Sickle Cell Anemia

SICKLE CELL DISEASE
  • Normal adult red cells contain mainly HbA(α2β2), along with small amounts of HbA2(αδ2) and fetal hemoglobin HbF(α2γ2)
  • Sickle cell disease is caused by a point mutation(missense mutation) at the 6th codon of β globin chain leading to substitution of glutamine by valine.
  • Sickle cell disease is inherited as Autosomal recessive.
  • Sickle cell anemia is the clinical manifestation of homozygous genes
  • Sickle cell trait (heterozygotes) gives protection against falciparum malaria
  • In sickle cell trait 40% is HbS and rest is HbA.
  • Sickle cell anaemia is commonly seen in black 
PATHOGENESIS OF SICKLE CELL DISEASE
  • Sickle cell disease causes extravascular hemolysis.
  • Sticky patch in sickle cell disease results from replacement of a polar residue (Glutamate) with a non polar residue (Valine) at the 6th position of the beta chain.
  • RFLP results from a single base change in Sickle cell disease.
  • Decreased Solubility is the cause of sickling of RBC in sickle cell disease.
  • Deoxygenated HbS undergo aggregation and polymerization, producing a distorted sickle or holly-leaf shaped RBC which block microcirculation.
  • Initial sickling is reversible on oxygenation, but after repeated aggregation, sickling is irreversible.
  • There is a positive correlation between HBS and polymerization of HBS in Sickle cell anemia.
  • HbF inhibit polymerization of HbS; hence infants are asymptomatic until 6 months
  • In hereditary persistence of HbF - the disease is less severe
  • HbC (lysine is substituted for glutamate in the 6th amino acid residue of β globin) has greater tendency to form aggregates than HbS - but disease is milder in HbSC
  • Factors precipitating sickling
  1. Dehydration (↑MCHC)
  2. Hypoxia
  3. Acidosis (↓ pH)
  4. Increased transit time of red cells through microvascular beds
  5. Infections
CLINICAL FEATURES OF SICKLE CELL DISEASE
  • Vaso-occlusive crisis or Pain crisis (hall mark) - most common clinical manifestation
  • Bones (especially the back and long bones) and the chest are commonly affected
  • Plugging of small vessels in bones - dactylitis (hand and foot syndrome)
  • Avascular necrosis of femoral head, Osteomyelitis due to Salmonella.
  • Reccurent infections is the most common cause of death in Sickle cell anemia.
  • Acute chest syndrome
  1. Chest pain, tachypnea, fever, cough, and arterial oxygen desaturation
  2. Pulmonary infarction and pneumonia are the most frequent underlying conditions
  • Extramedullary hematopoiesis prominent cheek bones and crew-hair cut appearance of skull
  • Occlusion of vertebral arteries - fish mouth deformity of vertebrae
  • Sequestration crisis - massive sequestration of sickled red cells leads to rapid splenic enlargement,hypovolemia and shock.
  • In chronic disease due to repetititve infarction, there is progressive shrinkage of spleen following repeated episodes of sequestration crisis - autosplenectomy
  • Children are more prone for Pneumococcus pneumoniae and H influenzae septicemia and meningitis with capsulated organisms like pneumococci
  • Aplastic crisis - transient cessation of marrow erythropoiesis due to an acute infection with parvovirus B19.
  • Unlike other crisis reticulocyte count is low
  • Stroke is especially common in children and less common in adults
  • Priapism may result in permanent impotence
  • Increased break down of hemoglobin can cause pigment gallstones and hyperbilirubinemia.
  • Renal papillary necrosis leads to hyposthenuria (inability to concentrate urine) and gross hematuria (less common in sickle cell disease)
  • Leg ulcers, delayed puberty, pulmonary hypertension, retinopathy
  • Granulocytosis is common
  • PAH,Cardiomegaly
  • Pulmonary hypertension.
  • 'Sea-Fan' retina is seen.
  • Decreased Osmotic Fragility
  • Sickle cell anemia is a non-metabolic cause of abdominal pain.
  • Female gender: less severe manifestations since HbF is high.
DIAGNOSIS OF SICKLE CELL DISEASE
  • Peripheral blood: sickled cells, target cells, Howell-Jolly bodies, Anemia (extravascular hemolysis), reticulocytosis
  • ↓ESR (raised in other anemias) Metabisulfite and sodium dithionite which consumes oxygen in a sample of blood, precipitates sickling if HbS is present - useful screening test
  • Definite diagnosis by - Hemoglobin electrophoresis (which reveal 60% HbS),HbA2 is normal; HbF in varying concentrations: HbA absent
  • Alkali denaturation method - to determine concentration of HbF (HbF is relatively resistant to denaturation by strong alkali)
  • Quantitative estimation of HbF - Kleihauer test.
  • Polymerase chain reaction with allele-specific oligonucleotide hybridization, Southern blot analysis ,DNA sequencing can be used to detect the point mutation in the beta globin gene that causes sickle cell anemia.
  • Gandy gamma bodies are seen in sickle-cell anaemia .
  • Vertebra plana ,Bone infarct , Marrow hyperplasia,'H' shaped vertebra are the radiological features of Sickle cell anemia.
MANAGEMENT OF SICKLE CELL DISEASE
  • Vaso-occlusive crisis managed by aggressive rehydration, oxygen therapy, analgesia and antibiotics
  • For sequestration crisis and acute chest syndrome exchange transfusion needed
  • A high HbF level inhibits sickling. Hydroxyurea induce increased synthesis of HbF
  • Omega-3 fatty acid supplementation may reduce vaso-occlusive episodes.
  • Splenectomy is indicated in Sickle cell anemia.
OTHER CLINICAL IMPLICATIONS IN A CASE OF SICKLE CELL DISEASE
  • IV regional anaesthesia is contraindicated in a young boy with sickle cell trait.
  • 0 and 100% is the chances of having children with sickle cell disease and sickle cell trait respectively in a mother diagnosed to have sickle cell disease, her husband is normal.
  • If both parents are sickle cell anemia patients then the likelyhood of offsprings having the disease is 100%.
  • Condom or Diaphragm is the safest contraceptive method for a woman with sickle-cell anaemia .
SICKLE CELL TRAIT
  • Hematologically normal - no anemia, normal red blood cells on peripheral blood smear.
  • Sickle cell trait patient do not have manifestations as that of Sickle cell disease, because 50% HbS is required for occurrence of sickling.
  • Hemoglobin electrophoresis - 40% of hemoglobin is hemoglobin S

Exam Question of:
  • Parvovirus B19 has been associated with transient aplastic crises in persons with sickle cell disease.
  • Target cells ,Jaundice ,Reticulocytosis,Sickle cells,Howell jolly bodies is seen in Sickle cell Anemia.
  • Sickle cell anemia leads to resistance towards P.Falciparum.
  • In Sickle cell disease,single nucleotide change results in change of Glutamine to Valine.
  • Sticky patch in sickle cell disease results from replacement of a polar residue (Glutamate) with a non polar residue (Valine) at the 6th position of the beta chain.
  • RFLP results from a single base change in Sickle cell disease.
  • HbS confers resistance against malaria in heterozygotes in Sickle cell disease.
  • Hydroxyurea is used in sickle cell anemia.
  • IV regional anaesthesia is contraindicated in a young boy with sickle cell trait.
  • Sickle cell disease is inherited as Autosomal recessive.
  • In Sickle Cell Anaemia defect is in beta chain.
  • Replacement of glutamate by valine in β-chain of HbA is the primary defect which leads to sickle cell anemia.
  • Sickle cell trait patient do not have manifestations as that of Sickle cell disease, because 50% HbS is required for occurrence of sickling.
  • 0 and 100% is the chances of having children with sickle cell disease and sickle cell trait respectively in a mother diagnosed to have sickle cell disease, her husband is normal.
  • If both parents are sickle cell anemia patients then the likelyhood of offsprings having the disease is 100%.
  • The decrease in size of spleen is most likely related to infarction in a 6 month old child with sickle cell anemia having a chronically enlarged spleen and by 5 years of age, the child's spleen is no longer palpable. 
  • Polymerase chain reaction with allele-specific oligonucleotide hybridization, Southern blot analysis ,DNA sequencing can be used to detect the point mutation in the beta globin gene that causes sickle cell anemia.
  • Decreased Solubility is the cause of sickling of RBC in sickle cell disease.
  • Reccurent infections is the most common cause of death in Sickle cell anemia.
  • There is a positive correlation between HBS and polymerization of HBS in Sickle cell anemia.
  • Patients require frequent blood transfusions in Sickle cell anemia.
  • Patients usually presents after the age of 6 months in Sickle cell Anemia.
  • In sickle cell anemia hemoglobin electrophoresis shows HbF , HbS , HbA2.
  • PAH ,Fish vertebra ,Leukocytosis,Cardiomegaly is seen in Sickle cell anemia.
  • The mechanism of increased susceptibility of Pneumococcal infection in patients with sickle cell anemia is Splenic dysfunction.
  • In sickle cell anaemia, the defect can be explained as having arisen from base substitution in DNA.
  • Sickle cell anemia is the clinical manifestation of homozygous genes for an abnormal haemoglobin molecule.
  • The event responsible for the mutation in the B chain in Sickle cell anemia is Point mutation.
  • Condom or Diaphragm is the safest contraceptive method for a woman with sickle-cell anaemia .
  • Sickle cell anaemia is commonly seen in black and R.B.C. size is altered.
  • HbS concentration , HbA , pH are the factors affecting Sickling.
  • Number of bands found in sickle cell trait is 2.
  • Autosplenectomy in sickle cell anaemia is due thrombosis and infarction.
  • Crew haircut appearance in X-ray skull and Gandy gamma bodies are seen in sickle-cell anaemia .
  • Sickle cell disease causes extravascular hemolysis.
  • Bone pain is the commonest presentation of sickle cell anemia.
  • Salmonellosis is most common in sickle cell anemia.
  • Vertebra plana ,Bone infarct , Marrow hyperplasia,'H' shaped vertebra are the radiological features of Sickle cell anemia.
  • Splenectomy is indicated in Sickle cell anemia. Dactylitis,Pulmonary hypertension ,Decreased osmotic fragility,Necrotizing pappillitis,pituitary apoplexy,Persistent priapism is seen in Sickle cell anemia.
  • 'Sea-Fan' retina is seen in SLE and Sickle cell disease.
  • Splenomegaly may be a feature of Sickle cell anemia but Hepatosplenomegaly is not a feature.
  • Sickle cell anemia is a non-metabolic cause of abdominal pain.
  • Missense mutation occurs in Sickle cell disease

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