Evolution of Thalassaemia Management Four Decades in Thalassaemia Care – Our Achievements and Challenges

Survival dependent on lifelong blood transfusion

Transfusion Dependent Thalassemia (TDT) is a form of hereditary blood disorder which renders the affected patients severely anaemic and dependent on life-long blood transfusion for survival. Although TDT is an uncommon condition affecting a few hundreds of patients in Hong Kong, it is an important disease as the patients need long term medical treatment and considerable health care resources.

Transfusion Dependent Thalassaemia is a broad term embracing heterogenous diseases such as β-thalassemia major, Haemoglobin E/β-thalassaemia syndrome and Hb Barts disease, due to combination of different genetic defects. The key molecule in fault is the haemoglobin, an essential iron-containing molecule inside our red blood cells. The function of haemoglobin is to deliver oxygen from lungs to body tissues, and in reverse bring wasted carbon dioxide from body tissues to the lungs for excretion. Adult haemoglobin is made up of 2 β-globin chains and 2 α-globin chains, embedded with each an iron-bound heme molecule. Fig. 1 Red blood cells are mainly produced at the bone marrow through differentiation of immature stem cells called haemopoietic stem cells (HSC) under a complex regulatory mechanism.

If both parents are carrier of a single copy of defective gene for a globin chain production, there will be a quarter (25%) chance that their offspring will inherit double copies of the defective genes. Fig. 2 As a result, there will be absent or insufficient production of the specific globin chain leading to impaired haemoglobin synthesis in the red blood cells. The blood cells containing unbalanced proportion of α-globin chains and β-globin chains cannot function normally and will degenerate prematurely.

The baby with double copies of defective α-globin genes has anaemia of early onset after birth, usually after 3 or 4 months of age. The affected patients will gradually develop severe anaemia with low blood haemoglobin level resulting in multiple deleterious complications. They lack energy in daily activities, have poor appetites and stunted growth. When anaemia lasts longer, their bone will gradually expand abnormally and become malformed causing abnormal facial features and can fracture easily. Fig. 3 Their liver and spleen get enlarged. Fig. 4 The heart is overstressed, and its functions are impaired leading to heart failure. Fig. 5 Blood producing tissues at abnormal sites outside the bone marrow are formed, named as extramedullary haematopoietic tissues (EMH tissues). In occasional patients, abnormal EMH tissues can cause spinal cord compression leading to neurological deficits such as paraparesis. Fig. 6 Furthermore, their immune system gets weaker with time rendering the patients prone to various infections. Quality of life is poor and premature death would result. Offspring from parents who are α-thalassaemia carrier may inherit double doses of defective α-globin gene has onset of anemia during fetal stage and may end up with premature birth or stillbirth.

The affected patients with TDT need blood transfusion at 3 – 5 weeks’ interval to maintain life and enable daily activities. Regular blood transfusion can largely abolish the signs and symptoms related to chronic anaemia. Fig. 7

Fig. 1: Haemoglobin molecule is a tetramer with 2 α-chains and 2 β-chains each embedded with iron containing heme.

Fig. 2: If a couple are carrier of thalassaemia gene, there is 25% chance an offspring can inherit double dose of thalassaemia gene resulting in TDT.

Fig. 3: X-ray of skull shows striation marks as “standing hair on end” appearance due to bone marrow expansion.

Fig. 4: The ink marks the outline of substantially enlarged liver and spleen in inadequately transfused patients with TDT.

Fig. 5: With long-standing severe anemia, a patient with TDT went into heart failure. The X-ray shows the heart is big and globular.

Fig. 6: A patient with TDT developed paraparesis due to spinal cord compression by extramedullary haematopoietic (EMH) tissue mass.

Fig. 7: Regular blood transfusion can abolish complications of chronic anemia but at the same time leads to iron overload in body organs.