Sophia Delicou

Background: Acute pain transfusion reaction (APTR) is a rare, under‐recognized condition of unknown etiology. It can cause significant distress in recipients, necessitating symptomatic management and, occasionally, hospitalization. Study Design and Methods: Here, we present an APTR event in an adult subject with transfusion‐dependent thalassemia (TDT). Patient and returned red blood cell (RBC) unit samples from this one, and additionally from preceding and subsequent transfusions, were compared with patient and unit reference groups, matched for genetic profile and storage duration, respectively, using laboratory, morphological, and multi‐omics approaches. Results: The patient had a pre‐transfusion hemoglobin concentration of 10.7 g/dL and evidence of coagulation and fibrinolysis. Following APTR, the patient RBCs showed acute oxidative stress, increased adhesiveness, phosphatidylserine exposure, and membrane‐specific proteostatic failure. Multi‐omics analyses revealed overexpression of biological response modifiers, like gamma‐aminobutyric acid derivatives, RANTES/DARC, and ongoing ephrin‐B reverse signaling. The implicated RBC unit displayed advanced storage lesions with overexpression of ophthalmate and STEAP3, among others, metabolic aging not matching its “chronological age”, and differential expression of potential immune mediators and neuromodulators. Functional enrichment analysis linked the differential proteome profile of the unit with RBC dysfunction and neuropathy. APTR‐related pathologies showed only partial resolution over a two‐week period, indicating sustained disturbances in proteostasis and hypercoagulability, as evidenced, among other markers, by thrombospondin binding to patient RBCs. Discussion: This study identified a series of patient and RBC unit stress markers and conditions potentially linked to APTR. These hypothesis‐generating variables and molecular signatures may facilitate prospective evaluation and mechanistic investigation of suspected APTR cases.

1. For patients with TDT, red cell transfusion is lifesaving but intrinsically iron-loading: humans have no regulated pathway for excreting excess iron, so transfusional iron accumulates unless rem...

Background: Delayed diagnosis of haemoglobinopathy in adulthood is a recognised but incompletely characterised clinical problem, particularly in populations with high carrier prevalence. Adults with thalassaemia syndromes and haemoglobin variants are frequently misclassified as having iron deficiency or other common causes of microcytic anaemia, leading to prolonged diagnostic uncertainty, inappropriate iron supplementation and deferred access to genetic counselling and disease‐specific management. The present exploratory study aimed to characterise diagnostic trajectories and candidate clinical cues associated with delayed recognition in a small single‐centre cohort. Methods: This was a retrospective, descriptive, single‐centre pilot study of 19 adults who received a confirmed haemoglobinopathy diagnosis after a prolonged diagnostic delay, defined as a documented interval of ≥ 12 months between the first recorded abnormal haematological finding or symptom onset and the final confirmed diagnosis. We extracted clinical presentation, laboratory parameters, diagnostic pathway and retrospectively identified candidate clinical cues. Data are reported descriptively. As a secondary, hypothesis‐generating exercise, we describe the components and cohort‐level distribution of a preliminary clinical suspicion framework—the Haemoglobinopathy Suspicion Score (HSS) derived from the recurrent features observed in this dataset. No external comparator group was available; all analyses are descriptive and exploratory only. Results: Median age at diagnosis was 39.0 years (IQR 31.0–53.5); five patients (26.3%) were diagnosed at age ≥ 54 years. The cohort was predominantly of Greek origin (18/19, 94.7%) with combined α/β phenotypes predominating (12/19, 63.2%). Recurring descriptive features within this small cohort included a combined microcytosis–hemolysis laboratory profile: median MCV was 63.6 fL (IQR 61.8–67.6), ferritin 201 ng/mL (IQR 89.6–283.9) and total bilirubin 1.8 mg/dL (IQR 1.1–2.3). Persistence of microcytic anaemia despite documented iron supplementation was retrospectively identified in 12/19 patients (63.2%; exact 95% CI 38.4%–83.7%). Iron deficiency anaemia was the initial misdiagnosis in 6/19 patients (31.6%). Patients consulted a median of 2.0 specialties (IQR 1.0–2.5) before a correct diagnosis was established. Applying HSS components retrospectively, a score of ≥ 3 was present in 18/19 patients (94.7%); this observation is descriptive only and cannot be interpreted as diagnostic performance in the absence of a comparator population. Conclusions: This exploratory single‐Centre pilot study identifies recurring descriptive features associated with diagnostic delay in a small cohort of adults with haemoglobinopathy. The proposed HSS is a preliminary, hypothesis‐generating clinical suspicion framework and has not been validated for clinical use. Larger, prospective, multicentric studies with appropriate comparator populations are required to derive and formally validate any bedside suspicion tool for this setting.

Summary: Omics technologies have transformed research in haemoglobinopathies, yet the proteome of RBCs remains largely unexplored in transfusion‐dependent thalassaemia (TDT). In this proteomic analysis, Red blood cell (RBC) membranes from 48 adults with TDT were compared with healthy controls. The resulting profile, corresponding to patient and donor RBCs, captured disease‐linked features and exposure to donor blood. Certain differentially expressed proteins were plasma‐absorbed or remnants of erythroid precursors, recapitulating findings in non‐transfusion‐dependent thalassaemia. Structural proteins were overexpressed en bloc, especially in severe haemoglobin subunit beta ( HBB ) mutations, though higher transfusion doses attenuate these abnormalities. Other changes suggested impaired volume regulation, increased RBC adhesion and features not included in storage lesions, like downregulation of galectin‐3 and septins (identified in TDT for the first time), which were modulated by genetic‐ and transfusion‐related variables. JAM‐A, an endothelium inflammation marker, was significantly related to heart T2*. Splenectomy correlated with oxidative, coagulative and inflammatory patterns. The moderate and severe genotype groups had similar proteomic and cell morphology profiles compared to the mildest cases. Upregulation of ferroportin, ICAM4, eryptosis and circadian rhythm‐related proteins further characterized severe HBB genotypes. Transfusion dose effects varied across clinical groups. Overall, the RBC membrane emerges as both a target and a sensitive reporter of the complex pathophysiology underlying TDT.

TDT and SCD are hereditary hemoglobinopathies that require lifelong red blood cell transfusions. Modern treatment has increased survival, exposing patients to transfusion-related problems such iron excess. Despite this movement toward an elderly patient population, transfusion-dependent adult comorbidity data is scarce, especially in Greece. A retrospective, descriptive observational analysis of 105 adult transfusion-dependent patients (92 with TDT and 13 with SCD) followed at a Greek tertiary hemoglobinopathy center in 2024 was conducted. Organ system-specific chronic comorbidities were identified from medical records. Multimorbidity distribution and comorbidity category frequencies and proportions were estimated. Mean ages were determined by comorbidity burden (≥2, ≥3, and ≥4 conditions). Means and standard deviations appear for continuous variables. Inferential analyses were avoided. All SCD patients and 84.8% of TDT patients had comorbidities. TDT most often affected other or miscellaneous illnesses (68.5%), musculoskeletal or metabolic problems (41.3%), endocrine disease (37.0%), and cardiovascular involvement (23.9%). All SCD patients had additional illnesses, 38.5% had cardiovascular problems, and 23.1% had endocrine and musculoskeletal/metabolic disorders. Multimorbidity was prevalent in both groups. Of TDT patients, 70.7% had ≥2 comorbidities, 52.2% had ≥3, and 41.3% had ≥4. SCD proportions were 92.3%, 84.6%, and 61.5%. Higher comorbidity counts were more commonly observed in older patients in both cohorts. Greek adult transfusion-dependent TDT and SCD patients have many chronic organ system comorbidities.Multimorbidity was more commonly observed in older patients, emphasizing the need for coordinated, multidisciplinary in this aging population.

Background. Thalassemia major and sickle cell disease now present as lifelong chronic conditions, with median survival extending into the 50s and 60s. This unprecedented shift transforms hemoglobinopathies from childhood emergencies into models of accelerated aging and cumulative multimorbidity, yet clinical literature remains pediatric-focused, leaving hematologists and internists unprepared for the functional and cognitive decline, vulnerability, and geriatric syndromes that characterize later life in these populations.Content. This review synthesizes evidence on the intersection of disease-driven pathology (anemia, hemolysis, vasculopathy), treatment burden (transfusion-related iron overload, chelation nephrotoxicity), and aging biology (weakness, indicators of aging, organ reserve depletion) in patients aged 45 years and older. We distinguish disease-specific priorities: thalassemia faces myocardial and hepatic iron deposition and endocrine failure, while sickle cell disease confronts cerebrovascular disease, chronic pain, and pulmonary complications. Critically, we reframe the clinical target from survival and organ-specific metrics to functional endpoints, disability prevention, cognitive health, and quality of life. A conceptual mapping links hemoglobinopathy mechanisms to established gerontology constructs (inflammaging, cellular senescence, vascular aging), revealing shared pathways between genetic disease and age-related decline.Conclusions. Three adjustments are necessary: (1) monitoring must detect treatable complications early rather than recording cumulative damage; (2) therapeutic decisions must weigh treatment acceptance, comorbidity burden, and life expectancy rather than defaulting to pediatric protocols; (3) care systems must embed palliative principles, shared decision-making, and multidisciplinary coordination into primary networks. Future research must prospectively characterize aging cohorts, test interventions to slow functional decline, and prioritize patient-reported outcomes and disability prevention alongside mortality.

Sickle cell disease (SCD) and transfusion-dependent β-thalassemia have transitioned from being mostly pediatric conditions to complicated, chronic disorders characterized by advancing multi-organ complications. The offering of end-of-life care for these patients is still poorly developed and applied sporadically even in the face of apparent needs. This review examines EOL treatment for hemoglobinopathies, focusing on symptom management, ethical difficulties, and psychosocial-spiritual support. The study utilized an analytical narrative technique, analyzing peer-reviewed literature from 2025, international norms, and European policy frameworks. Findings: The final stages of both SCD and β-thalassemia are characterized by persistent pain, permanent organ impairment, and significant psychological distress. Regardless of the variations in disease progression, both necessitate prompt and cohesive palliative care measures. Disparities in access to symptom management—particularly within marginalized communities—continue to endure. Cultural influences often play a significant role in shaping decision-making, especially in ethically sensitive contexts like transfusion withdrawal or gene therapy for advanced diseases. The psychosocial and spiritual aspects of suffering become more pronounced as one approaches the end of life, highlighting the need for interdisciplinary teamwork and care that is sensitive to cultural differences. In conclusion, it is essential to provide multidisciplinary, anticipatory, and culturally competent end-of-life care in the context of hemoglobinopathies. Health systems ought to implement referral criteria tailored to specific diseases and encourage adaptable hospice models, ensuring access to transfusions when clinically indicated. Access to opioids, enrolment in hospice care, and psychosocial support must be prioritized, especially in areas with a high prevalence of hemoglobinopathy.

Summary: This study examined mortality rates among 2475 patients with thalassaemia and sickle cell disease (SCD) per year over 12 years in Greece, recording 335 deaths (27.92/year), with an overall mortality rate of 1.13% per year. The primary aim was to identify causes of death, comorbidities, treatment efficacy and iron overload prevalence. Of the deaths, 239 were attributed to thalassaemia and 96 to SCD. For thalassaemia patients, cardiac failure, hepatocellular carcinoma and sepsis were the leading causes of death, with no neoplasms observed in β+/β+ genotypes. In SCD, sepsis, liver failure and stroke were the predominant causes, with sepsis‐related deaths higher in frequently transfused patients. The median age of death was significantly lower in thalassaemia (50 years) compared to SCD (58.49 years, p < 0.001). Differences in comorbidities and treatment effectiveness highlight the need for improved management strategies. Addressing iron overload, optimizing chelation therapy and expanding hydroxyurea use in SCD patients could enhance survival and quality of life. Strengthening treatment protocols and monitoring may reduce mortality, emphasizing the importance of targeted interventions in haemoglobinopathies.

It is important to recognize the significance of acute painful transfusion reactions (APTRs) as a complication of blood transfusions. These adverse reactions are characterized by the onset of acute pain after the administration of blood components. Despite their potential to cause significant discomfort and distress to patients, these reactions are frequently disregarded and under-reported in clinical practice. This review aims to provide a comprehensive analysis of the clinical features, pathophysiology, diagnosis, incidence, and management of APTRs, emphasizing the necessity for heightened awareness and further research in this field.