SICKLE CELL DISEASE

Sickle cell disease (SCD) or Sickle cell anemia (SCA) is the second commonest hemoglobinopathy in India, though more common in African or American blacks.

Epidemiology: In India, SCD is highly prevalent in some aboriginal tribes, e.g.

Genetic defect: SCD is an autosomal recessive defect of the #946;-globin gene located on chromosome 11, characterized by substitution of glutamic acid by valine at the 6^th position, leading to formation of an abnormal hemoglobin (HbS) instead of normal HbA, as follows:

• Homozygous sickle cell disease (SS) with complete replacement HbA by HbS, or

• Heterozygous sickle cell trait (AS) with HbS concentration of 35-45%

Many cases have mixed hemoglobinopathies, i.e. HbS- thalassemia, HbS-C disease.

Pathogenesis: In normal oxygenated state, HbS functions normally. However in hypoxic states, deoxygenated HbS develops abnormal coupling of globin chains to deform the shape of RBCs into a sickle form. While this sickling is reversible in initial stages, persistent hypoxia leads to irreversible sickling of RBCs, which are then trapped in microvasculature or spleen to produce vaso-occlusive crises and hemolysis, respectively. Sludging of deformed RBCs in small vessels further aggravates hypoxia and sickling.

Thus, three factors are mainly responsible for patho­genesis of SCA—(a) vaso-occlusive events, (b) chronic hemolysis, and (c) local as well as generalized hypoxia due to 'a' and 'b' respectively.

Clinical manifestations of SCA depend on whether the case is homozygous or heterozygous. Presence of high fetal Hb (which does not have #946;-chains) prevents manifestations of SCD during first few months of life.

Homozygous sickle cell disease usually manifests after

4- 6 months of age with:

• Chronic hemolytic anemia with moderate pallor and signs of chronic hypoxia, e.g. exertional dys­pnea and growth failure. Signs of hemodynamic decompensation, e.g. CCF and cardiomegaly may deve­lop in severe cases, while older children may also develop gall stones due to excess bilirubin production.

• Moderate splenomegaly with/without hypersplenism. Splenomegaly frequently regresses after 5-6 years due to repeated splenic infarcts (autosplenectomy). Altered splenic functions predispose these children for serious infections, e.g. sepsis, meningitis and osteomyelitis by capsular organisms, e.g. pneumococci, H. influenzae and Salmonella.

• Signs of microvascular ischemia and recurrent infarcts, e.g. clubbing, nephropathy, chronic leg ulcers, recurrent epistaxis, etc. Sickle cell nephropathy is characterized by recurrent hematuria and hyposthenuria, i.e. loss of concentration capacity due to recurrent medullary infarcts.

• Acute crises episodes, which may be spontaneous or develop after exposure to hypoxic events, e.g. fever,

infections, dehydration, acidosis and high altitudes. Four main types of crises, seen in SCD are as follows:

- Vaso-occlusive crises are most common and usually spontaneous with wide clinical spectrum, e.g. sudden painful swelling of hands and feet due to ischemic necrosis of small bones (Hand­foot syndrome), acute abdominal pain (mesenteric ischemia), cerebrovascular strokes, acute chest syndrome (pulmonary embolism), sudden blindness (retinal vein occlusion) and priapism (venous obstruction in corpora cavernosa).

- Sequestration crises with massive splenomegaly and circulatory collapse due to sudden pooling of blood in the spleen, are more common in younger children, usually after an acute febrile illness.

- Hyperhemolytic crises with sudden and severe hemolytic episodes are seen in cases with coexisting G6PD deficiency.

- Aplastic crises with sudden bone-marrow depres­sion and pancytopenia are usually associated with parvovirus B₁₉ infections.

Heterozygous sickle cell trait is usually asymptomatic, though mild vaso-occlusive manifestations may develop in severe hypoxic conditions. Identification of these cases by high-risk/family screening is important for genetic counseling.

Mixed hemoglobinopathies usually have milder pre­sentations, except HbS-#946; thalassemia, which is clinically indistinguishable with SS disease.

Laboratory diagnosis depends on:

• Peripheral smear showing characteristic sickled RBCs with poikilocytosis, target cells, nucleated RBCs and Howell-Jolly bodies (signs of splenic dysfunction).

• Sickling test—a simple screening test to demonstrate sickling in suspected cases.

Place two drop of freshly prepared 2% sodium hypochlorite solution (reducing agent) over blood smear and seal it with the wax. Examine this slide after 15-20 minutes (for early sickling) and again after 1-2 hours (for late sickling). Early sickling indicates sickle cell disease. Late sicking is also positive in sickle cell trait.

• Hb electrophoresis is confirmatory and helps to differentiate disease (HbS gt;80-90%) from carrier state (HbS ~30-40%). It also helps to detect mixed hemoglobinopathies (Table 19.13).

Other investigations may reveal non-specific evidences of hemolytic disease, e.g. moderate anemia, high reticulocyte count, hypercellular marrow with erythroid hyperplasia and mild hyperbilirubinemia.

Prenatal diagnosis is possible at 12 weeks, by DNA-PCR studies on fetal fibroblasts for genetic defect.

Management of these cases include:

• Prevention and early treatment Ofprecipitating events, e.g. fever, infections, dehydration, acidosis and hypoxia due to any cause including high altitude.

TABLE 19.13: Hb electrophoresis in sickle cell syndromes

All values in % of total Hb

• Supportive treatment in acute crises, with fluids/ electro­lyte correction, alkali therapy to prevent acidosis and blood transfusions.

• Treatment of chronic anemia: Repeated transfusions are generally not required, except in severe cases or during crises. However, life-long folic acid supplements are necessary in all cases due to increased erythropoietic activity.

• Prevention of infections (due to splenic dysfunction) with pneumococcal, meningococcal and H. influenza B vaccines. All cases are also advised oral penicillin prophylaxis from 3 months to 5 years to prevent these infections.

• Hydroxyurea-a myelosuppressive agent to stimulate HbF production, is known to reduce hospitalizations due to vaso-occlusive episodes and need for blood transfusions by ~50%. It is relatively safe and well tolerated in children gt;2 years of age, except potential but reversible risk of bone marrow suppression. Typical starting dose is 15-20 mg/kg/day OD, which may be increased by 5 mg/kg every 8 weeks to a maximum of 35 mg/kg/day. It should be temporarily discontinued if absolute neutrophil count falls lt;2,000/ mm³ or platelets fall lt;80,000/ mm³.

Newer therapeutic options in selected cases include

(a) other HbF stimulating agents, e.g. butyrate and

5- azacytidine, (b) HbS reducing agents, e.g. DDAVP and calcium channel blockers, (c) Membrane stabilizing agents, e.g. zinc, (d) Hb solubility increasing agents, e.g. urea, cynates, etc.

Some other drugs have also been recently approved to prevent SCD crises in older children including, L-Gutamine to reduce RBC adhesions to endothelium (PO 5-15 gm BD gt;5 years); Voxelotor to inhibit HbS polymerization (PO 1500 mg/day gt;12 years); and Crizanlizumab to prevent recurrent vaso-occlusive crises in cases gt;16 years.

Hematopoietic stem cell transplant must be considered in cases refractory to medical treatment.

Prevention: Genetic counseling, carrier detection and prenatal diagnosis is essential in all cases to prevent further morbidity in family.

19.5.5