The thalassemias are a group of hereditary disorders in which there is a decreased production of one or more of the normal polypeptide chain of hemoglobin. This results in the production of erythrocytes that have a low intrazellular hemoglobin content (hypochromia) and are smaller than normal (microcytosis). In addition, the normal synthesis of the unaffected globin chain leads to the accumulation of unstable aggregates which precipitate within the red cell leading to membrane damage and premature destruction in the peripheral circulation and at an earlier stage in the bone marrow (ineffective erythropoiesis). The thalassemia syndromes are usually classified according to the type of globin chain which is absent or present in decreased amounts (Table 1).
The combination of ineffective erythropoiesis and severe anemia results in increased erythropoietic activity in the marrow and extramedullary hematopoiesis in sites such as the liver, spleen and lymph nodes. The major clinical man' ifeatations in ß-thalassemia are due primarily to chronic hemolysis, the body's attempt to compensate for the anemia, and excess iron that accumulates from blood transfusions. This paper will discuss the complications and current management of ß-thalassemia major. The therapeutic considerations discussed are also applicable to the other less common forms of thalassemia which may or may not be transfusion' dependent with resultant hemosiderosis.
The complications of ß-thalassemia major result primarily from: 1) excessive hematopoiesis, 2) chronic hemolysis, and 3) iron overload with resultant organ damage.
Complications Due to Excessive Hematopoiesis
Marked bone marrow hypertrophy and extramedullary hematopoiesis are a result of the profound anemia. Radiologie bony abnormalities appear by the second year of life and are fully developed by 10 years. ' Bone changes are most prominent in the craniofacial area resulting in a "rodent facies" due to maxillary overgrowth, protrusion of the teeth and separation of the orbits. In addition, flattening of the nasal bridge and malar prominence can result in a "mongo loid facies."2 Other complications due to craniofacial changes are chronic sinusitis and impaired hearing.3
The conical thinning which results from marrow hyperplasia can cause recurrent pathologic fractures especially in weight bearing bones. In one series, over 30% of thalassemic children experienced one or more pathologic fractures.4 The aforementioned skeletal abnormalities are almost completely prevented if a high transfusion (HT) program is initiated before 4 years of age.5,7 In addition, facial deformities and certain orthodontic problems may be surgically corrected in rare cases (Figure 1).8
Spinal cord compression, although rare has been reported.9,10 It is due to direct expansion of hematopoietic tissue from the vertebral marrow into the epidural space. Surgical excision of the hematopoietic tissue is the treatment of choice.
Extramedullary hematopoiesis in lymph nodes can result in significant lymphadenopathy particularly the mediastinum,10 and hepatosplenomegaly is invariably present due to chronic hemolysis and extramedullary hematopoiesis.
Complications Due to Chronic Hemolysis
Gallstones are present in approximately 70% of thalassemic children over age 15 years. n·12 In these patients, cholecystectomy is done only if there is obstructive jaundice or biliary colic. However, prior to splenectomy, if gallstones are demonstrated by sonography, elective cholecystectomy can be performed at the time of splenectomy.
Leg ulcers are rare in this hemoglobinopathy and generally occur in late adolescence and early adulthood.13'16 A study demonstrated a beneficial effect of high doses of ascorbic acid in healing these ulcers.16 Although this study reported no complication of therapy, the potential cardiotoxic effect of vitamin C in these iron-overloaded patients must be kept in mind.
CLASSIFICATION OF THALASSEMIA
Complications Due to Iron Overload
The excess iron deposition in thalassemia secondary to transfusion is distributed throughout all the body tissues, with the liver, spleen, and pancreas having the highest concentrations. Secondary hemochromatosis is the major cause of morbidity and mortality in transfused children with thalassemia, with cardiac dysfunction being the primary cause of death.
There are three major cardiac problems which can develop: 1) pericarditis, 2) atrial and ventricular arrhythmias, and 3) congestive heart failure.
Pericarditis may often be the initial manifestation of cardiac iron deposition, with the majority of children being older than 10 years at the time of initial attack.17·18 Treatment includes bed rest, anti- inflammatory agents (aspirin, indomethicine) and analgesics. The acute phase is self-limited and generally lasts for 2 to 3 weeks. A chronic constrictive pericarditis is a rare but documented complication of iron overload which can cause cardiac tamponade. 19 In these cases, pericardiectomy is helpful.
Atrial and ventricular arrhythmias documented by 24hour electrocardiographic recordings can be found in most dialassemic children who have received 150 to 200 units of blood.20 The initial electrocardiographic abnormalities include a prolonged P-R interval, first degree heart block, and premature atrial contractions.17 More serious arrhythmias such as atrial fibrillation and supraventricular tachycardia require the use of digitalis, quinidine, propanolol, etc. for suppression. Appropriate biood levels should be obtained to assure therapeutic levels.
Cardiomegaly and left ventricular hypertrophy due to cardiac hemosiderosis eventually progress to chronic refractory heart failure. Standard therapy includes digitalis, diuretics, and salt restriction, but results are discouraging. The eventual mortality after the onset of heart failure is over 90% with the majority of children dying within 1 year.17,21
Hepatomegaly is invariably found in children with thalassemia major. Initially, this is due to extramedullary hematopoiesis which is reduced by hypertransfusions.22 As liver iron increases due to repeated transfusions, hepatic fibrosis usually develops by 7 years of age and older patients have histologie evidence of cirrhosis.23"25 However, tKalassemics rarely have problems related to liver dysfunction with the only evidence occasionally being mild prolongation in the coagulation mechanism due to decreased production of the liver-dependent factors.26 Complications of cirrhosis such as hypoproteinemia, portal hypertension and hepatic encephalopathy are extremely rare.
Although the majority of patients will have elevation of the serum transaminases, levels four or more times higher dian normal may indicate hepatitis. In one study, 77% of children biopsied because of persistent hypertransaminemia had histologie evidence of hepatitis.27
Growth and Endocrine Dysfunction
Children with thalassemia major on a high transfusion program grow normally until about 12 years of age.6·28 Thereafter, growth velocity declines and the pubescent growth spurt is absent. V9-32 Patients will continue to grow but more than 70% are below the 10th percentile at 21 years.33 The mechanism for growth failure is probably a combination of chronic disease and excess iron deposition. Growth hormone levels are normal or increased. 32,34,35
Delayed or incomplete sexual maturation occurs in almost all patients. Females exhibit either delayed or incomplete breast development; and menarche if it occurs is usually late. Males show either partial or complete failure of sexual development. In the few children who achieve normal sexual development, secondary hypogonadism may occur. Although gonadatropins are normal during childhood, the expected rise during puberty does not occur suggesting impaired pituitary and/or hypothalamic function.34,36,37 In patients with inadequate sexual development, hormone replacement can be utilized: testosterone injections for boys and low dose estrogen replacement for girls.
Acquired hypothyroidism, hypoparathyroidism, and diabetes mellirus due to Kemochromatosis occasionally occur.34,38-40 Management of these disorders is with standard endocrine replacement.
The current therapy of the patient with thaîassemia major entails red cell transfusions for correction of anemia, chelation therapy for transfusional hemosiderosis, splenectomy, and other therapy for specific complications.
Prior to the availability of red cell transfusions, children with thaiassemia had progressive deterioration and continued enlargement of the liver and spleen. Death occurred in a majority of the chiidren by 4 years of age due to congestive heart failure secondary to severe anemia or to intercurrent infections.
The majority of children with thaiassemia major will require a regular transfusion program to control the anemia. The benefits of a high transfusion (HT) program (maintaining hemoglobin above IO g/dt) compared to a low transfusion (LT) program (maintaining hemoglobin above 7 g/dl) have been clearly demonstrated.5·6·21·41"44 The benefits of a HT program include: 1) improved physical and psychologic wellbeing due to the ability to participate in normal activities, 2) decreased incidence of cardiomegaly due to anemia, 3) decrease in hepatosplenomegaly because of reduced extramedullary hematopoiesis, 4) fewer bone changes and orthodontic problems because of reduced bone marrow activity, 5) normal or near normal growth and development until adolescence and 6) fewer intercurrent infections. There is no evidence that patients on a HT program suffer symptoms of iron toxicity earlier than those on an LT program.
A transfusion program has been described in which the hemoglobin is maintained above 12 g/dl, ie, supertransfusion. *5 The initial study reports a decrease in the blood volume and a decrease in erythropoietic stimulus. A final evaluation of the effectiveness of this program should be forthcoming in the near future.
It is the policy at this institution to give the patient with thaiassemia major the first transfusion when the hemoglobin level falls below 6 g/d!. If severe anemia develops again, a regular transfusion program is initiated to maintain the hemoglobin level above 10 g/dl.
The majority of children require transfusions every 2-4 weeks. This is done in the pediatrie hematology outpatient transfusion room which minimizes time spent in the hospital and away from normal activities. In addition, one nurse is in charge of the thalassemic patients and this allows establishment of a special rapport which is extremely important in any chronic illness. On the morning of outpatient admissions, an interval history, physical examination, and complete blood count including reticulocyte count is performed. An intravenous tine is started and a type and cross match for 15 cc/kg of packed red blood cells is drawn.
The type of blood product used initially is packed red blood cells. The most frequent adverse reaction to this product is a febrile reaction due to sensitización to serum proteins or leukocyte surface antigens. This complication is avoided by switching to washed cells in which almost all the serum and 95% of the leukocytes are removed or red cells frozen in glycerol which is essentially free of serum proteins and leukocytes after thawing and washing several times. Although rare, febrile reactions which continue with the use of leukocyte poor blood can be treated with Tylenol and/or antihistamine prior to transfusion. An innovative technique to provide a superior transfusion product is the use of a continuous flow cell separator ( Aminco celltrifuge, IBM centrifuge) to obtain young cells from donors ie, neocytes.45 Since the average age of these "neocytes" is only 15 to 30 days, there is a dramatic increase in survival of the transfused cells. By using neocytes, the transfusion interval can be increased from approximately 2 to 4 weeks to 7 weeks and decrease the iron load from transfusions proportionately.
Figure 1. 15-year-old female with thaiassemia and severe craniofacial changes before A and after B orthognathic surgery
COMPARISON OF THE SAME DOSE OF DESFERRIOXAMINE (DF) GIVEN IM AND SC
Figure 2. Transfusional iron loading in children with rhalassemia on a high transfusion program. O = patients alive; X = patients deceased. (From Modell B, Berdoubas V: The Clinical Approach to Tfta/assewwa J 984; Gruñe & Stratton, London,!
In children receiving regular red cell transfusions, development of isoantibodies to minor blood group antigens may occur, ie, KeIl, Duffy, C, c, E.46 Performance of a red cell eluate and reacting the offending antibody wich a panel of test cells permits identification of the antibody and selection of appropriate donor blood. In rare instances, patients may develop several isoantibodies which can make it extremely difficult to obtain compatible blood. In those cases, blood may have to be obtained from a regional center which has access to a larger donor pool.
Repetitive blood transfusions enhance the risk for transmission of viral diseases. Homologous serum hepatitis is one of the most serious hazards of transfusion and can result in significant morbidity. Donor blood is routinely screened for hepatitis B surface antigen by radioimmunoassay. However, no methodology is able to detect every unit of donor blood capable of transmitting hepatitis, so the disease continues to occur with an incidence of 0.9/1, 000 units of volunteer blood transfused.47 Recently, hepatitis vaccine (purified hepatitis B surface antigen) has been shown to confer protection against transfusion induced hepatitis in several studies and is now approved for use in "high-risk" patients.48'50 Its use is warranted in those children with thalassemia-major who are hepatitis B surface antigen negative.
Other viral diseases which can be transmitted by transfusion include cytomegalovirus, toxoplasmosis and EpsteinBarr (EB) virus.
Chelation Therapy for Iron Overload
An inevitable consequence of chronic biood transfusions in thalassemia major is iron overload with secondary hemochromatosis. The excess deposition of iron in various tissues results in organ dysfunction of the heart, liver, and endocrine glands. The clinical manifestation of excess tissue iron in the aforementioned organs is referred to as secondary hemochromatosis.
Each unit of red cells contains 200 to 250 mg of elemental iron, so that the thalassemic patient who is on a proper transfusion program will have 5 5 to 60 g of iron deposited in various tissues by 12 years or" age (normal total body iron = 2 g) (Figure 2). The body has no effective means for excreting this excess iron.
Deferoxamine mesylate (desierai) is the only drug currently available for removal of body iron. In order for the drug to have any significant impact on total body iron stores, it must be given parenterally. The two most effective parental routes are continuous intravenous (IV) and subcutaneous (SQ) infusion. 51'57 The intramuscular route is considerably less effective52'54·58 and is rarely employed in modem chelation therapy programs (Table 2).
The optimal chelation program should result in negative iron balance defined as urinary iron excretion in excess of transfusional iron loading. In the majority of children, this can only be achieved by daily subcutaneous infusion of desferal and supplemental intravenous administration. Desferal's effectiveness depends on dose, time in the blood stream, and chelatable iron pool.55
The following chelation regimen is used which utilizes a combined SQ-IV regimen:
IRON BALANCE IN THALASSEMIA MAJOR
IRON BALANCE IN THALASSEMIA MAJOR
1 ) Desierai 40 mg/kg subcutaneously over 8 to 10 hours via a portable infusion pump, 6 days a week.
2) Desierai 120 mg/kg intravenously over 8 hours at the time of transfusion.
This regimen has been shown to result in negative iron balance in children over 5 years of age. Table 3 shows the iron balance records on a 7-year-old child on this regimen.
In older thalassemics who have accumulated a large total body iron burden prior to initiation of chelation therapy, more aggressive treatment is utilized to try and more rapidly reduce the iron stores. The regimen currently being utilized at our institution includes a high dose of intravenous desferai (400 mg/kg) given continuously over a 48-hour period prior to each transfusion in addition to daily subcutaneous desierai. This aggressive intravenous therapy results in considerable urinary iron excretion as shown in the iron balance records in Table 4 on a 21-year-old patient.
The daily subcutaneous infusion of desierai is administered with a portable infusion over an 8 to IO hour period at a concentration of 250 mg/cc. A 27-gauge butterfly is inserted into the thigh or lower abdominal wall at a 45° angle and taped in place. Most patients infuse themselves at night while sleeping so that normal activities are not interrupted.
Toxicity is minimal. Side effects with subcutaneous infusion include local irritation, abdominal discomfort, urticaria at the injection site, and mild cirrhosis. Rapid IV infusion may induce hypotension so that the maximum IV infusion is 15 mg/kg/hr. Cataracts may occur with high doses >100 mg/ kg so twice yearly ophthalmologic examinations are done. Recently, audio-visual neurotoxicity has been reported in thalassemia patients receiving desierai so audio-visual testing should be part of the routine care. 59
At this institution, chelation is started at about 4 years of age when compliance by parents and patient is possible.
Thalassemia patients with iron overload are frequently vitamin C deficient as evidenced by low leukocyte and serum vitamin C levels. The use of vitamin C supplementation has been shown to increase desierai urinary iron excretion from 20% to 250%.60"62 The mechanism by which vitamin C supplementation increases iron excretion is uncertain, but may include: 1) direct release of iron from stores to the chelating agent, and, 2) reduction of ferric ion to a ferrous intermediate which reacts with a ferroxidase-like ceruloplasmin to produce a ferric ion which is very accessible to desierai.63
Cardiac toxicity has been reported in patients receiving 500 mg of vitamin C and intramuscular desierai.64·65 It has been postulated that vitamin C combines with iron which has been released from storage sites to result in generation of free radicals which damage cell membranes by lipid oxidation.63 At our institution, the maximal dose of vitamin C given is 100 mg and only at the time of subcutaneous infusion to insure iron binding to desierai and prevent the toxic interaction of vitamin C and iron.
Vitamin E is an antioxidant that may protect erythrocyte membranes against peroxidation by free radicals that may be formed when an excess of iron is present. Vitamin E deficiency has been noted in many chronically transfused patients with thalassemia major.66-68 One study showed no improvement in transfusion interval with vitamin E supplementation.69 If supplementation is given the dose is IO to 15 units/kg/day in three divided doses.
Megaloblastic anemia due to folie acid deficiency may develop in patients with B-thalassemia major.70'71 Supplementation with 1 mg of folte acid daily is recommended.
Patients with thalassemia major invariably develop splenomegaly due to extramedullary hematopoiesis, reticuloendothelialhyperplasia, and iron deposition. Ingenerai, the degree of splenomegaly and incidence of hypersplenism is reduced when patients are on a HT program.6· 21 The main indication for splenectomy is hypersplenism. Hypersptenism may be reflected by leukopenia and thrombocytopenia, but in thalassemia patients, an increase in transfusion requirements to maintain an acceptable hemoglobin level is a more common manifestation. The yearly blood requirement for splenectomized patients with thalassemia major has been documented (Figure 3) and it is recommended that the spleen be removed if the patient's blood requirement exceeds the predicted amount by 50%, 72 For example, if the blood requirements to maintain a hemoglobin level >10 g/dl exceeds 250 to 275 cc/kg/year, a splenectomy is recommended.
Splenectomy predisposes the patient to an increased risk of severe pneumococcal, streptococcal or Hemophilia influenza infection.73-77 However, it is important to remember that severe infections may occur with organisms not covered by pneumovax and penicillin, ie, E Coli.77·78 Two weeks prior to splenectomy, 0.5 cc of pneumovax is given. Postsplenectomy, the patient is placed on penicillin 250 mg po bid. At our institution, this regimen has been successful in preventing severe infections in splenectomized children with Hodgkin's disease.80
Figure 3. Relationship between blood requirement and mean hemoglobin level maintained by transfusion. Splenectomy is recommended if patient* btood requirement exceeds the expected by 50%. (From Modell B: Total management of thalassemia major Arch Dis Child 1977; 52:489)
Patients are instructed to- come to the hospital if they develop fever above 38.50C. if a minor source is found for the fever, ie, pharyngitis, otitis media, upper respiratory tract infection, and the patient is not toxic, blood cultures are drawn and the patient placed on appropriate oral antibiotics. If the patient has a major source for fever, ie, pneumonia, or if no obvious source can be identified, appropriate cultures are taken and the patient is hospitalized for intravenous antibiotics whose duration depends on culture results and defervescence of fever. In patients who appear toxic, ampie i Il in and tobramycin are given initially, otherwise ampicillin alone is the initial treatment.
The aforementioned standard therapy is supportive: treat the anemia with red cell transfusions and the associated hemosiderosis with chelation therapy. Recently, reports have appeared utilizing bone marrow transplantation which destroys genetically abnormal marrow and replaces with hematopoietically normal marrow.81·82 With continued improvement in managing the complications of transplant as documented by the impressive long-term survival rates of patients transplanted for aplastic anemia, this modality may represent optimal therapy for severe thalassemia major in the future.
Another approach to therapy is to employ agents which would increase fetal hemoglobin synthesis and thus reduce transfusion requirements. One such agent is 5-azacytidine which is an anti-cancer agent used primarily in acute mvelogenous leukemia.83 The use of oncogenic agents on a chronic basis for this disease is highly controversial and has generated much discussion in the literature.84 The concept of stimulating fetal hemoglobin production is sound, but a non-mutagenic agent would obviously be preferable. A basic understanding of the switch from fetal hemoglobin to adult hemoglobin production may allow gene reswitching to become a means of therapy in the future.
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CLASSIFICATION OF THALASSEMIA
COMPARISON OF THE SAME DOSE OF DESFERRIOXAMINE (DF) GIVEN IM AND SC
IRON BALANCE IN THALASSEMIA MAJOR
IRON BALANCE IN THALASSEMIA MAJOR