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*This may be associated with a syndrome known as a-Thalassemia X-linked mental retardation syndrome characterized by hemoglobin H inclusions (3-globin tetramers), distinctive cranial features, genital anomalies, developmental delay with hypotonia and mental retardation.

Sequelae

1. Hyperplastic marrow (bone marrow expansion with cortical thinning and bony abnormalities)

2. Increased iron absorption and iron overload (especially with repeated blood transfusion), resulting in a. Fibrosis/cirrhosis of the liver b. Endocrine disturbances (e.g., diabetes mellitus, hypothyroidism, hypogo-nadism, hypoparathyroidism, hypopituitarism)

c. Skin hyperpigmentation d. Cardiac hemochromatosis manifesting as pericarditis, arrhythmias, car-diomegaly, pericarditis, and ultimately, cardiac failure

3. Hypersplenism a. Plasma volume expansion b. Shortened red cell life (of autologous and donor cells)

c. Leukopenia d. Thrombocytopenia.

Hematology

1. Anemia: Hypochromic, microcytic

2. Reticulocytosis

3. Leukopenia and thrombocytopenia (may develop with hypersplenism)

4. Blood smear: Target cells and nucleated red cells, extreme anisocytosis, contracted red cells, polychromasia, punctate basophilia, circulating normoblasts

5. 51Cr-labeled red cell life span reduced (but the ineffective erythropoiesis is more important in the production of anemia)

6. Hemoglobin F raised; hemoglobin A2 increased

7. Bone marrow: May be megaloblastic (due to folate depletion); erythroid hyper-plasia

8. Osmotic fragility: Decreased

9. Serum ferritin: Raised.

Biochemistry

1. Raised bilirubin (chiefly indirect)

2. Evidence of liver dysfunction (late, as cirrhosis develops)

3. Evidence of endocrine abnormalities, for example, diabetes (typically late), hypogonadism (low estrogen and testosterone).

Clinical Features

Because of the variability in the severity of the fundamental defect, there is a spectrum of clinical severity (major to intermedia) that considerably influences management. P-Thalassemia intermedia is defined as homozygous or doubly heterogeneous thalassemia, which is generally not transfusion dependent. Clinical manifestations include:

1. Failure to thrive in early childhood

2. Anemia

3. Jaundice, usually slight; gallstones

4. Hepatosplenomegaly, which may be massive; hypersplenism

5. Abnormal facies, prominence of malar eminences, frontal bossing, depression of bridge of the nose, and exposure of upper central teeth a. Skull radiographs showing hair-on-end appearance due to widening of diploic spaces b. Fractures due to marrow expansion and abnormal bone structure c. Generalized skeletal osteoporosis

6. Growth retardation, delayed puberty, primary amenorrhea in females, and other endocrine disturbances secondary to chronic anemia and iron overload

7. Leg ulcers

8. Skin bronzing

If untreated, 80% of patients die in the first decade of life. With current management, the life expectancy has dramatically increased. Patients now reach the fifth decade of life and are expected to live well beyond.

Complications

Complications develop as a result of:

• Chronic anemia in patients who are undertransfused or in untransfused tha-lassemia intermedia patients

• Chronic transfusion with resultant hemosiderosis and hemochromatosis

• Poor compliance with chelation therapy (generally).

Even in carefully managed patients, the following complications may develop:

• Endocrine disturbances (e.g., growth retardation, pituitary failure with impaired gonadotropins, hypogonadism, insulin-dependent diabetes mellitus, adrenal insufficiency, hypothyroidism, hypoparathyroidism)

• Cirrhosis of the liver and liver failure

• Cardiac failure due to myocardial iron overload (often associated with arrhythmias and pericarditis)

• Extramedullary hematopoiesis, resulting in bony deformities

• Marked osteoporosis is nearly uniformly present by the time patients reach adolescence. The causes of this include medullary expansion, deficiency of estrogen and testosterone, nutritional deficiency, and desferrioxamine toxicity. Manifestations include rickets, scoliosis, spinal deformities, nerve compression, fractures, and severe osteoporosis. Osteoporosis can be delayed by the early institution of chela-tion in childhood and sex hormone replacement early in adolescence.

Causes of Death

1. Congestive heart failure

2. Arrhythmia

3. Sepsis secondary to increased susceptibility to infection post-splenectomy

4. Multiple organ failure due to hemochromatosis.

Management

Hypertransfusion Protocol

The hypertransfusion protocol is used to maintain a pretransfusion hemoglobin between 10.5 and 11.0 g/dL at all times using 15 cc/kg leukocyte-depleted cross-matched packed red cells. Post-transfusion hemoglobin falls roughly 1 gram per week, necessitating transfusions every 3-4 weeks. Transfusion therapy should be started when a diagnosis is made and the hemoglobin level falls below 7 g/dL. Hypertransfusion results in:

1. Maximizing growth and development

2. Minimizing extramedullary hematopoiesis and decreasing facial and skeletal abnormalities

3. Reducing excessive iron absorption from gut

4. Retarding the development of splenomegaly and hypersplenism by reducing the number of red cells containing a-chain precipitates that reach the spleen

5. Reducing and/or delaying the onset of complications (e.g., cardiac). Chelation Therapy

The objectives of chelation therapy are:

1. To bind free extracellular iron

2. To remove excess intracellular iron

3. To attain a negative iron balance (i.e., iron excretion > iron input). Iron overload results from:

1. Ongoing transfusion therapy

2. Increased gut absorption of iron

3. Chronic hemolysis.

Chelation using desferrioxamine (Desferal) is recommended as follows:

1. Chelation should be instituted when the ferritin level is greater than 1000 ng/mL and adequate iron is excreted into the urine with the desferrioxamine challenge.

2. The desferrioxamine challenge is performed as follows:

a. A 24-hour urine collection is started.

b. Desferrioxamine 40 mg/kg is infused IV over 8 hours, starting at the beginning of the collection.

c. The urine collection continues for 16 more hours, and the urine is assayed for total iron content.

d. If the 24-hour urinary iron excretion is greater than or equal to 50% of the daily iron overload, the patient is ready for chelation.

e. Daily iron load is calculated using roughly 1 mg iron/1 mL packed red blood cells (PRBCs). For example, if a patient receives 210 cc PRBCs every 21 days, the daily iron load is 10 mg. If the patient excretes 5 mg iron with the 24-hour challenge, chelation should be started.

3. Desferrioxamine, 40-60 mg/kg/day, is infused subcutaneously over 8-10 hours nightly via a portable electronic pump 4-6 nights per week, depending on iron overload.

4. In selected cases, with severe iron overload, desferrioxamine is administered IV in a high dose, maximum 10 g/day. This may be done immediately posttransfusion to bind transiently increased free serum iron.

5. The aim is to maintain the serum ferritin level close to 1000 ng/mL. The ferritin level should be monitored every 3-6 months.

The complications of desferrioxamine administration include:

Swelling at infusion site

Local reactions: pruritus, rash, and hyperemia (add hydrocortisone 2 mg/mL to the desferrioxamine solution) Anaphylactoid reactions (treat by desensitization)

Toxic effects on the eye; cataracts, reduction of visual fields and visual acuity, and night blindness; occurs with prolonged or high-dose therapy or if desferrioxamine is used without sufficient iron overload Hearing impairment with prolonged or high-dose therapy, typically without sufficient iron overload

Metaphyseal dysplasias

Desferrioxamine toxicity exacerbated when there is insufficient excretable iron relative to the amount of desferrioxamine given.

Splenectomy

1. Splenectomy reduces the transfusion requirements in patients with hyper-splenism. It is usually performed in adolescents when transfusion requirements have increased secondary to hypersplenism.

2. Two weeks prior to splenectomy, a polyvalent pneumococcal and meningococ-cal vaccine should be given. If the patient has not received a Haemophilus influenzae vaccine, this should also be given. Following splenectomy, prophylactic penicillin 250 mg bid is given to reduce the risk of overwhelming post-splenectomy infection. Management of the febrile splenectomized patient is detailed in Chapter 26.

3. Indications for splenectomy include:

a. Persistent increase in blood transfusion requirements by 50% or more over initial needs for more than 6 months b. Annual packed cell transfusion requirements in excess of 250 mL/kg/year in the face of uncontrolled iron overload (ferritin greater than 1500 ng/mL or increased hepatic iron concentration)

c. Evidence of severe leukopenia and/or thrombocytopenia.

Supportive Care

1. Folic acid is not necessary in hypertransfused patients; 1 mg daily orally is given to patients on low transfusion regimens.

2. Hepatitis B vaccination should be given to all patients.

3. Appropriate inotropic, antihypertensive, and antiarrhythmic drugs should be administered when indicated for cardiac dysfunction.

4. Endocrine intervention (i.e., thyroxine, growth hormone, estrogen, testosterone) should be implemented when indicated.

5. Cholecystectomy should be performed if gallstones are present.

6. Patients with high viral loads of hepatitis C that are not spontaneously decreasing should be treated with PEG-interferon and ribavirin. Ribavirin increases hemolysis and transfusion requirements typically increase during therapy.

7. HIV-positive patients should be treated with the appropriate antiviral medications.

8. Genetic counseling and antenatal diagnosis (when indicated) should be carried out using chorionic villus sampling or amniocentesis.

9. Management of osteoporosis includes:

a. Periodic screening and prevention through early hormonal replacement.

b. Yearly screening of adolescents with bone densitometry and gonadal hormone evaluation.

c. Early in adolescence, patients should receive estrogen/progesterone or testosterone replacement to prevent gonadal insufficiency-induced bone loss, which may result in a decreased adult height due to fusion of the epi-physes. The possible increased risk of breast cancer with hormonal replacement therapy should be explained to female patients.

d. Two new agents are available to treat osteoporosis: (1) Calcitonin prevents trabecular bone loss by inhibiting osteoclastic activity. Parenteral and intranasal preparations are available. Miacalcin is the intranasal preparation. The dose is 1 spray into alternating nostrils daily. Miacalcin should be taken with calcium carbonate 1500 mg daily and vitamin D 400 units daily. (2) Bisphosphonates (alendronate sodium) also inhibit osteoclast-mediated bone resorption. The usual dose of Fosamax is 10 mg orally taken daily with a full glass of water 30 minutes before breakfast.

Follow-up of patients with thalassemia includes:

Monthly: Measure the pretransfusion hemoglobin.

Every 3 months: Measure height and weight; measure ferritin; perform complete blood chemistry, including liver function tests. Every 6 months: Complete physical examination and dental examination. Every ye"r: Evaluate growth and development; evaluate iron balance; complete evaluation of cardiac function (echocardiograph, ECG, Holter monitor as indicated); endocrine function (TFTs, PTH, FSH/LH, testosterone/estradiol, IGF-1, fasting cortisol); visual and auditory acuity; viral serologies (HAV, HBV panel, HCV [or if HCV+, quantitative HCV RNA PCR], HIV); bone densitometry; ongoing psychosocial support.

Every 1-2 ye"rs: Evaluation of tissue iron burden: SQUID (superconducting quantum interference device) measurement of liver iron; T2-star measurement of cardiac iron (in select patients with cardiac disease); liver biopsy for iron concentration and histology.

Future Directions

Ongoing research to investigate better therapies for thalassemia patients is critical. The National Institutes of Health recently established the Thalassemia Clinical Research Network to facilitate clinical research trials in thalassemia.

Alternative Methods of Chelation

Nightly subcutaneous administration of desferrioxamine is time consuming and interferes in many ways with the lifestyle of the patient. For this reason, compliance is often suboptimal and patients develop hemochromatosis.

Clinical testing of a number of oral chelating compounds is under way. Deferiprone (Ll) in a dose of 75 mg/kg/day is currently being used in Europe and is undergoing further clinical trials for FDA approval. Controversy exists at present about its potential toxicity, including idiosyncratic neutropenia, arthropathy, and possible adverse redistribution of iron. Many studies find deferiprone clinically useful without an unduly high risk of causing neutropenia. Preliminary data indicate that it may be particularly useful in reducing cardiac iron overload either as a single agent or in combination with desferrioxamine. ICL-670, a tri-dentate oral chelator, appears clinically effective in early trials. With a relatively long half-life, early results indicate that it may be equally as effective as desferrioxamine. A direct comparison trial must be completed to prove this and to study long-term efficacy and toxicity.

Pharmacologic Upgrading of Fetal Hemoglobin Synthesis

High levels of HbF ameliorate the symptoms of p-thalassemia by increasing the hemoglobin concentration of the thalassemic red cells and decreasing the accumulation of unmatched a-chains, which cause ineffective erythropoiesis. Hydroxyurea has been demonstrated to increase HbF production and mean hemoglobin levels in patients with thalassemia intermedia or Ep-thalassemia, decreasing or eliminating the need for transfusion. Additionally, there are reports of a few p-thalassemia major patients who became transfusion free using hydroxyurea. Butyric acid analogues and erythropoietin as well as further testing with hydroxyurea are avenues of further investigation. Although these agents can decrease transfusion dependence, they have serious side effects, including neutropenia, increased susceptibility to infection, and possible oncogenicity.

Hematopoietic Stem Cell Transplantation

1. Stem cell transplantation from an HLA-identical sibling is a curative mode of therapy.

2. The greater the degree of hepatomegaly, hemosiderosis, and portal fibrosis of the liver prior to transplant, the worse the outcome.

3. Stem cell transplantation is a controversial mode of therapy because its risks must be weighed against the fact that patients who are least symptomatic have the best transplant results.

The following information is available about transplantation:

Results are better among patients less than 3 years of age who have received few transfusions and are without significant complications. GVHD occurs less frequently in younger patients.

The refinement of methods of preparation for transplantation has brought about a drastic reduction in morbidity and mortality.

Gene Therapy

Research is under way on methods of inserting a normal P-globin gene into mammalian cells. Ultimately, the aim is to insert the gene into stem cells and utilize these for stem cell transplant.

Management of the Acutely Ill Thalassemic Patient

Acute illness requiring urgent treatment occurs secondary to:

• Sepsis, usually with encapsulated organisms

• Cardiomyopathy secondary to myocardial iron overload

• Endocrine crises such as diabetic ketoacidosis.

Prevention of these crises should be the primary treatment. Preventive measures include:

• Management of the splenectomized patient as outlined in Chapter 26

• Adequate chelation to prevent secondary hemochromatosis

• Routine monitoring of cardiac and endocrine function.

If a patient presents with signs of shock, the following measures should be instituted:

1. Determine hemoglobin, electrolyte, calcium, and glucose levels; perform urinalysis.

2. Obtain blood cultures.

3. Distinguish between cardiogenic shock and septic shock because the management of each differs. To distinguish between the two, obtain an ECG; echocar-diograph, looking at left ventricular contractility; and central venous pressure (CVP).

4. If the patient is in cardiogenic shock, management includes diuretics, inotropic support, and careful monitoring of CVP and cardiac output. Management also includes desferrioxamine chelation as a continuous intravenous infusion at a dose of 15 mg/kg/h. (Once cardiac iron toxicity has reached the point of cardiac failure, it is extremely difficult to reverse; however, approximately 50% of patients will survive if aggressive chelation and cardiac management are insti-

tuted.) If Deferiprone is available, it may be added to desferrioxamine to further increase iron excretion.

5. If the patient is in septic shock, management consists of: Blood cultures, at least two peripheral sites

Broad-spectrum antibiotics IV (e.g., third-generation cephalosporin and an aminoglycoside) Fluid boluses of 10 cc/kg normal saline to restore blood pressure Pressors such as dopamine, as indicated

Coagulation studies to evaluate for disseminated intravascular coagulation (DIC) CVP monitoring to guide fluid management Arterial blood gas and chest radiograph.

6. If the patient is in diabetic ketoacidosis, manage the ketoacidosis in the usual manner with careful monitoring of cardiac function when the patient is being vigorously hydrated.

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