The Peculiarities Of Sickle Cell Disease

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Introduction

Haemoglobin is a word that was coined from two words “haemo” which means blood and “globin” meaning protein. Globin is a protein substance of four different polypeptide chains that have (141-146)amino acids. Haemoglobin is a conjugated globular protein. There are two important oxygenbinding proteins in vertebrates namely haemoglobin (Hb or Hgb) and myoglobin. Haemoglobin supplies oxygen (O2) to tissues. Haemoglobin’s function is to transport oxygen (O2) in the blood from the lungs to other tissues of the body and provide cells with the oxygen they need for foodstuff oxidative phosphorylation. Haemoglobin is found in the blood within erythrocytes (red blood cells (RBC)) and is the most common family of carriers of O2. Haemoglobin is the main component of red blood cells which number about 250 million per cell and its combination with iron (Fe) and oxygen forms the bright red colour of RBC. Haemoglobin comprises more than 95% of the erythrocyte, it also carries nitric oxide, which controls vascular tone and blood pressure. Haemoglobin is equally involved in the transport of respiratory carbon dioxide (about 20–25% of the haemoglobin as carbamino-haemoglobin) in which carbon dioxide is bound to the globin protein.

Erythrocytes further contain carbonic anhydrase, an enzyme that rapidly interconverts carbon dioxide and bicarbonate allowing the efficient transport of carbon dioxide, produced by respiration in the peripheral tissues, to the lungs, where it is exhaled. The haemoglobin combination with O2 and CO2 is reversible and this forms the basis for the gas-transport capability of hemoglobin. However, the combination of Hg with carbon monoxide (CO) is irreversible. This reduces the cell capacity to transport O2 during carbon monoxide poisoning. Myoglobin, the other O2-binding protein, stores oxygen in body tissues until cells need it. The highest levels of myoglobin are found in cardiac and skeletal muscles, which require large amounts of oxygen during contraction. Catabolism of haemoglobin splits off the globin portion into an amino acid pool while the haem portion is converted into biliverdin. In humans, biliverdin is converted to bilirubin and secreted in the bile. Iron from haem is however reused for haemoglobin synthesis. Haemoglobin is known to have an O2-binding capacity of 1.34 cm3 of dioxygen per gram which increases the total oxygen capacity in the blood by 70 times compared to dissolved oxygen in the blood. For normal level tissue oxygenation, an optimum haemoglobin level must be maintained. The normal Hb level for males is 14 to 18 g/dl, and for females it is 12 to 16 g/dl. A low level of haemoglobin results in anaemia, while a level above the normal is called erythrocytosis. Myoglobin and haemoglobin describe both protein structure-function relationships and the molecular basis of genetic diseases such as hereditary persistence of foetal haemoglobin, thalassaemias and sickle cell anaemia. Haemoglobin has a quaternary structure, it is a tetrameric protein with two α chains and two β chains (α2β2), each with a haem unit as a prosthetic group, each polypeptide chain having a very strongly three-dimensional structure similar to the unique polypeptide chain in myoglobin. However, their amino acid sequences differ by 83%.

Haemoglobin comprise two identical pairs of polypeptide chains, i.e. Two identical alpha (α) chains encoded on chromosome 16 containing 141 amino acids and two identical non-α chains (beta (β), gamma (γ) or delta (δ)chains)that encoded on chromosome 11.

Hemoglobin A (Adult Hb): makes up about 95%-98% of hemoglobin found in adults; it contains two alpha (α) chains and two beta (β) protein chains(α2β2).
Hemoglobin A2 (minor Adult Hb): makes up about 2%-3% of hemoglobin found in adults; it has two alpha (α) and two delta (δ) protein chains(α2δ2).
Hemoglobin F (Hb F, fetal hemoglobin): makes up to 1%-2% of hemoglobin found in adults; it has two alpha (α) and two gamma (γ) protein chains (α2γ2). It is the primary hemoglobin produced by the fetus during pregnancy; its production usually falls shortly after birth and reaches adult level within 1-2 years.

Hemoglobin has two conformational states:

T-state(Tense): the deoxy form of hemoglobin (lacks an oxygen species) and is also known as ‘deoxyhemoglobin”.
R-state(Relaxed):is the fully oxygenated form: ‘oxyhemoglobin’.

Hemoglobinopathy

Hemoglobinopathy is a group of disorders in which there is abnormal production or structure of the hemoglobin molecule. It is passed down through families (inherited). This group of disorders includes hemoglobin C disease, hemoglobin S-C disease, sickle cell anemia, and thalassemias.

AA= two normal beta globin genes
SS= two sickle cell beta globin genes
AS/SA= one normal beta globin gene and one sickle cell beta globin gene

Sickle Cell disease

Sickle cell syndromes are hereditary hemoglobinopathies. Homozygous sickle cell anemia (HbSS, autosomal recessive) is the most common variant of the sickle cell syndromes. Sickle cell trait is asymptomatic occurs in heterozygous carriers (HbSA). Other rare variants of sickle cell syndrome occur in individuals with one HbS allele and one other allele (HbC or Hb-β thalassemia). A point mutation in the beta chain of hemoglobin leads to substitution of glutamic acid by valine, thus changing the structure (and properties) of hemoglobin. Abnormal hemoglobin polymerizes when deoxygenated, resulting in sickle-shaped erythrocytes, which cause vascular occlusion and ischemia.

Distribution

Sickle cell disease (SCD) affects millions of people throughout the world and is particularly common in America among those whose ancestors came from sub-Saharan Africa; Spanish-speaking regions in the Western Hemisphere (South America, the Caribbean, and Central America); Saudi Arabia; India; and Mediterranean countries such as Turkey, Greece, and Italy. Predominantly individuals of African and East Mediterranean. Africa has the highest prevalence of the disease (30% heterozygote prevalence).

HbS gene is carried by 8% of the African American population. Sickle cell anemia is the most common form of intrinsic hemolytic anemia world wide Sickle cell disease occurs more often among people from parts of the world where malaria is or was common. It is believed that people who carry the sickle cell trait are less likely to have severe forms of malaria.

Clinical Presentations

Signs and symptoms of sickle cell anemia usually appear between 4-6 months of age. They vary from person to person and change over time. When HbS is deoxygenated, the Hb molecules polymerise and the red cell membrane becomes distorted, producing characteristic sickle-shaped cells. Sickling is precipitated by hypoxia, dehydration and infection. Sickled cells have a shortened survival and plug vessels in the microcirculation. This results in a number of acute syndromes termed ‘crises’ and chronic organ damage.

Vaso-occlusive crisis: Plugging of small vessels in the bone results in avascular necrosis, producing acute severe bone pain. Commonly affected sites include the femur, humerus, ribs, pelvis and vertebrae. Vaso-occlusion in the spleen can give rise to recurrent splenic infarction and adults may have no functional spleen. Occlusion at other sites can result in cerebrovascular accidents and proliferative retinopathy.

Sickle chest syndrome: This may follow on from a vaso-occlusive crisis and is the most common cause of death in adult sickle disease. Bone marrow infarction results in fat emboli to the lungs, which cause sickling and infarction, leading to ventilatory failure.
Sequestration crisis: Thrombosis of the venous outflow from an organ causes loss of function and acute painful enlargement. Massive splenic enlargement may result in severe anaemia and circulatory collapse. Sequestration in the liver leads to severe pain due to capsular stretching.
Aplastic crisis: Infection with parvovirus B19 results in severe red cell aplasia, producing a very low Hb.

Investigations

Patients with sickle-cell disease have a compensated anaemia (usually 60–80 g/L) with a reticulocytosis and sickle cells on the blood film. Hb electrophoresis demonstrates a predominance of HbS with absent HbA.

Provoke Factors For Sickle Cell Crisis

Experts don’t fully understand the reasons behind a sickle cell crisis. But they do know that it involves complex interactions between RBCs, endothelium (cells lining the blood vessels), white blood cells, and platelets. These crises usually occur spontaneously.

Sickling may be triggered by conditions associated with low oxygen levels, increased blood acidity, or low blood volume.

Common sickle cell crisis triggers include:

sudden change in temperature, which can make the blood vessels narrow
very strenuous or excessive exercise, due to shortage of oxygen
dehydration, due to low blood volume
infections
stress
high altitudes, due to low oxygen concentrations in the air
alcohol
smoking
pregnancy
other medical conditions, such as diabetes

It’s not always possible to know exactly what caused a particular sickle cell crisis. Many times, there’s more than one cause.

Management

Patients with sickle disease should receive prophylaxis with folic acid. Pneumococcal infection may be lethal in the presence of hyposplenism; patients should therefore receive prophylaxis with daily penicillin V and vaccination against pneumococcus. Patients should also be vaccinated against Haemophilus influenzae B and hepa- titis B.

Vaso-occlusive crises are managed by aggressive rehydration, oxygen therapy and adequate analgesia (which often requires opiates) and antibiotics. Top-up transfusion may be used in seques- tration or aplastic crises. Exchange transfusion, where a patient is simultaneously venesected and transfused to replace HbS with HbA, may be used in life-threatening crises. The oral cytotoxic agent hydroxycarbamide(also known as hydroxyurea ) induces increased synthesis of fetal Hb (HbF- α2γ2), which in turn inhibits polymerisation of HbS and reduces sickling; this may be helpful in individuals with recurrent severe crises. Allogenic stem cell transplantation (also called allogenic bone marrow transplantation) is rarely performed but may be potentially curative it works by using healthy blood steam cells from a donor to replace diseased or damaged bone marrow of the patient. Sickle-cell anaemia has mortality of 15% by the age of 20 yrs and 50% by the age of 40 yrs.

Conclusion

Stem cell or bone marrow transplant seems to be only cure for sickle cell disease but not done for all patients,common treatments might include medications and blood transfusion, keeping the patient hydrated is very important to maintain blood volume at adequate level to prevent sickling.there are some known triggers that can provoke sickle cell crisis but in many times it’s not clear what exactly caused a particular sickle cell crisis, what is clear is that these crisis happen due to interactions between blood cells (especially red blood cells) and lining of blood vessels.signs and Symptoms mostly appear in early months of life. A blood film can show sickled red blood cells that formed after distortion of the membrane due to polymerization of HbS molecules that causes various signs and symptoms like vaso-occlusive crisis, sickle chest syndromes,and some others whilst the second is the most common cause of death among adult ages.carriers of HbS gene show to have some kind of resistance against severe forms of malaria at the same time this disease is prevalent in districts that malaria is endemic.although SCD affects millions of people around the world but Africa has the highest percentage of afflicted people.A point mutation in beta chain of hemoglobin causes replacement of glutamic acid by valine followed by changes in the structure and functions of hemoglobin which leads to sickling of red blood cells resulting in sickle cell anemia(among sickle hemoglobin-c disease and sickle beta-thalasemia)is the most common type of sickle cell syndromes and inherited recessively on chromosome 11.sickle cell syndromes are hereditary hemoglobinopathies which include disorders of hemoglobin. Normal hemoglobin has two states(Tense state>when deoxygenated and Relaxed state>oxygenated) comprise two identical alpha chains and two identical non-alpha chains that together known as globin with a heme group>a metal complex with iron that can bind or release molecular oxygyn O₂ or CO₂ molecules reversibly O₂ from lungs to tissues,CO₂ from tissues to lung and then pushing it out during exhaling.there are no incurable diseases only lack of will ,are we willing ?!

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