CLINICAL FEATURES AND LABORATORY FINDINGS OF THALASSEMIA

What are the types of beta thalassemia based on transfusion requirements? 

 

Transfusion dependent  

Non-transfusion dependent. 

What is non-transfusion dependent thalassemia? 

 

Thalassemia trait 

Silent carrier  

Thalassemia intermedia 

What are the clinical and laboratory features of silent trait? 

 

        β/ β0  or β/ β+ 

Asymptomatic carriers 

LAB: 

Mild Microcytic hypochromic anemia (RDW is usually normal) 

Hb - >10 g/dl 

Low MCV, low MCH and low MCHC 

High RBC count relative to hemoglobin 

HB electrophoresis is normal. 

Good to know 

Several patients who are homozygous for the silent carrier b-thalassemia gene have been described. 

These children rarely require transfusions.  

They have significant hepatosplenomegaly and have HbF of 10 to 15 percent with an elevated HbA2 (as seen in traits). 

Two-point mutations in the b-globin gene regions have been linked to the silent carrier phenotype. 

• The -101 promoter mutations seen in Italians, Bulgarians and Turkish population. 

• +1 Cap site Inv mutation in an Indian family. 

What are the clinical and laboratory features of thalassemia trait? 

 

Mild microcytic, hypochromic anemia with basophilic stippling, target cells and elliptical cells 

on peripheral blood smear. (RDW is usually normal) 

Hb >10 g/dl 

Low MCV, low MCH and low MCHC 

High RBC count relative to hemoglobin 

Hb electrophoresis: HbA2 and/or HbF are elevated   

     HbA2 (4% or more); HbF (up to 5%) 

 

What are the features of beta thalassemia intermedia? 

 

β+ /β+ 

This group of patients have variable presentations. 

Some patients may be asymptomatic with few clinical and lab features while other extreme may require transfusion and have significant features. 

Age of presentation: 

2-4 years  

They are usually non-transfusion dependent (NTDT) but become dependent in 3rd to 4th decade of life           or in conditions of excessive stress or extra blood requirement like pregnancy, surgery, severe illness. 

LAB 

Low Hb – 7-10 g/dl 

Low MCV, MCH and MCHC can be low or high depending upon hydration status of RBCs. 

PS: Hypochromic, microcytic, anis poikilocytosis, target cells, polychromasia, basophilic stippling, nucleated red cells and sometimes immature myeloid cells. 

High RDW 30 to 40% (normal is 12-16%) 

High reticulocyte count. 

 

What are the features of thalassemia major? 

 

  β0 /β0 

Almost similar to intermedia with few exceptions 

Age of presentation: 6 to 12 months of life  

Hb <7 

Transfusion dependent since infancy  

LAB 

Similar to intermedia with few exceptions  

Low to normal reticulocyte. 

What are the characteristic physical features of thalassemia? 

• Pallor due to anemia 
• Jaundice due to chronic hemolysis  
• Bile pigment stones but cholecystitis and cholangitis are rare. 
• Skeletal changes  
• Iron overload  
• Growth impairement. 
• Hepatosplenomegaly 
• Endocrine and metabolic abnormalities 
• Heart failure and arrhythmia  
• Pulmonary abnormalities and hypertension  
• Thrombosis 
• Leg ulcers  
• Increased risk of cancer  

 

What are the skeletal changes? 

• Facial abnormalities: 

        Chipmunk face  

Frontal bossing 

Saddle nose  

Prominent maxilla 

Crowding of teeth 

Delayed pneumatization of sinuses 

Widening of diploic spaces in skull give rise to characteristic hair on end appearenc in lateral view X –ray of skull.

• Bending of Long bones and ribs making box like habitus of body. 
• Premature fusion of epiphysis and shortening of limbs 
• Short stubby fingers and flat broad hands  
• Changes in hands become less prominent in 2nd decade as red marrow is replced by yellow marrow. 
• Osteopenia and osteoporosis 
• Bony masses – the hyperplastic bone marrow may invade bony cortex and brek through bone presenting as erythroid ectopic masses in sinuses, thoracic and pelvic cavity. 

These bony masses if present in vertebrae can compress the spinal cord. 

Why is there iron overload? 

 Discussed here. 

Why is there growth impairment? 

• Chronic anemia 
• Hypermetabolic state d/t hemolysis 
• Iron toxicity  
• Iron chelator toxicity 
• Nutritional deficiency 
• Endocrinopathies – hypogonadism and delayed puberty d/t iron deposition. 

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What is the cause of hepatosplenomegaly? 

• Chronic hemolysis leading to extramedullary hematopoiesis. 
• Iron deposition. 
• Viral infection post transfusion can cause viral hepatitis. 
• HCC can result from chronic hepatic infection and iron deposition. 
• Like sickle cell functional asplenia is not present in thalassemia. 

What are the endocrinopathies associated with thalassemia? 

• Hypogonadism and delayed puberty d/t pituitary deposition of iron  
• Diabetes- islets of pancreas deposited with iron  
• Hypothyroidism –d/t iron deposition. 

Gouty arthropathy d/t hyperuricemia is present after 3rd to 4th decade. 

What are the cardiovascular complications and why do they occur? 

• Cardiomyopathy 
• Cardiac failure 
• Arrhythmia  

Causes of heart disease are multifactorial 

• Anemia related heart failure and cardiac dilatation. 
• Restrictive cardiomyopathy d/t iron deposition.  
• Sterile pericarditis d/t iron. 
• Diabetes and vascular dysfunction d/t oxidative stress. 
• Pulmonary arterial hypertension. 
• Vitamin D deficiency. 

Why pulmonary hypertension occurs in thalassemia? 

Oxidative stress along with smoking can increase risk of pul htn in thalassemia. 

Low nitric oxide levels leading to vasoconstriction can lead to pul htn. 

Why thalassemia is associated with low Nitric oxide (NO)? 

In cases of hemolysis the free hemoglobin scavenges the NO thus reducing the concentration of NO which is a potent vasodilator. 

This effect is present in all kinds of hemolytic disease. 

Why leg ulcers are present in thalassemia? 

Due to iron overload  

Due to low oxygen tension 

 

Why is there low reticulocyte in major but high in intermedia? 

 

There is significant ineffective erythropoiesis preventing the precursor red cells from maturing to reticulocyte stage to be thrown into peripheral blood thus reticulocyte count is low in comparison to the degree of anemia.  

In thalassemia intermedia, since the ineffective erythropoiesis is milder,the reticulocytes are increased in peripheral blood due to the anemia. 

Why beta thalassemia major is usually diagnosed after 6 months? 

It is because of the presence of fetal hemoglobin. 

 

The gamma globin in HbF is available to bind with alpha globin thus preventing the precipitation of free alpha globin chains. 

  

After 6 months this gamma globin is replaced by beta globin the synthesis of which is impaired.  

 

What are changes in WBC and platelets? 

No direct effect but in some cases, neutrophils are found to be elevated which may be d/t associated infections or may be d/t myeloid hyperplasia along with the erythroid hyperplasia as BM is hyperactive. 

Low wbc and platelet count may be present in cases of hypersplenism. 

 

Can we find megaloblastic anemia in thalassemia? 

YES.  

Megaloblastic changes may be present in association with microcytosis when there is deficiency of folate due to excessive demand because of hemolysis. 

What are other supportive investigations? 

Coombs test – always negative and it is done to rule out autoimmune hemolysis 

LDH, serum bilirubin is elevated  

Serum haptoglobin is reduced. 

 

What is Mentzer index? 

If the quotient of the mean corpuscular volume (MCV, in fL) divided by the red blood cell count (RBC, in Millions per micolitre). 

If it is less than 13, thalassemia is said to be more likely.  

If the result is greater than 13, then iron-deficiency anemia is said to be more likely. 

What is the principle behind this index? 

        In iron deficiency, the marrow cannot produce as many RBCs and they are small (microcytic), so the                 RBC count and the MCV will both be low, and as a result, the index will be greater than 13.  

        Conversely, in thalassemia, which is a disorder of globin synthesis, the number of RBCs produced is                normal, but the cells are smaller and more fragile. Therefore, the RBC count is normal, but the MCV is            low, so the index will be less than 13. 

 

Why iron study is important in thalassemia? 

To identify iron overload  

To differentiate from IDA which also has microcytic anemia in peripheral smear. 

 

        Serum iron and ferritin are elevated in thalassemia but low in IDA.  

        Total iron saturation (TSAT) is high with low iron binding capacity in thalassemia but opposite in                       IDA. 

         SERUM FERRITIN IS USUALLY TESTED TO EVALUATE AND MONITOR IRON OVERLOAD IN                                 THALASSEMIA. 

 

How can we confirm the diagnosis? 

Hemoglobin analysis  

Genetic testing. 

Genetic testing is the most reliable test which can readily identify the defective beta gene. 

 

What are the methods of hemoglobin analysis? 

Various methods are present the most commonly used are: 

• Hb electrophoresis  

• High performance liquid chromatography (HPLC) 

• Microcolumn chromatography  

 

        The HPLC and microcolumn chromatography are commonly used these due to ease of use,                         reliability and reproducibility. 

 

How does HPLC diagnose? 

        It separates different types of Hb and quantifies each type. 

What are the radiological findings in thalassemia? 

Radiological findings include widening of medulla due to bone marrow hyperplasia, thinning of the cortex and trabeculations and fracture are seen in long bones, metacarpals and metatarsals. X-ray—skull AP and lateral views show “hair on end "appearance.