Diagnosis And Treatment Of Haemoglobinopathies Biology Essay

Haemoglobinopathy is a genetic inherited disorder. Haemoglobinopaty is associated to geographical distribution disease; it is most common in population of Africa, Middle East, Mediterranean, Asia and Southeast Asia. Haemogloninopathies are subdivided into two main significant genetic diseases thalassaemia and sickle cell disease. Transfusion treatment and bone morrow oar stem cell transplantation therapy use for treatment and management both diseases. But in sickle cell disease (SCD) there are some more treatment used as control the complication of disease such hydroxyurea, and vaccination against some pathogenic disease which are causes infection, and analgesic to relief the pain, and using prophylactic treatment against pneumococcal chest syndrome. Also the patient during the blood transfusion increased the amount of iron which is harmful for many organs in human body particularly the heart muscle tissue. In this case the patient need another therapy is iron chelation such as deferiprone with deferoxamine. The resent study declare that the most curative treatment and is bone marrow transplantation or stem cell transplantation.

The most accurate test for haemoglobinopathy is including high pressure liquid chromatography (HPLC), haemoglobin electrophoresis (EP) and neonatal screening test and DNA parental test.


Haemoglobinopathy is a genetic disease, associated with lack of normal haemoglobin in the red blood cells also the most common monogenic disease in the worldwide. Is inherited defect produce abnormal haemoglobin (Hb) in their structure, Hb playing an important role in red blood cells. This disorder is an autosomal recessive disorder. This disorder related to chronic haemolytic anaemia. (Marie and Fernando 2008) Haemoglobinopaty is geographical distribution disease; is most common in Africa, Middle East, Mediterranean, Asia and Southeast Asia. Also interaction between two genes among this people can causes to number types of thalassaemia disease, three aims for control are homozygous alpha-0 thallassaemia leading to Hb-Bart, homozygous beta-thalassaemia and beta-thalassaemia Hb-E. Hence that is important to detect very quick, immediate and accurate screening for prevention especially those parental are carrying the alpha-0 thalassaemia, beta-thalassaemia and Hb-E. (Fucharoen S et al 2000)

Haemoglobinopathy can spread in the many region of the world because of the mix ethnic and immigration from the countries which are prevalence the disease to non prevalence disease countries.

Haemoglobinopathies occurs due to of the haemoglobins reduced their ability to carry the oxygen. This disorder associated to haemoglobin molecule disorder also that is important to understanding the structure and function of haemoglobin. There are two main types of haemoglobinopathy, SCD and thalassaemia can be passed from parental to offspring trough abnormal haemoglobin genes. Individual can be effect with these disorder while they are be inherited with two abnormal haemoglobin one from paternal and the other from maternal. But individual with only one abnormal haemoglobin gene called as carrier or trait, does not shows any clinical symptom and healthier as well.

Individuals with haemoglobinopthies are either having clinical symptom of this disease, or if the individuals are carrier, unknown of their trait until screened, but If parent both carrier an abnormal hemoglobin gene there is a chance 25% of their pregnancy that offspring will affected with the clinical symptom of haemoglobinopathy

If the maternal affected with haemoglobinopathy, and the paternal only carrier therefore the child 50% can be affected and 50% will carrier.

The haemoglobin Hb molecule is a polymer consisting of four identical monomers. Hb molecule consist of two pairs of globins chains, each containing a haem group, every haem have an iron atom which is attached to oxygen in the lung and the haem which is responsible for transporting the oxygen from the lungs to the tissues and carrying the carbon dioxide (CO2) from the tissue to lung (Figure 1). For the period of foetus development, the foetal Hb predominate (two alpha chains and two gamma chains). Haemoglobin Hb molecule in adult composed of four globins chains two alpha subunit and two beta subunit. The structure Hb changes within embryonic, fetus and adult. Usually the main haemoglobin in normal adult is HbA, and little quantity of HbA2 and HbF. (Morven W et al 2009)

Diagram showing the location of haeme in haemoglobin.

Figure 1: shows the structure of haemoglobin (www.sciencelearn.org.nz) accessed 29/01/2011.

Classification of heamoglobinopaties: haemoglobinopathy can divided into two main parts (figure -2)


Sickle cell disease

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Fig 2: (Ronald J 2006)


Thalassemia is hereditary haemoglobin defect which failure the formation more than one polypeptide chain of haemoglobin protein causes mild or severe anaemia. thalassaemia classified into a few categories and each of them can causes different problems. Thalassamia is quantitative abnormality, frequently associated to chronic haemolytic anaemia, the clinical expression of disease including serious of haemolysis and some type of the disease not shows clinical symptom of the disease. Thalassaemia involved in the class of globins chain and number of defective of globins gene. The offspring with thalassamia at the birth frequently are healthy, the sign and symptom of anaemia appear in between age six month to two years old. Without detection and treatment the most of children in age one year old are death because of severe anaemia and infection. (Weatherall. D and Clegg. J 2001)

Some types of thalassaemia initiate with mild condition, but some of them cases serious and life threatening and it cause death. Nearly 5% of the population in the nationwide have been affected with this disease. Foetal Haemoglobin (Hb) is predominantly alpha2 and gama2. In the normal individual the dominating haemoglobin composition is HbA i.e. alpha 2 and beta 2. This implies that the frequent forms of thalassaemia are alpha and beta, each type causes different clinical manifestation. Foetal Haemoglobin (Hb) is predominantly alpha 2 and gamma 2. In the normal individual the dominating haemoglobin composition is HbA i.e. a2b2. This implies that the frequent forms of thalassaemia are alpha and beta. (Fucharoen et al 2007)

Alpha thalassemia:

Individual with alpha-thalassemia characterised by lack of alpha globin chains. It is prevalence in Africa, Middle East, Asia, south east of Asia, and also Mediterranean area.

The alpha-globin gene made up by four genes, found on chromosome 16p13.3 (Figure 4) and including the embryonic zeta-globins gene and two alpha globins genes, usually there are four alpha globins gene, mutation affected on one or more alpha-globins gene causes lack of formation of alpha- globin chain lead to alpha thalassaemia. (Weatherall. D and Clegg. J 2001) The patient with only one unusual alpha globin gene is called alpha thalassaemia carrier. In this case one globin genes defective or missing, and not show any clinical symptom of anaemia, and difficult to diagnosis also known as silent carrier. Normal carrier has an offspring with haemoglobin H (HbH). It is can be to detect by DNA examination. If the individual has missing two of four globin genes call as alpha thalasaemia trait, both abnormal alpha-globin genes can be found on one chromosome or one on each chromosome.

The parents both have alpha thalasaemia trait therefore their offspring effective with alpha thalassaemia trait. The patient with this disease has mild anaemia and the red cells are smaller the normal size call microcytosis. And the patient does not show the clinical manifestation. (Leung. W et al 2008)

Also if one of the parents has alpha thalassaemia trait and the other one has silent carrier there is 25% chance of their offspring born with HbH. But if the both parent have alpha thalassaemia trait there is 25% chance their offspring inherited with alpha-thalassaemia major. Individual with condition has no chance to live for long term and mostly die in childhood, the reason for that because of lack or defects of the alpha globin chain and causes the severe anaemia and causes health damaging such as spleenomegaly, bone malformation and tiredness.


The beta-thalassaemia is an inherited disease associated with haemoglobin disorder, is congenital anaemia, occur because of lack or reduce formation of beta-globin chain causes reduce the number of red cells or produce unfunctional red cells, most of erythrocyte are failure to mature from the bone marrow that is cause serious anaemia. The beta- globin chain deficit causes the intracellular precipitation and increases of alpha-globin chain, leading to ineffective erythropoiesis and haemolysis anaemia. (Ronald J 2006) Beta-thalassaemia is the most common molecular deficiency as the consequence of point mutation and deletion that effect the transcription and mRNA translation. Infants with homozygous beta-thalassaemia are healthy but after birth as the haemoglobin from fetus replaced to adult haemoglobin the absent of beta-globin causes the serious anaemia. Also the level of anaemia is deference rely on the level of beta-globin deficiency and the formation of fetal haemoglobin. (Lin. Y et al 2009)

The clinical manifestations of beta-thalassaemia including of anaemia shows in the first year of life, also the spleen enlargement resulting from accumulation large amount of destruction os erythrocyte in the spleen, growth of bone marrow because the body compensated the red cells destruction which is leading to abnormal growth the long bones and deformation the skull. Beta-thalassemia is most prevalence in the Asia, and became the main health problem among people. (Weatherall. J 2001)

In developing countries the patients with this disease are suffering and death within childhood. The recent study of the national thalassemia register reveals that the patients survive for longer in the UK, half population of patients with beta-thalassemia die under the age of 35 years old.

Sickle cell disease (SCD)

SCD is genetic defected haemoglobinopathy characterised by stiffen shaped cells which can block blood vessels and caused severe pain, organ damage and infection. Was found at the beginning the twentieth century, is an autosomal dominant genetic disorder, it is related to qualitative globin gene defect, and formation of abnormal globin chain, SCD results in morbidity and mortality. There are 500 unusual Hb found but only four of them are common such as HbS (beta 6 glu-val), HbC (beta 6 Glu-Lys), HbD (beta 87 Thr-Lys), HbE (beta 26 Glu-Lys). The disease is characterized by abnormality in shape of RBCs, the cell become sickle-shape which is rigid and stiffen and can leading to obstruction the blood vessels and tissue ischemia, which causes the organ damage. Also this abnormality can cause painful episodes, severe infection and chronic anaemia. SCD is the mutation in the haemoglobin gene and causes sickling the cells, mutation increased in different part of the Hb molecule, SCD can be detected through infant screening haemoglobin electrophoresis. SCD occur because of mutation on short arm of chromosome 11 (figure-4), this mutation leading to replace the valine to glutamine of the amino acid at the sixth positions of beta-globin chain of HbA, resulting in the production of HbS which is biochemically unstable molecule and it can precipitate at the deoxygenated state. (Hoffbrand. A.V. 2001)


Figure- 4 Globin encoding genes are found on chromosome 11 and 16. Figure 3

SCD was the first disease has been described as a molecular disorder in a gene, and it is detected by infant screening program. Its causes reduce lifespan and associated to chronic disease. SCD occur in that part of the world where Plasmodium Palciparum has endemic and then spread because of migration to other part of the world for example north of Europe and United States. SCD is more common in those people are originally came from the Africa, Mediterranean, middle and south of America, Asia and middle east. (Figure 4) SCD occurs due to the newborn inherited the defect haemoglobin gene from parental mother and father HB SS causes severe anaemia, if only one sickle haemoglobin gene from one parent and one normal haemoglobin gene from other parent transfer to infant, therefore the infant become a carrier also known as sickle cell trait. (Marie. J and Ronald. L 2004)


Reference: Marie. J and Ronald L 2004

Figure 5: Geographical distribution and representation of the sickle gene.

(A) Map identifies the three distinct areas in Africa and one in the Arab-India region where the sickle gene is present (dotted lines). Numbers of individuals with sickle-cell disease (red lines) in Senegal, Benin, and Bantu are higher near the coast, and falls concentrically inland.

(B) The β-globin gene cluster haplotype is determined by DNA polymorphic sites (boxes) that are identified by endonuclease enzymes. With this information, haplotypes are constructed as shown.

The pathophysiologies of CSD rely on the deoxy- HbS. That is association with two alpha globin chains with mutation of 2 beta-globin chains produce HbS. under deoxygenating circumstance, the lack of a polar amino acid at six locations of beta-globin chain lead to aggregation of Hb, which change the RBCs into sickle shape and reduced their elasticity. (Figure 5) The patients with the SCD are often visiting to hospital because of acute pain, and the patient treated by an analgesic to relief the pain, hydration and oxygen supply. The main common of clinical symptom of SCD including anaemia, episode painful, lung infection, infarctions of nervous system and strokes, spleenenlargment because of precipitation of large amount of haemoglobin in spleen, skin ulceration, organ damage, vaso-occlusive, and neurocongenitive dysfunction most common causes morbidity among the patient with this disease.

Figure- 5: Normal and sickle red cell morphology

SCD is known as chronic inflammatory disease,

Diagnosis of haemoglobinopathies:

Detection and identification of haemoglobinopathies relay on three stages:

Full blood count

Special haematological test

DNA analysis

Full blood account

Full blood account is used to detection of haemoglobinopaty specially the thalasaemia, which is the earliest of haematological information. Individual with thalassaemia shows low mean corpuscular volume (MCV) or mean corpuscular haemoglobin (MCH). Also in other anaemia for example the iron deficiency the MCV is low as well, it is possible this detection will shows the thalassaemia in those region with at high risk ethnic populations. The first step after initial abnormal blood count is to elimination of iron deficiency, to cure it. The blood count test is repeated if the MCV still lower than normal value. The test show most likely is thalassemia. Also the MCV increased because of some condition especially B12 and folic deficiency causes raised the MCV. In some condition the main evidence of thalassaemis disappears due to the MCV is wrongly normal or may be increased. Measuring the MVC is used as early stage test for heamoglobinopathy. Therefore that is very important for diagnosis of thalassaemia this is the HbS carrier, the health professionals who are dealing with those people in which HbS occurs must be including the HbEPG with the demand a full blood count.

Also blood film as part of full blood count can be used, it is detected the SCD (HBS) or unstable Hb. in some cases, finding the target cells and stippling in the blood film are not associated with a haemoglobinopathy but it can help as additional finding in case of thalassaemia if the MCV or MCH is lower than reference range.

Special haematological test

Some of test of haemoglobinopathy technically require skill the team of laboratory, must have knowledge and must be trained to use the laboratory’s instrument, and obtain an experience in understand the results. More haematological test is requiring especially after detecting the more unusual HbS. Also test the oxygen affinity, stability of haemoglobin and identify the methaemoglobin.

Mass spectrometry is used to characterise different mutation of HbS.( 10 )for diagnosis of individual cases is the DNA test.

DNA test is the most common haematology test, due to the DNA laboratory must to understand the characterised of alpha and beta globin genes. As DNA technology in haemoglobinopathy based on PCR (polymerase chain reaction) and southern blotting, also the DNA laboratory examination deciding whether there is a point mutations or deletions. Other major source of mistake to deceive the DNA laboratory is the not a success to detection HbH. Not occasionally, a DNA detection used to diagnosis the beta globin gene due to HbH inclusion was not be found, if not mutation in DNA sequencing is detected, at this point the DNA laboratory back to the haematology test to detected the HbH inclusion.

Another useful test to diagnosis a thalassaemia and it is because of an alpha and beta globin gene problem in the alpha and beta globin protein fraction. That is requiring to incubation of RBC with radioactive. The peaks indicative of alpha and beta globins are then provide an alpha and beta ratio which must equal one. If the ratio higher than one that is indicates beta thalassaemia, or if the ratio lower than one that is indicates alpha thalassaemia. The alpha and beta ratio is not longer available. That was took place due to DNA testing is became the common test and also alpha and beta ratios are now performed in those laboratory do have insufficient skill. Setting up of this assay needed fresh radioactive material. The alpha and beta ratio may be not useful while the interactions of genes are occurring.

DNA testing

DNA testing is requiring if the haemoglobinopathy difficult to detect by the haematological test, while it is may be suspected a haemoglobinopathy, but the haematology may not detected which gene has been involved. And the other reason to use DNA testing is the basic alteration been sought in an established haemoglobinopaty. This require as part of parental developed. (Ronald J 2006)

DNA test can be used for sickle cell in neonatal by analysing of the DNA of foetal tissue

Screening test for thalassaemia and haemoglobinopatphies

Usually the basic screening trial all type of thalassaemia depends on the guide of haematology cut- off, which effects on the correct count using an automatic blood cell counter. The patient with MCV values lower than (80 fL), and MCH values lower than (27 pg). Therefore more tests are requiring identifying of (alpha and beta) thalassaemia. (Kanokwan, S et al 2005) But the test needs an expensive an automatic blood cell counting but that is impossible to perform in the laboratory without good facilities. Also that has been proved the osmotic fragility test tube which is containing 0.36% of saline solution could be used as like other option test to detected alpha and beta salassaemia syndrome. (Kamala. R 2008)

The recent study indicated that specificity of the osmotic fragility test for detection of (beta and alpha-0) thalassaemia could be improved by reduce concentration of saline solution from 36% to 34%. But the carrier of Hb-E would not be available; in this case cichlorophenolindophenol (DCIP) test has been established for detection of Hb-E in the developing country of Southeast Asia, but this procedure is not suitable for pregnant woman because they have iron deficiency during their pregnancy. Hence the combination osmatic fragility test and DCIP test use for detection alpha,0- thalassaemia, beta thalassaemia and Hb E in pregnant woman tested and compared with other measure screening procedure linked to measure of RBCs indicator. (Kanokwan, S et al 2005)

There is some more special haematology tests require to diagnosis of haemoglobinopathies:

Hb EPG test can be measured by electrophoresis of globin. Different methods likely as gel and membrane based to high pressure liquid chromatography (HPLC). Unusual group separate as of normal HbA, HbF and also HbA2 can be detected.that dose mean provides some information about HbA2, and recognize some other Hb if available for example HbE and HbS.

HbA2 test is detected by globin electrophoresis and quantity the HbA2. And difference methods are used as a membrane, also the more use in the world is HPLC. That does mean the increased HbA2 shows the incident of beta- thalassaemia. It dose shows that the alternative haemoglobins could be increased the HbA2. Also unusual raised the HbA2 shows the mild beta thalassaemia, the low HbA2 delta thalassaemia.

HbF test detected by globin electrophoresis, and determine by deference technique. The normal value in of HbF adult is lower than 1%, if the HbF slightly increased to 2 or 3% that indicates the mild beta- thalassaemia. If HbF elevated to more than 5% are likely to be delta-beta thalassaemia in this case the level of HbA2 decreased. (Angela. H 2005)

Kleihauer test is staining the red cell to diagnosis the HbF. This test uses for separate the hetrocellular from pancellular. This test is unusual for differentiation the type of hereditary persistence of Hbf because they are not often available and difficult for laboratory staff to translate the results. This test useful only in foetal blood sample to detect that the HbF passed from the fetes to the mother’s blood circulation. (Liu. W et al 2007)

HbH inclusion test carry out by stain the red blood cells to identification of HbH inclusion, deposition of beta globin chain. This test used to detection of alpha-thalassaemia. This test causes problem due to false negative. Need a lot of knowledge and skill of laboratorian to detect HbH inclusion and with two gene deleted alpha-thalasaemia, only very HbH little inclusion can be detected. Therefore the laboratorian may miss it if do not have good experience. Must the person who is work in the laboratory must continuously look at the microscope. (Chan. A 1996)

Sickle solubility and stability test, there many different type of test performed to detected the HbS or unstable variation of HbS. There are interactions between the HbS with beta thalassaemia, hence the correct test for sickling test are require for haenoglobinopathy. (Baebara J 2004)

RBC count can be used for detection of thalassaimia and haemoglobinopathies while the red cells count is normal or increased. Also it is helpful if hypochromic, microcytic observed.

The Red cell Distribution Width (RDW) is a numerical value that represents the coefficient of variation of the red cell volume distribution. This value indicates the variation in red cell size (anisocytosis). Anisocytosis is an abnormally of red cell size variation that is apparent on the blood smear, is the anisocytosis is increased that is indicated the beta and alpha thalassaemia as it is seen before the haemoglobin decreased and MCV and MCH reduced.

Mean Cell Haemoglobin Concentration (MCHC) it is the other parameter is the concentration in g/L of haemoglobin in the RBC, But It is infrequently measured. If the MCHC reduced that is shows the hypochromic with any other causes microcytosis that is indicates the thalassaemia.

Haemoglobin electrophoresis for diagnosis of CSD

Diagnosis SCD can be performed by the haemoglobin electrophoresis. Simple and accurate method for diagnosis of SCD due to in can detect the Hbs, but the EP is reliable to identify the phenotype.

Sickle cell test the sodium metabisulphite used for remove the agent leads to precipitate in the buffer solution to formation the cloudy suspension. This test is not useful neonatal period because of lack HbS and presence high amount of HbF which has high solubility and may generate false negative result. Sickle cell test can be used after six month of age becouse the level of HbF dropped down. For distinguish the phenotype should relying on the haemoglobin electrophoresis. Separation of molecule in this test rely on the charge at add pH. H


There same key words have been used to find the journals which are related to finding the information for the topic of the project. The key words including (haemoglobinopathies, Thalassaemia (beta or alpha), Sickle cell disease, treatment of haemoglobinopathies and diagnosis of haemoglobinopathies).

Treatment for thalassaemia

More than 90% of the patient with thalassaemia needs to be treated by regular blood transfusion to regulate the anaemia and its side effects, transfusion therapy increase the life span of patient with quality of life. Infants who are sufficient treated by blood transfusion growth well. However the transfusion therapy causes increased the amount of iron in the organ, iron overload is fatal if untreated causes organ damage, late sexual growth, and osteoporosis.

Most individuals with beta-thalassaemia major can be survive for longer with blood transfusion therapy but increasing the damaging levels of iron overload if the patient not be treated with iron chelation therapy. Increased the level of iron from blood transfusions therapy leading to destruction the macrophages and then follow that damaging the liver and later on spreads to the heart tissue, pancreas, and also the iron overload effected on the same of glands such as pituitary, thyroid and parathyroid glands, the levels of iron must be controlled by chelating treatment. Due to the blood transfusion are usually started at the beginning in life, excess of iron effects on the endocrine system can causes unusual growth and hypogonadotrophic hypogonadism. Cardiac disease is the most causes of death among the patient with beta-thalassaemia major. Iron overload causes reduce the myocardial T2 vales is detected by cardiac magnetic resonance imaging, is prevalence in the patient with beta-thallassaemia. (Kirk P et al 2011)

Iron chelating therapy supports the patient with increased the level of iron from the accumulation the toxic iron and reduce the amount of iron that harmful for tissue and many organs. Iron chelating initially used by the end of the 1970s, it is not a curative for the patient with beta-thalasaemia major but it can reduce the number of death because of this disease. The patient with this has some side effects which are related to excess iron such as diabetes, hypogonadism, and hyper thyroidism, (Rugolotto S et al 2004)

The main purpose of using the iron chelation is sustain the balance of amount of iron at the safe stage in the organ tissue and stop accumulating of iron inside the organ.

To reduce the level of iron in body, there are deference ways to rescue the human body from iron overload. Venesection is procedure, part of treatment. Used to withdraw large amount of blood a through the vein and discarded, use for treatment of iron overload also is known by phlebotomy used for elimination of iron in the blood circulation, removes 200-250mg iron from unit of blood.

Also the iron chelating can help the patient to reduces the level of iron, iron chelation with deferoxamine causes the damaging of tissue and ultimately causes death, the resent study explore that the cardiac disease is causes death in more than 70% of patient who are treated with deferoxamine. The new oral chelater was started in 1995; oral chelater with deferiprone became very useful treatment in the clinical therapy. The prospective non randomized clinical test proved that the mortality because of the cardiac disease decreased in patient treated with deferiprone, combine and sequential the deferiprone with deferoxamine. (Aurelio. M et al 2009)

The diagnosis laboratory performed the experiment on 265 patients in one of the Italia laboratory from year 2000 to 2008, 124 patients treated deferoxamine and 11 patient was death, and 55 patients treated with deferiprone none of them death, 68 patients treated with sequential deferiprone and deferoxamine only one patient death and 18 patients treated with combine deferiprone and deferoxamine none of them death. This trial give clue the best treatment for iron chelating is deferoxamine or combination between deferiprone and deferoxamine.

Figure 6: trial profile 265 patient treated with iron chelater.

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