DrMaysem M Alwash Sickle cell disaese Sickle cell disease SCD is an inherited chronic haemolytic anaemia whose clinical manifestations arise from the tendency of the haemoglobin ID: 1045311
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1. Hb Variants Assistant Prof.:Dr.Maysem M. Alwash
2. Sickle cell disaeseSickle cell disease (SCD) is an inherited chronic haemolytic anaemia whose clinical manifestations arise from the tendencyof the haemoglobin (HbS or sickle haemoglobin) to polymerize and deform red blood cells into the characteristic sickle shape.
3. -Single nucleotide change in the β-globingene leading to substitution of valine for glutamic acid at position 6 of the β-globin chain ( β6glu→val or βs).
4. Molecular pathology of sickle cell anaemia.
5. Hb S (Hb α2β2 S) is insoluble and forms crystals when exposed to low oxygen tension ,Deoxygenated sickle haemoglobin polymerizes into long fibres, each consisting of seven intertwined double strands with cross‐linking .The red cells sickle and may block different areas of the microcirculation or large vessels causing infarcts of various organs. The carrier state is widespread and is found in up to 30% of West African people, maintained at this level because of the protection against malaria that is afforded by the carrier state.
6. The formation of the sickle polymer
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8. The homozygous state (HbSS or sickle cell anaemia) is the most common form ofsickle cell disease, but interaction of HbS with thalassaemia and certain variant haemoglobins also leads to sickling.
9. The term ‘sickle cell disease’ is used to denote all entities associated with sickling of haemoglobin within red cells.
10. The sickling syndromes.
11. Homozygous disease-Clinical featuresClinical features are of a severe haemolytic anaemia punctuated by crises.The symptoms of anaemia are often mild in relation to the severity of the anaemia because Hb S gives up oxygen (O2) totissues relatively easily compared with Hb A
12. The clinical expression of Hb SS is very variable, some patients having an almost normal life, free of crises, but others develop severe crises even as infants and may die in early childhood or as young adults. Crises may be vaso‐occlusive (painful or visceral), aplastic or haemolytic. There may be serious damage to many organs.
13. Vaso‐occlusive crisesPainful These are the most frequent-sporadic and unpredictable or -precipitated by infection, acidosis, dehydration or deoxygenation (e.g. altitude, operations, obstetric delivery, stasis of the circulation, exposure to cold, violent exercise).
14. The ‘hand– foot’ syndrome (painful dactylitis caused by infarcts of the small bones) is frequently the first presentation of the disease .
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16. VisceralThese are caused by sickling within organs causing infarction and pooling of blood, often with a severe exacerbation of anaemia. -The acute sickle chest syndrome is the most common cause of death both in children and adults.
17. -Splenic sequestration is typically seen in infants and presents with an enlarging spleen, falling haemoglobin and abdominalpain. -Priapism and liver and kidney damage due to repeated small infarcts are other complications-
18. Aplastic crisesThese occur as a result of infection with parvovirus or from folate deficiency. It is characterized by a sudden fall in haemoglobin and reticulocytes, usually requiring transfusion.
19. Haemolytic crisesThese are characterized by an increased rate of haemolysis and fall in haemoglobin but rise in reticulocytes -usually accompany a painful crisis.
20. Other organ damageThe most serious is of the brainThis may be associated with cognitiveimpairment and predicts for strokes in children
21. -Ulcers of the lower legs are common, as a result of vascular stasis and local ischaemia.Autosplenectomy .Pulmonary hypertension
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23. proliferative retinopathy and priapism . -Chronic damage to the liver may occurthrough microinfarcts. Pigment (bilirubin) gallstones are frequent.-The kidneys are vulnerable to infarctions of the medulla with papillary necrosis. Failure to concentrate urine aggravates the tendency to dehydration and crisis, and nocturnal enuresis
24. Infections are frequent partly due to hyposplenism.Pneumonia, urinary tract infections and Gram‐negative septicaemia are common. Osteomyelitis may also occur, usually from Salmonella spp.
25. Laboratory findings1 -The haemoglobin is usually 60–90 g/L low in comparison to mild or no symptoms of anaemia.**The haemoglobin level is normal in the newborn period, but anaemia develops and sickle or cigar-shaped can be observed in the peripheral blood by 6 months ofage as HbF declines.
26. 2-Blood filmThe blood film is usually normal at birth and in the early neonatal period as the haemoglobin S percentage is relatively low, but this is not necessarily so . Abnormalities are usually detectable around 6 months of age
27. Sickle cells and target cells occur in the blood .Features of splenic atrophy (e.g. Howell–Jolly bodies) .
28. In an adult with sickle cell disease, the blood film shows a variable number of crescent or sickle-shaped sickle cells (These represent irreversibly sickled cells, which have not corrected their shape on exposure to atmospheric oxygen. The number of sickle cells is very variable .
29. In addition to classical sickle cells, there are elongated cells pointed at one or both ends, these have been referred to as boatshaped or oat-shaped cells or as plump sickle cells.There is polychromasia and small numbers of irregularlycontracted cells may be seen
30. Blood films of a child with sickle cell anaemia: at the age of 5 months showing mild anisopoikilocytosis and one sickle cell
31. at the age of 13 years showing more marked anisocytosis and sickle cell formation.
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35. 3- Tests to detect the presence of haemoglobin S depend onthe decreased solubility of this haemoglobin at low oxygentensions:
36. Sickling in whole bloodThe sickling phenomenon may be demonstrated in a thin wet film of blood (sealed with a petroleum jelly/paraffin wax mixture or with nail varnish).If haemoglobin S is present, the red cells lose their smooth, round shape and become sickled. This process may take up to 12 h in haemoglobin S trait, whereas changes are apparent in homozygotes and compound heterozygotes after 1 h at 37 °C.These changes can be hastened by the addition of areducing agent such as sodium dithionite
37. Haemoglobin S solubility test Sickle cell haemoglobin is insoluble in the deoxygenated state in a high molarity phosphate buffer. The crystals that form refract light and cause the solution to be turbid
38. A positive solubility test merely indicates the presence of a sickling haemoglobinand does not differentiate between homozygotes, compoundheterozygotes and heterozygotes
39. Haemoglobin electrophoresisHbS can be identified by cellulose acetate electrophoresis at Ph 8.4 . HbD and HbG have the same electrophoretic mobility with this method, but can be distinguished using citrate agar electrophoresis at pH 6.2 or thin-layer isoelectric focusing
40. HPLC or haemoglobin electrophoresis in Hb SS, no Hb A is detected. The amount of Hb F is variable and is usually 5–15%, larger amounts are usually associated with a milder disorder
41. Sickle cell traitThis is a benign condition with no anaemia and normal appearance of red cells in a blood film. Haematuria is the most common symptom and is thought to be caused by minor infarcts of the renal papillae.Care must be taken with anaesthesia,pregnancy and at high altitudes ..
42. The diagnosis rests on the demonstration of the presence of haemoglobin S and haemoglobin A, with the percentage of haemoglobin S being less than the percentage of haemoglobin A.Hb S varies from 25–45% of the total haemoglobin
43. Haemoglobin CHaemoglobin C is the second most common structuralhaemoglobin variant in people of African descent. The replacement of glutamic acid in position 6 of the β chain by lysine results in a haemoglobin molecule with a highly positive charge, decreased solubility and a tendency to crystallise. Haemoglobin C does not give a positive sickle solubility test.
44. -Heterozygotes are asymptomatic, but targetcells and irregularly contracted cells may be presentin blood films. -Homozygotes may have mild haemolyticanaemia with numerous target cells and irregularly contracted cells
45. HomozygousHb C disease: peripheral blood film showing many target cells deeply staining rhomboidal and spherocytic cells.
46. Polygonal inclusions displacing the hemoglobin in Hgb CC. Crystals nearly fill the cell and distort its shape. Inclusions also occur in individuals doubly heterozygous for Hb C ( e.g., Hb SC disease), are not seen in Hb C trait
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48. Haemoglobin D diseaseThe substitution in HbD is a glutamic acid to glutamine at the 121 amino acid of the β-globin chain (β121Glu→Gln).This is a group of variants all with the same electrophoretic mobility .Heterozygotes show no haematological abnormality while homozygotes have a mild haemolytic anaemia.
49. Haemoglobin E diseaseHbE (β 26 Glu→Lys)In the homozygous state, there is a mild microcytic, hypochromic anaemia .
50. Combination of haemoglobin S with other genetic defects of haemoglobinSickle cell/C diseasePatients with Hb SC disease have a particular tendency to thrombosis and pulmonaryembolism, especially in pregnancy. In general, when compared with Hb SS disease, they have a higher incidence of retinal abnormalities, milder anaemia, splenomegaly andgenerally a longer life expectancy.
51. Sickle cell / 𝛃-thalassaemiaThe majority of these patients have the β+-phenotype, with the proportion of HbA ranging from 3 to 25%. The clinical phenotype is mild and disease severity correlates with the amount of HbA present. .
52. The clinical manifestations of the less frequent HbS/β0-genotype are similar in severity to those of HbSS
53. The red cells are microcytic and hypochromic, and variable numbers of target cells and sicklecells are observed. Reticulocytosis (10–20%) is present and thelevel of HbA2 is elevated.
54. Sickle cell anaemia with coexistent𝛂-thalassaemia Coinheritance of αα-thalassaemia (−α/αα or −α/−α) with SCD is common, and such patients have less severe anaemia anddemonstrate hypochromia and microcytosis..
55. Sickle cell/HbE diseaseHbSE disease causes mild haemolysis and no remarkable abnormality of red blood cell morphology.
56. -Sickle cell / HbD disease gives rise to severe sickle cell disease.2 - Sickle cell / HbO Arab disease gives rise to severe sickle cell disease.2
57. -Sickle cell/Hb Lepore disease producesa clinical picture similar to that of HbS/β-thalassaemia, but with a lowHbA2 level.-Sickle cell / HPFH
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