Sickle cell disease | Pathophysiology and Treatment

Sickle cell disease | Pathophysiology and Treatment

Sickle cell disease (SCD) is a chronic hemolytic anemia resulting from a point mutation in the β globin gene (Hb S). It is an autosomal recessive disease. SCD is used to describe all those condition in which sickling of RBCs occurs.

Sickle cell disease | Pathophysiology and Treatment


Sickle cell disease is a common disorder of people from African descent; however, it is also seen in people of Mediterranean, South and Central American and East Indian ancestry. Approximately 8% of African – Americans have sickle cell trait (a heterozygous form of Hb S), whereas approximately 1 in 600 are affected by sickle cell disease.


(The genetic defect in sickle cell disease is a point mutation in codon 6 of the β – globin gene (GTG for GAG) that results in the formation of hemoglobin S (Hb S). The mutation results in the substitution of a hydrophobic valine residue for a hydrophilic glutamic acid residue. Homozygosity for the Hb S mutation is the most common form of SCD disease and is also known as sickle cell anemia.

However, SCD can also be caused by compound heterozygosity for Hb S and either a β -thalassemia mutation or one of several β – globin variants (e.g., Hb C, Hb Lepore and Hb E) that support Hb S polymerization.


Hb S polymerizes on deoxygenation. Polymerization of Hb S occurs in microvascular beds, where hypoxia and acidosis induce Hb to release oxygen, increasing the intracellular concentration of the deoxygenated form of Hb S. Polymerization of Hb S induces deformation and rigidity of the RBC membrane and impairs the transit of SCD RBCs through the microvasculature.

The polymerization of Hb S is reversible after return of the RBCs to the arterial circulation. After multiple cycles of Hb S polymerization, RBCs become irreversibly damaged and are trapped in microvascular beds, where they are lysed (intravascular hemolysis).

Chronic hemolysis in SCD leads to the release of free Hb. Free Hb produces reactive oxygen species and is a potent scavenger of nitric oxide. Nitric oxide is responsible for vasodilation and inhibition of adhesion molecule expression. Decreased availability of nitric oxide is responsible for endothelial dysfunction and vasoconstriction, one of the causes of pulmonary and systemic hypertension in these patients.

In patients with sickle cell trait (genotype AS), the concentration of Hb S (usually approximately 40% of total Hb) falls below the threshold necessary to initiate pathologic polymerization in vivo . These patients are hematologically normal, except at high altitudes or after extreme physical exercise.

Clinical presentation

Sickle cell disease is characterized by periodic episodes of acute vascular occlusion (painful crisis) that have their onset in the first or second year of life. Painful crisis may be precipitated by events that impair tissue oxygenation, perfusion, or acid – base status. Infection, especially pneumonia, and systemic dehydration are common precipitation events.

Vascular occlusion may lead to severe impairment of organ perfusion, leading to bone necrosis, acute chest syndrome; defined as a new infiltrate on chest radiograph associated with fever or respiratory symptoms, stroke, and skin ulcers.

Acute chest syndrome and pulmonary hypertension are the most common causes of death in SCD patients. In patients with the SS genotype, recurrent splenic infarction results in complete splenic involution at a young age, also known as autosplenectomy.

However, failure of the spleen to infarct may result in a life -threatening acute complication, i.e., splenic sequestration crisis, which is generally seen only before 5 years of age. Evidence of impaired or absent splenic function is documented on the peripheral blood smear by the appearance of Howell – Jolly bodies. These are round, purple staining nuclear fragments of DNA in the red blood cell which are usually removed by the spleen.

Patients with SS disease are especially susceptible to infection with encapsulated bacteria due to “autosplenectomy”, hence pneumococcal vaccination and antibiotic prophylaxis are standard components of treatment of children. Patients with SC and HbS/ β – thalassemia genotypes have a milder form of sickle cell disease than SS patients.

In HbS/ β – thalassemia this occurs because the net reduction in intracellular Hb concentration that accompanies thalassemia trait also reduces Hb S concentrations. Painful crisis is generally less frequent, though it may be severe in some individuals.

Autosplenectomy is less likely to occur in these two genotypes. Thus, patients with SC and HbS/ β – thalassemia are more prone to splenic sequestration crisis compared to patients with SCD. Patients with SC disease have a significant increased risk for retinal vascular damage (retinopathy), which may lead to blindness and aseptic necrosis of head of femur and humerus.

Treatment of sickle cell diseas

Treatment for patients with sickle cell disease is supportive. Hydration and pain medication are used to treat acute painful crisis. Strokes can be prevented in SCD patients by exchange RBC transfusion. The aim is to decrease the Hb S concentration to 30%.


Chronic RBC transfusion is also recommended for children at high risk for stroke as defined by transcranial Doppler ultrasound. In young individuals with severe clinical diseases and a matched sibling donor, allogeneic hematopoietic cell transplantation can be curative.

Because increased levels of Hb F inhibit Hb S polymerization, medications that increase γ – globin synthesis may be useful in decreasing the frequency of acute painful crisis. Hydroxyurea, an orally – administered chemotherapeutic agent is approved for the treatment of patients with frequent painful crisis. It has been shown to increase Hb F and may also have a role in generation of nitric oxide which may play a partial role in reversal of pulmonary vasoconstriction, an inhibitor of ribonucleotide reductase, has been shown to increase Hb F levels and is approved for the treatment of patients with frequent painful crisis. Penicillin prophylaxis should be given to the children of SCD to prevent infections.



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