Sickle cell anemia
Types of adult hemoglobin
Hb A1 = 97% of adult hemoglobin, composed of 2 α and 2 β chains (α2β2).
Hemoglobin (Hb A2) = 2.2-3.5% of adult hemoglobin, composed of 2 alpha and 2 delta chains (α2δ2).
Hb F = 70-90% at birth, 25% at 1 month of age, and 5% at 6 months, composed of 2 alpha and 2 gamma chains (α2γ2).
Hereditary Hb Disorders (Haemoglobinopathies)
- Qualitative (Structural defect) (Variant Hb)
This is a structural change in the globin chain (sickle cell anemia).
- Quantitative (Synthesis defect) (Thalassemias)
The synthesis rate of one or more globulin chains is absent or reduced.
- HPFH (Hereditary Persistence of Fetal Hb)
This is because HbF to HbA cannot be switched normally
Sickle cell anemia
- It is a qualitative problem in the B globin chain
- Sickle cell disease is a type of hemoglobin disorders in which a sickle β globin gene is inherited as an autosomal recessive disease.
- Sickle cell anemia is a β-chain qualitative disease in which glutamic acid is replaced by valine at position 6 of the β-chain.
Who is at risk of Sickle cell anemia?
Most common in people whose families come from:
▪ Africa.
▪ South or Central America (especially Panama).
▪ Caribbean islands
▪ Mediterranean countries (e.g. Turkey, Greece, and Italy).
▪ India
▪ Saudi Arabia.
Change in properties of Sickle Cell RBC
▪ Deoxygenation cause hydrophobic interaction between adjacent Hb S molecules.
▪ Distortion of RBC into sickle form cells.
▪ Rapid hemolysis.
▪ Decreased elasticity of cell wall of RBC.
▪ Decreased life span 10 – 20 days.
▪ Clogging of RBC in microcirculation.
Normal Vs. Sickle Red Cells.
Normal Sickle
● Disc-Shaped ● Sickle-Shaped
● Deformable ● Rigid
● The lifespan of 120 days ● Can live for 20 days or Less
Sickle Cell Anemia vs. Sickle Cell Trait
- People with sickle cell anemia are born. This means the life-long condition of inheritance.
- They inherited two copies of the sickle cell gene, one for each parent.
- There is a difference between sickle cell trait and sickle cell anemia.
People with sickle cell traits do not have this condition, but they have one of the genes that cause it.
- People with sickle cell anemia and sickle cell traits can inherit it when they have children.
Inheritance of Sickle Cell Anemia
- If one parent has sickle cell anemia (HbSS) and the other parent is completely normal (HbAA), all children will have sickle cell anemia.
None will have sickle cell anemia.
Parents with sickle cell anemia (HbSS) can only pass the sickle hemoglobin gene to each of their children.
- If both parents have sickle cell anemia (HbAS), there is a quarter (25%) chance that any given child will have sickle cell anemia at birth.
There is also a one in four chance that any given child will be completely normal.
The probability that any given child has sickle cell characteristics is one in two (50%).
- The probability that any given child has sickle cell characteristics is one in two (50%).
(50%) the chance that any given child could be born with sickle cell anemia or normal according to the other parent.
Sickle Cell Disease
- SCD Genotype
Genotype Genotype prevalence
Sickle cell anemia (SS) 65%
Sickle Hb C disease (SC) 25%
Sickle S beta plus 8%
(Sβ+ thalassemia)
Sickle Beta zero 2%
(Sβ° thalassemia)
- Pathophysiology:
▪ HbS is insoluble and will form crystals when exposed to low oxygen pressure.
▪ This deoxygenated HbS polymerize into long fibers.
▪ The condition is reversible first upon reoxygenation.
Repeated or prolonged sickling irreversible sickling then damage of RBCs.
▪ Sickle cells are difficult to move in the blood. They are stiff and sticky, tend to clump and get stuck in blood vessels.
▪ The sickle cell clumps block the blood flow in the blood vessels leading to the limbs and organs.
Blocked blood vessels can cause pain, severe infections, and organ damage.
▪ The red cells sickle and may block different areas in the microcirculation causing various organs to infarct
Hemolysis and Vaso-occlusion
Hemolysis:
- Anemia in SCD is caused by red blood cell destruction or hemolysis, and the degree of anemia varies greatly between patients.
- The red blood cells produced by the bone marrow increased sharply but could not keep up with the pace of destruction.
Vaso-occlusion:
- This happens when rigid sickle cells cannot move through small blood vessels, thereby preventing local blood flow to the microscopic area of the tissue.
- These events will produce tissue hypoxia after being amplified many times.
Resulting in pain and often organ damage.
Clinical picture:
▪ Presented after 6 months when β chain replaces γ chain through normal switch mechanism (no manifestation in newborn) due to high HbF which has high O2 affinity which protect cells from sickling.
▪ Anemia manifestations the symptoms of anemia are usually mild concerning the severity of the anemia because HbS gives up oxygen to the tissues relatively easily compared with HbA.
▪ Severe hemolytic anemia
▪ Severe crisis: vaso-occlusive (pain), hemolytic, or aplastic.
▪ Infection, dehydration, low oxygen content in high altitude areas, stagnant blood circulation, and cold can exacerbate the vaso-occlusive crisis
Acute exacerbation of anemia occurs with:
▪ Acute painful episodes (vaso-occlusive crisis)
- Hand-Foot Syndrome (Dactylitis): Common in children. Infarction of phalanges leads to a shortening of fingers and toes.
- Pain in the limbs, back, and abdomen: Common in adults and older children.
- Auto splenectomy:
In infancy: the spleen is enlarged.
In childhood: fibrosis and auto splenectomy.
▪ Aplastic Crisis:
- Due to parvovirus B19 infection, it is characterized by reticulocytopenia lasting 7-10 days, followed by fever and UTI or GIT infection.
▪ Splenic Sequestration: (Hypovolemic chock)
- A large amount of blood collects in the spleen.
- It usually occurs in young children before splenic fibrosis.
- The attack may be caused by a viral disease.
- Sharp ↓ Hgb with reticulocytosis.
▪ Infection:
- The most common cause of death in children, occurs due to early loss of spleen function.
- The commonest pathogens are encapsulated organisms (such as Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitides meningitis).
- Common infections are pneumonia, meningitis, osteomyelitis, respiratory infections, and urinary tract infections.
- Lifelong penicillin prophylaxis is recommended.
▪ Chest Complication:
- chest complication consider is the most common cause of death in elderly patients.
- Acute chest syndrome (vaso-occlusion and infection).
- Chronic pulmonary complications (COPD)
▪ Renal Complication:
- Chronic renal insufficiency (vaso-occlusion).
▪ Neurological Complication:
- Stroke (infarction or hemorrhage).
▪ Pigmented gall stones.
▪ Chronic leg ulcers.
The complication of Sickle Cell Anemia
▪ Hand-Food Syndrome ▪ Priapism
▪ Splenic Crisis ▪ Gallstone
▪ Infections ▪ Ulcers on the legs
▪ Acute Chest Syndrome ▪ Pulmonary Arterial
Hypertension
▪ Delayed growth and ▪ Multiple Organ Failure
puberty in children
▪ Stroke ▪ Eye problem
Laboratory Diagnosis
1. Features of Anemia:
- Low RBCs count, and Hct.
- Normocytic Normochromic Anemia
- If iron deficiency anemia is present at the same time, MCV decreases.
- WBCs and Platelets: Increased because of hemolysis, decreased in aplastic crisis, Normal in between attacks.
Blood Film:
- shows Sickled cells, target cells, and Howell jolly bodies (auto splenectomy).
2. Features of Hemolysis:
- Increased level of LDH, Indirect bilirubin, Urinary Urobilinogen, and Fecal Stercobilinogen.
- Low Haptoglobin and hemopexin.
- Features of RBCs production: Reticulocytosis
3. HbS Solubility test: Positive.
4. Sickling test: Sickle cells seen (Na2HPO4).
5. Hb Electrophoresis:
- In SCA, HbA=0 HbS=80%-95% HbF=1%-15%
- In Sickle cell trait, HbA˂ 50% HbS˃50% HbF=1%-5%
6. Prenatal screening test: Suspicious families need PCR.
Specific tests:
1- Sickle cell test:
- When the RBC containing HbS is deoxygenated, hemoglobin crystals form a sickle shape.
- Deoxygenation is done by 2% sodium metabisulfite solution when sickle hemoglobin is present, cells begin to deform within 10 minutes and examined under the microscope.
2- Solubility test for hemoglobin S:
- Whole blood is used
- TWO steps:
1- lysis of RBCs.
2- Addition of deoxygenated agent.
- Add potassium dihydrogen phosphate solution to dissolve RBC, add sodium hyposulfite to reduce hemoglobin.
- A turbid suspension indicates a positive test
3-Hemoglobin electrophoresis & HPLC:
For detection of hemoglobin S
Hb Electrophoresis
Detection of the carrier state:
- DNA study by PCR.
- Prenatal diagnosis can be confirmed by CVS (chorionic villus sampling) or amniocentesis.
Hemoglobin electrophoresis
- The main test to distinguish between thalassemia and hemoglobinopathies
- Types
Cellulose acetate: Alkaline pH
Citrate agar: Acid pH
- Hemoglobin electrophoresis is a method used to separate, detect, and identify the type of hemoglobin (normal or abnormal).
Principle:
- It is the directional migration of charged particles in an electric field at pH 8.4 (alkaline) and pH 6.2 (acid).
- In an alkaline solution (pH > 8) hemoglobins have a negative charge and move towards the anode with mobility proportional to their net negative charge.
▪ Specimen: EDTA blood. Followed by the preparation of hemolysate.
▪ Electrophoresis can perform on cellulose acetate with pH 8.4-8.8 using tris EDTA borate buffer.
▪ Should include the Patient and control in the test.
▪ Scanning can quantify the hemoglobin present, and bands can be seen by staining.
▪ After the electrophoresis is completed, the membrane is stained, and the hemoglobin is identified by its relative position.
▪ Scan the percentage of hemoglobin in the paper or gel
Treatment:
- Lifelong preventive penicillin 250mg bd PO can replace folic acid.
- Pneumovax II vaccination advisable.
- Management during pregnancy and anesthesia
- Early and effective treatment of crises.
- Consider exchange blood transfusion (if there are neurological symptoms, stroke, or visceral damage).
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