Speaker: Dr JS Arora, June 26, 2022, Sunday 

• Sickle cell disease is a disease of abnormal sickle hemoglobin (HbS). The genetic defect is substitution of valine for glutamic acid at 6^th position of the beta globin chain. When deoxygenation occurs, the red cells undergo sickling due to polymerization of HbS.
• After recurrent episodes of sickling, membrane damage occurs and cells are unable to resume their biconcave shape upon re-oxygenation. The deformed sickle cells adhere to endothelium and macrophages and induce hemolysis.
• Sickle red cells are sickle shape; they are rigid and have a sticky surface. Their life span is 20 days or less, whereas the life span of a normal red cells is 120 days.
• Mixture of HbS in a reducing solution (sodium metabisulfite) gives a turbid appearance due to precipitation of HbS. Normal Hb gives a clear solution.
• If A>S, it is sickle cell trait/sickle alpha thalassemia; if S, F and no A, then it is sickle cell anemia, sickle beta thalassemia and if S>A and F also present, then it is sickle beta thalassemia.
• Lab parameters: TLC and platelet count are mildly raised, anemia (5-10g); anisopoikilocytosis, sickle cells and target cells on peripheral smear; iron studies show increase serum iron, ferritin and transferrin; increase in urine urobilinogen; reticulocytes 5-20% and low ESR.
• If both parents are sickle cell carriers, then 25% chances of having a normal child; 50% may have sickle trait like parents and 25% may be homozygous with SCD.
• Patients with HbS are relatively protected against falciparum malaria. The sickled red cells with the malarial parasite inside them are sequestered early in spleen, so they don’t give symptoms of malaria.
• Sickle cell disease is more common where malaria is more common – Africa, Middle East and Asian countries. The sickle cell map overlaps the malaria map. 
• Sickle cell disease is considered to be mild in India. It is very severe in Africa and Middle East. Hence, it is not very frequently seen and many cases go undiagnosed.
• It is not very common in north India. It mainly affects tribal communities. The prevalence of carrier state (HbAS) is high up to 40%.
• There is no sickle cell disease in north India and Andaman islands. SCD is less in the state of Bihar, while the prevalence is high in Orissa, MP, Tamil Nadu, Gujarat, Kerala, Rajasthan and Maharashtra.
• Vaso-occlusive crisis results from the sickle red cells obstructing and reducing blood flow to vital organs leading to ischemia, necrosis and pain.
• Red cells containing HbS pass through splenic microcirculation and sickling occurs because of low oxygen tension. When cells pass through circulation with good oxygen tension in other organs, desickling occurs. The various cycles of sickling and desickling lead to irreversible sickling.
• The amount of HbS and interaction with other Hb chains in the cells influences the rate and degree of sickling. In the heterozygous state, sickling occurs only with severe hypoxia; hence, these individuals must be careful about travelling to the hills. The homozygous state is full blown sickle cell anemia. 
• The fetal hemoglobin inhibits polymerization of Hbs and so newborns do not manifest the disease until the age of 5-6 months.
• The rate of HbS polymerization is strongly dependent upon Hb concentration per cell (MCHC); intracellular dehydration increases MCHC and sickling as a result.
• Decrease in pH reduces oxygen affinity of Hb leading to increase in sickling.
• The rate and degree of sickling is also influenced by the length of time the red cells are exposed to low oxygen tension. Sickling of red cells is confined to microvascular beds with sluggish blood flow such as in the spleen and bone marrow. Inflammation and increase in red cell adhesion prolongs the red cell transit time leading to increase in sickling.
• Sickle cell trait (heterozygous AS) is mild and may remain undetected. Sickle cell anemia (homozygous SS) manifests at 3-12 months of age with splenomegaly, growth retardation, hand and foot syndrome, leg ulcers, abdominal pain, infections, gallstones, cardiovascular symptoms etc. in double heterozygous cases, the clinical features of SCD depends upon the combination of HbS with b/C/D/E/Q.
• In SCD/homozygous, Hb is 5-7 gm, sickling test is positive in 30 minutes, HbS is 70-90%, HbF is 10-30%, pallor is more severe and splenomegaly and hand foot disease is more common. Vaso-occlusion also occurs. Reticulocytes are increased.
• In SC trait/heterozygous, Hb I 10-13 gm, sickling test becomes positive in 4 hours. HbS is 25-40%, HbF is less than one percent, HbA is 60-75% (it is absent in homozygous). Jaundice, splenomegaly/hand foot disease/ vaso-occlusion are not seen. Reticulocytes are normal.
• Sickle cell crisis is an acute illness characterized by exacerbation of clinical features of SCD such as pain, anemia or jaundice. The polymerization of deoxygenated HbS molecule occurs, which is unstable and damages the red cells. The polymerized red cells occlude the blood flow by interacting with white cells and platelets.
• Hemolysis and vaso-occlusion are two major features of SCD. The anemia in SCD is caused by hemolysis of red cells. Though the production of red cells increases dramatically in the bone marrow, it is unable to keep pace with the destruction.
• Vaso-occlusion is initiated by rigid and abnormally shaped sickled red cells, which adhere to the endothelium. The activation of WBCs, RBS and the endothelial surface enhances the vaso-occlusive crisis. This results in tissue damage, hypoxia, necrosis and organ dysfunction.
• The acute manifestations include bacterial sepsis, meningitis, splenic sequestration, aplastic crisis, acute chest syndrome, stroke, hematuria. Among the chronic manifestations are anemia, jaundice, splenomegaly followed by functional asplenia, cardiomegaly, restrictive lung disease, pulmonary HT, hypoesthenuria.
• The challenges of vaso-occlusive crisis include hand and foot syndrome, bone and joint crisis, stroke, acute chest syndrome, hematologic crisis (sudden severe anemia), aplastic crisis, splenic sequestration, hemolysis, megaloblastosis and infections like pneumonia, meningitis, influenza etc.
• The triggers of SCD crisis are infection, extensive trauma, hypoxia, exposure to cold, dehydration, physical exertion, acidosis, psychological stress and malaria.
• The presentations of acute ischemic (infarctive) damage include pain episodes, stroke, priapism, acute chest syndrome, splenic infarction and infection due to functional asplenia.
• SCD involves almost every organ in the body. There is progressive dysfunction of lungs leading to pulmonary HT, hypoestheuria (low specific gravity urine) – vaso-occlusion of blood vessels in renal medulla and renal papillary necrosis, gall bladder (cholelithiasis), eyes (proliferative retinopathy, hemorrhage, damage to macular leading to blindness) and joints (hip and shoulder joints mainly, but occasionally knees and ankle joints also). Hip necrosis is very common in SCD.
• Clinical markers of phenotypic heterogeneity include dactylitis, pain episodes, stroke, acute chest syndrome, cholelithiasis, pulmonary HT, priapism, osteonecrosis and proliferative retinopathy.
• Lab markers of phenotypic heterogeneity: Hb level at steady state, high HbF (less sickling, longer cell survival and less anemia), LDH directly correlates with pulmonary HT. Free Hb in circulation, which is due to red cell hemolysis, it reduces NO and decreases the ability to vasodilate leading to pulmonary HT.
• Brain MRI and MRA should be done from 2 years of age.
• TCD or transcranial Doppler should be done from 2 years of age. If it is less than 170, it is normal. If 170-200, it is borderline; if >200, it is severe.
• The common variants of SCD are SCD-SS, SCD-SC, SCD-Sb^o thal, SCD-Sb⁺ thal and SCD-S(db^o) thal. Alpha-thalassemia may be inherited independently of the type of SCD and can influence the clinical course.
• HbSC is more severe than sickle beta thalassemia. Beta thalassemia with D is not severe; sickle cell with D is very severe.
• Risk factors for severity are dactylitis (if dactylitis develops within one year of age, severe disease by 10 years), WBC count (12-24 months very high WBC neutrophils, more severe disease by 10 years) and Hb level (if <7g/dL in second year of life, more severe).
• Early dactylitis plus severe anemia, severity is ++++, severe anemia but no dactylitis +++, early dactylitis but no severe anemia ++ and no early dactylitis or severe anemia +.
• Anemia results in higher rate of mortality in children, leg ulcers, stroke, silent infarct and small for gestational age babies. Preoperative transfusions lower the rate of SCD related postop complications.
• To prevent the crisis, avoid infection, dehydration, acidosis, hypoxemia (pO2 <75), exposure to cold, exhaustion and high altitude. Pneumonia/H influenza/hepatitis B vaccination, penicillin prophylaxis, folate supplementation, analgesics (paracetamol), avoid weight bearing in early phases of bone necrosis, splenectomy.
• Management involves making the patient comfortable with effective analgesia, oxygen is hypoxia, optimal oral rehydration, dextrose/dextrose saline, antibiotics, hydroxyurea and blood transfusion if signs of anemia, absolute retic count <100x10⁹ and fall in Hb is >2 g/dL.
• Pneumonia vaccine is given repeatedly every 3 years.
• Hydroxyurea reduces hemolysis and relieves symptoms. Strict monitoring with CBC is recommended as it may cause cytopenia. If TLC <3000 or neutrophils <1000 or platelets <1lakh, then stop hydroxyurea for a short term and restart again in low dose.
• Treatment is very individualized.
• Treatment of leg ulcers includes bed rest, elevation of affected extremities, wet to dry dressing, systemic antibiotics, Unna boots (low compression bandage containing zinc, gelatin, glycerin and water), blood transfusion to bring HbS to <40%, skin grafting and zinc.
• Routine blood transfusions are not required. Challenges of blood transfusions are viral infections, alloimmunization and hemosiderosis.
• Indications for chronic transfusion are prevention of recurrent stroke, primary stroke prevention (TCD >200), recurrent severe acute chest syndrome, chronic hypoxic lung disease, chronic debilitating pain episodes, severe anemia of renal failure and chronic heart failure. Additionally, blood transfusions decrease hospitalization, pain episodes, infections and improve growth and well-being.
• Glutamine has been uses as treatment for SCD. It reduces oxidant damage to red cells by improving the redox potential of NAD coenzyme which is the primary regulator of oxidation. Glutamine reduces frequency of sickle cell crisis by 25% and hospitalizations by 33%. The cumulative hospital days are also reduced by 41% and the incidence of acute chest syndrome is reduced by more than 60%.
• P-selectin is upregulated and overexpressed in the chronic proinflammatory state in SCD. Blocking the function of P-selectin may prevent vaso-occlusion and improve blood flow and may avert acute vaso-occlusive crisis in patients with SCD. The humanized monoclonal antibody – crezanlizumab – binds P-selectin with high affinity and specificity blocking its ability to bind to its receptors.
• Two sicklers do not behave the same even if the genotype is same. The multigenetic and environmental factors decide the severity.
• SCD is preventable.
• Avoid cold exposure or extremes of temperature. Adequate hydration is very important. Avoid physical exertion, penicillin prophylaxis and patient education.
• If the child is not growing well, has repeated episodes of pain.

Excerpts from presentation by Dr JS Arora