strategies such as hydroxyurea. NTDT patients, who tended to be older and had more vascular comorbidities, might benefit from closer cardiopulmonary monitoring and supportive oral therapies aimed at preserving microvascular health and reducing recurrence. Furthermore, addressing regional disparities in transfusion access, particularly for TDT patients, may further reduce ulcer burden in resource‐limited settings where standard transfusion protocols are not always consistently followed.

Limitations of this study include the small sample size (n = 12), single‐centre setting, and retrospective design, which may limit the generalisability of results. Part of the clinical information was obtained through structured telephone interviews that relied on a predefined set of variables rather than a formally validated questionnaire; this approach is subject to recall bias and to variation in how information is captured, and some historical details could not be independently confirmed. In addition, liver and cardiac iron were not assessed by MRI‐based techniques in this cohort, so iron burden could be characterised only by serum ferritin, which does not reliably reflect tissue iron. While our findings did not reach statistical significance due to the small sample size, the observed differences in ulcer frequency, size, and healing outcomes between TDT and NTDT patients highlight clinically relevant patterns that merit further prospective investigation. The limited statistical power likely contributed to non‐significant results; however, consistent trends across variables such as ferritin, HbF, and trauma suggest meaningful biological contributions that warrant validation in larger, multi‐centre cohorts. Future prospective studies are warranted to further evaluate the protective role of HbF and define standardised management approaches tailored to TDT patients at risk of ulceration.

5. Conclusion

In this small retrospective series, clinically relevant leg ulcers occurred in both transfusion‐dependent and non‐transfusion‐dependent β‐thalassaemia patients, with larger and slower‐healing ulcers and higher ferritin in the TDT group. These findings suggest that ulcer surveillance and preventive wound care should extend to transfusion‐dependent patients and not be reserved for NTDT. Early intervention, including appropriate wound care and optimised transfusion and chelation, may reduce ulcer severity and recurrence. Given the sample size and descriptive design, these observations require confirmation in larger, prospective, multi‐centre studies before firm management recommendations can be made.

Funding

The authors have nothing to report.

Ethics Statement

This study was approved by the Institutional Review Board of the American University of Beirut (protocol ID: BIO‐2024‐0502) and by the Chronic Care Center, and all methods were carried out in accordance with the Declaration of Helsinki.

Consent

Oral informed consent was obtained.

Conflicts of Interest

Ali Taher reports receiving consultancy fees and research funding from Roche, Agios Pharmaceuticals, Novo Nordisk, Bristol Myers Squibb, and Pharmacosmos. The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.