Hemoglobin Malaria Haemoglobinopathies

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1st Jan 1970 Health Reference this

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Despite major advances in the understanding of the molecular pathophysiology and control and management of the inherited disorders of hemoglobin (haemoglobinopathies), thousands of infants and children with this disease are dying. As a result in heterozygote advantage against malaria the inherited hemoglobin disorders are the commonest monogenic disease. Population migrations have ensured that haemoglobinopathies are now encountered in most countries including the UK. Haemoglobinopathies have spread from areas in the Mediterranean, Africa and Asia and are now endemic throughout Europe, the Americas and Australia. This review examines the available literature to find out more about the prevalence of haemoglobinopathies in the UK. The data on the demographics and prevalence of the gene variants of haemoglobinopathies was extracted from books, journals, reference sources, online databases and published review articles from the WHO.

  • Introduction

It has been estimated that approximately 7% of the world population are carriers of such disorders and that 3000 000 – 4000 000 babies with severe forms of haemoglobinopathies. Haemoglobinopathy disorders occur at their highest frequency in tropical regions and population migrations have ensured that they are now encountered in most countries. Because of this, haemoglobinopathies have become a global endemic, so the World Health Organization published journals and reviews with recommendations on screening programmes and management of haemoglobinopathies. The programmes are tailored to specific socioeconomic and cultural contexts and aimed at reducing the incidence, morbidity and mortality associated with these diseases. www.who.int/en/

The WHO Executive Board wrote a review on haemoglobinopathies. In this article, the WHO Executive Board recognized that the prevalence of haemoglobinopathies varies between communities, and that insufficiency of relevant epidemiological data may hamper effective and equitable management of haemoglobinopathies. On this note England implemented the LIVE programmes. The Executive Board also recognizes that haemoglobinopathies are not yet officially recognized as priorities in Public Health Sector. This raised an issue about awareness of haemoglobinopathies. The WHO Executive Board’s advice for prevention and management of haemoglobinopathies was to design, implement and reinforce in a systematic equitable and effective manner, comprehensive national, integrated programs for prevention and management of haemoglobinopathies, including surveillance, dissemination, such programs being tailored to specific socioeconomic and cultural contexts and aimed at reducing the incidence, morbidity and mortality associated with these diseases. www.who.int/en/

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With immigration in the UK on its highest, the prevalence of haemoglobinopathies is expected to increase. The NHS has implemented programmes for individuals with haemoglobinopathies by implementation of LIVE program (NHS Plan, 2000). LIVE program is set-up to implement variant screening in the whole of UK by the year 2007. LIVE program started as early as January 2004 in high prevalence. The NHS Trusts involved are to offer variant screening by end of 2004/5 (NHS Plan, 2000). Low prevalence Trust are expected to have implemented the screening program by January 2008 and so far 86 out of 90 Trusts have successfully implemented the program. Antenatal and Newborn Screening programs have compiled a training pack to assist Low Prevalence Trusts with the implementation of haemoglobinopathies screening programmes. The NHS Plan (2000) made a commitment to implement effective and appropriate screening programs for women and children including a new national linked Antenatal and Newborn screening programs for haemoglobinopathies. The NHS Plan (2000) recommends that all pregnant women living in high prevalence areas are offered screening for haemoglobinopathies. All pregnant women living in low prevalence areas are offered screening for haemoglobinopathies. If a woman is identified as being at increased risk using the family origin questionnaire, she will then be offered screening for haemoglobinopathies (NHS Plan, 2000). The Low Prevalence Trust is where the fetal prevalence of sickle cell disease is less than 1.5 per 10 000 pregnancies. Low prevalence trusts are to offer screening for variants based on an assessment of risk determine by a question to women about their baby’s father’s family origin by the end of 2005/6 (NHS Plan, 2000).

  • Background on Haemoglobinopathies

Haemoglobin: is the oxygen carrying capacity of the blood and it is also a protein. Haem is iron containing pigment, while globin is made up of chains which are a globular tetrameric protein which accounts for 97.4% of the mass of the haemoglobin molecule (Tortora et.al., 2006) . The globin tetramer consists of four polypeptides which are two alpha (α) chains and two non-alpha chains. The synthesis of ζ and ε chains is done during the first 10 to 12 weeks of fetal life. Within the fourth to the fifth week of intrauterine life α and β chains are synthesized. The non-alpha is beta (β), gamma (γ), delta (δ), epsilon (ε) zeta (ζ) chains. Haemoglobin transports oxygen from the lungs to all parts of the body and it gives blood its red colour (Fleming, 1982)

Haemoglobin synthesis

Haem and globin synthesis occur separately but in a carefully coordinated fashion. Globin synthesis is under the genetic control of eight functional genes arranged in two clusters, the α globin gene cluster on chromosome 16 and the β globin gene cluster on chromosome 11. The major haemoglobin in the foetus is HbF (αβ) 2 and in adults HbA (αβ) 2 (Fleming, 1982).

Haemoglobin Structure

The primary structure of haemoglobin is made-up of amino acid sequence of globin. And the secondary structure comprise of nine non-helical sections joined by eight helices; tertiary structure describes globin chain folding to form a sphere and the quaternary structure of haemoglobin describes the tetrahedral arrangements of the four globin subunits ( Fleming, 1982). The external surface of each folded globin is hydrophilic and the inner surface is hydrophobic, this protects the haem from oxidation, which is also why each haem chain sits in a protective hydrophobic pocket. In haemoglobin A, α β dimmers are held together strongly at the α1 β1 or α2β2 junction. The tetramer is held together much less tightly at the α1 β2 and α2 β1 contact areas (Fleming, 1982).

Haemoglobin function

Each haemoglobin molecule can carry four oxygen molecules. Oxygenation and deoxygenation are accompanied by molecular expansion and contraction via haem – haem interaction (Bienz, 2007). Under physiological conditions, blood in the aorta carries about 19.5ml of oxygen per 100ml of blood. Upon entering the tissues about 4.5ml of oxygen are donated per 100ml of blood. 2,3-DPG is an important modulator of haemoglobin A oxygen affinity in red cells (Fleming, 1982).

  • Haemoglobin disorder (haemoglobinopathies)

Haemoglobinopathies is a hematological disorder due to alteration of a genetically defect, that results in abnormal structure of one of the globin chains of the haemoglobin molecule (Bienz, 2007). Haemoglobinopathies are any of a group of diseases characterized by abnormalities, both quantitative and qualitative in the synthesis of haemoglobin (Hb) (Bienz, 2007). Qualitative – affecting the quality of haemoglobin e.g. Sickle cell disorder and quantitative – affecting the amount of haemoglobin produced e.g. Thalassaemias. Most of them are genetically inherited but occasionally they can be caused by a spontaneous mutation. Haemoglobinopathies are the world’s most common monogenic autonomic and recessive disease in humans (Anionwu et.al., 2001).

2.1Haemoglobinopathies fall into two main types;

There are two categories of haemoglobinopathies. The two categories are: qualitative and quantitative;

  • Qualitative – affecting the quality of the haemoglobin e.g. Sickle cell disorder. In this disease the globin structure is abnormal.
  • Quantitative – the haemoglobin structure is normal but the amount of haemoglobin produced is affected. e.g. alpha and beta thalassaemias (Bienz, 2007).
  • History of haemoglobinopathies

In 1910 Herrick wrote an article in it he used the term “sickle” to describe the shape of the red blood cells of a 20 year old medical student from Grenada. This student had consulted Dr Herrick in 1994 complaining of a cough, fever and Feeling weak and dizzy. He constantly had anaemia episodes, jaundice, chest complications as well as recurring leg ulcers on both ankles. When his blood was examined, his red blood cells showed a large number of thin, elongated, sickle shaped and crescent- shaped forms (Herrick, 1990).

The name thalassaemia was coined by the eminent haematologist George Whipple in 1936 as an alternative to the eponymous ‘Cooley’s anaemia’. He wanted a name that would convey the sense of an anaemia which is prevalent in the region of the Mediterranean Sea, since most of the early cases originated there. Thalassaemia is derived by contraction of thalassic anaemia (from the Greek thalassa -sea, an – none and anemia – blood) (Fleming,1982).

Origins and Geographic distribution of haemoglobinopathies

Carriers are found in all parts of the world: people from the North Mediterranean (South Europe) coast are 1-19% carriers. People of Arab origin are over 3% carriers. In Central Asia 4-10% and in South East Asia, the Indian subcontinent and China 1-40% carriers (the very high rates in this part of the world are due to HbE). In the Americas, North Europe, Australia and South Africa the local population has very low carrier rates but thalassaemia is still present because of the significant immigration from high prevalence area (Anionwu et.al.; 2001). Sickle cell and thalassaemia disorder mainly affect individual who are descended from families where one or more members originated from parts of the world where falciparum malaria was, or is still endemic. Population with such ancestry include those from many parts of Africa, the Caribbean the Mediterranean (including southern Italy, Northern Greece and Southern Turkey), Southeast Asia and thalassaemia gene is much wider now due to the historical movements of at-risk populations to North and South America, the Caribbean and Western Europe (Livingstone 1985).

The geographic distribution of the thalassaemias overlaps with that of sickles cell disease. This is because carriage of these abnormal genes affords some protection against malaria. Thus, being heterozygous for one of these conditions offers a selective survival advantage and increases the opportunity for these genes to be passed on (Campbell et.al.,2004)

4Types and terminology of sickle cell and thalassaemia

There are various types of sickle cell and thalassaemia disorders. The thalassaemia syndromes include alpha and beta thalassaemia major as well as beta thalassaemia intermedia. Sickle cell disorders (or Fickle cell disease include sickle cell anaemia (Hb SS), Sickle haemoglobin C disease (Hb SC) β disease and E beta thalassaemia (www.sickle-thalassaemia.org/sickle.cel.htm)

4.1Sickle Cell Disorder: affects the normal oxygen carrying capacity of the red blood cells. The red blood cell forms a crescent or a sickled shape when it is deoxygenated. The ‘sickled’ cells are unable to pass freely through capillaries; the sickle cells also get stuck in blood vessels forming clusters which block the blood vessels and the blood flow. They don’t last as long as normal, round red blood cells, which leads to anemia. This results in a lack of oxygen to the tissues in the affected area, resulting in hypoxia and pain (sickle cell crisis). Other symptoms include severe anaemia, damage to major organs and infection (NHS Antenatal and Newborn; 2006).

There are several types of Sickle cell disease. The most common are: sickle cell anemia (SS), sickle – hemoglobin C disease (SC), sickle beta – plus thalassaemia and sickle beta zero thalassaemia. Each of these can cause pain episodes and complications.

HbSS – sickle is due to two sickle cell genes (“S”), one from each parent. This is commonly called sickle cell anemia. An individual with sickles cell anemia have a variation in the β-chain gene, which then causes a change in the properties of hemoglobin which results in sickling of red blood cells (www.sickle-thalassaemia.org/sickle.cel.htm)

HbSc – inherited one sickle cell gene and one gene from an abnormal type of haemoglobin called “C”. It is due to the variation in the β-chain gene. An individual with this variant suffers from mild chronic haemolytic anaemia. (NHS Antenatal and Newborn; 2006).

HbS beta thalassaeamia: This form of sickle is due to inherited one sickle cell gene and one gene for beta.

4.2Thalassaemias: is a term used for the description of a globin gene disorders that results from a diminished rate of synthesis of one or more globin chains and a consequently reduced rate of synthesis of the haemoglobin or haemoglobins of which that chain constitutes a part ; α thalassaemia indicates a reduced rate of synthesis of the α globin chain, similarly, β, δ, δ β and ε γ δ β thalassaemia indicate a reduced rate of synthesis of the h, δ, δ, +β and ε + γ + δ + β chains, respectively (Modell et.al, 2001). Thalassaemia is the most common single gene disorder known. It is autosomal recessive syndromes, which is divided into α- and β thalassaemia.

Types of thalassaemia

There are two types of thalassaemia:

(i)Thalassaemia minor (thalassaemia trait)

(ii)Thalassaemia major

Thalassaemia minor is when a person inherits one thalassaemia gene, while thalassaemia major is a severe form of anaemia if a person inherits two thalassaemia genes, one from each parent (Bienz, 2007).

Subtypes of thalassaemia

Alpha (α) thalassaemia results from inadequate production of α – chains, which are normally controlled by two pairs of chromosomes. If one or two are malfunctioning, then there is a healthy carrier state. If three are non- functional then anaemia results, known as HbH Disease, which can be quite severe but usually does not need blood transfusions and is compatible with a normal life span (Anionwu et al, 2001). If all four genes are non – functional then the result is severe anaemia of the unborn child, leading to heart failure and death (miscarriage). This condition is known as hydrops felalis (Fleming, 1982).

Beta (β) Thalassaemia is caused by the body’s inability to produce normal haemoglobin, leading to a life threatening anaemia (Bienz, 2007). The severity of illness depends on whether one or both genes are affected and the nature of the abnormality. If both genes are affected, anemia can range from moderate to severe. Beta thalassaemia results from inadequate or lack of production of β – chains (Anionwu et.a.l, 2001). Homozygous, β – thalassaemia has two forms: major, in which the patient can survive only with regular transfusions of blood and intermedia in which the patient can survive with occasional or even with no transfusions at all. The condition requires frequent blood transfusions and treatment to prevent complications from iron overload, such as diabetes and other endocrine disorders (Anionwu et.a.l, 2001). Both of these conditions can restrict a child or adults ability to conduct their normal daily activities and can have profound psychological affects on individuals and their families This form of thalassaemia is the most important and constitutes a major public health problem in many parts of the world, because of the high frequency of carriers and the demanding treatment that must be followed (Fleming, 1985).

  • Association of Haemoglobinopathies with Malaria

Malariais a vector – borne infectious disease caused by protozoan parasites. It is widespread in tropical and subtropical regions, including parts of the Americans, Mediterranean, Asia and Africa. It causes diseases in approximately 515 million people and kills between one and three million people, the majority of whom are young children. Malaria parasites are transmitted by female Anopheles mosquitoes. The parasites multiply within red blood cells, causing symptoms that include symptoms of anemia (Campbell et al, 2004).

Sickle cell developed as a by product of human defense mechanisms against malaria. The most severe form of malaria, falciparum malaria, leads to very high death rate in young infants. This is particularly a problem between the time immediately after birth, when they are protected by immunity from the mother, and the time when they are old enough to acquire their own immunity. Malaria is a parasite which lives within the red blood cells and feeds off the protein that is contained within those red cells, haemoglobin (Campbell et al, 2004). When the malarial parasite enters the blood stream through a mosquito bite, it penetrates the red blood cells by attaching to the outside membrane or envelope of the red blood cell and gaining entry (Franklin, 1990). Once in the red blood cell, the malarial parasites use the haemoglobin as a source of energy, so that they multiply within the red cells. The parasites multiple filling-up the red blood cells and once they are filled-up the red cells burst, thereby releasing the multiple parasites in the blood. Each new young parasite enters a single cell again and multiplies again, thereby causing a disease or infection. Whenever the parasites burst out of the cells they cause illness and fever in patients. Malaria can be severe by causing death; death is believed to be caused by red cells not being able to pass through the narrow gaps in the smallest blood vessels and by blockage of tissues when so many parasites are in the red blood cell (Campbell et al, 2004).

Over the years human genes developed ways to prevent malaria becoming serious and potentially lethal, the developments were to prevent malarial parasites from spreading and multiplying (Tortora et.al,2006). The most changes were changes (mutation) in the type of haemoglobin (haemoglobin S) within the red blood cell which would in turn slow down the multiplying of the parasite (Campbell et al, 2004). The individuals with haemoglobin S are known to have a sickle cell trait or being carriers of sickle cell haemoglobin. When sickle-cell haemoglobin has given up its oxygen in the cells, the red cells stick together to form crystalline groupings of haemoglobin known as polymers. The red blood cells become deformed into sickle shapes and the presence of these crystalline polymers within the red cells inhibits the growth of the malarial parasite (Beinz, 2007). Even though individuals with haemoglobin S stills suffer from malaria, they are protected from the most severe effects of malaria (Livingstone, 1985).

  • Diagnosis

Diagnosis for sickle cell disease

The most used diagnose test for sickle cell is the haemoglobin electrophoresis. HbS and HbC amino acid substitutions change the electrical charge of the protein, the migration pattern of the haemoglobin with electrophoresis or isoelectric focusing results in diagnostic patterns with each of the different haemoglobin variants. HbSBeta-thal requires careful evaluation of red blood cell count and mean corpuscular red cell volume (MCV) and specifically quantifying HbA, S, A2 and F. In emergency setting, the presence of HbS is detected using a five minute solubility test called sickledex. Sickledex test does not differentiate sickle syndromes from the benign carrier state (HbAS or a sickle trait (NHS Antenatal and Newborn; 2006).

Diagnosis for thalassaemias

When testing for thalassaemias, a blood test is the simplest and most effective test for diagnosis and also the use of a test called Haemoglobin Electrophoresis. The blood of individuals with thalassaemias tend to be microcytic (smaller in size) and hypochromic (paler in colour) (NHS Antenatal and Newborn; 2006).

7 Pathophysiology

7.1Sickle-cell

Sickle-cell anemia is caused by changes (mutation) in the structure of the β -globin chain of the haemoglobin replacing the amino acid glutamic acid with the less polar amino acid valine at the sixth position of the β chain. When two wild type α-globin subunits associate with two mutant β-globin subunits forms hemoglobin S. Haemoglobin S polymerizes under low oxygen conditions, which causes distortion of red blood cells and also causes red blood cells to lose their elasticity, resulting in red blood cells forming an irreversible sickle shape (Fleming,1982). Very often a cycle occurs, as the cells sickle they cause a region of low oxygen concentration which causes more red blood cells to sickle. Repeated occurrence of sickling causes cells to not return to normal even when oxygen levels are normal. The deformation of cells makes it difficult for the cells to pass through capillaries resulting in vessel occlusion, severe anemia, ischemia and other problems (Beinz, 2007).

7.2Thalassaemias

The pathophysiologic effects of the thalassaemias range from mild microcytosis to death in uterus. The anaemia manifestation of thalassaemia is microcytic – hypochromic haemolytic anaemia (Belcher, 1993). The haemoglobin abnormality is caused by substitution of a single amino acid for another; or substitution of two amino acids, also amino acid deletion or fusion (point of mutation) and the synthesis of elongated chains. In alpha trait, one of the genes that form the alpha chain is defective (Beinz, 2007). In alpha-thalassaemia minor, two genes are defective and in haemoglobin H disorder, three genes are defective. Alpha-thalassaemia major is most fatal thalassaemia disorder; this is because four of the chains forming genes are defective. Without alpha chains, oxygen cannot be released to the tissues (Belcher, 1993). In beta-thalassaemia haemoglobin abnormality is due to the uncoupling of alpha and beta-chain synthesis. This causes a depression in beta-chain synthesis, resulting in erythrocytes with a reduced amount of haemoglobin and accumulation of free alpha chains, which are unstable and easily precipitate the in cell (Bienz, 2007).

8.Causes

Genetic control of haemoglobin synthesis

The synthesis of structurally normal haemoglobin chains is determined by allelic genes situated on the autosomal chromosome (Beniz, 2007). Haemoglobinopathies occur due to an inheritance of one or more faulty copy of gene(s) that contain the information for the cells to make the globin chains. The gene may result in abnormality in the production or structure of the haemoglobin protein causing haemoglobinopathies (Franklin, 1990).

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Thalassaemia is an inherited autosomal recessive blood disorder. Genetic defects in Thalassaemia results in reduced synthesis of one of the globin chains which make up haemoglobin. Reduced synthesis of one of the globin chains causes the formation of abnormal haemoglobin molecules, which in turn causes anaemia. Anaemia is a symptom of the Thalassaemias. It is caused by under production of globin proteins, often through mutations in regulatory genes (Franklin, 1990).

Inheritance of Haemoglobin Disorder

Due to haemoglobin mutation, individuals who had haemoglobin trait had a resistance to dying from malaria, therefore passed on their haemoglobin trait gene to their children (Campbell et.al,2004). As time went on more individuals with the trait were born and eventually individuals who had haemoglobin trait had children together (Franklin, 1990). In that satiation (partnership), if both parents carry the trait gene, there is a one in four chance that any one child will receive the haemoglobin trait gene from one parent and also from the other, thereby having a haemoglobin disorder(Franklin, 1990) .

  • Clinical Manifestations

9.1Thalassaemias’ clinical manifestations

Individuals who inherited the alpha trait are usually asymptomatic, with possible mild microctyosis. Alpha- thalassaemia minor has signs and symptoms almost identical to those of beta-thalassaemia; mild microcytic hypochronic anemia, enlargement of the liver and spleen, and bone marrow hyperplasia (Belcher, 1993).

Alpha- thalassaemia major cause hydrops fetalis and fulminana intrauterine congestive heart and liver, edema and massive ascites. The disorder usually is diagnosed post mortem (Bienz, 2007).

Beta-thalassaemia minor causes mild to moderate microcytic-hypochronic anemia, mild splenomegaly, bronze coloring of the skin, and hyperplasia of the bone marrow. Skeletal changes depend on the degree of reticulocytosis, which in turn depends on the severity of the anaemia (Bienz, 2007).

People who have beta-thalassaemia minor usually are asymptomatic, whereas those with beta- thalassaemia major the anemia is severe, resulting in a great cardiovascular burden, with high output congestive heart failure (Belcher, 1993). Blood transfusions can increase the person’s life span by a decade or two. Individuals with beta-thalassaemia major have an enlarged liver and spleen, and growth and maturation are retarded (Belcher, 1993). A characteristic deformity develops on the face as the bones expand to accommodate hyperplastic marrow (Belcher, 1993).

Both and beta – thalassaemias major are life threatening. Children with thalassaemia major usually are week, fail to thrive, how poor development and experience cardiovascular compromise with high-output failure; if the condition goes untreated, these children die by 6 years of age (Modell et.al., 2001)

Blood transfusions can return haemoglobin and hematocrit to normal levels, alleviating the anaemia induced cardiac failure. Iron overload and hemochromatosis, which are complications of transfusion therapy, are treated with chelating agents (Bienz, 2007). .

9.2.Sickle-cell clinical manifestations

The severity of sickle cell disorder depends on the amount of haemoglobin S and the clinical manifestations, which are signs and symptoms of the individuals with sickle-cell (Belcher, 1993) . Manifestations of the sickling are those of hemolytic anemia; pallor, jaundice, fatigue and irritability. Extensive sickling can precipitate four types of crises: vaso-occlusive or thrombotic crises and a plastic crisis (Belcher, 1993).

A vaso-occlusive crises begins with red blood cells sickling in the microcirculation. Vasospasm brings a log-jam effect causing blood flow to stop flowing in the vessels and this will lead to thrombosis (blood clot formation) and infarction of local tissue occur, resulting in ischemia, pain and organ damage (Modell et.al.,2001). Vaso-occlusive crisis is believed to be extremely painful and lasts an average of 4 to 6 days. This crisis may develop spontaneously or may be precipitated by localized hypoxemia (low PO2) exposure to cold, dehydration, acidosis (low pH), or infection. In infancy, sickle-cell’s first manifestation is the symmetric painful swelling of the hands (see Fig 3) and feet, but in older children and adults, the large joints and surrounding tissues become swollen and painful. Individuals with the sickle-cell disorder suffer from severe abdominal pain caused by infarction in abdominal structures (Belcher, 1993). Any cerebral vascular accidents may cause paralysis or other central nervous system deficits, and if penile veins are obstructed priapism may occur. Studies have shown that bone, especially weight- bearing bones, are also a common target of vaso-occlusive damage, this is due to bone ischemia (Bienz, 2007).

The spleen of individuals with sickle-cell disorder is frequently affected due to its narrow vessels, functions in clearing defective red blood cells and this results in a sequestration crisis (Belcher,1993). A sequestration crises, is occurrence of large amounts of blood pool in the liver and spleen. It only occurs in young children and death results from cardiovascular collapse (NHS Antenatal and Newborn,2006).

An aplastic crisis develops when a compensatory increase in erythropoiesis is compromised; this then results in profound anemia (Belcher,1993).

A hyperhemolytic crisis is rare but may occur with certain drugs or infections. G-6-PD deficiency, when also present, contributes to this type of crisis (Belcher,1993).

Clinical manifestations of sickle cell disease do not usually appear until an infant is at least 6 months old. The most cause of death in individuals with sickle-cell anemia is infections, but it is major problem at all ages. Infections are due to splenic dysfunction from sickle damage (Belcher,1993). This occurs from a few months of age especially with certain bacteria e.g. pneumococcal sepsis. Infection tends to rapidly overwhelm the immune system (NHS Antenatal and Newborn,2006) . Sickle-cell haemoglobin C is known to be milder, with symptoms related to vaso-occlusive crises resulting from higher hematocrit and blood viscosity. Obstructive crises cause sickle cell retinopathy is most common in older children, and this include renal necrosis, and aseptic necrosis of the femoral head (Belcher, 1993).

The mildest of sickle-cell is the sickle-cell thalassaemia the individuals with this form of sickle-cell tend to be microcytic and hypochromic, which makes the cells less likely to clog the microcirculation even when sickling (Belcher, 1993).

Severe hypoxia can be seen in individuals with the sickle cell trait and may cause vaso-occlusive episodes. The cells in these people form an ivy shape (Belcher, 1993).

Recent studies have shown that stroke is co-exiting with Sickle cell disease. At least 1% of patients with sickle cell disorder suffer from stroke and those individuals result in physical disability, IQ reduction, Learning difficulties, TIAs and seizures (Beinz, 2007).

  • Treatment of haemoglobinopathies.

10.1Treatment in Sickle-cell anemia.

Febrile illness: Children with fever are screened (a full blood count, reticulocyte count and blood culture taken) for bacteremia. In young children the fever is treated with intravenous antibiotics, the children would be admitted at the hospital so that they can be monitored (Belcher, 1993).. But older children with reassuring white blood cell counts are managed at home with oral antibiotics, but if the older children have a history of bacteremia episodes, they get a hospital admission. (Modell et al, 2001)

Zn administration: is when zinc is given to stabilize the cell membrane (Beinz, 2007).

Painful (vaso-occlusive) crises: individuals with sickle cell disorder experiences painful episodes called vaso-occlusive crises. Vaso-occlusive crises is often treated symptomatically with analgesics (Beinz,2007). Pain management requires opioid administration at regular intervals until the crises has gone. The frequency, severity and duration of these crises episodes vary tremendously form episodes to episode or from person to person (Belcher,1993). Individuals who suffer from milder vaso-occlusive crises manage their pain on NSAIDs e.g. diclofenac or naproxen. And if the crises is severe, individuals require inpatient management, where intravenous opioids. Diphenhydramine is used to stop the itchiness associated with the opioids (Modell et al, 2001).

Acute chest crises management is similar to vaso-occlusive crises treatment with the addition of antibiotics, oxygen supplementation for hypoxia, and close observation. If the pulmonary infiltrate worsen or the oxygen requirements increase,

Despite major advances in the understanding of the molecular pathophysiology and control and management of the inherited disorders of hemoglobin (haemoglobinopathies), thousands of infants and children with this disease are dying. As a result in heterozygote advantage against malaria the inherited hemoglobin disorders are the commonest monogenic disease. Population migrations have ensured that haemoglobinopathies are now encountered in most countries including the UK. Haemoglobinopathies have spread from areas in the Mediterranean, Africa and Asia and are now endemic throughout Europe, the Americas and Australia. This review examines the available literature to find out more about the prevalence of haemoglobinopathies in the UK. The data on the demographics and prevalence of the gene variants of haemoglobinopathies was extracted from books, journals, reference sources, online databases and published review articles from the WHO.

  • Introduction

It has been estimated that approximately 7% of the world population are carriers of such disorders and that 3000 000 – 4000 000 babies with severe forms of haemoglobinopathies. Haemoglobinopathy disorders occur at their highest frequency in tropical regions and population migrations have ensured that they are now encountered in most countries. Because of this, haemoglobinopathies have become a global endemic, so the World Health Organization published journals and reviews with recommendations on screening programmes and management of haemoglobinopathies. The programmes are tailored to specific socioeconomic and cultural contexts and aimed at reducing the incidence, morbidity and mortality associated with these diseases. www.who.int/en/

The WHO Executive Board wrote a review on haemoglobinopathies. In this article, the WHO Executive Board recognized that the prevalence of haemoglobinopathies varies between communities, and that insufficiency of relevant epidemiological data may hamper effective and equitable management of haemoglobinopathies. On this note England implemented the LIVE programmes. The Executive Board also recognizes that haemoglobinopathies are not yet officially recognized as priorities in Public Health Sector. This raised an issue about awareness of haemoglobinopathies. The WHO Executive Board’s advice for prevention and management of haemoglobinopathies was to design, implement and reinforce in a systematic equitable and effective manner, comprehensive national, integrated programs for prevention and management of haemoglobinopathies, including surveillance, dissemination, such programs being tailored to specific socioeconomic and cultural contexts and aimed at reducing the incidence, morbidity and mortality associated with these diseases. www.who.int/en/

With immigration in the UK on its highest, the prevalence of haemoglobinopathies is expected to increase. The NHS has implemented programmes for individuals with haemoglobinopathies by implementation of LIVE program (NHS Plan, 2000). LIVE program is set-up to implement variant screening in the whole of UK by the year 2007. LIVE program started as early as January 2004 in high prevalence. The NHS Trusts involved are to offer variant screening by end of 2004/5 (NHS Plan, 2000). Low prevalence Trust are expected to have implemented the screening program by January 2008 and so far 86 out of 90 Trusts have successfully implemented the program. Antenatal and Newborn Screening programs have compiled a training pack to assist Low Prevalence Trusts with the implementation of haemoglobinopathies screening programmes. The NHS Plan (2000) made a commitment to implement effective and appropriate screening programs for women and children including a new national linked Antenatal and Newborn screening programs for haemoglobinopathies. The NHS Plan (2000) recommends that all pregnant women living in high prevalence areas are offered screening for haemoglobinopathies. All pregnant women living in low prevalence areas are offered screening for haemoglobinopathies. If a woman is identified as being at increased risk using the family origin questionnaire, she will then be offered screening for haemoglobinopathies (NHS Plan, 2000). The Low Prevalence Trust is where the fetal prevalence of sickle cell disease is less than 1.5 per 10 000 pregnancies. Low prevalence trusts are to offer screening for variants based on an assessment of risk determine by a question to women about their baby’s father’s family origin by the end of 2005/6 (NHS Plan, 2000).

  • Background on Haemoglobinopathies

Haemoglobin: is the oxygen carrying capacity of the blood and it is also a protein. Haem is iron containing pigment, while globin is made up of chains which are a globular tetrameric protein which accounts for 97.4% of the mass of the haemoglobin molecule (Tortora et.al., 2006) . The globin tetramer consists of four polypeptides which are two alpha (α) chains and two non-alpha chains. The synthesis of ζ and ε chains is done during the first 10 to 12 weeks of fetal life. Within the fourth to the fifth week of intrauterine life α and β chains are synthesized. The non-alpha is beta (β), gamma (γ), delta (δ), epsilon (ε) zeta (ζ) chains. Haemoglobin transports oxygen from the lungs to all parts of the body and it gives blood its red colour (Fleming, 1982)

Haemoglobin synthesis

Haem and globin synthesis occur separately but in a carefully coordinated fashion. Globin synthesis is under the genetic control of eight functional genes arranged in two clusters, the α globin gene cluster on chromosome 16 and the β globin gene cluster on chromosome 11. The major haemoglobin in the foetus is HbF (αβ) 2 and in adults HbA (αβ) 2 (Fleming, 1982).

Haemoglobin Structure

The primary structure of haemoglobin is made-up of amino acid sequence of globin. And the secondary structure comprise of nine non-helical sections joined by eight helices; tertiary structure describes globin chain folding to form a sphere and the quaternary structure of haemoglobin describes the tetrahedral arrangements of the four globin subunits ( Fleming, 1982). The external surface of each folded globin is hydrophilic and the inner surface is hydrophobic, this protects the haem from oxidation, which is also why each haem chain sits in a protective hydrophobic pocket. In haemoglobin A, α β dimmers are held together strongly at the α1 β1 or α2β2 junction. The tetramer is held together much less tightly at the α1 β2 and α2 β1 contact areas (Fleming, 1982).

Haemoglobin function

Each haemoglobin molecule can carry four oxygen molecules. Oxygenation and deoxygenation are accompanied by molecular expansion and contraction via haem – haem interaction (Bienz, 2007). Under physiological conditions, blood in the aorta carries about 19.5ml of oxygen per 100ml of blood. Upon entering the tissues about 4.5ml of oxygen are donated per 100ml of blood. 2,3-DPG is an important modulator of haemoglobin A oxygen affinity in red cells (Fleming, 1982).

  • Haemoglobin disorder (haemoglobinopathies)

Haemoglobinopathies is a hematological disorder due to alteration of a genetically defect, that results in abnormal structure of one of the globin chains of the haemoglobin molecule (Bienz, 2007). Haemoglobinopathies are any of a group of diseases characterized by abnormalities, both quantitative and qualitative in the synthesis of haemoglobin (Hb) (Bienz, 2007). Qualitative – affecting the quality of haemoglobin e.g. Sickle cell disorder and quantitative – affecting the amount of haemoglobin produced e.g. Thalassaemias. Most of them are genetically inherited but occasionally they can be caused by a spontaneous mutation. Haemoglobinopathies are the world’s most common monogenic autonomic and recessive disease in humans (Anionwu et.al., 2001).

2.1Haemoglobinopathies fall into two main types;

There are two categories of haemoglobinopathies. The two categories are: qualitative and quantitative;

  • Qualitative – affecting the quality of the haemoglobin e.g. Sickle cell disorder. In this disease the globin structure is abnormal.
  • Quantitative – the haemoglobin structure is normal but the amount of haemoglobin produced is affected. e.g. alpha and beta thalassaemias (Bienz, 2007).
  • History of haemoglobinopathies

In 1910 Herrick wrote an article in it he used the term “sickle” to describe the shape of the red blood cells of a 20 year old medical student from Grenada. This student had consulted Dr Herrick in 1994 complaining of a cough, fever and Feeling weak and dizzy. He constantly had anaemia episodes, jaundice, chest complications as well as recurring leg ulcers on both ankles. When his blood was examined, his red blood cells showed a large number of thin, elongated, sickle shaped and crescent- shaped forms (Herrick, 1990).

The name thalassaemia was coined by the eminent haematologist George Whipple in 1936 as an alternative to the eponymous ‘Cooley’s anaemia’. He wanted a name that would convey the sense of an anaemia which is prevalent in the region of the Mediterranean Sea, since most of the early cases originated there. Thalassaemia is derived by contraction of thalassic anaemia (from the Greek thalassa -sea, an – none and anemia – blood) (Fleming,1982).

Origins and Geographic distribution of haemoglobinopathies

Carriers are found in all parts of the world: people from the North Mediterranean (South Europe) coast are 1-19% carriers. People of Arab origin are over 3% carriers. In Central Asia 4-10% and in South East Asia, the Indian subcontinent and China 1-40% carriers (the very high rates in this part of the world are due to HbE). In the Americas, North Europe, Australia and South Africa the local population has very low carrier rates but thalassaemia is still present because of the significant immigration from high prevalence area (Anionwu et.al.; 2001). Sickle cell and thalassaemia disorder mainly affect individual who are descended from families where one or more members originated from parts of the world where falciparum malaria was, or is still endemic. Population with such ancestry include those from many parts of Africa, the Caribbean the Mediterranean (including southern Italy, Northern Greece and Southern Turkey), Southeast Asia and thalassaemia gene is much wider now due to the historical movements of at-risk populations to North and South America, the Caribbean and Western Europe (Livingstone 1985).

The geographic distribution of the thalassaemias overlaps with that of sickles cell disease. This is because carriage of these abnormal genes affords some protection against malaria. Thus, being heterozygous for one of these conditions offers a selective survival advantage and increases the opportunity for these genes to be passed on (Campbell et.al.,2004)

4Types and terminology of sickle cell and thalassaemia

There are various types of sickle cell and thalassaemia disorders. The thalassaemia syndromes include alpha and beta thalassaemia major as well as beta thalassaemia intermedia. Sickle cell disorders (or Fickle cell disease include sickle cell anaemia (Hb SS), Sickle haemoglobin C disease (Hb SC) β disease and E beta thalassaemia (www.sickle-thalassaemia.org/sickle.cel.htm)

4.1Sickle Cell Disorder: affects the normal oxygen carrying capacity of the red blood cells. The red blood cell forms a crescent or a sickled shape when it is deoxygenated. The ‘sickled’ cells are unable to pass freely through capillaries; the sickle cells also get stuck in blood vessels forming clusters which block the blood vessels and the blood flow. They don’t last as long as normal, round red blood cells, which leads to anemia. This results in a lack of oxygen to the tissues in the affected area, resulting in hypoxia and pain (sickle cell crisis). Other symptoms include severe anaemia, damage to major organs and infection (NHS Antenatal and Newborn; 2006).

There are several types of Sickle cell disease. The most common are: sickle cell anemia (SS), sickle – hemoglobin C disease (SC), sickle beta – plus thalassaemia and sickle beta zero thalassaemia. Each of these can cause pain episodes and complications.

HbSS – sickle is due to two sickle cell genes (“S”), one from each parent. This is commonly called sickle cell anemia. An individual with sickles cell anemia have a variation in the β-chain gene, which then causes a change in the properties of hemoglobin which results in sickling of red blood cells (www.sickle-thalassaemia.org/sickle.cel.htm)

HbSc – inherited one sickle cell gene and one gene from an abnormal type of haemoglobin called “C”. It is due to the variation in the β-chain gene. An individual with this variant suffers from mild chronic haemolytic anaemia. (NHS Antenatal and Newborn; 2006).

HbS beta thalassaeamia: This form of sickle is due to inherited one sickle cell gene and one gene for beta.

4.2Thalassaemias: is a term used for the description of a globin gene disorders that results from a diminished rate of synthesis of one or more globin chains and a consequently reduced rate of synthesis of the haemoglobin or haemoglobins of which that chain constitutes a part ; α thalassaemia indicates a reduced rate of synthesis of the α globin chain, similarly, β, δ, δ β and ε γ δ β thalassaemia indicate a reduced rate of synthesis of the h, δ, δ, +β and ε + γ + δ + β chains, respectively (Modell et.al, 2001). Thalassaemia is the most common single gene disorder known. It is autosomal recessive syndromes, which is divided into α- and β thalassaemia.

Types of thalassaemia

There are two types of thalassaemia:

(i)Thalassaemia minor (thalassaemia trait)

(ii)Thalassaemia major

Thalassaemia minor is when a person inherits one thalassaemia gene, while thalassaemia major is a severe form of anaemia if a person inherits two thalassaemia genes, one from each parent (Bienz, 2007).

Subtypes of thalassaemia

Alpha (α) thalassaemia results from inadequate production of α – chains, which are normally controlled by two pairs of chromosomes. If one or two are malfunctioning, then there is a healthy carrier state. If three are non- functional then anaemia results, known as HbH Disease, which can be quite severe but usually does not need blood transfusions and is compatible with a normal life span (Anionwu et al, 2001). If all four genes are non – functional then the result is severe anaemia of the unborn child, leading to heart failure and death (miscarriage). This condition is known as hydrops felalis (Fleming, 1982).

Beta (β) Thalassaemia is caused by the body’s inability to produce normal haemoglobin, leading to a life threatening anaemia (Bienz, 2007). The severity of illness depends on whether one or both genes are affected and the nature of the abnormality. If both genes are affected, anemia can range from moderate to severe. Beta thalassaemia results from inadequate or lack of production of β – chains (Anionwu et.a.l, 2001). Homozygous, β – thalassaemia has two forms: major, in which the patient can survive only with regular transfusions of blood and intermedia in which the patient can survive with occasional or even with no transfusions at all. The condition requires frequent blood transfusions and treatment to prevent complications from iron overload, such as diabetes and other endocrine disorders (Anionwu et.a.l, 2001). Both of these conditions can restrict a child or adults ability to conduct their normal daily activities and can have profound psychological affects on individuals and their families This form of thalassaemia is the most important and constitutes a major public health problem in many parts of the world, because of the high frequency of carriers and the demanding treatment that must be followed (Fleming, 1985).

  • Association of Haemoglobinopathies with Malaria

Malariais a vector – borne infectious disease caused by protozoan parasites. It is widespread in tropical and subtropical regions, including parts of the Americans, Mediterranean, Asia and Africa. It causes diseases in approximately 515 million people and kills between one and three million people, the majority of whom are young children. Malaria parasites are transmitted by female Anopheles mosquitoes. The parasites multiply within red blood cells, causing symptoms that include symptoms of anemia (Campbell et al, 2004).

Sickle cell developed as a by product of human defense mechanisms against malaria. The most severe form of malaria, falciparum malaria, leads to very high death rate in young infants. This is particularly a problem between the time immediately after birth, when they are protected by immunity from the mother, and the time when they are old enough to acquire their own immunity. Malaria is a parasite which lives within the red blood cells and feeds off the protein that is contained within those red cells, haemoglobin (Campbell et al, 2004). When the malarial parasite enters the blood stream through a mosquito bite, it penetrates the red blood cells by attaching to the outside membrane or envelope of the red blood cell and gaining entry (Franklin, 1990). Once in the red blood cell, the malarial parasites use the haemoglobin as a source of energy, so that they multiply within the red cells. The parasites multiple filling-up the red blood cells and once they are filled-up the red cells burst, thereby releasing the multiple parasites in the blood. Each new young parasite enters a single cell again and multiplies again, thereby causing a disease or infection. Whenever the parasites burst out of the cells they cause illness and fever in patients. Malaria can be severe by causing death; death is believed to be caused by red cells not being able to pass through the narrow gaps in the smallest blood vessels and by blockage of tissues when so many parasites are in the red blood cell (Campbell et al, 2004).

Over the years human genes developed ways to prevent malaria becoming serious and potentially lethal, the developments were to prevent malarial parasites from spreading and multiplying (Tortora et.al,2006). The most changes were changes (mutation) in the type of haemoglobin (haemoglobin S) within the red blood cell which would in turn slow down the multiplying of the parasite (Campbell et al, 2004). The individuals with haemoglobin S are known to have a sickle cell trait or being carriers of sickle cell haemoglobin. When sickle-cell haemoglobin has given up its oxygen in the cells, the red cells stick together to form crystalline groupings of haemoglobin known as polymers. The red blood cells become deformed into sickle shapes and the presence of these crystalline polymers within the red cells inhibits the growth of the malarial parasite (Beinz, 2007). Even though individuals with haemoglobin S stills suffer from malaria, they are protected from the most severe effects of malaria (Livingstone, 1985).

  • Diagnosis

Diagnosis for sickle cell disease

The most used diagnose test for sickle cell is the haemoglobin electrophoresis. HbS and HbC amino acid substitutions change the electrical charge of the protein, the migration pattern of the haemoglobin with electrophoresis or isoelectric focusing results in diagnostic patterns with each of the different haemoglobin variants. HbSBeta-thal requires careful evaluation of red blood cell count and mean corpuscular red cell volume (MCV) and specifically quantifying HbA, S, A2 and F. In emergency setting, the presence of HbS is detected using a five minute solubility test called sickledex. Sickledex test does not differentiate sickle syndromes from the benign carrier state (HbAS or a sickle trait (NHS Antenatal and Newborn; 2006).

Diagnosis for thalassaemias

When testing for thalassaemias, a blood test is the simplest and most effective test for diagnosis and also the use of a test called Haemoglobin Electrophoresis. The blood of individuals with thalassaemias tend to be microcytic (smaller in size) and hypochromic (paler in colour) (NHS Antenatal and Newborn; 2006).

7 Pathophysiology

7.1Sickle-cell

Sickle-cell anemia is caused by changes (mutation) in the structure of the β -globin chain of the haemoglobin replacing the amino acid glutamic acid with the less polar amino acid valine at the sixth position of the β chain. When two wild type α-globin subunits associate with two mutant β-globin subunits forms hemoglobin S. Haemoglobin S polymerizes under low oxygen conditions, which causes distortion of red blood cells and also causes red blood cells to lose their elasticity, resulting in red blood cells forming an irreversible sickle shape (Fleming,1982). Very often a cycle occurs, as the cells sickle they cause a region of low oxygen concentration which causes more red blood cells to sickle. Repeated occurrence of sickling causes cells to not return to normal even when oxygen levels are normal. The deformation of cells makes it difficult for the cells to pass through capillaries resulting in vessel occlusion, severe anemia, ischemia and other problems (Beinz, 2007).

7.2Thalassaemias

The pathophysiologic effects of the thalassaemias range from mild microcytosis to death in uterus. The anaemia manifestation of thalassaemia is microcytic – hypochromic haemolytic anaemia (Belcher, 1993). The haemoglobin abnormality is caused by substitution of a single amino acid for another; or substitution of two amino acids, also amino acid deletion or fusion (point of mutation) and the synthesis of elongated chains. In alpha trait, one of the genes that form the alpha chain is defective (Beinz, 2007). In alpha-thalassaemia minor, two genes are defective and in haemoglobin H disorder, three genes are defective. Alpha-thalassaemia major is most fatal thalassaemia disorder; this is because four of the chains forming genes are defective. Without alpha chains, oxygen cannot be released to the tissues (Belcher, 1993). In beta-thalassaemia haemoglobin abnormality is due to the uncoupling of alpha and beta-chain synthesis. This causes a depression in beta-chain synthesis, resulting in erythrocytes with a reduced amount of haemoglobin and accumulation of free alpha chains, which are unstable and easily precipitate the in cell (Bienz, 2007).

8.Causes

Genetic control of haemoglobin synthesis

The synthesis of structurally normal haemoglobin chains is determined by allelic genes situated on the autosomal chromosome (Beniz, 2007). Haemoglobinopathies occur due to an inheritance of one or more faulty copy of gene(s) that contain the information for the cells to make the globin chains. The gene may result in abnormality in the production or structure of the haemoglobin protein causing haemoglobinopathies (Franklin, 1990).

Thalassaemia is an inherited autosomal recessive blood disorder. Genetic defects in Thalassaemia results in reduced synthesis of one of the globin chains which make up haemoglobin. Reduced synthesis of one of the globin chains causes the formation of abnormal haemoglobin molecules, which in turn causes anaemia. Anaemia is a symptom of the Thalassaemias. It is caused by under production of globin proteins, often through mutations in regulatory genes (Franklin, 1990).

Inheritance of Haemoglobin Disorder

Due to haemoglobin mutation, individuals who had haemoglobin trait had a resistance to dying from malaria, therefore passed on their haemoglobin trait gene to their children (Campbell et.al,2004). As time went on more individuals with the trait were born and eventually individuals who had haemoglobin trait had children together (Franklin, 1990). In that satiation (partnership), if both parents carry the trait gene, there is a one in four chance that any one child will receive the haemoglobin trait gene from one parent and also from the other, thereby having a haemoglobin disorder(Franklin, 1990) .

  • Clinical Manifestations

9.1Thalassaemias’ clinical manifestations

Individuals who inherited the alpha trait are usually asymptomatic, with possible mild microctyosis. Alpha- thalassaemia minor has signs and symptoms almost identical to those of beta-thalassaemia; mild microcytic hypochronic anemia, enlargement of the liver and spleen, and bone marrow hyperplasia (Belcher, 1993).

Alpha- thalassaemia major cause hydrops fetalis and fulminana intrauterine congestive heart and liver, edema and massive ascites. The disorder usually is diagnosed post mortem (Bienz, 2007).

Beta-thalassaemia minor causes mild to moderate microcytic-hypochronic anemia, mild splenomegaly, bronze coloring of the skin, and hyperplasia of the bone marrow. Skeletal changes depend on the degree of reticulocytosis, which in turn depends on the severity of the anaemia (Bienz, 2007).

People who have beta-thalassaemia minor usually are asymptomatic, whereas those with beta- thalassaemia major the anemia is severe, resulting in a great cardiovascular burden, with high output congestive heart failure (Belcher, 1993). Blood transfusions can increase the person’s life span by a decade or two. Individuals with beta-thalassaemia major have an enlarged liver and spleen, and growth and maturation are retarded (Belcher, 1993). A characteristic deformity develops on the face as the bones expand to accommodate hyperplastic marrow (Belcher, 1993).

Both and beta – thalassaemias major are life threatening. Children with thalassaemia major usually are week, fail to thrive, how poor development and experience cardiovascular compromise with high-output failure; if the condition goes untreated, these children die by 6 years of age (Modell et.al., 2001)

Blood transfusions can return haemoglobin and hematocrit to normal levels, alleviating the anaemia induced cardiac failure. Iron overload and hemochromatosis, which are complications of transfusion therapy, are treated with chelating agents (Bienz, 2007). .

9.2.Sickle-cell clinical manifestations

The severity of sickle cell disorder depends on the amount of haemoglobin S and the clinical manifestations, which are signs and symptoms of the individuals with sickle-cell (Belcher, 1993) . Manifestations of the sickling are those of hemolytic anemia; pallor, jaundice, fatigue and irritability. Extensive sickling can precipitate four types of crises: vaso-occlusive or thrombotic crises and a plastic crisis (Belcher, 1993).

A vaso-occlusive crises begins with red blood cells sickling in the microcirculation. Vasospasm brings a log-jam effect causing blood flow to stop flowing in the vessels and this will lead to thrombosis (blood clot formation) and infarction of local tissue occur, resulting in ischemia, pain and organ damage (Modell et.al.,2001). Vaso-occlusive crisis is believed to be extremely painful and lasts an average of 4 to 6 days. This crisis may develop spontaneously or may be precipitated by localized hypoxemia (low PO2) exposure to cold, dehydration, acidosis (low pH), or infection. In infancy, sickle-cell’s first manifestation is the symmetric painful swelling of the hands (see Fig 3) and feet, but in older children and adults, the large joints and surrounding tissues become swollen and painful. Individuals with the sickle-cell disorder suffer from severe abdominal pain caused by infarction in abdominal structures (Belcher, 1993). Any cerebral vascular accidents may cause paralysis or other central nervous system deficits, and if penile veins are obstructed priapism may occur. Studies have shown that bone, especially weight- bearing bones, are also a common target of vaso-occlusive damage, this is due to bone ischemia (Bienz, 2007).

The spleen of individuals with sickle-cell disorder is frequently affected due to its narrow vessels, functions in clearing defective red blood cells and this results in a sequestration crisis (Belcher,1993). A sequestration crises, is occurrence of large amounts of blood pool in the liver and spleen. It only occurs in young children and death results from cardiovascular collapse (NHS Antenatal and Newborn,2006).

An aplastic crisis develops when a compensatory increase in erythropoiesis is compromised; this then results in profound anemia (Belcher,1993).

A hyperhemolytic crisis is rare but may occur with certain drugs or infections. G-6-PD deficiency, when also present, contributes to this type of crisis (Belcher,1993).

Clinical manifestations of sickle cell disease do not usually appear until an infant is at least 6 months old. The most cause of death in individuals with sickle-cell anemia is infections, but it is major problem at all ages. Infections are due to splenic dysfunction from sickle damage (Belcher,1993). This occurs from a few months of age especially with certain bacteria e.g. pneumococcal sepsis. Infection tends to rapidly overwhelm the immune system (NHS Antenatal and Newborn,2006) . Sickle-cell haemoglobin C is known to be milder, with symptoms related to vaso-occlusive crises resulting from higher hematocrit and blood viscosity. Obstructive crises cause sickle cell retinopathy is most common in older children, and this include renal necrosis, and aseptic necrosis of the femoral head (Belcher, 1993).

The mildest of sickle-cell is the sickle-cell thalassaemia the individuals with this form of sickle-cell tend to be microcytic and hypochromic, which makes the cells less likely to clog the microcirculation even when sickling (Belcher, 1993).

Severe hypoxia can be seen in individuals with the sickle cell trait and may cause vaso-occlusive episodes. The cells in these people form an ivy shape (Belcher, 1993).

Recent studies have shown that stroke is co-exiting with Sickle cell disease. At least 1% of patients with sickle cell disorder suffer from stroke and those individuals result in physical disability, IQ reduction, Learning difficulties, TIAs and seizures (Beinz, 2007).

  • Treatment of haemoglobinopathies.

10.1Treatment in Sickle-cell anemia.

Febrile illness: Children with fever are screened (a full blood count, reticulocyte count and blood culture taken) for bacteremia. In young children the fever is treated with intravenous antibiotics, the children would be admitted at the hospital so that they can be monitored (Belcher, 1993).. But older children with reassuring white blood cell counts are managed at home with oral antibiotics, but if the older children have a history of bacteremia episodes, they get a hospital admission. (Modell et al, 2001)

Zn administration: is when zinc is given to stabilize the cell membrane (Beinz, 2007).

Painful (vaso-occlusive) crises: individuals with sickle cell disorder experiences painful episodes called vaso-occlusive crises. Vaso-occlusive crises is often treated symptomatically with analgesics (Beinz,2007). Pain management requires opioid administration at regular intervals until the crises has gone. The frequency, severity and duration of these crises episodes vary tremendously form episodes to episode or from person to person (Belcher,1993). Individuals who suffer from milder vaso-occlusive crises manage their pain on NSAIDs e.g. diclofenac or naproxen. And if the crises is severe, individuals require inpatient management, where intravenous opioids. Diphenhydramine is used to stop the itchiness associated with the opioids (Modell et al, 2001).

Acute chest crises management is similar to vaso-occlusive crises treatment with the addition of antibiotics, oxygen supplementation for hypoxia, and close observation. If the pulmonary infiltrate worsen or the oxygen requirements increase,

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