Thalassemia major

Zeimer, R, Belkin, M., Leitersdorff, E. and Rachmilewitz, E.A. (1978). A non-invasive method for the evaluation of tissue iron deposition in beta-thalassemia major. J. Lab. Clin. Med. 91, 24-31. 

Other diseases Autoimmune diseases Amyloidosis Aplastic anemia Paroxysmal nocturnal hemoglobinuria Fanconi s anemia Thalassemia major Sickle cell anemia Severe combined immunodeficiency Inborn errors of metabolism... 

Tablets/Capsules/Oral solution Ribavirin may cause birth defects or death of the exposed fetus. Ribavirin is contraindicated in women who are pregnant or in men whose female partners are pregnant (see Warnings), in patients with a history of hypersensitivity to ribavirin or any component of the drug, and in patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).

Patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia). 

Chronic iron toxicity (iron overload), also known as hemochromatosis, results when excess iron is deposited in the heart, liver, pancreas, and other organs. It can lead to organ failure and death. It most commonly occurs in patients with inherited hemochromatosis, a disorder characterized by excessive iron absorption, and in patients who receive many red cell transfusions over a long period of time (eg, patients with thalassemia major). 

Chronic iron overload in the absence of anemia is most efficiently treated by intermittent phlebotomy. One unit of blood can be removed every week or so until all of the excess iron is removed. Iron chelation therapy using parenteral deferoxamine is much less efficient as well as more complicated, expensive, and hazardous, but it may be the only option for iron overload that cannot be managed by phlebotomy, such as the iron overload experienced by patients with thalassemia major. 

Rapid intravenous administration may result in hypotension. Adverse idiosyncratic responses such as flushing, abdominal discomfort, and rash have also been observed. Pulmonary complications (eg, acute respiratory distress syndrome) have been reported in some patients undergoing deferoxamine infusions lasting longer than 24 hours, and neurotoxicity and increased susceptibility to certain infections (eg, with Yersinia enterocolitica) have been described after long-term therapy of iron overload conditions (eg, thalassemia major). 

Thalassemia Major. Transfusion-dependem thalassemia major patients liuvc abnormal growth and sexual maturation al puberty, presumably as a result of pituitary iron overload. Still poorly understood, this disorder is reported to respond well to deferoxamine iron chelation therapy, particularly if administered before the age of maturity. 

Susceptibility factors genetic (unoperated or palliated cyanotic congenital heart disease beta-thalassemia major) sex (conflicting results) altered physiology (iodine intake, conflicting results)... 

Patients with beta-thalassemia major have an increased risk of primary hypothyroidism. In 23 patients with beta-thalassemia amiodarone was associated with a high risk of overt hypothyroidism (33 versus 3% in controls) (43). This occurred at up to 3 months after starting amiodarone. The risk of subclinical hypothyroidism was similar in the two groups. In one case overt hypothyroidism resolved spontaneously after withdrawal, but the other patients were given thyroxine. After 21-47 months of treatment three patients developed thyrotoxicosis, with remission after withdrawal. There were no cases of hyperthyroidism in the controls. The authors proposed that patients with beta-thalassemia may be more susceptible to iodine-induced hypothyroidism, related to an underlying defect in iodine in the thyroid, perhaps associated with an effect of iron overload. 

Freedman MH, Grisaru D, Olivieri N, etal. Pulmonary syndrome in patients with thalassemia major receiving intravenous deferoxamine infusions. Am J Dis Child 1990 144 565-569. 

Tsironi M, Deffereos S, Andriopoulos B et al. Reversal of heart failure in thalassemia major by combined chelation therapy a case report. Eur J Haematol 2005 74(l) 84-85. 

Hemoglobinopathy (such as thalassemia major and sickle-ceU anemia) Decompensated liver disease Autoimmune diseases Renal function impairment... 

Brittenham, G.M., Cohen, A.R., McLaren, C.E., Martin, M., Griffith, PM., Nienhuis, A.W., Young, N.S., Allen, C.J., Farrell, D.E., Harris, J.W. Hepatic iron stores and plasma ferritin concentration in patients with sickle-cell anemia and thalassemia major. Amer. J. Hema-... 

In 1969 Schwartz (S29) described an Albanian family of two children with mild j8-thalassemia major. Their mother had a classical j8-thalassemia heterozygosity, but the father had a normal red cell morphology and normal levels of Hb-A, and Hb-F. The synthesis of /8 chains in this individual was impaired, although to a lesser extent than is usually observed in the classical jS-thalassemia. Interaction of this type of j8-thalassemia with the classical type results in a thalassemia major of reduced severity because the apparent homozygous children from this marriage are only mildly affected with levels of Hb-F of less than 12%. 

Fig. 12. The separation of globin chains prepared from cells incubated with leucine- H by chromatography on a column of CM-cellulose. Solid line represents the optical density at 280 nm, and the dotted line, the radioactivity. (A) A normal subject the P chain is eluted in tubes 20-30 and the a chain in tubes 42-52. The a p ratio of radioactivity is 1.0. (B) A patient with /3-thalassemia major the y chain is found in tubes 10-20, the p chain in tubes 22-32, and tiie a chain in tubes 38-50. The a. p ratio of radioactivity is greater than 60. (C) A patient with Hb-S-/3-thalassemia the normal p chain is found in tubes 25-33, the p chain in tubes 35-42, and the a chain in tubes 46-55. The a -P ratio of radioactivity is 2.9. From Marks and Bank (M7) with permission of the authors and publisher.

B12. Bank, A., and Marks, P. A., Excess a chain synthesis relative to 8 chain synthesis in thalassemia major and minor. Nature (London) 212, 1198-1200 (1966). 

Mariotti S, Loviselli A, Murenu S, Sau F, Valentino L, Mandas A, Vacquer S, Martino E, Balestrieri A, Lai ME. High prevalence of thyroid dysfunction in adult patients with beta-thalassemia major submitted to amiodarone treatment. J Endocrinol Invest 1999 22(l) 55-63. 

Ascorbic acid promotes the absorption of iron, a reason for caution in giving high doses to patients with iron overload (SEDA-9, 324). In particular, patients with hemochromatosis, polycythemia, and leukemia who present with marked iron overload should keep their intake of ascorbic acid to a minimum (42). However, ascorbic acid can also interfere with the distribution of iron in the body in these patients. One consequence is that in patients with iron overload who also have scurvy, iron tends to be deposited in the reticuloendothelial system rather than the parenchymal cells, which may reduce the risks of damage to the liver, heart, or endocrine glands. It has conversely been noted that in beta-thalassemia major... 

Cohen A, Cohen IJ, Schwartz E. Scurvy and altered iron stores in thalassemia major. N Engl J Med 1981 304(3) 158-60. 

De Virgiliis S, Galanello R, Cao A. Plasmodium malariae transfusion malaria in splenectomized patients with thalassemia major. J Pediatr 1981 98(4) 584-5. 

Poonkuzhali B, Chandy M, Srivastava A, Dennison D, Krishnamoorthy R. Glutathione S-transferase activity influences busulfan pharmacokinetics in patients with beta thalassemia major undergoing bone marrow transplantation. Drug Metab Dispos 2001 29(3) 264-7. 

Erer B, Polchi P, Lucarelli G, Angelucci E, Baronciani D, Galimberti M, Giardini C, Gaziev D, Maiello A. CsA-associated neurotoxicity and ineffective prophylaxis with clonazepam in patients transplanted for thalassemia major analysis of risk factors. Bone Marrow Transplant 1996 18(l) 157-62. 

In a Lebanese study in 17 patients, mainly with thalassemia major, there were no serious adverse reactions to deferiprone 50-75 mg/kg/day (11). Joint pain, stiffness, or sweUing occurred in six patients the symptoms were severe in two and mild in four patients. Seven patients had nausea, especiaUy in the first month of treatment, and two had a reduced appetite. Headache developed in four patients. Mouth ulcers, sore throat, bitter taste, and fatigue occurred in single cases. In one patient there was a weakly positive ANE after 6 months. There were no cases of granulocytopenia and in none of the patients did adverse effects require drug withdrawal. The authors suggested that environmental or hereditary factors might have influenced the results. 

Deferiprone paradoxically worsened hepatic fibrosis in patients with thalassemia major, based on hepatic biopsies in 19 patients (7). On the other hand, in another study of 20 liver biopsies, worsening of hepatic fibrosis was not mentioned (9). 

Olivieri NF, Brittenham GM, McLaren CE, Templeton DM, Cameron RG, McQelland RA, Burt AD, Fleming KA. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med 1998 339(7) 417-23. 

Pati HP, Choudhry VP. Deferiprone (LI) associated neutropenia in beta thalassemia major an Indian experience. Eur J Haematol 1999 63(4) 267-8. 

Ohvieri NF, Brittenham GM, Matsui D, Berkovitch M, Blendis LM, Cameron RG, McClelland RA, Liu PP, Templeton DM, Koren G. Iron-chelation therapy with oral deferipronein patients with thalassemia major. N Engl J Med 1995 332(14) 918-22. 

Deferiprone and deferoxamine have been compared in Lebanese patients, mainly with thalassemia major, of whom 17 used oral deferiprone, 75 mg/kg/day for 2 years, and 40 received subcutaneous deferoxamine 20-50 mg/kg/day on 5 days a week (6). Those who received deferoxamine had done so for 4-24 years and were followed for 2 years. Infusion site reactions occurred in 34 patients, including pain, tenderness, itching, burning, erythema, swelling, induration, and lipodystrophy. Five patients had disturbances of vision and hearing, three had growth retardation. Six patients had increased heart rates, four had dizziness, and one had leg cramps. 

Pneumonia during treatment with high doses of deferoxamine (2-2.5 g by continuous infusion) in a patient with thalassemia major was found to be caused by Pneumocystis jiroveci (29). 

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