Thalassemia Intermedia

Normal hemoglobin is a tetramer composed of two alpha-like and two beta-like globin chains.  The predominant hemoglobin at birth is hemoglobin F (HbF) with the structure α2γ2.  A switch from γ to beta globulin synthesis occurs such that by 4-6 months of life, the main circulating hemoglobin is hemoglobin A (HbA), with a structure of α2β2.

The beta-globin gene cluster, found on the short arm of chromosome 11, can be affected by over 200 known (primarily point) mutations that give rise to beta thalassemia. The following terminology is commonly used:

• β ⁰ - Mutations causing a complete absence of beta-globin chains
• β ⁺ - Mutations resulting in a variable decrease in the production of beta globin

Patients with beta thalassemia intermedia are considered typically to have two β+ mutations. However, owing to the heterogeneity of the beta-globin mutations and the multitude of disease modifiers, difficulties remain regarding the prediction of phenotype from genotype. Thus, transfusion independence is still the best means of defining beta thalassemia intermedia.[1]

In beta thalassemia, beta-globin gene mutation leads to the decrease or absence of beta-globin chain production.[1]  The two main implications of this defect are as follows:

• Decreased hemoglobin production
• Imbalanced alpha-chain–to–beta-chain ratio

Decreased hemoglobin production

Impairment in the production of functional hemoglobin tetramers takes the form of microcytosis and hypochromasia, as readily demonstrated in peripheral smears from patients with beta thalassemia intermedia.

Imbalanced ratio of alpha-to-beta chains

Another consequence of impaired beta-globin synthesis is the imbalanced ratio of alpha to beta chains. It is essential to understand that the clinical severity of beta thalassemia arises not from the absolute deficit in beta-globin production but from the degree of globin chain imbalance.[1]  The excess alpha chains precipitate, the result being that red blood cell precursors in the bone marrow and circulation are destroyed, leading, via ineffective erythropoiesis and hemolysis, to anemia. This erythropoiesis/hemolysis inefficacy also results in iron overload, erythroid marrow expansion, and a hypercoagulable state. Iron overload can develop even in non–transfusion-dependent patients owing to inappropriately low hepcidin levels, which result in increased intestinal iron absorption.

The heterogeneity of the beta thalassemia intermedia phenotype can also be attributed to other variables that may affect the alpha-globin–to–beta-globin ratio and, thus, disease severity, including the following:

• Coinherited genetic determinants, such as differential molecular forms of alpha thalassemia, can reduce the alpha-chain/beta-chain production imbalance ^[1]
• HbF levels will rise in association with gamma-chain production increases; such is the case with beta-/delta-deletion mutations, which, in association with a beta thalassemia gene mutation, lead to thalassemia intermedia via a combined heterozygous condition ^[1]
• Patients with HbE/beta thalassemia (in which HbE interacts with beta thalassemia) exhibit the clinical course of thalassemia intermedia

Being clinically heterogenous, beta thalassemia intermedia can range from a manifestation in which patients rarely, if ever, require transfusion to one in which individuals have chronic hemolytic anemia and in later life become transfusion dependent.[1]  

Although these patients sustain hemoglobin levels adequate for survival, the underlying ineffective erythropoiesis can fuel various complications, including iron overload, extramedullary hematopoiesis, hemolysis, and hypercoagulability. (Presentation/Clinical Manifestations)

Beta thalassemia intermedia refers to beta thalassemia with non–transfusion-dependent anemia. Characterized by a less-severe phenotype than beta thalassemia major, the condition nonetheless has a wide range of clinical presentations. The presentation of beta thalassemia intermedia tends to occur later than that of beta thalassemia major, often in the third or fourth decade of life.[5, 1]

Beta thalassemia does not present in infants aged less than six months, because gamma-globulin synthesis predominates over beta-globulin synthesis in this age group.

Despite maintaining a level of hemoglobin sufficient for tissue oxygenation, patients with thalassemia can develop a range of complications due to longstanding hemolytic anemia and ineffective erythropoiesis, including jaundice, splenomegaly, bone deformities, osteoporosis, fractures, growth retardation, extramedullary hematopoietic pseudotumors,[2]  pulmonary hypertension, thromboembolism,[3] iron overload, and skin ulcers.

Anemia

Patients tend to have a moderate level of anemia that is not transfusion dependent. By convention, this generally corresponds to a hemoglobin of 7-7.5 g/dL.  However, transfusions are often required episodically during periods of stress, such as infection or pregnancy. Patients can develop transfusion dependency in later adulthood.

Jaundice

Patients can have jaundice from chronic hemolytic anemia. Bilirubin gallstones can result in cholelithiasis.

Splenomegaly

Most patients have a palpable spleen, a consequence of chronic hemolysis and extramedullary hematopoiesis.[1]

Extramedullary hematopoietic pseudotumors

Extramedullary hematopoiesis can occur in almost any region of the body to compensate for ineffective red cell production by the bone marrow. Affected areas include the spleen, liver, lymph nodes, thymus, heart, breasts, prostate, kidneys, adrenal glands, pleura, skin, and spinal canal.[1, 6] Paraspinal involvement can have debilitating clinical consequences due to spinal cord compression.[4]  

Bone deformities and disease

Changes described in thalassemia major, such as frontal bossing, cortical thinning, dilation of the medullary cavities, prominence of the zygomatic bones, and shortening of the long bones, can also be seen in patients with thalassemia intermedia. In addition, many patients have osteoporosis, likely from a combination of endocrine dysfunction, 25-hydroxy vitamin D deficiency, and bone marrow expansion. Pathologic fractures, especially in long bones and vertebrae, can result.

Thromboembolic disease

Thalassemia intermedia is associated with a hypercoagulable state.[1] A multicenter study to assess the incidence of thrombotic events in patients with thalassemia found that 4% of patients with thalassemia intermedia develop thrombotic events, compared with only 0.9% of individuals with thalassemia major.[7]  The etiology of the hypercoagulability state is multifactorial,[8]  involving endothelial dysfunction,[9]  lack of bioavailability of nitrous oxide (NO),[10]  increased platelet aggregation, and the membrane phospholipid contribution of red blood cells.[11]

Pulmonary hypertension

Although the cause is not entirely clear, pulmonary hypertension likely develops from longstanding chronic anemia, hypoxia, iron overload, and microthrombotic disease of the pulmonary circulation. It is the leading cause of right-sided heart failure in patients with thalassemia major. 

Skin ulcers

Older thalassemia intermedia patients can develop leg ulcers, as oxygen reduction causes subcutaneous tissue to thin.

Iron overload

Iron overload is a potential complication of thalassemia, even in patients who do not require red blood cell transfusions. It results from excessive absorption of dietary iron, mediated by the down-regulation of hepcidin, which is a hepatic hormone that acts as a major regulator of systemic iron homeostasis.[12, 13]  Hepcidin inhibits iron absorption from the diet and inhibits the recycling of iron by the macrophages. It is increased by iron loading and inhibited by erythropoietic activity.

A study by Meloni et al indicated that in patients with thalassemia intermedia who are regularly transfused, pancreatic iron overload predicts cardiac iron accumulation and alterations in glucose metabolism. Moreover, the investigators reported that pancreatic iron loading is lower in patients with thalassemia intermedia who are nontransfused than in those who are regularly transfused.[14]

Initial workup

The initial workup for a patient with suspected thalassemia should include a complete blood count (CBC), review of the blood smear, and iron studies, as follows:

• CBC - Thalassemia involves microcytic anemia with a high red blood cell count, with the high count possibly helping to distinguish between thalassemia and iron deficiency ^[1]
• Peripheral smear - Review of the peripheral smear reveals hypochromasia and microcytosis; more severely affected patients can demonstrate poikilocytosis, with target cells, teardrop cells, and cell fragments ^[1] (see the image below)
• Iron studies - Iron studies should be obtained to differentiate iron deficiency anemia from thalassemia and also to monitor for ongoing iron overload in patients with an established diagnosis of thalassemia; in thalassemia intermedia, iron studies reveal a normal to high ferritin level, elevated serum iron, and elevated transferrin saturation ^[1]

Ancillary laboratory studies may include analyses for hemolytic anemia, such as Coombs testing, haptoglobin, lactate dehydrogenase, and indirect bilirubin. Study results found in thalassemia—including negative Coombs testing, low haptoglobin, elevated lactate dehydrogenase, and elevated indirect bilirubin—are also derived in nonimmune hemolytic anemia.

Peripheral blood film in thalassemia intermedia.

Confirmatory testing

Thalassemia is diagnostically confirmed via hemoglobin analysis and genetic testing.[1]

Hemoglobin analysis

High-performance liquid chromatography (HPLC) or hemoglobin electrophoresis is used in the execution of hemoglobin analysis.[1] In beta thalassemia intermedia, hemoglobin analysis reveals elevated levels of HbF and HbA2. However, beta thalassemia may still exist when the HbA2 level is normal, with such concentrations dropping into the normal range in the presence of conditions such as concomitant iron deficiency and delta-chain mutations.[1]

Genetic testing

The diagnosis of beta thalassemia intermedia does not always require DNA-based genotyping, but such analysis may aid in recognizing complex thalassemias such as delta-beta and gamma-delta-delta thalassemia.[1] Genetic analysis may also help to differentiate thalassemia intermedia from thalassemia major. For example, the presence of IVSI‐5 homozygous with Xmn‐1 is a strong indicator of thalassemia intermedia, but genetic heterogeneity means that this method is not in routine use.[15]

Using the following studies, patients with beta thalassemia intermedia can be monitored for complications during routine health visits with a specialist[1] :

• CBC, reticulocyte count, hepatic panel, and renal function
• Iron studies
• Baseline cardiac magnetic resonance imaging (MRI) with iron deposition quantification
• Echocardiographic evaluation 
• Liver iron concentration assessed via magnetic resonance evaluation
• Dual-energy radiographic absorptiometry (DRA) scan or skeletal survey for pediatric patients
• Screens for thyroid dysfunction, diabetes mellitus, gonadal dysfunction (in the presence of delayed puberty), hypoparathyroidism, growth hormone deficiency (in the presence of failure to thrive), and adrenal insufficiency 

Thalassemia intermedia therapy is aimed not only at treating the anemia, but also at addressing iron overload and inhibiting the clinical consequences of ineffective erythropoiesis.

The treatment of most cases of thalassemia intermedia involves close monitoring and observation, with pediatric patients being monitored for such characteristics as adequate growth, appropriate development, and skeletal deformities.[1] Clinicians should strive to prevent all patients from suffering complications from extramedullary hematopoiesis and iron overload. 

Blood transfusions

Patients undergo transfusions as needed, most often in response to stressors such as illness, pregnancy, surgery, and periods of rapid growth.[1] In later life, some patients become transfusion dependent. When regular transfusions are deemed necessary, many clinicians target a pretransfusion hemoglobin of around 9.5-10 g/dL as a means of suppressing bone marrow activity.[1] Evidence of cardiopulmonary compromise, significant extramedullary hematopoiesis, poor growth and development, and functional impairment all suggest that chronic transfusion therapy is required. In the the OPTIMAL CARE study, transfused thalassemia intermedia patients experienced fewer complications related to chronic anemia, ineffective erythropoiesis, and hemolysis (extramedullary hematopoiesis, pulmonary hypertension, thromboembolic events), while suffering higher rates of iron overload–related endocrinopathy[16] .

Lowering the risk of transfusion complications involves efforts such as extended cross-matching to prevent alloimmunization and leukocyte depletion to reduce febrile nonhemolytic reactions. (See also Transfusion and Autotransfusion, Transfusion-Induced Iron Overload, Alloimmunization From Transfusions, and Transfusion Reactions.)

Chelation therapy

Even without chronic transfusion, iron overload can develop in the presence of beta thalassemia intermedia consequent to increased iron absorption from the gut.[1] Available chelation therapy agents include deferoxamine (parenterally administered) and deferiprone and deferasirox (both orally administered). With the introduction of deferiprone and deferasirox, deferoxamine, due to its cumbersome administration schedule, fell out of favor in North America and Europe.  

A 5-year, prospective European study reported on 555 children and adults who were divided into two groups, the first of which was treated with deferasirox for a total of 5 years (deferasirox cohort), and the second of which was started on deferoxamine for the first year and then switched to deferasirox (cross-over cohort). At the end of the treatment period, a liver biopsy was obtained and hepatic iron content (HIC) was measured in the two groups and compared with the initial level before treatment. In the deferasirox cohort, HIC decreased by 7.8 ±11.2 mg Fe/g dry weight. In the cross-over cohort, the decrease was somewhat less, at 3.1 ±7.9 mg Fe/g dry weight.[17]

These findings support the long-term efficacy of this oral chelating agent, which also was proven to be safe with only minimal adverse effects reported, including increased blood creatinine in 11.2%, abdominal pain in 9%, and nausea in 7.4%. No adverse effects on growth in children or sexual development in adolescents were noted.[17]

Patients should be started on chelation therapy under the following circumstances:

• The liver iron concentration is 5 mg Fe/g dry weight or greater
• The serum ferritin level is 800 ng/mL or greater
• In cases when evaluation of the liver iron concentration is not possible, the serum ferritin level is in the range between greater than 300 and less than 800 ng/mL, and other clinical or laboratory measures point to iron overload

Chelation therapy is aimed at obtaining a liver iron concentration of 3 mg Fe/g dry weight or a serum ferritin level of 300 ng/mL.[4]

Paraspinal extramedullary hematopoietic pseudotumors

Prompt evaluation for paraspinal extramedullary hematopoietic pseudotumors should conducted, via spinal MRI, in patients with beta thalassemia in whom the symptoms and signs of spinal cord compression are present.[4] Urgent referrals should be made to neurology, neurosurgery, and radiational oncology so that a multiple disciplinary decision can be made regarding treatment. Stimulation of fetal hemoglobin by way of a short course of hypertransfusion and hydroxyurea can be used to treat mild symptoms.[1] Low-dose radiotherapy and steroids can also be considered. Laminectomy may be required to address severe symptoms that fail to respond to medical therapy.[1]  Caution should be taken with a laminectomy, as immediate total resection of extramedullary hematopoietic pseudotumors can result in clinical deterioration due to acute loss of hematopoietic centers.  

Thromboprophylaxis

Beta thalassemia intermedia is associated with a hypercoagulable state, with splenectomized patients especially at risk for thrombotic events. Although there are no available results from clinical trials on the use of antiplatelet or anticoagulant therapy for thrombosis prevention, data suggest that aspirin use prevents thrombosis recurrence in splenectomized beta thalassemia intermedia patients.[16]

Splenectomy

Splenectomy should be reserved for patients with massive splenomegaly, worsening pancytopenia, or hypersplenism. Among its many risks, the greatest dangers related to splenectomy are postsplenectomy sepsis and thrombosis, with these being particular hazards in patients with beta thalassemia intermedia. Observational studies suggest that following splenectomy, the risks for venous thromboembolism, pulmonary hypertension, and leg ulcers are raised five-, four-, and four-fold, respectively, in patients with beta thalassemia intermedia, with the likelihood of silent cerebral infarcts also increased.[16, 18, 1]

Bone marrow transplantation

In patients with severe thalassemia intermedia who require aggressive therapy to sustain life, bone marrow transplantation, similar to that performed in patients with thalassemia major, is a reasonable alternative to transfusion and chelation if a matched sibling donor is available.

No specific medications are currently available for the treatment of thalassemia intermedia that have been proven in large-scale trials. Most patients with severe disease are prone to developing megaloblastic anemia due to folate deficiency, which primarily results from the extreme demand of the very active bone marrow for folic acid, and a low daily dose of folate is advisable. Agents such as hydroxyurea have been found to induce erythropoiesis in a subset of patients and to raise Hb levels.[19] Thalidomide has also been found to be effective in some patients in raising hemoglobin, presumably by inducing fetal Hb production, but large-scale studies are lacking.[20]

Many patients with thalassemia intermedia may ultimately require regular blood transfusions, usually about every 3-5 weeks. Similar to patients with thalassemia major, patients with thalassemia intermedia who receive regular transfusions are usually premedicated with an antipyretic, such as acetaminophen, and an antihistamine, such as diphenhydramine, 30 minutes before transfusion to prevent both febrile and allergic reactions.

Patients with iron overload should be treated with chelation therapy. The drugs of choice in current practice are the oral agents deferasirox and deferiprone. Alternatively, deferoxamine may be administered subcutaneously by infusion pump overnight 5-7 times per week while the patient sleeps. Low-dose vitamin C with each infusion of deferoxamine is beneficial in enhancing iron chelation. Combination therapy with more than one agent has proved to be effective in certain situations.

Patients with iron overload who develop fever of unknown origin may have Yersinia enterocolitica infection. Treatment with gentamicin and oral trimethoprim-sulfamethoxazole should be initiated if no other cause for the fever is identified.

Other agents that may be of value in patients with thalassemia intermedia include vitamin E, which may prevent some of the toxic effects of the free radicals and other iron-related toxicity. Penicillin or one of its derivatives should be prophylactically administered for patients who have undergone a splenectomy. A daily low dose of aspirin is advised as prophylactic treatment to prevent thrombotic events in patients with thalassemia intermedia who have undergone a splenectomy.

Class Summary

Analgesic antipyretic agents can help prevent febrile reactions in patients who are frequently transfused and who thus may develop sensitization to blood products.

Acetaminophen (FeverAll, Tylenol, Mapap, Acephen)

Acetaminophen has an antipyretic effect through action on the hypothalamic heat-regulating center. Although this drug is equal to aspirin in action, acetaminophen is preferred, because it has fewer adverse effects.

Class Summary

Antihistamine agents prevent or ameliorate allergic reactions that are associated with the transfusion of blood products.

Diphenhydramine hydrochloride (Benadryl, Diphenhist, Aler-Cap)

Diphenhydramine elicits anticholinergic and sedative effects.

Class Summary

Chelating agents are an integral part of successful treatment of thalassemia. They remove excess iron deposits that are the main cause of long-term morbidity and mortality in this condition.

Deferoxamine mesylate (Desferal)

Deferoxamine chelates iron from ferritin and hemosiderin but not from transferrin, cytochrome, or hemoglobin (Hb). This agent helps prevent damage to the liver and bone marrow from iron deposition.

Deferasirox (Exjade)

Deferasirox is available as a tablet for oral suspension. It is an oral iron-chelating agent that reduces liver iron concentration and serum ferritin levels. Deferasirox binds iron with high affinity in a 2:1 ratio. It is approved for treatment of treat chronic iron overload due to multiple blood transfusions and non–transfusion-dependent thalassemia.

Class Summary

Antimicrobial agents are known to be effective against organisms that may cause infection in patients with iron overload who are also receiving deferoxamine therapy. Y enterocolitica infections are rare in healthy patients, because the organism requires siderophores, which are present in patients with thalassemia but not in healthy patients. The appropriate therapy is a combination of trimethoprim-sulfamethoxazole and gentamicin. Patients who require splenectomy must receive prophylactic antibiotics to prevent fulminating sepsis, especially patients younger than 5 years.

Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS, Septra DS)

By blocking tetrahydrofolic acid, trimethoprim-sulfamethoxazole selectively inhibits synthesis of nucleic acids and proteins by bacteria.

Penicillin V

Penicillin V is the drug of choice (DOC) for prophylaxis in patients with thalassemia who have undergone a splenectomy (erythromycin is used in patients allergic to penicillin). This agent is active against most microorganisms that are considered to be major pathogens in splenectomized patients (ie, streptococcal, pneumococcal, and some staphylococcal microorganisms) but not penicillinase-producing species. Prophylaxis with penicillin V is provided for more than 3 years after splenectomy.

Erythromycin (E.E.S., Ery-Tab, Erythrocin)

Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It is used for the treatment of staphylococcal and streptococcal infections.

Class Summary

Vitamins are compounds that are present in small amounts in food, and they are essential for normal metabolism, cell function, and healthy tissues.

Ascorbic acid (Cecon, Cevalin, Vita-C)

Vitamin C has been shown to enhance the function of deferoxamine by keeping iron in a form that can be chelated. When administered with deferoxamine, vitamin C allows more iron to be removed.

Folic acid (Folvite)

Folic acid is required for DNA synthesis; therefore, patients with all conditions associated with rapid cellular turnover, such as hyperactive marrow in thalassemia, have greatly increased demand. Because use of folic acid in hemolytic anemias is extreme, deficiency states are fairly common in most of these patients. Patients who do not receive folic acid supplementation may develop megaloblastic anemia, thereby increasing the severity of the original disease process.

Class Summary

The antioxidant effects of vitamin E have been shown to help in decreasing iron-mediated toxic effects on cells by preventing or decreasing membrane-lipid peroxidation.

Vitamin E (Key-E, Aqua Gem-E, E-Gems, Aquasol E)

The mechanism of action (MOA) of vitamin E has been known for many years. In newborn or premature infants, in particular, vitamin E deficiency has resulted in peculiar red blood cell (RBC) morphology, leading to hemolysis; these changes are reversed by vitamin E. Peroxidation of membrane lipids by various oxidants, including iron-mediated oxygen radicals, is the main cause of this hemolysis and can be prevented by antioxidants such as vitamin E.

Class Summary

Corticosteroid agents can help prevent local and systemic reactions to exogenous agents.

Hydrocortisone (Solu-Cortef, Cortef)

Hydrocortisone is an anti-inflammatory adrenocortical steroid. This agent helps prevent local reaction to subcutaneous (SC) perfusion of deferoxamine. Both sodium succinate (Solu-Cortef) and sodium phosphate (Cortef) forms are used for intravenous (IV) infusions, but sodium acetate form (Hydrocortone) is not.

Class Summary

Patients who have undergone a splenectomy are prone to developing infections with any of 3 common encapsulated organisms (ie, Pneumococcus species [spp], H influenzae, and Meningococcus spp). Patients who are to undergo splenectomy now receive immunizations against these organisms 1-2 weeks before the procedure. This practice allows the spleen to participate in production of antibodies before being removed.

Pneumococcal vaccine polyvalent (Pneumovax-23)

The older polyvalent/polysaccharide pneumococcal vaccine contains the 23 most prevalent serotypes responsible for about 70% of all invasive infectious diseases, but it cannot be administered to children younger than 2 y. A new generation of this vaccine, called conjugate vaccine, is now available; it has only 7 serotypes, but it can be administered to infants as young as 2 months. This is a very important achievement, because splenectomized infants are more prone to develop pneumococcal infections than any other group of patients. The conjugate form is administered in a series of 2-3 doses at ages 2, 4, and 6 months.

Haemophilus influenza type b vaccine (ActHIB, PedvaxHIB)

Haemophilus influenzae type b vaccine is recommended 2 weeks before splenectomy. Patients who have already received their primary vaccination early in life and also received a booster at 12 months or later are usually protected, even though they may benefit from an additional dose before the procedure. The conjugate form is administered in a series of 2-3 doses at ages 2, 4, and 6 months.

Meningococcal vaccine (Menomune A/C/Y/W-135)

Meningococcal vaccine is similar to polyvalent pneumococcal vaccine. This vaccine is used in children older than 2 years who are at risk (eg, complement deficiency, asplenia). Meningococcal vaccine contains a serogroup specific against groups A, C, Y, and W-135 N meningitides.

Pneumococcal 7-valent conjugate vaccine (Prevnar)

Pneumococcal 7-valent conjugate vaccine is a sterile solution of saccharides of capsular antigens of Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F individually conjugated to diphtheria CRM197 protein. These 7 serotypes have been responsible for over 80% of invasive pneumococcal disease in children younger than 6 years in the United States; they also accounted for 74% of penicillin-nonsusceptible S pneumoniae (PNSP) and 100% of pneumococci with high-level penicillin resistance. The customary age for the first dose of pneumococcal 7-valent conjugate vaccine is 2 months, but it can be administered to infants as young as 6 weeks.

Class Summary

Hydroxyurea was found to induce erythropoiesis and raise hemoglobin (Hb) levels.[19] Thalidomide has been found effective in raising hemoglobin in case reports and small case series but large-scale studies are lacking[20]

Hydroxyurea (Hydrea, Droxia)

It inhibits deoxynucleotide synthesis. S-phase specific non-DNA hypomethylation chemotherapeutic agent. Mechanism of action for thalassemia is unknown but has shown HbF-inducing activity.

Thalidomide (Thalomid)

Mechanism of action for thalassemia is unknown but has shown HbF-inducing activity.