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HAEMOGLOBINOPATHIES Dr Daljeet Kaur Assis Prof Pathology,GMCH
Introduction • Haemoglobin in RBC is responsible for transport of oxygen from lungs to the tissues and of carbon dioxide from tissues to the lungs. • Haemoglobin (Hb),MW64,500 daltons, protein constituting 1/3 of the red blood cells. • Synthesis begins in proerythroblast ,evident in intermediate normoblast and is composed of haem (consisting of iron and protoporphyrin) and globin.
Structure of haemoglobin • Haemoglobin is a tetramer composed of four polypeptide chains (α1,α2, β1, and β2) and four haem groups. • α chains consists of 141 amino acids . • β chains consists of 146 amino acids. • Each polypeptide chain is arranged in a helical conformation. • There are eight helical segments designated A to H. • Iron of haem is covalently bound to histidine at the eight position of the F helical segments.
Synthesis of Haem • Haem is a complex of protoporphyrin and iron. • Biosynthesis of haem requires mitochondrial and cytosolic enzymes. • Only erythroid precursors can synthesize haem not mature red cells.
Alpha & beta chains
Synthesis of globin • Various types of globin combines with haem to from different haemoglobin • Eight functional globin chains, arranged in two clusters the • - cluster (, ,  and  globin genes) on the short arm of chromosome 11 • - cluster ( and  globin genes) on the short arm of chromosome 16
Synthesis of globin
Normal hemoglobin variants Embryonic hemoglobin – 2 alpha + 2 epsilon chains Fetal hemoglobin - 2 alpha + 2 gamma chains Hemoglobin A - 2 alpha + 2 beta chains Hemoglobin A2 - 2 alpha + 2 delta chains Adult red cell – contains mixes of Hb A 95-98%, HbA2 2-3%, Hb F < 2%. Neonates Hb F predominates.
Inherited disorders of Hemoglobin are the commonest genetic disorders in the world . Classification : These disorders are divided into three broad groups. 1. structural(Qualitative) abnormalities in the globin proteins themselves.called hemoglobinopathies-eg-SCA 2.usually result in underproduction of normal globin proteins(Quantitative) , often through mutations in regulatory genes eg-Thalassemia 3.Heriditary Persistance of Foetal Hb-It is characterised by failure of normal neonatal switch from haemoglobin F to haemoglobin A.
Haemoglobinopathies • Inherited disorders of haemoglobin due to Qualitative alteration of the globin polypeptide chain are called haemoglobinopathies. • Majority of qualitative haemoglobinopathies results from substitution of a single amino acid in globin chain due to a point mutation in the β globin gene. • More than 700 hemoglobinopathies have been reported so far.Majority of them clinically insignificant. • More systemic nomenlature consists of denoting the type of polypeptide chain, position,and the amino acid substitution ,eg : HbS is denoted by β⁶ᴳˡ ͧ - ᵛᵅˡ , which represents substitution for glutamic acid at position 6 of β globin chain
• Hb C • Hb E • Hb D Punjab • Hb O Arab • Hb G Philadelphia • Hb Hasharon • Hb Korle –Bu • Hb Lepore • Hb M • Hb Kansas (β109 Asn> Thr )⁽⁶⁾ • Hb Constant Spring. • The most frequent haemoglobinopathies are- HbS HbC and HbE
Hereditary disorders of haemoglobin prevalent in India
Sickle Cell Disease • Sickle Cell Disease is a common hereditary hemoglobinopathy by a point mutation in β- globin that promotes the polymerization of deoxygenated Hb,leading to • RBC distortion • Hemolytic anemia • microvascular obstruction & Ischemic tissue damage.
◼ SICKLE CELL DISORDERS First described in Chicago in 1910 by James Herrick as an inherited condition in which the red cells become sickle shaped when they are subjected to low oxygen tension . Mason gave the name Sickle cell anemia in 1922. Linus Pauling first described electrophoretic mobility of HbS compared to Hb A. Sickle cell disorders include following conditions- 1.Sickle cell anemia 2.Sickle cell trait
1).Sickle cell diseases are divided into following types- (i).Sickle cell anaemia – This is the homozygous state for hemoglobin S (HbSS) that results when the sickle cell gene βѕ is inherited from both the parents .The genotype isβsβs . (ii).Sickle cell β trait – This is the heterozygous state in which the sickle cell gene is inherited from one parent and normal gene from the other parent. (Iii).Combination of hemoglobin S(HbS) with other structural haemoglobin variants can produce a double heterozygous state such as sickle cell thal,Hb SD disease,Hb SC disease ,Hb SO-Arab disease ,Hb SE disease,etc.
• Sickle cell disease is a common hereditary hemoglobinopathy that occurs primarily in individuals of African descent. • It is caused by a point mutation in the sixth codon of β- globin that leads to the replacement of a glutamate residue with a valine residue. • The abnormal physiochemical properties of the resulting sickle hemoglobin (HbS) are responsible for the disease. • It is usually only in the homozygous state that the disease is so devastating
HEMOGLOBIN S
Prevalence of HbS ▪ Prevalence- In parts of Africa, the Mediterranean basin, the Middle East, Central and Southern India. • HbS has a high prevalence in those parts of the world where malaria is common. • Young children with sickle cell trait develop comparatively mild falciparum malaria. Children who inherited one sickle hemoglobin gene and who, therefore, carried the sickle cell trait - had a survival advantage.
Pathogenesis • The Sickle cell disorders all results from inheritance of sickle cell gene that codes for abnormal β globin chain. • There is a change of a single base A→ T in the sixth codon of globin gene so that there is substitution of thymine for adenine . • This in turn results in substitution of valine for glutamic acid at position 6 of β polypeptide chain. • The amino acid substitution in HbS is represented as β⁶Glu →Val.
▪ Polymerization of Hb S : polymerization of Hb S molecules inside the red cells is responsible for sickling of red cells. Polymerization occurs only on deoxygenation and causes→ 1. Chronic hemolysis 2. Microvascular occlusion 3. Tissue damage Initially RBC cytosol is converted from freely flowing liquid to a viscous gel ,but with continued deoxygenation-→ long needle like fibres are formed within RBCs , damaging the RBC membrane →producing a distorted sickle or holly leaf shape.
– When oxygenated, Hb S is soluble. – When oxygen tension decreases, Hb S in the deoxyhemoglobin state polymerizes into insoluble aggregates leading to sickled cells. – This leads to increased blood viscosity which leads to decreased circulation and increased exposure to low oxygen. This, in turn, leads to more sickling. – Upon reoxygenation, polymerized HbS (viscous gel state) returns to depolymerized (fluid-liquid) state and the RBC may return to its original shape. – The small microvasculature may become clogged with the rigid sickle cells leading to hypoxia and infarction of organs and a “sickle cell crisis”.
– However, repeated sickling and unsickling damages the permeability of the RBC membrane leading to the formation of irreversively sickled cell and even with reoxygenation ,the shape of red cell does not return to normal. – 5 to 50% of cells from individuals with sickle cell anemia are ISCs, permanently stabilized in their abnormal crescent or oval shape . – ISCs contain substantially less Hb F than reversibly sickled cells , and their endowment of Hb F appears to be the primary determinant of irreversible sickling. – In addition, after repeated sickling events, the cells have rigid cell membrane and are trapped and destroyed in the spleen. – The severity of hemolysis correlates with the number of these cells in circulation.
• When red cells are sickled, they leak K+ and gain Na+, a phenomenon previously ascribed to partial failure of the Na+, K+-adenosine triphosphatase (ATPase) pump . • Because the net flux of Na+ and K+ is approximately equal in reversibly sickled cells, no change occurs in intracellular hydration or Hb concentration . • The intracellular concentration of Ca2+ is increased during sickling, owing in part to increased membrane permeability for Ca2+ and possibly to impairment of the ATPase-dependent Ca2+ pump .
Formation of sickled red cells in circulation
Pathophysiology of sickle cell disease.
Normal Vs. Sickle Red Cells Normal • Disc-Shaped • Deformable • Life span of 120 days Sickle • Sickle-Shaped • Rigid • Lives for 20 days or less
• Factors which influence sickling- • (i)Intracellular concentration of Hbs and other haemoglobins(SCT- has 40%HbS & 60% HbA,HbF prevents polymerization-So infants protected till 6 M. • (ii)Associations with α-thalassaemias –reduced Hb synthesis→milder ds. • (iii)Interactions with other abnormal haemoglobins: HbS=50% ,so increased sickling in HbSC • (iv)Mean corpuscular haemoglobin concentration (MCHC)- Increase (due to î HbS→ î sickling→ î intracellular dehydration-→ î further sickiling • (v)Decreased oxygen tension→facilitates sickling
• Intracellular pH-decrease favours sicling (as decrease in pH reduces O2 affinity of Hb) • Transit time through microvascular bed→ Increase-→ favours sickling
Clinical Features  The clinical features of sickle cell anemia result more from the vaso- occlusive consequences of sickle cells than from the anemia itself.  These features may be divided into those that characteristically are acute and episodic and those that are chronic and often progressive.  Most common, is Vaso-occlusive crisis(Pain Crisis)- It results from obstruction of microcirculation by stiff sickled red cells with ischaemia and infarction in the area of distribution of artery along with supporting factors inflammation, vasoconstriction that slow the movement of RBCS and favour more sickling and occlusion  Free Hb released from lysed sickle cells also bind & inactivate NO→further aggravates vaso constriction .  Precipitating factors –include infection particularly in children,exposure to cold ,and physical and emotional stress .
HAND FOOT SYNDROME • Dactylitis or Painful swelling of digits of hand and feet . It is sudden in onset. • Occurs in < 5yrs, small bones of hands and feet involved. • Manifests as: fever, puffy, tender, warm feet & hands. • Leukocytosis : 20,000 – 60,000 cells/cu mm. • Radiograph – after 1-2 weeks, subperiostal new bone, cortical thinning, short digits
Acute Central Nervous System Event  Infarctive stroke was most frequent in children (5-10 yrs age) and whereas hemorrhagic stroke had the highest incidence ( 20 to 29 yrs of ages).  The mortality rate was 26% after hemorrhagic stroke and 0% after infarctive stroke.  Lesion – internal carotid artery stenosis or obstruction,middle cerebral or anterior cerebral artery obstruction. • Manifests as : severe headache, vertigo, nystagmus, neck pain, ptosis, meningismus. • If detected early,exchange transfusion reduces the risk of subsequent stroke and brain damage.
Acute Chest Syndrome  Medical emergency with mortality around 10%.  Reflects in situ sickling within lung with microinfarction producing pain, temporary pulmonary dysfunction.  Presents with – fever, cough, hemoptysis ,pleuritic chest pain, arterial hypoxemia, pulmonary hypertension, lung infiltration of bases, rib infarcts.  Recurrent episodes – pulmonary fibrosis, respiratory insufficiency. • Priapism- due to involvement of penile venous outflow tracts, permanent impotence is a frequent consequence. RETINOPATHY-causing blindness
Hemolytic crisis  Characterized by rapidly developing anaemia, leukocytosis, jaundice and fever with splenomegaly.  Serious decrease in red blood cells within a few hours.  Characteristic finding – reticulocytes in peripheral smear, fragmented RBCs .  Vicious circle of events – low oxygen tension in tissues causes sickling, leads to ruptured red cells, which causes a further decrease in oxygen tension and still more sickling and red cell destruction.
Acute Splenic Sequestration Crisis  Occurs in children with intact spleen.  Defined by rapid increase in size of spleen over a period of several hours with abdominal fullness, decrease in circulatory volume ,progressive anaemia and circulatory failure .  Due to massive intrasplenic trapping of red cells,erythrostasis leads to tissue hypoxia,thrombosis,infarction,fibrosis. -Rx-prompt exchange transfusion ❖Continuous scarring-- shrinkage of spleen, fibrous tissue remains called Autosplenectomy .  1st attack between 3months - 5yrs age  Manifests as: sudden weakness, pallor, tachycardia, tachypnea, abdominal fullness.  Risk of infection by Streptococcus pneomoniae
AUTOINFARCTED SPLEEN
Aplastic Crisis  There is a cessation in red cell production resulting in an acute, severe drop in hemoglobin levels.  Reticulocyte count - less than 1 percent.  It is usually associated with infections mostly viral parvovirus.  Decreased red cell survival is compensated by 6-8 fold increase in bone marrow output.  Hematocrit to fall by- 10-15% / day.
Chronic Organ Damage • Growth and develooment-Although normal at birth, the heights and weights of children with sickle cell anemia are significantly delayed by 2 years of age. • Skin- Leg ulcers are common and have tendency to recur. • Proliferative retinopathy- Due to vessel occlusion – hemorrhage, neovascularization, detachments.
• Infections –Childrens susceptible to fulminant infections by encapsulated organisms especially Streptococcus pneumoniae, Salmonella, Ecoli, H. influenzae and Shigella.(d/t altered splenic functions) • During pregnancy –risk of spontaneous abortion,prematurity, stillbirth and intrauterine growth retardation . • Hepatobiliary system-Hepatic damage, A significant pts have bilirubin gallstones. • Genitourinary system-Impairment of renal concentrating function (Hyposthenuria) is a common and the earliest sign of kidney damage.Sudden onset of haematuria.Few pts develop protenuria and nephrotic syndrome.
1. Complete blood count: Hb level low ,between 6-9 g/dl 2. Peripheral smear: sickle cells,Howell jolly bodies,target cells. 3. Sickling test: positive. 4. Hb electrophoresis: HbS predominates, reduced normal HbA, HbF present around 2-20% 5. Hemoglobin HPLC: for identification and quantification of variant Hb as well as HbA2 , HbF 6. DNA analysis: for defining the mutation 7. Serum urea,creatinine,electrolytes: to assess renal function 8. Liver function tests: deranged liver enzymes, 9. Unconjugated bilirubin is increased 10. ECG: for evidence of cardiac damage 11. Chest X-ray: cardiac size, lung fields 12. Echocardiography, neurologic imaging Diagnosis
• PBS : demonstrates moderate to severe degree of anisopoikilocytosis .Red cells are normocytic normochromic to mildly hypochromic. • Irreversibly Sickled cells make up about 5-10% 0f red cells. • Target cells are especially frequent in Sickle cell βthalassemia. • There is polychromatophilia with stippled RBC s and nucleated RBCs. • Few red cells demonstrates Howell –jolly bodies . • Reticulocyte count is increased. • Mild Polymorphonuclear leucocytosis is usual. • Platelet count is raised as splenic trapping is lacking or is decreased. • Thrombocytopaenia occurs during vaso-occlusive crisis.
Other investigation- • Erythrocyte sedimentation rate is low despite reduced haemoglobin concentration. This is because of inability of red cells to form rouleaux . • Unconjugated Serum Bilirubin is increased.
Sickle cell disease (peripheral blood smear). A, Low magnification shows sickle cells, anisocytosis, and poikilocytosis. B, Higher magnification shows an irreversibly sickled cell in the center
A. Peripheral smear shows anisopoikilocytosis with target cells, tear drop and cells with Howell Jolly bodies. B.-Peripheral smear shows many dark staining sickle cells (without central pallor), occasional target cells and cells with Howell Jolly bodies.
Blood from a patient with HbSS disease demonstrates prominent anisopoikilocytosis.Many elongated sickle cells and boat shaped cells are seen in the smear.
A, Spleen in sickle cell disease (low power). Red pulp cords and sinusoids are markedly congested; between the congested areas, pale areas of fibrosis resulting from ischemic damage are evident. B, Under high power, splenic sinusoids are dilated and filled with sickled red cells.
Specific test for Haemoglobin S Two test are availavle- Sickling Test and Solubility Test In sickling test, a drop of anticoagulated venous blood is mixed with a drop of 2% sodium metabisulphite A coverslip is placed over the mixture and sealed with petroleum jelly- paraffin wax. Examined under the microscope after 30 minutes ,2 hrs,and 24hrs Test is negative,if red cells are round. Test is positive if the red cells become sickle shaped
• Positive test indicates presence of HbS.It is necessary to perform haemoglobin electrophoresis for confirmation . • False negative test results in Inactive ,outdated reagent,sample containing low proportion of HbS,improper sealing of cover slip. • False positive test results in high conc. Of sodium metabisulphite,mistaking crenated red cells for sickled cells.
Solubility test- Works on principle that HbS is insoluble in deoxygenated state forming crystals that refract light and cause the solution to be turbid. • In this test the, anticoagulated blood is added to the reagent solution consisting of phosphate buffer,saponin , and sodium dithinonite. • Red cells are hemolyzed and Hb S, if present is reduced by dithionite. • Hb S forms tactoids which refract light and the solution is turbid and bg lines become invisible.
Sickle cell solubility test. In negative test,lines of the reader scale kept behind the tubes are clearly visible. In positive test, lines are not seen due to turbidity.
Haemoglobin electrophoresis at alkaline pH. Lane 1: Control; Lane 2: Normal or AA pattern; Lane 3: Sickle cell anaemia or ss pattefh; Lane 4: Sickle cell trait or AS patern.
Sickle cell anemia: Bone marrow aspirate smear is hypercellular with erythroid hyperplasia and there is increase in lron stores. B. Sickling test .2% Sodium metabisulfite preparation shows sickled red cells. C. Starch agarose electrophoresis demonstrates a single band of HbS (Homozygous). The other patient is of HbE trait with 2 bands of HbA and HbE.
Prenatal Diagnosis • Two distinct approaches are available for prenatal diagnosis of sickle cell anaemia- • Foetal blood analysis and foetal DNA analysis. • Foetal blood analysis- • This involves globin chain synthesis studies in foetal blood using CM –cellulose chromatography. • Done in second trimester of pregnancy only after 18 weeks of pregnancy. • Foetal blood is aspirated from umbilical cord under ultrasound guidance (cordocentesis).Risk of foetal loss is comparatively greater.
Foetal DNA analysis •In aminocentasis ,20-30 ml of amniotic fluid is aspirated at 14-20 weeks of gestation and DNA is extracted from amniotic fluid cells after culture. •Studies on amniotic fluid cells need to be performed relatively late in pregnancy. •Risk of foetal loss is 0.5%. •Chorionic villus biopsy can be obtained at 8-12 weeks of gestation . •It consists of obtaining a small piece of developing placenta under ultrasound guidance . •It is preferred because if required termination of pregnancy can be done earlier.
Various methods are available for analysis of foetal DNA . Some of them are- • Southern blot analysis • Restriction fragment length polymorphism analysis(RFLP) • Methods employing DNA amplification – Direct detection of mutation with restriction enzymes Allel-specific oligonucleotide probe analysis Colour DNA amplification
Treatment of Sickle cell Anemia is symptomatic and supportive. Measures to prevent all crisis. ✓ HYDROXYUREA- INCREASES HbF Anti-inflammatory effect
Sickle cell trait • This is the asymptomatic heterozygous state for sickle cell gene (βs /β) in which sickle cell gene is inherited from one parent and gene for Hb A from the other. • In Sickle cell trait , Hb S comprises around 40% of total Hb, the remaining 60% being HbA. • Since Hb A is the predominant Hb it prevents red cells from sickling at low oxygen tensions occuring physiologically .
• Rarely It is associated with clinical or hematologic manifestations of significance. • Some patients may show some abnormalities like deficient urine concentration , infarction of spleen and vaso-occlusive crises at high altitudes, and hematuria (renal papillary necrosis ).
• Individuals have no anemia . • Hemoglobin varies from 11--13 gm/dl. • Red cells are normocytic normochromic with very few target cells and mild degree of anisopoikilocytosis. • Diagnosis is confirmed – • by sickling test ( + ve within 4 hours) • Electrophoresis containing bands of both Hb A and Hb S, with more Hb A than Hb S . • Life expectancy and overall mortality rate for persons with sickle cell trait are the same as for the general population.
Sickle cell trait: A. Peripheral blood film shows mild degree of anisopoikilocytosis with few target cells. Red cells show mild hypochromia. Sickle cell trait is suspected because of the presence of target cells.
Conclusions  Hemoglobinopathy is an important cause of disease world wide with significant implications for genetic counseling.  An increasing number of individuals are at risk and ethnic history is unreliable, prompting moves to universal antenatal haemoglobinopathy screening.  Increasing number of tests being preformed necessitates the use of fast, accurate and efficient HPLC with DNA analysis for further clarification.
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I am sharing 'hemoglobinopathies - Copy' with you.pdf

  • 1.
  • 2.
    Introduction • Haemoglobin inRBC is responsible for transport of oxygen from lungs to the tissues and of carbon dioxide from tissues to the lungs. • Haemoglobin (Hb),MW64,500 daltons, protein constituting 1/3 of the red blood cells. • Synthesis begins in proerythroblast ,evident in intermediate normoblast and is composed of haem (consisting of iron and protoporphyrin) and globin.
  • 3.
    Structure of haemoglobin •Haemoglobin is a tetramer composed of four polypeptide chains (α1,α2, β1, and β2) and four haem groups. • α chains consists of 141 amino acids . • β chains consists of 146 amino acids. • Each polypeptide chain is arranged in a helical conformation. • There are eight helical segments designated A to H. • Iron of haem is covalently bound to histidine at the eight position of the F helical segments.
  • 4.
    Synthesis of Haem •Haem is a complex of protoporphyrin and iron. • Biosynthesis of haem requires mitochondrial and cytosolic enzymes. • Only erythroid precursors can synthesize haem not mature red cells.
  • 5.
  • 6.
    Synthesis of globin •Various types of globin combines with haem to from different haemoglobin • Eight functional globin chains, arranged in two clusters the • - cluster (, ,  and  globin genes) on the short arm of chromosome 11 • - cluster ( and  globin genes) on the short arm of chromosome 16
  • 7.
  • 8.
    Normal hemoglobin variants Embryonichemoglobin – 2 alpha + 2 epsilon chains Fetal hemoglobin - 2 alpha + 2 gamma chains Hemoglobin A - 2 alpha + 2 beta chains Hemoglobin A2 - 2 alpha + 2 delta chains Adult red cell – contains mixes of Hb A 95-98%, HbA2 2-3%, Hb F < 2%. Neonates Hb F predominates.
  • 9.
    Inherited disorders ofHemoglobin are the commonest genetic disorders in the world . Classification : These disorders are divided into three broad groups. 1. structural(Qualitative) abnormalities in the globin proteins themselves.called hemoglobinopathies-eg-SCA 2.usually result in underproduction of normal globin proteins(Quantitative) , often through mutations in regulatory genes eg-Thalassemia 3.Heriditary Persistance of Foetal Hb-It is characterised by failure of normal neonatal switch from haemoglobin F to haemoglobin A.
  • 10.
    Haemoglobinopathies • Inherited disordersof haemoglobin due to Qualitative alteration of the globin polypeptide chain are called haemoglobinopathies. • Majority of qualitative haemoglobinopathies results from substitution of a single amino acid in globin chain due to a point mutation in the β globin gene. • More than 700 hemoglobinopathies have been reported so far.Majority of them clinically insignificant. • More systemic nomenlature consists of denoting the type of polypeptide chain, position,and the amino acid substitution ,eg : HbS is denoted by β⁶ᴳˡ ͧ - ᵛᵅˡ , which represents substitution for glutamic acid at position 6 of β globin chain
  • 11.
    • Hb C •Hb E • Hb D Punjab • Hb O Arab • Hb G Philadelphia • Hb Hasharon • Hb Korle –Bu • Hb Lepore • Hb M • Hb Kansas (β109 Asn> Thr )⁽⁶⁾ • Hb Constant Spring. • The most frequent haemoglobinopathies are- HbS HbC and HbE
  • 12.
    Hereditary disorders ofhaemoglobin prevalent in India
  • 13.
    Sickle Cell Disease •Sickle Cell Disease is a common hereditary hemoglobinopathy by a point mutation in β- globin that promotes the polymerization of deoxygenated Hb,leading to • RBC distortion • Hemolytic anemia • microvascular obstruction & Ischemic tissue damage.
  • 14.
    ◼ SICKLE CELLDISORDERS First described in Chicago in 1910 by James Herrick as an inherited condition in which the red cells become sickle shaped when they are subjected to low oxygen tension . Mason gave the name Sickle cell anemia in 1922. Linus Pauling first described electrophoretic mobility of HbS compared to Hb A. Sickle cell disorders include following conditions- 1.Sickle cell anemia 2.Sickle cell trait
  • 15.
    1).Sickle cell diseasesare divided into following types- (i).Sickle cell anaemia – This is the homozygous state for hemoglobin S (HbSS) that results when the sickle cell gene βѕ is inherited from both the parents .The genotype isβsβs . (ii).Sickle cell β trait – This is the heterozygous state in which the sickle cell gene is inherited from one parent and normal gene from the other parent. (Iii).Combination of hemoglobin S(HbS) with other structural haemoglobin variants can produce a double heterozygous state such as sickle cell thal,Hb SD disease,Hb SC disease ,Hb SO-Arab disease ,Hb SE disease,etc.
  • 16.
    • Sickle celldisease is a common hereditary hemoglobinopathy that occurs primarily in individuals of African descent. • It is caused by a point mutation in the sixth codon of β- globin that leads to the replacement of a glutamate residue with a valine residue. • The abnormal physiochemical properties of the resulting sickle hemoglobin (HbS) are responsible for the disease. • It is usually only in the homozygous state that the disease is so devastating
  • 17.
  • 18.
    Prevalence of HbS ▪Prevalence- In parts of Africa, the Mediterranean basin, the Middle East, Central and Southern India. • HbS has a high prevalence in those parts of the world where malaria is common. • Young children with sickle cell trait develop comparatively mild falciparum malaria. Children who inherited one sickle hemoglobin gene and who, therefore, carried the sickle cell trait - had a survival advantage.
  • 19.
    Pathogenesis • The Sicklecell disorders all results from inheritance of sickle cell gene that codes for abnormal β globin chain. • There is a change of a single base A→ T in the sixth codon of globin gene so that there is substitution of thymine for adenine . • This in turn results in substitution of valine for glutamic acid at position 6 of β polypeptide chain. • The amino acid substitution in HbS is represented as β⁶Glu →Val.
  • 20.
    ▪ Polymerization ofHb S : polymerization of Hb S molecules inside the red cells is responsible for sickling of red cells. Polymerization occurs only on deoxygenation and causes→ 1. Chronic hemolysis 2. Microvascular occlusion 3. Tissue damage Initially RBC cytosol is converted from freely flowing liquid to a viscous gel ,but with continued deoxygenation-→ long needle like fibres are formed within RBCs , damaging the RBC membrane →producing a distorted sickle or holly leaf shape.
  • 22.
    – When oxygenated,Hb S is soluble. – When oxygen tension decreases, Hb S in the deoxyhemoglobin state polymerizes into insoluble aggregates leading to sickled cells. – This leads to increased blood viscosity which leads to decreased circulation and increased exposure to low oxygen. This, in turn, leads to more sickling. – Upon reoxygenation, polymerized HbS (viscous gel state) returns to depolymerized (fluid-liquid) state and the RBC may return to its original shape. – The small microvasculature may become clogged with the rigid sickle cells leading to hypoxia and infarction of organs and a “sickle cell crisis”.
  • 23.
    – However, repeatedsickling and unsickling damages the permeability of the RBC membrane leading to the formation of irreversively sickled cell and even with reoxygenation ,the shape of red cell does not return to normal. – 5 to 50% of cells from individuals with sickle cell anemia are ISCs, permanently stabilized in their abnormal crescent or oval shape . – ISCs contain substantially less Hb F than reversibly sickled cells , and their endowment of Hb F appears to be the primary determinant of irreversible sickling. – In addition, after repeated sickling events, the cells have rigid cell membrane and are trapped and destroyed in the spleen. – The severity of hemolysis correlates with the number of these cells in circulation.
  • 24.
    • When redcells are sickled, they leak K+ and gain Na+, a phenomenon previously ascribed to partial failure of the Na+, K+-adenosine triphosphatase (ATPase) pump . • Because the net flux of Na+ and K+ is approximately equal in reversibly sickled cells, no change occurs in intracellular hydration or Hb concentration . • The intracellular concentration of Ca2+ is increased during sickling, owing in part to increased membrane permeability for Ca2+ and possibly to impairment of the ATPase-dependent Ca2+ pump .
  • 25.
    Formation of sickledred cells in circulation
  • 26.
  • 28.
    Normal Vs. SickleRed Cells Normal • Disc-Shaped • Deformable • Life span of 120 days Sickle • Sickle-Shaped • Rigid • Lives for 20 days or less
  • 29.
    • Factors whichinfluence sickling- • (i)Intracellular concentration of Hbs and other haemoglobins(SCT- has 40%HbS & 60% HbA,HbF prevents polymerization-So infants protected till 6 M. • (ii)Associations with α-thalassaemias –reduced Hb synthesis→milder ds. • (iii)Interactions with other abnormal haemoglobins: HbS=50% ,so increased sickling in HbSC • (iv)Mean corpuscular haemoglobin concentration (MCHC)- Increase (due to î HbS→ î sickling→ î intracellular dehydration-→ î further sickiling • (v)Decreased oxygen tension→facilitates sickling
  • 30.
    • Intracellular pH-decreasefavours sicling (as decrease in pH reduces O2 affinity of Hb) • Transit time through microvascular bed→ Increase-→ favours sickling
  • 31.
    Clinical Features  Theclinical features of sickle cell anemia result more from the vaso- occlusive consequences of sickle cells than from the anemia itself.  These features may be divided into those that characteristically are acute and episodic and those that are chronic and often progressive.  Most common, is Vaso-occlusive crisis(Pain Crisis)- It results from obstruction of microcirculation by stiff sickled red cells with ischaemia and infarction in the area of distribution of artery along with supporting factors inflammation, vasoconstriction that slow the movement of RBCS and favour more sickling and occlusion  Free Hb released from lysed sickle cells also bind & inactivate NO→further aggravates vaso constriction .  Precipitating factors –include infection particularly in children,exposure to cold ,and physical and emotional stress .
  • 32.
    HAND FOOT SYNDROME •Dactylitis or Painful swelling of digits of hand and feet . It is sudden in onset. • Occurs in < 5yrs, small bones of hands and feet involved. • Manifests as: fever, puffy, tender, warm feet & hands. • Leukocytosis : 20,000 – 60,000 cells/cu mm. • Radiograph – after 1-2 weeks, subperiostal new bone, cortical thinning, short digits
  • 33.
    Acute Central NervousSystem Event  Infarctive stroke was most frequent in children (5-10 yrs age) and whereas hemorrhagic stroke had the highest incidence ( 20 to 29 yrs of ages).  The mortality rate was 26% after hemorrhagic stroke and 0% after infarctive stroke.  Lesion – internal carotid artery stenosis or obstruction,middle cerebral or anterior cerebral artery obstruction. • Manifests as : severe headache, vertigo, nystagmus, neck pain, ptosis, meningismus. • If detected early,exchange transfusion reduces the risk of subsequent stroke and brain damage.
  • 34.
    Acute Chest Syndrome Medical emergency with mortality around 10%.  Reflects in situ sickling within lung with microinfarction producing pain, temporary pulmonary dysfunction.  Presents with – fever, cough, hemoptysis ,pleuritic chest pain, arterial hypoxemia, pulmonary hypertension, lung infiltration of bases, rib infarcts.  Recurrent episodes – pulmonary fibrosis, respiratory insufficiency. • Priapism- due to involvement of penile venous outflow tracts, permanent impotence is a frequent consequence. RETINOPATHY-causing blindness
  • 35.
    Hemolytic crisis  Characterizedby rapidly developing anaemia, leukocytosis, jaundice and fever with splenomegaly.  Serious decrease in red blood cells within a few hours.  Characteristic finding – reticulocytes in peripheral smear, fragmented RBCs .  Vicious circle of events – low oxygen tension in tissues causes sickling, leads to ruptured red cells, which causes a further decrease in oxygen tension and still more sickling and red cell destruction.
  • 36.
    Acute Splenic SequestrationCrisis  Occurs in children with intact spleen.  Defined by rapid increase in size of spleen over a period of several hours with abdominal fullness, decrease in circulatory volume ,progressive anaemia and circulatory failure .  Due to massive intrasplenic trapping of red cells,erythrostasis leads to tissue hypoxia,thrombosis,infarction,fibrosis. -Rx-prompt exchange transfusion ❖Continuous scarring-- shrinkage of spleen, fibrous tissue remains called Autosplenectomy .  1st attack between 3months - 5yrs age  Manifests as: sudden weakness, pallor, tachycardia, tachypnea, abdominal fullness.  Risk of infection by Streptococcus pneomoniae
  • 37.
  • 38.
    Aplastic Crisis  Thereis a cessation in red cell production resulting in an acute, severe drop in hemoglobin levels.  Reticulocyte count - less than 1 percent.  It is usually associated with infections mostly viral parvovirus.  Decreased red cell survival is compensated by 6-8 fold increase in bone marrow output.  Hematocrit to fall by- 10-15% / day.
  • 40.
    Chronic Organ Damage •Growth and develooment-Although normal at birth, the heights and weights of children with sickle cell anemia are significantly delayed by 2 years of age. • Skin- Leg ulcers are common and have tendency to recur. • Proliferative retinopathy- Due to vessel occlusion – hemorrhage, neovascularization, detachments.
  • 41.
    • Infections –Childrenssusceptible to fulminant infections by encapsulated organisms especially Streptococcus pneumoniae, Salmonella, Ecoli, H. influenzae and Shigella.(d/t altered splenic functions) • During pregnancy –risk of spontaneous abortion,prematurity, stillbirth and intrauterine growth retardation . • Hepatobiliary system-Hepatic damage, A significant pts have bilirubin gallstones. • Genitourinary system-Impairment of renal concentrating function (Hyposthenuria) is a common and the earliest sign of kidney damage.Sudden onset of haematuria.Few pts develop protenuria and nephrotic syndrome.
  • 42.
    1. Complete bloodcount: Hb level low ,between 6-9 g/dl 2. Peripheral smear: sickle cells,Howell jolly bodies,target cells. 3. Sickling test: positive. 4. Hb electrophoresis: HbS predominates, reduced normal HbA, HbF present around 2-20% 5. Hemoglobin HPLC: for identification and quantification of variant Hb as well as HbA2 , HbF 6. DNA analysis: for defining the mutation 7. Serum urea,creatinine,electrolytes: to assess renal function 8. Liver function tests: deranged liver enzymes, 9. Unconjugated bilirubin is increased 10. ECG: for evidence of cardiac damage 11. Chest X-ray: cardiac size, lung fields 12. Echocardiography, neurologic imaging Diagnosis
  • 43.
    • PBS :demonstrates moderate to severe degree of anisopoikilocytosis .Red cells are normocytic normochromic to mildly hypochromic. • Irreversibly Sickled cells make up about 5-10% 0f red cells. • Target cells are especially frequent in Sickle cell βthalassemia. • There is polychromatophilia with stippled RBC s and nucleated RBCs. • Few red cells demonstrates Howell –jolly bodies . • Reticulocyte count is increased. • Mild Polymorphonuclear leucocytosis is usual. • Platelet count is raised as splenic trapping is lacking or is decreased. • Thrombocytopaenia occurs during vaso-occlusive crisis.
  • 44.
    Other investigation- • Erythrocytesedimentation rate is low despite reduced haemoglobin concentration. This is because of inability of red cells to form rouleaux . • Unconjugated Serum Bilirubin is increased.
  • 45.
    Sickle cell disease(peripheral blood smear). A, Low magnification shows sickle cells, anisocytosis, and poikilocytosis. B, Higher magnification shows an irreversibly sickled cell in the center
  • 46.
    A. Peripheral smearshows anisopoikilocytosis with target cells, tear drop and cells with Howell Jolly bodies. B.-Peripheral smear shows many dark staining sickle cells (without central pallor), occasional target cells and cells with Howell Jolly bodies.
  • 47.
    Blood from apatient with HbSS disease demonstrates prominent anisopoikilocytosis.Many elongated sickle cells and boat shaped cells are seen in the smear.
  • 48.
    A, Spleen insickle cell disease (low power). Red pulp cords and sinusoids are markedly congested; between the congested areas, pale areas of fibrosis resulting from ischemic damage are evident. B, Under high power, splenic sinusoids are dilated and filled with sickled red cells.
  • 49.
    Specific test forHaemoglobin S Two test are availavle- Sickling Test and Solubility Test In sickling test, a drop of anticoagulated venous blood is mixed with a drop of 2% sodium metabisulphite A coverslip is placed over the mixture and sealed with petroleum jelly- paraffin wax. Examined under the microscope after 30 minutes ,2 hrs,and 24hrs Test is negative,if red cells are round. Test is positive if the red cells become sickle shaped
  • 50.
    • Positive testindicates presence of HbS.It is necessary to perform haemoglobin electrophoresis for confirmation . • False negative test results in Inactive ,outdated reagent,sample containing low proportion of HbS,improper sealing of cover slip. • False positive test results in high conc. Of sodium metabisulphite,mistaking crenated red cells for sickled cells.
  • 51.
    Solubility test- Workson principle that HbS is insoluble in deoxygenated state forming crystals that refract light and cause the solution to be turbid. • In this test the, anticoagulated blood is added to the reagent solution consisting of phosphate buffer,saponin , and sodium dithinonite. • Red cells are hemolyzed and Hb S, if present is reduced by dithionite. • Hb S forms tactoids which refract light and the solution is turbid and bg lines become invisible.
  • 52.
    Sickle cell solubilitytest. In negative test,lines of the reader scale kept behind the tubes are clearly visible. In positive test, lines are not seen due to turbidity.
  • 53.
    Haemoglobin electrophoresis atalkaline pH. Lane 1: Control; Lane 2: Normal or AA pattern; Lane 3: Sickle cell anaemia or ss pattefh; Lane 4: Sickle cell trait or AS patern.
  • 54.
    Sickle cell anemia:Bone marrow aspirate smear is hypercellular with erythroid hyperplasia and there is increase in lron stores. B. Sickling test .2% Sodium metabisulfite preparation shows sickled red cells. C. Starch agarose electrophoresis demonstrates a single band of HbS (Homozygous). The other patient is of HbE trait with 2 bands of HbA and HbE.
  • 55.
    Prenatal Diagnosis • Twodistinct approaches are available for prenatal diagnosis of sickle cell anaemia- • Foetal blood analysis and foetal DNA analysis. • Foetal blood analysis- • This involves globin chain synthesis studies in foetal blood using CM –cellulose chromatography. • Done in second trimester of pregnancy only after 18 weeks of pregnancy. • Foetal blood is aspirated from umbilical cord under ultrasound guidance (cordocentesis).Risk of foetal loss is comparatively greater.
  • 56.
    Foetal DNA analysis •Inaminocentasis ,20-30 ml of amniotic fluid is aspirated at 14-20 weeks of gestation and DNA is extracted from amniotic fluid cells after culture. •Studies on amniotic fluid cells need to be performed relatively late in pregnancy. •Risk of foetal loss is 0.5%. •Chorionic villus biopsy can be obtained at 8-12 weeks of gestation . •It consists of obtaining a small piece of developing placenta under ultrasound guidance . •It is preferred because if required termination of pregnancy can be done earlier.
  • 57.
    Various methods areavailable for analysis of foetal DNA . Some of them are- • Southern blot analysis • Restriction fragment length polymorphism analysis(RFLP) • Methods employing DNA amplification – Direct detection of mutation with restriction enzymes Allel-specific oligonucleotide probe analysis Colour DNA amplification
  • 58.
    Treatment of Sicklecell Anemia is symptomatic and supportive. Measures to prevent all crisis. ✓ HYDROXYUREA- INCREASES HbF Anti-inflammatory effect
  • 59.
    Sickle cell trait •This is the asymptomatic heterozygous state for sickle cell gene (βs /β) in which sickle cell gene is inherited from one parent and gene for Hb A from the other. • In Sickle cell trait , Hb S comprises around 40% of total Hb, the remaining 60% being HbA. • Since Hb A is the predominant Hb it prevents red cells from sickling at low oxygen tensions occuring physiologically .
  • 60.
    • Rarely Itis associated with clinical or hematologic manifestations of significance. • Some patients may show some abnormalities like deficient urine concentration , infarction of spleen and vaso-occlusive crises at high altitudes, and hematuria (renal papillary necrosis ).
  • 61.
    • Individuals haveno anemia . • Hemoglobin varies from 11--13 gm/dl. • Red cells are normocytic normochromic with very few target cells and mild degree of anisopoikilocytosis. • Diagnosis is confirmed – • by sickling test ( + ve within 4 hours) • Electrophoresis containing bands of both Hb A and Hb S, with more Hb A than Hb S . • Life expectancy and overall mortality rate for persons with sickle cell trait are the same as for the general population.
  • 62.
    Sickle cell trait:A. Peripheral blood film shows mild degree of anisopoikilocytosis with few target cells. Red cells show mild hypochromia. Sickle cell trait is suspected because of the presence of target cells.
  • 63.
    Conclusions  Hemoglobinopathy isan important cause of disease world wide with significant implications for genetic counseling.  An increasing number of individuals are at risk and ethnic history is unreliable, prompting moves to universal antenatal haemoglobinopathy screening.  Increasing number of tests being preformed necessitates the use of fast, accurate and efficient HPLC with DNA analysis for further clarification.
  • 64.