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Sickle Cell Anemia

It is a autosomal recessive condition.
This is a hemolytic anemia resulting from the homozygous inheritance of a gene which causes an amino acid substitution in the hemoglobin molecule (beta – 6 glutamate valine) creating HbS due to point mutation.

HbS (Beta 6 glue Valine)
HbC (Beta 6 glue → Lysine)
HbE (Beta 26 glue → Lysine)

Important Points: Sickle cell disease is caused by a mutation in the beta gene


  1. Homozygote (SS) – sickle cell anemia
  2. Heterozygote (AS) – sickle cell trait (protects from falciparum malaria). (LQ 2012)
    Symptomatic sickling occurs in homozygotes. Heterozygotes are asymptomatic, and present with mild anemia except in situation of hypoxia, Anaesthesia, when veno-occlusive events occur.
Factors influencing sickling
  1. Amount of HbS directly proportional to sickling
    1. Homozygous – 100%                                              
    2. ​Heterozygous – 40%
  2. Presence of other type of hemoglobin
    1. Hb C, D - Increase sickling                      
    2. Hb F - Prevent sickling
  3. Acidosis – Increase sickling
  4. Hemoglobin concentration (MCHC)
    1. MCHC ↑ ↑ - Sickling ↑              
    2. Intracellular dehydration – sickling ↑          
    3. Viscosity ↑ - Sickling ↑
  5. O2 tension:       
    a. ↓ O2 tension - ↑ sickling
  6. Length of time RBC exposed to ↓ O2 tension :
    a. It flow is sluggish (time ↑) – sickling ↑
  7. Presence of α - thalassemia - ↓ sickling
    2, 3. DPG - ↑ sickling
Important Points:
  1. The most important factor affecting the rate and degree of sickling is the amount of HBs and its interaction with other hemoglobin chains in the cell.
  2. Patients with sickle cell trait (Heterozygotes) have 40% of haemoglobin in the form of HbS, the rest being HbA, which interacts only with HbS when deoxygenated.
  3. Both the low concentration of HbS and the presence of interfering HbA act to prevent effective HBs aggregation and polymerization and thus red cells in sickle cell trait (heterozygotes) do not sickle.
  1. In the deoxygenated state the HbS molecules polymerize and causes sickling of RBCs.
  2. Sickle cells are rigid, and hemolyses, and block small vessels to cause infarction.
  3. Deoxygenated Hb align in parallel forming tactoid that distort the RBC into the classic sickle and oak leaf shaped cells. 
Fig: Pathophysiology of sickle cell crisis

Clinical Features
  1. Anemia (Hb 6 –8 gm/dl), reticulocytosis (10 –20%), jaundice, painful swelling of hands and feet. 
  2. Splenomegaly is not a feature (autosplenectomy occurs Q). 
  3. Chronic ill – health, renal failure, bone pain necrosis, infections, leg ulcers can result, Pulmonary arterial hypertension  
Important Points: “Sickle cell anemia is characterized by Hyposplenism due to Autosplenectomy”
The clinical feature
  1. Acute : 
    1. Infarctive or painful crisis: Severe skeletal pain but no change in Hb%
    2. Sequestration crisis: Sudden massive pooling of red cells in spleen with an acute fall in Hb concentration.
    3. Hemolytic crisis (uncommon): Fall in hemoglobin concentration with marked increase in jaundice.
  1. Chronic:   
    1. Hemolysis:         
      1. Anemia              
      2. Cardiomegaly        
      3. Hepatomegaly   
      4. Bone marrow hyperplasia    
      5. Leg ulcer          
      6. Jaundice    
      7. Pigment gall stone
  2. Increase viscosity:  
Table -Clinical Features of Sickle Hemoglobinopathies
Condition Clinical Abnormalities Hb Level g/L (g/dL) MCV, fL Hb Electrophoresis
Sickle cell trait None; rare painless hematuria Normal Normal Hb S/A:40/60
Sickle cell anemia Vaso-occlusive crises with infarction of spleen, brain, marrow, kidney, lung; aseptic necrosis of bone; gallstones; priapism; ankle ulcers 7–10 80–100 Hb S/A:100/0
Hb F:2–25%
S/b° thalassemia Vaso-occlusive crises; aseptic necrosis of bone 7–10 60–80 Hb S/A:100/0
Hb F:1–10%
S/b+ thalassemia
Rare crises and aseptic necrosis 10–14 70–80 Hb S/A:60/40
Hemoglobin SC Rare crises and aseptic necrosis; painless hematuria 10–14 80–100 Hb S/A:50/0
Hb C:50%
  1. Thrombotic crisis/infarction crisis: 
  2. Aplastic crisis: This is usually due to parvovirus infection and is characterized by a low reticulocyte count. 
  3. Sequestration crisis: Due to RBC trapping, the spleen and liver enlarge. Anemia becomes very severe which can be an acute manifestation and cause death in infants. Later, repeated infarction and fibrosis of spleen leads to ‘autosplenectomy’. Functional asplenia occurs much earlier (early childhood).
  4. Hemolytic crisis – 


Extra Edge: 
  1. Infants with sickle cell anemia have abnormal immune function. 
  2. As early as 6 month of age, some children, and by 5 yr of age, most children have functional asplenia. 
  3. Bacterial sepsis is one of the greatest causes of morbidity and mortality in this patient population. 
  4. Children with sickle cell anemia also have deficient levels of serum opsonins of the alternate complement pathway against pneumococci. 
  5. Regardless of age, all patients with sickle cell anemia are at increased risk for infection and death as a result of bacterial infection, particularly with encapsulated organisms, such as Streptococcus pneumoniae and Haemophilus influenzae type B. 
  6. Children with sickle cell anemia should receive prophylactic oral penicillin at least until 5 yr of age.  No established guidelines exist for penicillin prophylaxis beyond 5 yr of age.


Thus sickle cell anemia can present before 6 Months of age but usually presents after 6 Months. 


Sequence of events in sickle cell anemia:
  1. Mild hemolytic anemia appear by 10-12 week of age [HbF (α2 d2) is protective.]
  2. Splenomegaly – after 6 month. Later on autosplenectomy
  3. Veno occlusive crisis – between 8-12 month of age
  4. Aplastic crisis – Any time offer 6 month.
Extra Edge:
  1. Sickle cell anemia is associated with granulocytosis (Leukocytosis) Both total and segmental leucocyte number increase during vas occlusive crisis and infections.
  2. Chronic acute or subacute pulmonary crisis (Pulmonary vas occlusive disease) lead to pulmonary hypertension and cor pulmonale.
  3. The heart is enlarged with a hyperdynamic precordium and systolic murmurs.
  4. Reactive hyperplasia of bone marrow with associated widening of medullary cavities produces a characteristic biconcave vertebra i.e. fish mouth vertebra.
  5. Most common cause of death :- Sepsis & acute chest syndrome


  1. Peripheral smear: Shows Howell – Jolly bodies due to autosplenectomy, target cells, nucleated RBCs, RBC fragments, occasional thrombocytosis and leucocytosis (Characteristic). 
  2. Hb electrophoresis at alkaline pH: HbS can be detected by starch or agar gel electrophoresis
  3. “Sickle Prep” test: This is performed by depriving RBCs of oxygen using metabisulfite or dithionite compounds as reducing agents and placing a coverslip over a drop of blood on a glass side. The RBCs sickle in situ. 
Extra Edge:
Gamma Gandy bodies are most characteristic of congestive splenomegaly and sickle cell anemia (so also seen in Portal hypertension, hemolytic anemia, Hemochromatosis) 
  1. Severity of sickle cell disease may be decreased by HbF
  2. Hydroxyurea causes an increase in the levels of HbF in red cells. This may in part, be responsible for the mechanism of action of hydroxyurea in sickle cell disease.
  3. Efforts are currently being directed towards gene therapy that would increase the production of HbF.
  4. Veno-occlusive crisis is a cause of morbidity
Bone Changes during sickle cell anemia:
  1. Crew haircut appearance (Hair on end)
  2. Fish mouth vertebrae


  1. Infraction crisis: Analgesia (sustained release morphine) IV fluids (100 – 200 ml/hr)
  2. Blood transfusion: If PCV or reticulocytes fall sharply, in CNS or lung complications or when Hb level is < 6gm/dl, blood transfusion can be given. 
  3. Treatment of infection by antibiotics. 
  4. Antisickling agents
    1. Hydroxyurea – increases HbF to 14 – 15%
    2. Butyrate compounds – increases HbF by increasing number of erythroblasts expressing gamma globin
Recent Advances: Newer Drug – Decitabine


Recent Advances:

  1. The most significant advance in the therapy of sickle cell anemia has been the introduction of hydroxyurea as a mainstay of therapy for patients with severe symptoms. Hydroxyurea (10–30 mg/kg per day) increases fetal hemoglobin.
  2. The antitumor drug 5-azacytidine was the first agent found to elevate HbF. It never achieved widespread use because of concerns about acute toxicity and carcinogenesis. However, low doses of the related agent 5-deoxyazacytidine (decitabine) can elevate HbF with more acceptable toxicity.
  3. Reestablishing high levels of fetal hemoglobin synthesis should ameliorate the symptoms of chain hemoglobinopathies.
  4. Cytotoxic agents such as hydroxyurea and cytarabine promote high levels of HbF synthesis, probably by stimulating proliferation of the primitive HbF-producing progenitor cell population (i.e., F cell progenitors).
  5. Butyrate stimulate HbF production, but only transiently.

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