Pregnancy and assisted reproductive technology use in Australian female transfusion-dependent haemoglobinopathy patients: a 20-year retrospective analysis.

BACKGROUND: In the last few decades, the life expectancy of patients with transfusion-dependent thalassaemia (TDT) and sickle cell disease (SCD) has improved significantly, in part because of improved iron chelation. Fertility challenges and pregnancy complications have historically limited reproductive options in this group; however, improved multi-disciplinary care has made infertility a chronic disease complication requiring attention. Despite this, there are very few reports and no Australian data describing fertility and pregnancy outcomes in this population. AIMS: To identify the rate of assisted reproductive technologies (ART) utilisation in our female transfusion-dependent haemoglobinopathy patients and to establish the nature of maternal and neonatal complications in this cohort. METHODS: A 20-year retrospective analysis (1997-2017) at an Australian centre captured data on conception rates, use of assisted reproductive techniques (ART), and pregnancy and neonatal outcomes in female transfusion-dependent haemoglobinopathy patients. RESULTS: Conception was attempted in 14 women (11 TDT and three SCD) during the study period. A total of 28 pregnancies resulting in 25 live births were recorded. ART supported 13 conceptions. A positive association was not identified between elevated mean serum ferritin and ART use; however, all patients with an established diagnosis of hypogonadotropic hypogonadism (HH) required ART. Maternal complications included gestational diabetes mellitus and post-partum haemorrhage. There were no cardiac complications. Two-thirds of women underwent lower segment caesarean section, with prematurity complicating 20% of births. There were no neonatal or maternal deaths. CONCLUSION: Pregnancy is an achievable goal for women with transfusion-dependent haemoglobinopathies, although the support of ART may be required in a subset of patients.

ß-Thalassemia in childhood: Current state of health in a high-income country.

ß-thalassemia is an haemoglobinopathy characterized by a defective synthesis of the ß-globin chain. To assess the current state of health of paediatric patients with ß-thalassemia, data from the French national registry regarding children born between 2005 and 2020 with ß-thalassemia intermedia (TI) or major (TM) were collected. A total of 237 patients (median age 7.1 years at last visit) were analysed, of whom 156 (65.8%) were born in France and 162 (68.4%) had a TM phenotype. The probability of survival for children with TM born in France was 98.3% at 15 years. Fifty-four (22.8%) children received a haematopoietic stem cell transplant with a success rate of 88.8%. Hepatic and cardiac iron overload monitoring in non-transplanted patients showed moderate overload in 15.7% (18/115) and 7.1% (7/99) of cases, respectively, while clinical complications were found in only 4 patients with TM (hepatic in 3 cases). At last visit, mean ferritinemia was 1293 ng/ml (±759). Overall, less than 10% of children underwent splenectomy. No significant impact of the disease on growth or academic achievement was observed. Deferasirox was the main first-line chelator, prescribed in 78.2% of cases, with side effects reported in 11.7% of instances.

Endocrinopathies in Hemoglobinopathies: What Is the Role of Iron?

Hemoglobinopathies, including ß-thalassemia and sickle cell disease (SCD), are common genetic blood disorders. Endocrine disorders are frequent manifestations of organ damage observed mainly in patients with ß-thalassemia and rarely in SCD. Iron overload, oxidative stress-induced cellular damage, chronic anemia, and HCV infection contribute to the development of endocrinopathies in ß-thalassemia. The above factors, combined with vaso-occlusive events and microcirculation defects, are crucial for endocrine dysfunction in SCD patients. These endocrinopathies include diabetes mellitus, hypothyroidism, parathyroid dysfunction, gonadal and growth failure, osteoporosis, and adrenal insufficiency, affecting the quality of life of these patients. Thus, we aim to provide current knowledge and data about the epidemiology, pathogenesis, diagnosis, and management of endocrine disorders in ß-thalassemia and SCD. We conducted a comprehensive review of the literature and examined the available data, mostly using the PubMed and Medline search engines for original articles. In the era of precision medicine, more studies investigating the potential role of genetic modifiers in the development of endocrinopathies in hemoglobinopathies are essential.

Prevalence and aetiologies of anaemia among first trimester pregnant women in Sri Lanka; the need for revisiting the current control strategies.

BACKGROUND: The Sustainable development goals, which focus strongly on equity, aim to end all forms of malnutrition by 2030. However, a significant cause of intergenerational transfer of malnutrition, anaemia in pregnancy, is still a challenge. It is especially so in the low- and middle-income settings where possible context-specific aetiologies leading to anaemia have been poorly explored. This study explores the prevalence of etiological factors significantly contributing to anaemia in pregnancy in Sri Lanka, a lower-middle-income country with a high prevalence of malnutrition albeit robust public health infrastructure. METHODS: All first-trimester pregnant women registered in the public maternal care programme in the Anuradhapura district from July to September 2019 were invited to participate in Rajarata Pregnancy Cohort (RaPCo). After a full blood count analysis, high-performance liquid chromatography, peripheral blood film examination, serum B12 and folate levels were performed in anaemic participants, guided by an algorithm based on the red cell indices in the full blood count. In addition, serum ferritin was tested in a random subsample of 213 participants. Anaemic women in this subsample underwent B12 and folate testing. RESULTS: Among 3127 participants, 14.4% (95%CI 13.2-15.7, n = 451) were anaemic. Haemoglobin ranged between 7.4 to 19.6 g/dl. 331(10.6%) had mild anaemia. Haemoglobin ≥13 g/dl was observed in 39(12.7%). Microcytic, normochromic-normocytic, hypochromic-normocytic and macrocytic anaemia was observed in 243(54%), 114(25.3%), 80(17.8%) and two (0.4%) of full blood counts in anaemic women, respectively. Microcytic anaemia with a red cell count ≥5 * 106 /µl demonstrated a 100% positive predictive value for minor haemoglobinopathies. Minor hemoglobinopathies were present in at least 23.3%(n = 105) of anaemic pregnant women. Prevalence of iron deficiency, B12 deficiency and Southeast Asian ovalocytosis among the anaemic was 41.9% (95%CI 26.4-59.2), 23.8% (95%CI 10.6-45.1) and 0.9% (95%CI 0.3-2.3%), respectively. Folate deficiency was not observed. CONCLUSION: Even though iron deficiency remains the primary cause, minor hemoglobinopathies, B 12 deficiency and other aetiologies substantially contribute to anaemia in pregnancy in this study population. Public health interventions, including screening for minor hemoglobinopathies and multiple micronutrient supplementation in pregnancy, should be considered in the national programme for areas where these problems have been identified.

Curcuminoids supplementation ameliorates iron overload, oxidative stress, hypercoagulability, and inflammation in non-transfusion-dependent ß-thalassemia/Hb E patients.

Curcuminoids, polyphenol compounds in turmeric, possess several pharmacological properties including antioxidant, iron-chelating, and anti-inflammatory activities. Effects of curcuminoids in thalassemia patients have been explored in a limited number of studies using different doses of curcuminoids. The present study aims to evaluate the effects of 24-week curcuminoids supplementation at the dosage of 500 and 1000 mg/day on iron overload, oxidative stress, hypercoagulability, and inflammation in non-transfused ß-thalassemia/Hb E patients. In general, both curcuminoids dosages significantly lowered the levels of oxidative stress, hypercoagulability, and inflammatory markers in the patients. In contrast, reductions in iron parameter levels were more remarkable in the 1000 mg/day group. Subgroup analysis revealed that a marker of hypercoagulability was significantly decreased only in patients with baseline ferritin ≤ 1000 ng/ml independently of curcuminoids dosage. Moreover, the alleviation of iron loading parameters was more remarkable in patients with baseline ferritin > 1000 ng/ml who receive 1000 mg/day curcuminoids. On the other hand, the responses of oxidative stress markers were higher with 500 mg/day curcuminoids regardless of baseline ferritin levels. Our study suggests that baseline ferritin levels should be considered in the supplementation of curcuminoids and the appropriate curcuminoids dosage might differ according to the required therapeutic effect. Thai Clinical Trials Registry (TCTR): TCTR20200731003; July 31, 2020 "retrospectively registered".

High-oxygen-affinity hemoglobinopathy-associated erythrocytosis: Clinical outcomes and impact of therapy in 41 cases.

We describe presenting features, treatment strategies, and follow-up events involving 41 patients (median age 39 years, range 1-81; 54% males) with high oxygen affinity (HOA) hemoglobinopathy-associated erythrocytosis, seen at our institution (1973-2020). Thirty-four (83%) patients carried ß-chain (13 Malmo, 4 Olympia, 3 San Diego, 2 Wood) and 7 (17%) α-chain (4 Dallas and one each Columbia-Missouri, Jackson, and Wayne) variants. Median (range) hemoglobin (Hgb)/hematocrit (Hct), serum erythropoietin and p50 were 18 g/dL/52.9% (16-21.9/48-66), 10.4 mIU (4-36.3), and 20 mmHg (12-25), respectively. Family history was documented in 24 patients and history of thrombosis in two (5%). Treatment included phlebotomy in 23 and antiplatelet therapy in 21 patients. At a median follow-up of 10 years, 23 (56%) patients reported one or more symptoms that were thought to be related to their increased Hct while thrombosis was documented in 10 (24%) patients. Neither Hgb/Hct level nor active phlebotomy showed a significant correlation with either thrombotic or nonthrombotic symptoms (p > .1 in all instances). Among 23 pregnancies recorded, 78% resulted in live births and no fetal loss was attributed to erythrocytosis. The current study does not implicate Hgb/Hct level as a major contributor of morbidity in HOA hemoglobinopathy-associated erythrocytosis and suggests limited therapeutic value for phlebotomy.

Pregnancy outcomes in women with a hemoglobinopathy trait: a multicenter, retrospective study.

PURPOSE: To determine the risk of adverse maternal and neonatal outcomes in pregnant women with a hemoglobinopathy trait. MATERIALS AND METHODS: Retrospective cohort study was conducted to compare adverse maternal and neonatal outcomes between pregnant women with a hemoglobinopathy trait (study group; n = 172), and without a hemoglobinopathy trait (control group; n = 360). The medical data were extracted from clinical records of pregnant women attending antenatal care and delivering at the University Hospital Basel or University Hospital Zurich between 2015 and 2018. RESULTS: A total of 172 pregnant women with a hemoglobinopathy trait and 360 controls were recruited. Apart from fetal acidosis, the groups did not differ significantly in any variables of adverse neonatal outcomes. Whereas, among the maternal outcomes the rate of abortion, gestational diabetes mellitus, bacteriuria or urinary tract infection, intrahepatic cholestasis, abnormal placentation and anemia postpartum were significantly increased in women with a hemoglobinopathy trait. CONCLUSION: In our study, a hemoglobinopathy trait increased the risk of adverse maternal outcomes but did not increase adverse neonatal outcomes.

Frequency and types of haemoglobinopathies in children with microcytic anaemia.

OBJECTIVE: To study the frequency and types of haemoglobinopathies in children with microcytic anaemia. METHODS: The prospective study was conducted at the Paediatric Out-patient Department of Shifa Falahi Community Health Centre, Islamabad, Pakistan, from July to December, 2018, and comprised patients aged from 3 months to 14 years who had haemoglobin <10mg/dl and mean corpuscular volume <70fL. Serum ferritin and haemoglobin electrophoresis were done to check for iron deficiency anaemia and haemoglobinopathies. Data was analysed using SPSS 23. RESULTS: Of 175 subjects, 33(18.9%) had haemoglobinopathies and 142(81.1%) had iron deficiency anaemia. Thalassemia trait 18(10.3%) was the leading cause amongst haemoglobinopathies, followed by thalassemia major 8(4.6 %) and intermedia 5(2.9%). There were 2(1.1%) patients with haemoglobin D. CONCLUSIONS: The prevalence of haemoglobinopathies was high. Identification of haemoglobinopathies is important for proper treatment, antenatal screening and future genetic counselling.

Tilt-table Echocardiography Unmasks Early Diastolic Dysfunction in Patients With Hemoglobinopathies.

Individuals with hemoglobinopathy (sickle cell anemia and thalassemia major) are at risk for cardiac complications such as heart failure and cardiomyopathy. Diastolic dysfunction is known to precede systolic dysfunction in many cardiac diseases. This study sought to determine whether changes in left atrial (LA) function during manipulation of cardiac preload by tilt-table echocardiography can unmask subclinical diastolic dysfunction in pediatric patients with hemoglobinopathies. Eleven sickle cell anemia, 9 transfusion-dependent thalassemia major, and 10 control subjects underwent tilt-table echocardiogram in the supine (loading) and 30-degree upright (unloading) positions and cardiac magnetic resonance imaging (MRI). Echocardiography assessed LA and left ventricular (LV) strain, strain rate, mitral inflow, and annular velocities. MRI assessed LV function, myocardial T1 and T2* for iron deposition. Both thalassemia major and sickle cell anemia patients had normal LV function and no evidence of cardiac iron deposition on MRI T2* measurements. During cardiac loading, controls appropriately increased LA conduit (P=0.002) and reservoir strain (P=0.002), mitral e' velocity (P<0.0001) and medial e' velocity (P=0.002), while the hemoglobinopathy patients showed no change in these parameters. In pediatric sickle cell anemia and thalassemia, tilt-table echocardiography unmasked a failure to augment LA function in response to loading, suggesting altered myocardial relaxation is present, before evidence of iron overload or systolic dysfunction.

Serious adverse events in African-American cancer patients with sickle cell trait and inherited haemoglobinopathies in a SEER-Medicare claims cohort.

African-American (AA) cancer patients have long-experienced worse outcomes compared to non-Hispanic whites (NHW). No studies to date have evaluated the prognostic impact of sickle cell trait (SCT) and other inherited haemoglobinopathies, of which several are disproportionately high in the AA population. In a cohort analysis of treated patients diagnosed with breast or prostate cancer in the linked SEER-Medicare database, the relative risk (RR) for ≥1 serious adverse events (AEs), defined as hospitalisations or emergency department visits, was estimated for 371 AA patients with a haemoglobinopathy (AA+) compared to patients without haemoglobinopathies (17,303 AA-; 144,863 NHW-). AA+ patients had significantly increased risk for ≥1 AEs compared to AA- (RR = 1.19; 95% CI 1.11-1.27) and NHW- (RR = 1.23; 95% CI 1.15-1.31) patients. The magnitude of effect was similar by cancer type, and in analyses of AA+ with SCT only. Our findings suggest a novel hypothesis for disparities in cancer outcomes.

National registry of hemoglobinopathies in Greece: updated demographics, current trends in affected births, and causes of mortality.

National registries constitute an invaluable source of information and contribute to the improvement of hemoglobinopathy management. Herein, we present the second updated report of the National Registry for Haemoglobinopathies in Greece (NRHG) and critically discuss the time trends in demographics, affected births, and causes of mortality. Thirty-eight Greek hemoglobinopathy units reported data from diagnosis to the last follow-up or death by retrospectively completing an electronic form. Four thousand thirty-two patients were eligible for inclusion; more than half of them had thalassaemia major. Compared to the previous report, a reduction in the total number of all hemoglobinopathies except for hemoglobinopathy "Η" was evident. The total number of affected births was also reduced; most of them were attributable to diagnostic errors and lack of awareness. Importantly, data on iron overload are reported for the first time; although most patients had low or moderate liver iron concentration (LIC) values, a non-negligible proportion of patients had high LIC. The burden due to heart iron overload was less prominent. Cardiac- and liver-related complications are the major causes of morbidity and mortality. From 2000 to 2015, a decrease in heart-related deaths along with an increase in liver-associated fatalities was observed. The Hellenic Prevention Program along with advances in chelation regimens and iron status monitoring have resulted in improved patient outcomes. The NRHG gives insight into the effectiveness of prevention programs, the therapeutic management of hemoglobinopathies and associated outcomes. NRHG may contribute to the formulation of a roadmap for hemoglobinopathies in Europe and promote the implementation of effective public health policies.

Regional Overview on Maternal Nutrition and Examples of Health System Programme and Policy Responses: Asia and the Pacific.

BACKGROUND: The double burden of malnutrition in Asia and the Pacific is driving a renewed focus on maternal malnutrition. SUMMARY: Though adverse consequences of maternal malnutrition have been long recognized, there is slow progress in addressing nutritional problems of women/adolescent girls. Coverage and quality of current maternal nutrition interventions, mostly delivered through antenatal care programmes vary across countries, and are often sub-optimum. Further, despite a marked increase in overweight and obesity in women of reproductive age, at present, most programmes are focused on under-nutrition and micronutrient deficiencies. Key Messages: The recent antenatal care recommendations released by World Health Organization provide a benchmark for countries to evaluate their programmes and identify gaps and challenges to improving maternal nutrition. Asian and Pacific countries need to address all forms of maternal malnutrition. For countries that historically focused on maternal under-nutrition, expanding their programmes to incorporate interventions to address overweight and obesity will be challenging. Innovative methods for nutrition counselling, both in terms of content and using novel channels of communication, are needed. Protocols and guidance on managing excessive weight gain as well as determining appropriate pregnancy weight gains are needed, while managing micronutrient deficiencies, particularly in settings where inherited disorders of red blood cells exist.

Translational and Implementation Research to Bridge Evidence and Implementation.

BACKGROUND: The role of science in guiding interventions and programs and contributing to progress in achieving global targets is undeniable. In public health nutrition, biological research in the past century focused largely on single nutrients and provided the basis for addressing nutritional deficiencies. This focus has now expanded to consider evidence including, but not limited, to knowledge about food, diet, behavior, context, and culture. The complex double burden of malnutrition will need to be addressed through a wider lens that appreciates the multiple and interrelated facets that underpin it. SUMMARY: Despite the acknowledged importance of translational research in improving nutritional outcomes, significant gaps remain in the process leading from science to practice. This article sheds light on 2 examples that demonstrate this, namely, anemia and stunting. Further, much work is still required to translate the current evidence base into effective actions that result in impact at scale, pointing toward the need for more implementation research in nutrition. Key Messages: While discoveries may take time to surface and implementers are impatient to address the challenge at hand, it is essential to identify and deploy the best available evidence while continuously advancing the evidence base, and to seek the right balance between action and inaction.

Severe Drug-Induced Hemolysis in a Patient with Compound Heterozygosity for Hb Peterborough (HBB: c.334G>T) and Hb Lepore-Boston-Washington (NG_000007.3: g.63632_71046del).

Unstable hemoglobins (Hbs) are often overlooked in the differential diagnoses of drug-induced hemolysis. Hb Peterborough [ß111(G13)Val→Phe; HBB: c.334G>T] is a rare unstable Hb variant, predominantly found in individuals of Italian descent, due to a structural defect involving a single amino acid substitution (phenylalanine for valine at position 111 of the ß-globin chain). Unstable Hb variants are often inherited in the heterozygous state with Hb A (α2ß2) and rarely in compound heterozygosity with other Hb variants. The presence of another variant Hb often alters the phenotype, occasionally resulting in more severe disease. Using a combination of molecular techniques; multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing, we identified a compound heterozygosity for Hb Peterborough and Hb Lepore-Boston-Washington (Hb LBW) [δ87, ß116; NG_000007.3: g.63632_71046del] in a middle-aged gentleman with a history of chronic microcytic anemia and splenomegaly, presenting with severe drug-induced hemolysis, which was managed conservatively. The clinical history and presentation reflect the dual pathology due to the presence of two variant Hbs and their associated phenotypes. In this article, we discuss the phenotype resulting from the interaction of Hb Peterborough and Hb LBW and emphasize the importance of molecular testing in the diagnosis of rare Hb variants.

Caution is Needed in Interpreting Hemoglobin A1c Levels in the Muslim Bedouin Population of Southern Israel.

BACKGROUND: The Bedouins living in southern Israel are a Muslim-Arab population that is transitioning from a nomadic lifestyle to life in permanent settlements. The population has unique characteristics that could affect hemoglobin A1c (HbA1c) measurements. The objective of this study was to describe the socio-demographic and unique morbidity characteristics of this community and their effect on HbA1c measurements. Consanguinity, especially among cousins in the Bedouin population, results in a high prevalence of autosomal recessive genetic diseases such as thalassemia (underestimate of HbA1c), hemoglobinopathies (underestimate and overestimate), Gilbert's disease, and glucose-6-phosphate dehydrogenase deficiency, an X-linked disorder, which can cause hyperbilirubinemia with an overestimate of HbA1c. Furthermore, nutritional deficiencies, autosomal recessive diseases, high birth rates, parasitic infections, and poverty can all cause high rates of anemia (iron and vitamin B12 deficiencies) that can raise HbA1c levels. Congenital dyserythropoietic anemia is found among Bedouin tribes in the Negev region and can lead to an underestimation of HbA1c levels. Pregnancy can also affect HbA1c levels. Medical teams working in the Bedouin community and in other Muslim populations with similar morbidity characteristics throughout the world should identify patients with medical conditions that can affect HbA1c measurements and be aware of possible measurement alternatives such as fructosamine and glycated albumin.

Artemisinin Therapy for Malaria in Hemoglobinopathies: A Systematic Review.

Artemisinin derivatives are widely used antimalarial drugs. There is some evidence from in vitro, animal and clinical studies that hemoglobinopathies may alter their disposition and antimalarial activity. This review assesses relevant data in α-thalassemia, sickle cell disease (SCD), ß-thalassemia and hemoglobin E. There is no convincing evidence that the disposition of artemisinin drugs is affected by hemoglobinopathies. Although in vitro studies indicate that Plasmodium falciparum cultured in thalassemic erythrocytes is relatively resistant to the artemisinin derivatives, mean 50% inhibitory concentrations (IC50s) are much lower than in vivo plasma concentrations after recommended treatment doses. Since IC50s are not increased in P. falciparum cultures using SCD erythrocytes, delayed post-treatment parasite clearance in SCD may reflect hyposplenism. As there have been no clinical studies suggesting that hemoglobinopathies significantly attenuate the efficacy of artemisinin combination therapy (ACT) in uncomplicated malaria, recommended artemisinin doses as part of ACT remain appropriate in this patient group.

Rheumatic Manifestations of Haemoglobinopathies.

PURPOSE OF THE REVIEW: To provide a clinically useful literature review on the rheumatic manifestations of haemoglobinopathies, critically analysing the literature from the past 5 years. RECENT FINDINGS: There are limited new data to guide the management of rheumatic manifestations of haemoglobinopathies. Data further confirm the wide spectrum of potential rheumatic/MSK involvement in haemoglobinopathies, which poses both a diagnostic and therapeutic challenge. Inflammatory arthritis may be more common than previously believed. Steroid therapy by any route of administration can provocate a potential life-threatening vaso-occlusive crisis. Vitamin D deficiency is common. There are limited data to guide the drug treatment of reduced bone density in haemoglobinopathies. There have been a number of studies examining pain in sickle cell anaemia. Plasma levels of Klotho may represent a novel biomarker in patients with ß-Thalassemia. There are little new data on the rheumatic manifestations in haemoglobinopathies and future high-quality research is needed.

Effect of inherited red cell defects on growth of Plasmodium falciparum: An in vitro study.

BACKGROUND & OBJECTIVES: High prevalence of certain polymorphic alleles of erythrocytes in malaria endemic area has been linked to the resistance provided by these alleles against parasitic infestations. Numerous studies undertaken to demonstrate this correlation have generated conflicting results. This study was undertaken to investigate the abilities of various polymorphic erythrocytes to support in vitro growth of Plasmodium falciparum parasites. METHODS: In this study under in vitro condition the ability of P. falciparum parasites to grow was assessed in the erythrocytes obtained from a total of 40 patients with various haemoglobinopathies, such as ß-thalassaemia (ß-Thal), sickle cell anaemia, erythroenzymopathy-like glucose-6-phosphate dehydrogenase deficiency and membranopathy-like hereditary spherocytosis. RESULTS: Significantly reduced in vitro invasion and growth of parasites was seen in the cultures containing abnormal erythrocytes than in control cultures containing normal erythrocytes (P< 0.05). The mean per cent parasitaemia comparison was also carried out among the three polymorphic erythrocyte groups, i.e. ß-Thal, sickle cell anaemia and enzyme-membranopathies. INTERPRETATION & CONCLUSIONS: Erythroenzymopathies and membranopathies were found to provide a more hostile environment for parasites, as the least parasitaemia was observed in these erythrocytes. The present in vitro study showed that P. falciparum did not grow well and did not invade well in erythrocytes obtained from common inherited red cell disorders.

Rare Association of Hb D-Los Angeles (HBB: c.364G>C) with Hb H Disease: Diagnosis and Clinical Implications.

Hb D-Los Angeles (or Hb D-Punjab) (HBB: c.364G > C) is found worldwide and is derived from a point mutation in the ß-globin gene prevalent in the Punjab region of Northwestern India. Heterozygous or homozygous inheritance does not cause significant medical problems, whereas association with other hemoglobinopathies, especially ß-thalassemia (ß-thal) and sickle cell disease, changes the phenotype. Coinheritance of Hb D-Los Angeles with Hb H disease (α-/- -) has never been reported before. The presence of this rare combination in a family of Greek origin is herein described, and the challenges involving clinical management are discussed.