End-of-Life Care in Sickle Cell Disease and Transfusion-Dependent β-Thalassemia: Clinical, Psychosocial, and Ethical Considerations


Sophia Delicou¹, Katerina Xydaki¹, Maria Moraki¹ and Theodoros Aforozis².





1 Thalassaemia and Sickle Cell Unit, Expertise Center of Hemoglobinopathies and Their Complications, Hippokrateio General Hospital of Athens, 114 Vas. Sofias Ave, Athens, Greece.
2 Psychiatric Outpatient Department, Hippokrateio General Hospital of Athens, 114 Vas. Sofias Ave, Athens, Greece




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Correspondence to: Dr. Sophia Delicou. E-mail: sophiadelicou@hippocratio.gr  
Published: January 01, 2026
Received: August 17, 2025
Accepted: December 21, 2025
Mediterr J Hematol Infect Dis 2026, 18(1): e2026015 DOI 10.4084/MJHID.2026.015

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Sickle cell disease (SCD) and transfusion-dependent β-thalassemia are no longer pediatric death sentences. With newborn screening, transfusions, and chelation therapy, patients now survive into their 4th-6th decade. Yet as they age, they face mounting complications -pain that never truly resolves, organs failing one by one, and profound isolation. Ironically, palliative care remains scarce despite the clinical complexity. This narrative review examines end-of-life care in these hemoglobinopathies, focusing on pain management, ethical tensions, and the psychosocial needs that intensify as death approaches. We reviewed literature from 2020 to 2025, international guidelines, and European frameworks. The evidence is clear: terminal SCD involves unpredictable crises and intractable pain; β-thalassemia brings slow cardiac decline and iron-laden organ failure. Both demand early palliative integration, yet both are drastically undertreated. Cultural beliefs heavily shape how families accept or reject end-of-life discussions. Disparities in opioid access, lack of disease-specific referral criteria, and absence of flexible hospice models create barriers that disproportionately harm marginalized patients. We conclude that hemoglobinopathy patients deserve the same anticipatory, culturally informed, multidisciplinary palliative care that we increasingly offer to cancer patients. Health systems must establish referral pathways specific to these diseases, permit palliative transfusions in hospice when appropriate, ensure equitable opioid access, and embed psychosocial support in hemoglobinopathy centers.

Introduction

Sickle cell disease and transfusion-dependent β-thalassemia represent a striking paradox in modern hematology. Both have evolved from rapidly fatal childhood illnesses to chronic conditions compatible with adult life, yet patients now die of complications their predecessors never lived to see. In high-income countries, improvements in transfusion medicine, iron chelation, hydroxyurea therapy, and screening have pushed median survival into the 4th-6th decades - a remarkable achievement that masks a sobering reality: these extended years are often filled with pain, organ failure, and inadequate symptom management.[3] Meanwhile, in sub-Saharan Africa and resource-poor regions,[1,2] many children still do not survive early childhood due to a lack of basic diagnosis and transfusion support.[4] This disparity is not merely statistical; it reflects how the global trajectory of hemoglobinopathy care bifurcates based on geography and resources.
The clinical reality for aging SCD and thalassemia patients is sobering. Progressive organ damage, chronic pain, and endocrine dysfunction make both disorders profoundly morbid.[3] Yet palliative and hospice services remain criminally underutilized. A 2022 analysis of inpatient data in the U.S. found that less than 0.5% of hospital admissions for SCD patients involved a palliative care consultation, despite the clinical complexity inherent in these diseases.[4] Greek clinicians in a 2023 survey reported limited formal training in end-of-life communication and symptom management, translating into delayed referrals to palliative specialists and fragmented care across the disease trajectory.[5] The consequence is tangible: patients endure prolonged suffering, undergo unnecessary intensive interventions, and die in settings misaligned with their preferences. Why does this happen? Several factors converge: physicians struggle to prognosticate non-malignant diseases; opioid access remains restricted in many regions; cultural beliefs complicate discussions of withdrawal of treatment; and there simply are no disease-specific pathways guiding when and how to refer a thalassemia or SCD patient to hospice.
International hematology and palliative care organizations have begun to acknowledge this gap.[6] Early palliative care - not waiting for terminal decline - can improve pain control, quality of life, symptom management, and patient coping.[6] The evidence now suggests that palliative care should be offered alongside disease-directed therapy, not as a substitute when curative options are exhausted. This narrative review synthesizes literature from 2020 to 2025, international guidelines, and clinical expert consensus to outline how hemoglobinopathy patients can receive comprehensive end-of-life care grounded in clinical evidence, ethical reasoning, and cultural sensitivity. We address clinical manifestations at end-stage, psychosocial support needs, moral dilemmas, and practical referral pathways.

Clinical Manifestations and Disease Progression at End-Stage

SCD and β-thalassemia end-stage presentations could hardly be more different, yet both are devastating (Table 1). SCD is capricious. Patients experience sudden, life-threatening crises punctuated by periods of relative stability, making it nearly impossible to predict when the final decline will come.
Table 1
Table 1. End-Stage Clinical Features Comparing SCD and β-Thalassemia.
In advanced SCD, chronic pain dominates. Unlike acute pain crises, which are episodic, chronic pain from repeated vaso-occlusions-causing avascular necrosis, joint destruction, and non-healing leg ulcers becomes the patient's constant companion. Opioid tolerance develops over years, and patients may require extraordinary doses just to achieve partial relief.[7] Acute chest syndrome, pulmonary hypertension, and cardiac arrhythmias lurk in the background. Silent strokes and overt strokes erode cognition and motor function. Progressive chronic kidney disease, often overlooked until it is severe, compounds morbidity. Hepatic dysfunction emerges from transfusion-related iron overload or hepatitis C acquired from older blood supplies. Functional asplenia renders patients vulnerable to fulminant infections and sepsis.[7-11] These complications rarely announce themselves in an orderly sequence; instead, they accumulate in unpredictable ways, making the prognosis frustratingly elusive.
β-thalassemia is more predictable: a slow, relentless accumulation of iron in the heart and liver, year after year of transfusions and chelation, until cardiac restrictive cardiomyopathy or cirrhosis becomes terminal, but its trajectory is more insidious.[12] Cardiac complications account for major mortality in thalassemia cohorts.[11] Despite three decades of iron chelation therapy, many patients accumulate myocardial iron over decades, resulting in restrictive cardiomyopathy and life-threatening ventricular arrhythmias.[11] Hepatic cirrhosis, particularly in patients with chronic hepatitis C, becomes a major source of morbidity and mortality. Endocrine complications, such as hypogonadism, diabetes, hypothyroidism, and adrenal insufficiency, weaken immune function and physiological reserve. Osteoporosis from iron overload, hypogonadism, and chronic transfusion causes chronic pain and fragility fractures. Splenectomy, performed in some patients for transfusion dependence reduction, paradoxically increases infection risk.[12-15] A recent Greek study tracking 2,475 thalassemia and SCD patients over 12 years found that hepatocellular carcinoma (17.5%), sepsis (11.5%), and heart failure (21.8%) dominated thalassemia mortality; while sepsis (14.9%), hepatic failure (13.9%), and stroke (13.6%) were most common in SCD.[16]

Psychosocial and Spiritual Dimensions of End-of-Life Care

 Ask an SCD patient about their suffering, and they will tell you about more than pain. They talk about lost opportunities. The hospital stays that derailed their education. The job they couldn't keep because of unpredictable crises. The relationships that didn't survive the demands of chronic illness. As terminal illness approaches, these accumulated losses crystallize into existential despair. Depression and anxiety are common; post-traumatic stress symptoms emerge in patients who have endured decades of medical crises.[11,17-19] The stigma surrounding pain management, the accusation that they seek opioids for their own purposes rather than for legitimate relief, leaves deep psychological scars and erodes trust in healthcare providers.[2,17-19]
For thalassemia patients, the psychological burden is different but equally profound. Lifelong medical dependence, visible body changes from iron overload, and the knowledge that their life expectancy has always been limited create a particular kind of existential weight. Many express guilt about the burden they place on families. Some grieve about the possibility of never having children or raising them. Discrimination in employment and education narrows opportunities, deepening hopelessness.[20,21] Clinical social workers, psychologists, and peer support groups have demonstrated value in reducing isolation and restoring dignity. Spiritual and religious frameworks matter enormously. Some patients find profound meaning in prayer or meditation; others find it in serving their communities. Palliative teams must respect these frameworks and, when possible, facilitate connection with spiritual advisors who understand both their faith traditions and their medical reality.[20,21]
The Council of Europe has explicitly stated that people with life-limiting conditions deserve access to mental health services and family-centered psychosocial support throughout their illness.[22] This is not a luxury; it is a human right. Yet in practice, psychiatrists and psychologists are rarely embedded in hemoglobinopathy centers. Families are often left to navigate existential questions on their own.

Multidisciplinary Palliative Care: Why It Matters

Comprehensive end-of-life care for patients with hemoglobinopathies cannot be delivered by a single physician. SCD demands hematologists who understand the disease, palliative care specialists who excel at symptom control, pain management experts for opioid-tolerant patients, cardiologists, nephrologists, hepatologists, psychiatrists, psychologists, and social workers.[23] β-thalassemia requires similar breadth: cardiologists because cardiac failure dominates; hepatologists because cirrhosis is common; endocrinologists because multiple gland dysfunction is the rule.
The critical insight is that palliative care should not replace disease-directed care; it should complement it. A patient approaching end-of-life may still benefit from a transfusion, not to prolong life indefinitely, but to manage a painful complication or allow attendance at a family milestone. This "concurrent care" model, wherein palliative specialists and hematologists work alongside one another, has been shown to improve both symptom control and quality of life.[21,23] It also facilitates earlier, more authentic conversations about goals of care. In Europe, the ERN-EuroBloodNet network has begun promoting multidisciplinary care standards and sharing best practices across specialized centers.[24] Such coordination can reduce disparities and ensure that patients across different healthcare systems receive comparable quality of end-of-life support (Figure 1).
Figure 1
Figure 1. Global Hemoglobin-Opathy Care.
Early integration of palliative principles - not late integration - improves pain control, quality of life, coping, symptom self-management, and patient satisfaction.[25,26] Outpatient palliative clinics can initiate these conversations and begin symptom optimization months or years before terminal decline. This approach reduces crisis-driven emergency care and hospitalization. The evidence is strong; the barriers are organizational and cultural.


Ethical and Cultural Complexities at End-of-Life

End-of-life decisions for patients with hemoglobinopathy are never purely medical. Patients from African American, Afro-Caribbean, Middle Eastern, South Asian, and Mediterranean communities bring deep cultural and religious frameworks that shape how they understand illness, treatment, and death. Some patients prefer personal autonomy in decision-making; others defer to family or religious elders. Clinicians must navigate this diversity thoughtfully, as some ethicists call it, "negotiated autonomy", exploring what information patients want, how much control they desire, and what role family should play.[27,28]
Emerging gene therapies and HSCT add ethical complexity. When should a desperately ill patient with severe end-organ damage be offered a high-risk curative intervention? Denying it might feel like abandonment; offering it might constitute harm. The answer lies in transparent dialogue grounded in bioethical consultation. The principle of non-maleficence ("do no harm") must be weighed against respect for autonomy and hope.[29-31]
De-escalation or withdrawal of transfusions in thalassemia, or of mechanical ventilation in severe acute chest syndrome, raises profound questions about what constitutes "giving up". In reality, these decisions reflect a compassionate shift from prolonging life to permitting death with dignity and minimal suffering. Yet families shaped by historical trauma and systemic racism often interpret withdrawal of care as rejection. Effective communication demands professional medical interpretation when needed, genuine respect for cultural values, and collaboration with trusted community or religious leaders.[32-34]
The Council of Europe's Resolution 2249 (2018) explicitly recognizes access to pain relief and palliative care as fundamental human rights and calls for the removal of legal barriers to opioid access. In some regions, high-dose opioids raise ethical concerns. Yet, they are ethically defensible under the principle of "double effect" when the intent is symptom control, not hastening death, and when the dose is proportionate to the therapeutic goal. Meticulous documentation of clinical reasoning and dosing protects both patients and clinicians.


Referral Guidelines and Practical Implementation

Prognostication in patients with hemoglobinopathies is notoriously difficult. Unlike cancer, where predictable terminal decline is common, SCD can cause sudden death at nearly any time, and β-thalassemia's decline is gradual but variable. This unpredictability has led to late or missed palliative care referrals. The solution is to base referral criteria not solely on life expectancy estimates, but also on functional status and objective signs of end-organ failure.[16]
Specific referral triggers should include: (1) severe cardiomyopathy or pulmonary hypertension requiring continuous oxygen; (2) hepatic failure with synthetic dysfunction; (3) recurrent ICU admissions for vaso-occlusive crises, acute chest syndrome, or sepsis; (4) functional decline (Palliative Performance Scale <50% or ECOG ≥4); (5) cessation of meaningful benefit from disease-modifying therapy; or (6) explicit patient preference for comfort-focused care.[35] When any are present, palliative care consultation should be offered (Figure 2).
Figure 2
Figure 2. Initial assessment, referral criteria evaluation and final outcome.
A major structural barrier exists in the U.S.: Medicare hospice eligibility criteria are cancer-focused and poorly accommodate hemoglobinopathy patients. Physicians must carefully document specific clinical scenarios, e.g., "end-stage SCD with multiorgan dysfunction and intractable pain" or "β-thalassemia with severe cardiac iron overload and ventricular arrhythmias", to justify hospice eligibility. The proposed Hospice CARE Act would permit limited transfusions within hospice, removing a primary barrier to enrollment among transfusion-dependent patients.[36] Current regulations often force an impossible choice: enroll in hospice and forget transfusions or continue transfusions and delay hospice — a false dichotomy that results in late or missed referrals.
Early integration of outpatient palliative clinics is the antidote to abrupt, crisis-driven transitions. These clinics can support symptom management and advance care planning months in advance, while concurrent care models permit disease-modifying therapies to continue when used primarily for symptom relief.[37,38] Such integration bridges hematologic and palliative philosophies and promotes genuine long-term shared decision-making.
Structured, culturally sensitive conversations, especially during periods of clinical stability, should precede major deterioration. Discussions should occur at transitions (pediatric to adult care), after sentinel events (stroke, heart failure), and periodically thereafter. These repeated conversations align interventions with evolving priorities: returning home comfortably, attending important family events, or minimizing procedures. Data from England in 2022 reveal that only 4.7% of hemoglobinopathy patients died in hospice, while 56.6% died at home, suggesting systemic underutilization or inaccessibility of structured palliative services.[39] Institutions should track outcomes, place of death, adequacy of pain control, bereavement satisfaction, and implement quality improvements when gaps appear.
Countries including Italy, France, and Greece have pioneered integrated care models with multidisciplinary clinics, seamless transitions from pediatric to adult care, and embedded psychosocial support. These models deserve replication and study. A persistent obstacle is limited access to transfusions in home-hospice settings. Emerging evidence supports flexible hospice models that permit palliative transfusions when they improve comfort, without artificially prolonging life.[40] As disease-specific hospice guidelines evolve, core principles are clear: early referral, functional and clinical criteria (not just life expectancy), flexibility in protocols, and genuinely holistic, culturally grounded care ensure dignified, patient-centered end-of-life experiences.

Conclusions and Future Directions

Sickle cell disease and transfusion-dependent β-thalassemia are no longer death sentences in childhood; they are chronic illnesses that demand lifelong engagement with healthcare systems and carry substantial morbidity even with optimal disease-modifying therapy. As these patients age and approach end-of-life, they merit the same high-quality, anticipatory, multidisciplinary, and culturally informed palliative care that we have come to expect for cancer patients. Yet the evidence shows they do not receive it. Palliative services remain fragmented, referrals are delayed or absent, opioid access is restricted, and few healthcare systems have established disease-specific end-of-life pathways. This is not an insurmountable problem but a care-delivery gap that can be closed through deliberate health system redesign. Healthcare organizations must develop explicit, disease-specific referral criteria and pathways for patients with hemoglobinopathies. Flexible hospice models should be implemented, permitting palliative transfusions and other disease-specific therapies when they meaningfully improve comfort. Equitable access to opioids and other analgesics must be ensured, particularly in resource-limited regions where opioid availability remains catastrophically low. Psychosocial and spiritual support must be systematically embedded within hemoglobinopathy centers rather than added as an afterthought. Hematology trainees require formal education in end-of-life communication, symptom management for opioid-tolerant patients, and cultural humility. Finally, patients and families need disease-specific education about palliative care and hospice, correcting persistent misconceptions that these services equate to abandonment. The evidence is available; the clinical pathway is clear. What remains is the will to implement it.

Author Contributions

All authors made substantial contributions to the conception and design of the review, the acquisition, analysis, and interpretation of the literature, and the drafting and critical revision of the manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work, ensuring its accuracy and integrity.


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