Thalassemia, a human blood disorder / Talassemia, uma doença do sangue humano

A group of inherited blood defects is known as Thalassemia is among the world's most prevalent hemoglobinopathies. Thalassemias are of two types such as Alpha and Beta Thalassemia. The cause of these defects is gene mutations leading to low levels and/or malfunctioning α and β globin proteins, respectively. In some cases, one of these proteins may be completely absent. α and β globin chains form a globin fold or pocket for heme (Fe++) attachment to carry oxygen. Genes for alpha and beta-globin proteins are present in the form of a cluster on chromosome 16 and 11, respectively. Different globin genes are used at different stages in the life course. During embryonic and fetal developmental stages, γ globin proteins partner with α globin and are later replaced by β globin protein. Globin chain imbalances result in hemolysis and impede erythropoiesis. Individuals showing mild symptoms include carriers of alpha thalassemia or the people bearing alpha or beta-thalassemia trait. Alpha thalassemia causes conditions like hemolytic anemia or fatal hydrops fetalis depending upon the severity of the disease. Beta thalassemia major results in hemolytic anemia, growth retardation, and skeletal aberrations in early childhood. Children affected by this disorder need regular blood transfusions throughout their lives. Patients that depend on blood transfusion usually develop iron overload that causes other complications in the body systems like renal or hepatic impairment therefore, thalassemias are now categorized as a syndrome. The only cure for Thalassemias would be a bone marrow transplant, or gene therapy with currently no significant success rate. A thorough understanding of the molecular basis of this syndrome may provide novel insights and ideas for its treatment, as scientists have still been unable to find a permanent cure for this deadly disease after more than 87 years since it is first described in 1925.

Um grupo de defeitos sanguíneos hereditários é conhecido como talassemia e está entre as hemoglobinopatias mais prevalentes do mundo. As talassemias são de dois tipos, como talassemia alfa e beta. As causas desses defeitos são as mutações genéticas que levam a níveis baixos e/ou proteínas de globina com mau funcionamento, respectivamente. Em alguns casos, uma dessas proteínas pode estar completamente ausente. As cadeias de globina α e β formam uma dobra ou bolsa de globina para a fixação de heme (Fe ++) para transportar oxigênio. Os genes das proteínas alfa e beta globina estão presentes na forma de um cluster nos cromossomos 16 e 11, respectivamente. Diferentes genes de globina são usados em diferentes estágios do curso de vida. Durante os estágios de desenvolvimento embrionário e fetal, as proteínas γ globina se associam à α globina e, posteriormente, são substituídas pela proteína β globina. Os desequilíbrios da cadeia de globina resultam em hemólise e impedem a eritropoiese. Indivíduos que apresentam sintomas leves incluem portadores de talassemia alfa ou as pessoas com traços de talassemia alfa ou beta. A talassemia alfa causa condições como anemia hemolítica ou hidropsia fetal fatal, dependendo da gravidade da doença. A beta talassemia principal resulta em anemia hemolítica, retardo de crescimento e aberrações esqueléticas na primeira infância. As crianças afetadas por esse distúrbio precisam de transfusões de sangue regulares ao longo da vida. Os pacientes que dependem de transfusão de sangue geralmente desenvolvem sobrecarga de ferro que causa outras complicações nos sistemas do corpo, como insuficiência renal ou hepática, portanto as talassemias agora são classificadas como uma síndrome. A única cura para as talassemias seria um transplante de medula óssea ou terapia genética sem atualmente uma taxa de sucesso significativa. Uma compreensão completa da base molecular dessa síndrome pode fornecer novos insights e ideias para seu tratamento, [...].

Heart failure as the first manifestation of renal cell carcinoma

We report the rare case of a patient with advanced renal cell carcinoma (RCC) who initially presented to the hospital with symptoms of cardiac failure. Preoperative cardiac studies did not reveal any underlying ischemia. After resection of a large 14-cm left renal tumor, cardiac function was noted to improve dramatically. We discuss this case of concomitant RCC and nonischemic cardiomyopathy.

Rotação ventricular esquerda anormal em mulher com talassemia / Abnormal left ventricular torsion in woman with thalassemia

Introdução: Cardiomiopatia induzida pelo ferro é bem documentada em pacientes com talassemia. A ecocardiografia convencional associada a novas tecnologias pode detectar, precocemente, alterações na função ventricular esquerda nesses pacientes. Relato do caso: Mulher, 50 anos, assintomática, com diagnóstico de talassemia, mostra parâmetros ecocardiográficos convencionais e Doppler tecidual normais com alteração na torção e rotação ao speckle tracking. Comentários:A detecção precoce de alterações da função cardíaca por meio de novas tecnologias, em pacientes com talassemia, tem demonstrado importância prognóstica.

Introduction: Iron induced cardiomyophathy is well documented in patients with thalassemia. Conventional echocardiogram associated with new technologies has provided parameters for early detection of changes in left ventricular function. Case report: Woman, 50 years old, asymptomatic, diagnosed with thalassemia, shows normal conventional echocardiogram and tissue Doppler parameters but altered torsion and rotation parameters using speckle tracking. Comments: Early echocardiographic findings using speckle tracking in patients with thalassemia is important and may improve prognosis in these patients.

Avaliação da função diastólica em portadores de talassemia major / Diastolic function in patients with thalassemia major

Portadores de talassemia major (TM) permanecem assintomáticos e com funções ventriculares preservadas por longo tempo, porém, duas condições básicas podem ser responsáveis pelo comprometimento da função cardíaca nesse indivíduos, a anemia e a hemocromatose. Recentes avanços na ecocardiografia possibilitaram a utilização dessa técnica para a identificação precoce de disfunção ventricular secundária à hemocromatose. Além disso, esse exame constitui instrumento valioso para o acompanhamento evolutivo de pacientes, permitindo comparações de variáveis estruturais e funcionais cardíacas em diferentes momentos.

Evaluation of osteopathy in thalassemia by bone mineral densitometry and biochemical indices.

Objective To evaluate osteopathy in thalassemia by bone mineral densitometry (BMD) and biochemical indices. Methods Prospective review analysis with no follow up from 2006 to 2007 of 42 regularly transfused thalassemics aged 10–25 years (27 boys, 15 girls) was done. Anthropometry, pubertal stage and symptomatology were noted. Urinary C–terminal cross–linked telopeptide of type–1 collagen (Crosslaps) by ELISA; serum 25–OH vitamin D and osteocalcin by RIA; parathyroid hormone (PTH) and ferritin by chemiluminescence and IGF–1 by Enzyme immunoassay were evaluated. Dual Energy X-ray Absorptiometry (DEXA) of lumbar spine and femur was done on Lunar prodigy system. Data was entered and analyzed using the SPSS for Windows software. Mean comparisons were done by ANOVA 1 and data was compared using Chi–square test and p value<0.05 was taken as significant. Results Of 42 patients, 81% had osteoporosis by Z–score of DEXA. Urinary crosslaps was high in 55%; 36% had increased osteocalcin; 62% had low vitamin D levels; 38% had high parathyroid levels and IGF–1 was low in 52%. Mean serum ferritin level was 5344±2855 ng/dl. There was statistical significance (p=0.046) between chronological age and BMD. All 42 cases were divided into two groups: Group–1 (Normal DEXA), Group–2 (Abnormal DEXA) and analysis of biochemical indices between two groups showed no significant difference in any of the biochemical parameters. Conclusion This study revealed majority of thalassemics with inadequate chelation have bone resorption with advancing chronological age and BMD should be evaluated regularly for early diagnosis to prevent morbidity.

Bone marrow transplantation in thalassemia [Part 1]

During the last two decades conventional therapy has improved the prognosis of thalassemia. However, despite such improvement it still remains a progressive disease with treatment-related complications such as hepatitis, liver fibrosis, and cardiac disease. Bone marrow transplantation [BMT] can prevent or delay progression of the aforementioned complications. The importance of clinical research in the field of BMT was recognized with the award of the 1990 Nobel Prize in Physiology and Medicine to E. Donnall Thomas, one of the pioneers of BMT in humans. George Mathe' was a pioneer in the early development of clinical BMT. Mathe' et al. were the first to describe graft-versus-host-disease [GVHD] and its treatment, and the graft-versus- leukemia [GVL] effect in human. The first BMT for beta-thalassemia major was performed successfully by Thomas et al. in Seattle, in 1981. In the same year another patient with beta-thalassemia major underwent BMT in Pesaro, Italy, by Lucarelli et al. Since then, several hundred transplantations have been performed worldwide, the majority of these in Italy. From 1991 through 2007 BMT have been performed on 497 [Tehran=342, Shiraz=155] blood transfusion dependent patients with thalassemia major in Iran, with disease-free survival of 71-77% respectively. Due to high graft failure and GVHD rates, BMT from alternative donors should be restricted to patients who have poor life expectancies because they cannot receive adequate conventional treatment or because of alloimmunization to minor blood antigens. Beginning in the early 1980s, it was shown that umbilical cord blood contained high levels of hematopoietic progenitor cells

Enoxaparin plus ticlopidine: an effective combination therapy for intracardiac thrombi in thalassemia intermedia

Patients with thalassemia intermedia have an increased risk of thrombotic events as compared to the general population. We describe two cases of thalassemia intermedia with intracardiac thrombi who failed to response to traditional anticoagulation therapy with Unfractionated Heparin and Aspirin; but thrombolysis occurred following combination therapy with Ticlopidine and Enoxaparin. Our experience in patients shown combination of Enoxaparin and Ticlopidine is effective for treatment of ventricular thrombus in TI patients

The prevalence and persistence of human parvovirus B19 infection in thalassemic patients.

Human parvovirus B19 infection was studied in 60 thalassemic patients in Thailand. Seroprevalence, persistence of parvovirus B19 and their genotypes were identified in blood samples. Prevalence of anti-parvovirus B19 IgG and DNA found in thalassemic patients were 38% and 13%, respectively. Anti-parvovirus B19 IgM could be detected in 4% of these positive anti-parvovirus B19 IgG patients. The seroprevalence and parvovirus B19 DNA in patients with a history of blood transfusion were not significantly higher than those without such a history (44% vs. 34% and 20% vs. 9%, respectively). Phylogenetic analysis of NS1 nucleotide sequences of three parvovirus B19 samples revealed that they were parvovirus B19 genotype 1. They showed low genetic diversity from prototype (Au) strain. We concluded that acute and chronic persistent parvovirus B19 infection were found in the thalassemic Thai patients. Chronic persistence of parvovirus B19 infection might play important clinical role in thalassemic patients because of the high prevalence of parvovirus B19 DNA. Blood transfusion had no significant influence to increase the prevalence of parvovirus B19 infection in thalassemic patients.

HFE mutation H63D predicts risk of iron over load in thalassemia intermedia irrespective of blood transfusions.

Iron overload is a well-documented complication in thalassemia intermedia. Moreover, it is seen that the number of blood transfusions received does not correlate with the degree of overload. Since, HFE gene is associated with iron overload; the present study was conducted in an attempt to evaluate its role in thalassemia intermedia. The subjects were consecutive thalassemia intermedia cases attending the Hematology outpatient clinic. Controls were healthy hospital staff with negative family history of hemolytic anemia or liver disease. The molecular analysis for HFE mutations H63D and C282Y were done with primers described earlier. ELISA was used to measure serum ferritin. Sixty-three patients of thalassemia intermedia including 48 beta-homozygous/heterozygous thalassemia intermedia and 15 HbE-beta-thalassemia were studied. Six (12.5%) of the former and two (13.3%) of the latter were heterozygous for H63D; one of which, a 51-year old male also had clinical features of hemochromatosis. In healthy controls, prevalence of H63D heterozygosity was 7.5% (6/80). An interesting feature observed was that though the age and transfusions taken were similar in both groups, the serum ferritin greater than 500 ng/dl were observed in all patients (100%) with HFE mutation whereas it was seen in 12/42 (28.6 %) of patients without the mutation (p = 0.002). Thus, it is concluded that thalassemia intermedia patients with co-existent HFE mutation have a higher likelihood of developing iron overload and may require early iron chelation.

Spinal cord compression due to intraspinal extramedullary hematopoiesis in thalassemia intermedia

Extramedullary hematopoiesis is a common phenomenon in thalassemia. During the disease there are very rare occasions when compensatory hematopoietic tissue is located in the intraspinal epidural space, causing spinal cord compression. This complication requires urgent neurosurgical consideration and decision for further treatment. We present a case of thoracic spinal cord compression secondary to extramedullary hematopoiesis in thalassemia intermedia, treated with irradiation therapy. The therapeutic options are discussed, and the need for more explicit therapeutic directions is highlighted

High-dose deferoxamine treatment [intravenous] for thalassaemia patients with cardiac complications

As a means to manage cardiac conditions, we determined the effects of high-dose intravenous [IV] deferoxamine in 15 thalassaemia patients with cardiomyopathy and high ferritin and haemoglobin levels. The patients received IV deferoxamine, 130 mg/kg per day over 10-14 hours [maximum 5 g] for 5 consecutive days. All patients underwent a full evaluation before receiving deferoxamine, and 2 days and 1 month after completing the treatment. Visual and auditory examinations were done to detect any side-effects. After treatment, cardiovascular symptoms decreased considerably and systolic function showed significant improvement, but there was no significant effect on diastolic function, electro-cardiography and physical findings. There were no significant side-effects reported

Physical growth patterns and dental caries in thalassemia.

This study was conducted to assess the effect of age, ferritin level, hemoglobin level and chelating agents on the physical growth in thalassemic children and to determine the prevalence of dental caries in thalassemic children. Weight, standing height, sitting height and subischial leg length were measured in 65 children attending the Thalassemia day care center at a tertiary hospital in Delhi. Their mean pre transfusion hemoglobin and ferritin levels over the previous two years were calculated. Dental caries indices, DMFT and DMFS were measured and compared with age matched controls. Weight, standing height, sitting height and subischial leg length expressed as percentage for age in children >or=10 y were significantly lower than those of children < 6 y, and those 6 to 10 y. Mean hemoglobin and ferritin did not affect growth significantly. Sitting height for age in children receiving Desferrioxamine alone or Desferrioxamine with Deferiprone was significantly lower than that of children receiving Deferiprone alone or no chelating agent. Dental caries were significantly higher in thalassemics.

HBsAg seropositivity among multi-transfused thalassemic children.

Thalassemia major patients are transfusion dependent; they are at high risk of post transfusion viral infections including Hepatitis B virus (HBV). The present study was undertaken to find out the proportion of HBV infection among multiple transfused patients. This cross-sectional study was conducted among thalassemic children of either sex between 2 to 13 years of age, who attended the tertiary care hospital (G. G. Hospital, Jamnagar). Subjects were divided according to number of transfusions and the immunization status. HBsAg was detected by ELISA. Of 90 patients 6 (6.6%) were positive for HBsAg. Of 29 patients who had received above hundred transfusions 3 (10.34%) were sero-positive for HBV. Un-immunized patients were at double risk for acquiring HBV infection. This study suggests that the screening of blood of donors for HBV should be strictly followed and implementation of immunization against HBV is a must, especially in a high-risk group like thallasemic patients.

Anti Kell allo-antibody in a thalassaemic.

We describe a case of incidental detection of anti Kell antibody in a child with transfusion dependent thalassaemia. Kell antibody detection may be missed by routine indirect antiglobulin test (IAT) crossmatch procedure because of low prevalence of Kell antigen in the general population. A false negative result can be avoided by using sensitive cross matching techniques and screening cells representing antigens in homozygous state, against all clinically significant antibodies. A transfusion alert card describing the nature of antibody and future transfusion policy should be given to such allo-immunized patients.

Abnormalities in lung function among multiply-transfused thalassemia patients: results from a thalassemia center in Malaysia.

The aim of this study was to: (1) determine the prevalence and patterns of lung dysfunction among transfusion dependent thalassemics; (2) determine the associated factors that might contribute to this problem. This was a cross-sectional study involving 66 patients with transfusion dependent thalassemia aged 10 years and above. All patients underwent physical examination, standardized pulmonary function tests including spirometry, lung volume, and the carbon monoxide diffusion capacity. A restrictive pattern of lung dysfunction was observed in 22 patients (33.3%) and none showed the presence of obstructive ventilatory impairment. A reduction in the carbon monoxide diffusion capacity (DLCO) was seen 87.9% of the patients, including 7.6% who had evidence of hypoxemia. Ten patients showed a reduction in the FEF25-75% although they did not fulfil the criteria for small airway disease. No correlation was found between lung dysfunction and serum ferritin levels in the patients. Restrictive lung dysfunction and diffusion impairment were the predominant abnormalities found in our cohort of patients.

Incidence of febrile seizures in thalassemic patients.

BACKGROUND: Febrile seizures are the most common seizures in children. Their incidence is 2-5% or 4.8/1000 person-years. To date, the pathophysiology of febrile seizures is unknown. But several hypotheses have been proposed that it may relate with plasma iron level. Such low incidence in thalassemic patients whose plasma iron level is high could give some clues to this hypothesis. PATIENTS AND METHOD: Four hundred and thirty thalassemic patients from the hematology clinic at two hospitals in Northeastern Thailand were consecutively enrolled between Febuary 2003 and January 2004. The authors reviewed all the medical records of the patients and interviewed their parents for occurrence of febrile seizures. RESULTS: The patients included 208 males and 222 females with an age ranged of 6 months to 10 years (mean = 6.36 years). Twenty patients (4.7%) had siblings who had febrile seizures. There were 3 episodes out of 2,734 person-years. The incidence was 1.10 per 1,000 person-years (95% CI: 0.23 to 3.20). This was statistically lower than that of the general population (p-value = 0.002). Therefore, the rate in thalassemic patients was 4.4 times less than that of the general population (95% confidence interval: 1.4 to 22.6). CONCLUSIONS: The incidence of febrile seizures in thalassemic patients was very low compared to that of the general children population. Thus, iron overload may be a major factor involving the brain metabolism that prevents febrile seizures.

Concomitant Gilbert's syndrome and thalassemia trait.

A 23 years old male presented with fluctuating jaundice since age of five years. He was diagnosed to have thalassemia trait along with Gilbert's syndrome. He had disproportionately higher bilirubin concentration for either disorder alone. The importance of the concomitance of these disorders is highlighted.