Overview
Definition:
Thalassemia major, also known as Cooley's anemia, is a severe inherited blood disorder characterized by reduced or absent synthesis of beta-globin chains, leading to ineffective erythropoiesis and severe, life-threatening anemia
It is an autosomal recessive disorder.
Epidemiology:
Most common inherited blood disorder globally, with a high carrier frequency in Mediterranean, Middle Eastern, South Asian, and Southeast Asian populations
In India, carrier rates vary significantly by region, with higher prevalence in certain ethnic groups
Incidence of major forms necessitates regular transfusions.
Clinical Significance:
Thalassemia major is a chronic, lifelong condition requiring intensive management
Without appropriate treatment, patients develop severe anemia, growth retardation, skeletal deformities, extramedullary hematopoiesis, and life-threatening iron overload from frequent blood transfusions
Effective management is crucial for survival and quality of life.
Clinical Presentation
Symptoms:
Severe anemia presenting in infancy (typically 3-6 months of age)
Pallor
Jaundice
Poor feeding
Failure to thrive
Abdominal distension due to splenomegaly and hepatomegaly
Bone deformities (frontal bossing, maxillary prominence, thinning of long bones)
Delayed puberty
Pathological fractures.
Signs:
Marked pallor
Icterus
Hepatosplenomegaly
Characteristic facial dysmorphorphism (thalassemic facies)
Skeletal abnormalities (e.g., "chipmunk facies", "hair-on-end" appearance on skull X-ray)
Growth retardation
Signs of iron overload: cardiac dysfunction (arrhythmias, heart failure), hepatic dysfunction (fibrosis, cirrhosis), endocrine dysfunction (diabetes mellitus, hypogonadism, hypothyroidism, hypoparathyroidism).
Diagnostic Criteria:
Clinical presentation of severe anemia in infancy
Confirmation by hemoglobin electrophoresis demonstrating absence or severe reduction of adult hemoglobin (HbA) and a high proportion of fetal hemoglobin (HbF)
Genetic testing (beta-globin gene sequencing) can identify specific mutations
Diagnosis is often made based on typical clinical and hematological findings.
Diagnostic Approach
History Taking:
Detailed family history of anemia or similar blood disorders
Age of onset of symptoms
History of blood transfusions and response
Previous investigations
Growth parameters
Signs of complications like fever, bone pain, or abdominal pain.
Physical Examination:
Assessment of vital signs
Thorough assessment for pallor and jaundice
Palpation for hepatosplenomegaly
Detailed examination of skeletal system for deformities
Assessment of growth and development
Examination for signs of endocrine dysfunction.
Investigations:
Complete Blood Count (CBC): severe microcytic hypochromic anemia (Hb < 7 g/dL), high reticulocyte count, anisopoikilocytosis
Peripheral smear: target cells, basophilic stippling, nucleated red blood cells
Hemoglobin electrophoresis: HbF > 90%, absence of HbA, presence of HbA2
Serum ferritin: elevated, indicating iron overload
Liver function tests (LFTs), Renal function tests (RFTs), Thyroid function tests (TFTs), Serum amylase, Glycosylated hemoglobin (HbA1c)
Echocardiogram for cardiac function and iron deposition
MRI of liver and heart for quantitative iron assessment.
Differential Diagnosis:
Other severe microcytic hypochromic anemias (e.g., iron deficiency anemia - typically responds to iron, megaloblastic anemia - different red cell morphology, anemia of chronic disease)
Sickle cell disease (different hemoglobin electrophoresis pattern)
Alpha thalassemia major (rare, hydrops fetalis)
Congenital dyserythropoietic anemias.
Management
Initial Management:
Immediate initiation of regular blood transfusions (hypertransfusion regimen) to maintain pre-transfusion hemoglobin levels between 9-10.5 g/dL and post-transfusion levels of 12-14.5 g/dL
This suppresses ineffective erythropoiesis and reduces bone marrow expansion.
Medical Management:
Iron Chelation Therapy: Essential to prevent and manage iron overload
- Deferoxamine: Subcutaneous or intravenous infusion, typically 5-7 nights/week
Requires adherence and can cause injection site reactions, hearing and vision abnormalities
- Deferasirox: Oral iron chelator, once daily
Dosage adjusted based on serum ferritin levels and body weight
Common side effects include gastrointestinal upset, rash, and renal impairment
- Deferiprone: Oral iron chelator, 3 times daily
Primarily removes cardiac iron
Can cause agranulocytosis and neutropenia, requiring regular blood count monitoring
Combination therapy with deferasirox and deferiprone is often used for severe iron overload, particularly cardiac iron
Dosing for chelators is critical and guided by serum ferritin and organ iron levels
Folic acid supplementation (1 mg/day) is standard for patients on transfusions
Hydroxyurea may be used in select cases to increase HbF levels but is less effective in beta-thalassemia major.
Surgical Management:
Splenectomy: May be considered in patients with massive splenomegaly leading to hypersplenism (increasing transfusion requirements or causing significant discomfort), but it increases the risk of overwhelming post-splenectomy infection (OPSI) and thromboembolic events
Vaccination against encapsulated organisms is crucial post-splenectomy
Bone marrow or stem cell transplantation (BMT/SCT) is the only curative option, indicated for appropriately matched sibling donors
Allogeneic hematopoietic stem cell transplantation is the preferred treatment if a suitable donor is available.
Supportive Care:
Nutritional support to ensure adequate growth
Management of complications like osteoporosis, diabetes, hypothyroidism, cardiac dysfunction
Psychological support for patients and families
Regular monitoring of growth parameters, organ function, and iron levels.
Complications
Early Complications:
Transfusion reactions (febrile, allergic, hemolytic)
Volume overload
Iron overload due to transfusions and increased absorption
Infection from transfusions (Hepatitis B, C, HIV - significantly reduced with modern screening).
Late Complications:
Severe iron overload leading to cardiac failure, arrhythmias, liver cirrhosis, diabetes mellitus, hypogonadism, hypothyroidism, osteoporosis, and bone fractures
Extramedullary hematopoiesis causing mass effect (e.g., spinal cord compression)
Thromboembolic events
Delayed puberty and infertility.
Prevention Strategies:
Strict adherence to regular blood transfusions and effective iron chelation therapy is paramount
Pre-transfusion screening for infections
Regular monitoring of iron levels (serum ferritin, MRI) and organ function
Vaccination against common infections, especially in splenectomized patients.
Prognosis
Factors Affecting Prognosis:
Age of initiation of adequate transfusions and chelation therapy
Efficacy and adherence to chelation
Development of organ damage from iron overload
Presence of complications
Availability of stem cell transplantation
Genetic mutation type.
Outcomes:
With optimal transfusions and chelation, survival into adulthood is now common, with many patients achieving good quality of life
However, long-term complications of iron overload can still occur
Stem cell transplantation offers a potential cure.
Follow Up:
Lifelong follow-up is essential
Regular clinical assessment, hematological monitoring, serum ferritin levels, echocardiograms, liver MRI, endocrine assessments, and bone density scans
Management of comorbidities and complications.
Key Points
Exam Focus:
The cornerstone of management for thalassemia major is regular blood transfusions and iron chelation therapy
Understand the indications and side effects of deferoxamine, deferasirox, and deferiprone
Recognize signs and symptoms of iron overload in various organs
Know the diagnostic criteria and typical hemoglobin electrophoresis findings.
Clinical Pearls:
Always check for signs of iron overload, especially cardiac and hepatic involvement, even in well-managed patients
Dosing of chelators is individualized and requires careful monitoring
Consider BMT/SCT as a curative option if a suitable donor exists
Vaccinate patients who have undergone splenectomy.
Common Mistakes:
Delaying initiation of transfusions or chelation
Inadequate chelation therapy leading to progressive iron overload
Underestimating the cardiac impact of iron overload
Failing to monitor for rare but serious side effects of chelators (e.g., agranulocytosis with deferiprone).