Sylvia T. Singer

Heterogeneity of Hemoglobin H Disease in Childhood

BACKGROUND Early diagnosis during newborn screening or infancy has enabled the observation of the natural history of hemoglobin H disease, a subtype of α-thalassemia. METHODS We analyzed longitudinal clinical data for patients with hemoglobin H disease arising from the deletion of three of four α-globin genes (HbH) and from hemoglobin H Constant Spring (HCS), caused by the deletion of two α-globin genes and the Constant Spring mutation. RESULTS We identified 86 patients with hemoglobin H disease (48 through newborn screening). Of these patients, 60 (70%) had HbH, 23 (27%) had HCS, and 3 (3%) had other, nondeletional forms of hemoglobin H disease. The parental ethnic background was Asian in 81% of patients, Hispanic in 5%, and African American in 3%, whereas mixed ancestry was observed in 10% of patients. Among the patients with deletional hemoglobin H disease, 15% had one or both parents with African-American ancestry. Growth was normal in patients with HbH during the first decade, but growth deficits began during infancy in those with HCS. Anemia was more severe in patients with HCS at all ages (P<0.001). Acute worsening of anemia with infections requiring urgent blood transfusion was observed in patients with HCS but not in those with HbH. The probability of receiving at least one transfusion by the age of 20 years was 3% for patients with HbH and 80% for those with HCS (P<0.001). Among patients with HCS, transfusions occurred in 13% of infants and 50% of children under the age of 6 years; splenectomy was associated with a significant improvement in hemoglobin levels (P=0.01) and a reduction in the number of transfusions. CONCLUSIONS HCS should be recognized as a distinct thalassemia syndrome with a high risk of life-threatening anemia during febrile illnesses. HbH was not associated with an increased rate of severe anemia with infections and was managed without blood transfusions. Many patients with these disorders had mixed ethnic backgrounds, which highlights the need for extended newborn screening in populations that are traditionally considered to be at low risk for hemoglobin H disease.

Erythrocytapheresis for chronically transfused children with sickle cell disease: An effective method for maintaining a low hemoglobin S level and reducing iron overload

Cerebrovascular accident (CVA) is a major complication of sickle cell disease during childhood. Long‐term transfusion reduces the hemoglobin S level and generally prevents recurrent stroke, but it also results in progressive iron overload that requires regular chelation therapy. Erythrocytapheresis offers an alternative approach aimed at reducing the iron accumulation. We reviewed the results of erythrocytapheresis in eight sickle cell patients (mean age of 12.1 years) at high risk for a first or recurrent stroke. They were maintained at the standard pre‐transfusion hemoglobin S (Hb S) level of 30%.

Red cell alloimmunization in a diverse population of transfused patients with thalassaemia

Red blood cell (RBC) transfusion is the primary treatment for severe forms of thalassaemia. Pre‐storage screening has resulted in decreased transfusion‐transmitted infections, but anti‐RBC antibodies remain a major problem. We report on 697 participants who had ever received transfusions. Allo‐ and autoantibody rates were compared with respect to splenectomy status, ethnicity, diagnosis, duration of transfusions, treatment centre, and age at transfusion initiation, together with rates before and after 1990, when leucoreduction methods were routine at thalassaemia treatment centres. Allo‐ and autoantibodies were reported in 115 (16·5%) and 34 (4·9%) subjects, respectively. Splenectomized patients were more likely to have alloantibodies [odds ratio (OR) = 2·528, P ≤ 0·0001], or autoantibodies (OR = 2·590, P = 0·0133). Alloantibodies occurred in 19 of 91 (21%) splenectomized subjects who started transfusion after 1990, and only 18 of 233 (7·7%) nonsplenectomized subjects (P < 0·001). Data from this study demonstrate that RBC antibodies continue to develop in chronically transfused thalassaemia patients at a high rate. Splenectomy preceded the development of antibodies in most cases. Increased rates of RBC sensitization among splenectomized patients is concerning and deserves further study.

Thalassemia: current approach to an old disease

This article discusses the approach for recognition, diagnosis, and management of the thalassemias, and reviews new prospects of therapy, focusing mostly on the beta-thalassemias--the more severe and clinically important type, beta-thalassemia major is typically treated with regular transfusion and chelation therapy. New strategies for specific therapy including monitoring of iron induced organ damage, fetal hemoglobin augmentation as an alternative for transfusions, bone marrow transplantation offer hope for prevention of complications and better care of the beta-thalassemias.

Fetal haemoglobin augmentation in E/β0 thalassaemia: clinical and haematological outcome

Patients with E/β0 thalassaemia, the most common haemoglobinopathy in many Asian countries, might benefit from drugs that increase fetal and total haemoglobin and thereby decrease the need for transfusions. The long‐term clinical efficacy and safety of such therapy is unknown, limiting its use in countries where resources for safe and regular transfusion are scarce. In this study, 45 patients were treated with hydroxyurea (18–20 mg/kg) for 24 ± 9 months, hydroxyurea with sodium phenyl butyrate (n = 8) and hydroxyurea with erythropoietin (n = 9), each for ∼6 months, and followed for 3 years from study exit. Hydroxyurea had minimal toxicity, resulted in a mean 1·3 g/dl steady‐state increase in haemoglobin in 40% of patients, and a milder response (≤1 g/dl) in the others. Baseline haemoglobin F was significantly associated with an increase in haemoglobin (P < 0·001). Combined treatment with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate had no effect. Of the 27/45 patients who discontinued regular transfusions before the study, 13 remained transfusion independent during long‐term follow‐up, 6/13 continued hydroxyurea. Hydroxyurea moderately increased steady‐state haemoglobin in a sub‐group of E/β0 thalassaemia patients and can be considered for patients with intermediate severity disease, thus delaying or avoiding the need for life‐long transfusions. Continuous monitoring of toxicity and growth is required.

Changing outcome of homozygous α-thalassemia : Cautious optimism

Only a few long-term survivors of homozygous alpha-thalassemia, a usually fatal condition, have been reported. The authors present a surviving infant with this disorder and discuss the complications, treatments, and implications of this genetic hemoglobinopathy. The child had no antenatal intervention and has been treated with regular transfusions. She has had normal growth and development and is currently 2.5-years-old. A literature review of survivors with Bart hemoglobinopathy reveals an intense perinatal course and a great prevalence of congenital urogenital and limb defects. Advances in antenatal diagnosis, intrauterine intervention, and postnatal treatments have resulted in extended survival of children with congenital defects that until recently were considered invariably fatal. Transfusion and chelation therapy and bone marrow transplantation provide long-term treatment and potential curative options.

Deferoxamine treatment during pregnancy: Is it harmful?

The use of the iron chelator, Deferoxamine (DFO), in pregnant thalassemia women with iron overload has been generally avoided due to fear of its potential teratogenicity. We describe a case of a pregnant thalassemia major patient with iron overload, who received DFO throughout her second and third trimesters and gave birth to a healthy infant, who had no findings of DFO toxicity at birth and at a later follow‐up. Review of the literature discloses over 40 other cases in which DFO was given in various periods of gestation without evidence of teratogenic effect. Sufficient documentation exists, therefore, to suggest that DFO can be considered for use in cases of pregnant women who need iron chelation treatment. Am. J. Hematol. 60:24–26, 1999.

Reproductive capacity in iron overloaded women with thalassemia major.

The pathophysiology of iron-induced compromised fertility in women with thalassemia major (TM) was evaluated in 26 adult TM females. Low gonadotropin secretion resulted in reduced ovarian antral follicle count and ovarian volume, but levels of anti-müllerian hormone (AMH), a sensitive marker for ovarian reserve independent of gonadotropin effect, were mostly normal. AMH correlated with non-transferrin-bound iron (NTBI), suggesting a role of labile iron in the pathogenesis of decreased reproductive capacity, possibly occurring in parallel to cardiac iron toxicity, as cardiac iron was associated with the presence of amenorrhea and with NTBI levels. AMH emerges as an important biomarker for assessment of reproductive capacity in TM, demonstrating that fertility is preserved in the majority of those younger than 30 to 35 years. AMH can be useful in future studies aiming at improved chelation for fertility preservation, whereas NTBI and labile plasma iron may be valuable for monitoring iron effect on the reproductive system.

Sildenafil therapy in thalassemia patients with Doppler-defined risk of pulmonary hypertension

Pulmonary hypertension is a common but often overlooked complication associated with thalassemia syndromes. There are limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. We, therefore, designed a 12-week, open-label, phase 1/2, pilot-scale, proof-of-principle trial of sildenafil therapy in 10 patients with β-thalassemia and at increased risk of pulmonary hypertension based on an elevated tricuspid regurgitant jet velocity >2.5 m/s on Doppler-echocardiography. Variables compared at baseline and after 12 weeks of sildenafil treatment included Doppler-echocardiographic parameters, 6-minute walked distance, Borg Dyspnea Score, New York Heart Association functional class, pulmonary function, and laboratory parameters. Treatment with sildenafil resulted in a significant decrease in tricuspid regurgitant jet velocity by 13.3% (3.0±0.7 versus 2.6±0.5 m/s, P=0.04), improved left ventricular end systolic/diastolic volume, and a trend towards a improved New York Heart Association functional class. No significant change in 6-minute walked distance was noted. Sildenafil was well tolerated, although minor expected adverse events were commonly reported. The total dose of sildenafil (mg) was strongly correlated with percent change in nitric oxide metabolite concentration in the plasma (ρ=0.80, P=0.01). There were also significant increases in plasma and erythrocyte arginine concentrations. Our study suggests that sildenafil is safe and may improve pulmonary hemodynamics in patients at risk of pulmonary hypertension; however, it was not demonstrated to improve the distance walked in 6 minutes. Clinical trials are needed to identify the best treatment strategy for pulmonary hypertension in patients with β-thalassemia. (clinicaltrials.gov identifier: NCT00872170)

Clinical hemoglobinopathies: iron, lungs and new blood.

Purpose of reviewSickle cell disease and β-thalassemia major are clinically significant hereditary anemias that elicit worldwide attention due to the frequency and severity of these disorders. Historically, most children who inherited these disorders died in the first decade of life. Recently, however, supportive care has extended lifespan through the fifth decade of life and beyond, with survival through early adulthood now indistinguishable from those unaffected by these disorders. As a result, chronic health impairments that significantly reduce the quality of life such as pulmonary hypertension and the consequences of transfusional iron overload have become principal challenges. Recent findingsWe focus on important recent advances that are very likely to alter the nature of supportive care of these disorders or make it possible to identify prospectively high-risk patients who might benefit from novel therapies or even curative treatment in the form of hematopoietic cell transplantation. The availability of the latter, traditionally constrained by the requirement of a human leukocyte antigen-identical sibling donor, is very likely to be broadened as results after unrelated donor hematopoietic cell transplantation improve. SummaryIn this review, several areas that are very likely to have a significant impact in the management of patients who inherit these disorders are discussed.