Published on September 26, 2018
1. Sickle Cell Anemia (OMIM#603903) 9/26/2018 1 The frequency (f) of sickle cell trait (hemoglobin SA) among emiratis is 1.5% (0.015) and the frequency of sickle cell anemia (f2) is 0.000225 (0.015 x 0.015) or 2.25 per 10,000). Al Hosani H, Salah M, Osman HM, Farag HM, Anvery SM. Incidence of haemoglobinopathies detected through neonatal screening in the United Arab Emirates. East Mediterr Health J. 2005;11:300-7. Abdul-Kader Souid https://www.omim.org Sickle cell anemia results from mutant beta globin gene (HBB; OMIM#141900, AR, c.20A>T, p.Glu6Val, p.E6V, β6Glu-Val / β6Glu-Val) causing sickling of hemoglobin. Fetal hemoglobin is a key modulator of the severity of sickle cell anemia. Hemoglobin analysis http://www.uniprot.org/uniprot/P68871 Hydroxyurea is the Principle Treatment of Sickle Cell Disease.
2. https://www.omim.org OMIM
3. • Hallmarks of the disease is chronic hemolytic anemia, pain (venoocclusive episodes), infection, and damage to all organs (brain, lungs, bones, heart, eyes, kidneys). Sickle Cell MutationMust know Exposed hydrophobic valines at position six of the β-globin form aggregates (fibrous precipitates).
4. 9/26/2018 4 Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. 1997;337:762-9. PMID: 9287233.
5. 9/26/2018 5 Sickle Cell Trait, Sickle Cell Anemia, and Sickle Cell Diseases Must know Beta hemoglobinopathy HBB Alleles Globins Symbols Newborn Phenotypes Normal / β6Glu-Val (heterozygous) (2a + 2b) / (2a + 2 bs) AS FAS Sickle cell trait Normal / β6Glu-Lys (heterozygous) (2a + 2b) / (2a + 2 bc) AC FAC C trait Normal / β121Glu-Gln (heterozygous) (2a + 2bs) / (2a + 2 bD) AD FAD D trait Normal / βo (heterozygous) (2a + 2b) Abo FA b-thalassemia trait β6Glu-Val / β6Glu-Val (homozygous) (2a + 2bs) / (2a + 2 bs) SS FS Sickle cell anemia β6Glu-Val / β6Glu-Lys (homozygous) (2a + 2bC) / (2a + 2 bC) CC FC C disease β121Glu-Gln / β121Glu-Gln (homozygous) (2a + 2bD) / (2a + 2 bD) DD FD D disease β6Glu-Val / β121Glu-Gln (double heterozygous) (2a + 2bs) / (2a + 2 bD) SD FSD S/D disease βo / β6Glu-Val (double heterozygous) (2a + 2 bs) S/b0 FS S/b-thalassemia
6. • Father: Hb 157 g/L, MCV 91 fL, hemoglobin A = 52%, S = 43%; sickle cell trait (Hb AS). • Mother: Hb 112 g/L, MCV 63 fL (microcytosis), hemoglobin A = 80% and A2 = 6.5% (elevated); b-thalassemia trait. • Son (5-y-old): Hb 43 g/L (anemia), MCV 69 fL (microcytosis); hemoglobin A = 0, S = 65%, F = 30%, A2 = 5.9%; Sbo-thalassemia. Family Sickle cell allele Normal allele Normal allele bo-thalassemia allele Sickle cell allele bo-thalassemia allele Must know Nucleated red cells (blue arrows), sickled cells (red arrow), & target cells (green arrow, indicative of b-thalassemia)
7. Complications of Sickle Cell Anemia • Chronic hemolytic anemia: Hb 50 to 90 g/L; reticulocyte count 100- 300 x109/L; jaundice; red cell life span ↓from 120 days to 10-30 days. • Venoocclusive episodes: Bouts of pain in the abdominal muscles, bones/joints. • Infection: Blood (pneumococci) infection due to asplenia. – Patients with fever require CBC, reticulocyte count, CXR, blood culture and antibiotics. – Patients with acute chest syndrome require antibiotics that cover mycoplasma and chlamydia (eg, azithromycin). In addition, exchange transfusion is usually necessary. • Strokes: Large vessel (transcranial Doppler) & subtle microvascular (brain MRI) • Proliferative sickle retinopathy (eye examination every 2 y) • Avascular necrosis of the hip pain; • Sickle cell nephropathy (proteinuria; yearly urinalysis) • Gallstones • Bone marrow aplasia following viral infection (e.g., parvovirus B19). 9/26/2018 7 Must know
8. Complications of Sickle Cell Disease • Acute chest syndrome: Cough, dyspnea, fever, hypoxia, pulmonary hypertension. • Splenic sequestration (presents in infants as pallor and left upper quadrant pain; requires blood transfusion) • Dactylitis: Painful swelling in the hands and feet of young infants (predicts severe disease) • Iron overload • Delayed growth and puberty • Priapism (impotence) 8 Must know • Prolonged QTc (38% of 10-24 y patients had prolonged QTc). • Pre-operative complications (transfusion to a hemoglobin of 100 g/L ↓complications). • Cardiac (cardiomegaly, ischemic damages)
9. Large vessel and subtle microvascular strokes • Prevalence of microvascular strokes (silent infarcts) is 10%. • The frontal lobe and areas involved in executive function and complex memory processing are particularly affected. – Abnormalities are common in adolescents and manifest as loss of academic performance in subjects requiring abstract reasoning and combination of abstract concepts (inability to compare and contrast events or explain chemical reactions). • The frequency of large vessel stroke has been reduced because of transfusion after detection of at risk patients with regular screening with transcranial Doppler (TCD) ultrasonography. • Small vessel lesions cannot be detected by TCD; which is not technically possible after 16 y because of skull maturation. 9/26/2018 9 Optional
10. Strong recommendations for patients with sickle cell disease • Hydroxyurea is for infants, children and adults. • Prophylactic penicillin up to 5 y + regular immunizations. • Daily folic acid (1 mg) • Annual transcranial Doppler (TCD) ultrasonography from 2-16 y. – Long-term transfusion to prevent stroke in those with Hb SS or Hb S/bo-thalassemia and transcranial Doppler (TCD) ≥200 cm/s. • Opioids for severe pain due to vasoocclusive episode. • Incentive spirometry in patients hospitalized for a vasoocclusive episode. • Analgesics and physical therapy for treatment of avascular necrosis. • Angiotensin-converting enzyme inhibitor for microalbuminuria. • Referral to specialists for laser photocoagulation for patients with proliferative sickle cell retinopathy. • Assess iron overload to begin iron chelation therapy when indicated. • Echocardiography to evaluate pulmonary hypertension. 10 Must know
11. Hydroxyurea is the Principle Treatment of Sickle Cell Anemia • It exerts its beneficial effects by ↑Hb F, ↓Hb S polymerization, ↓leukocytes and platelets, ↓endothelial cell activation, ↓thrombosis, and ↓vasoconstriction. 9/26/2018 11 Must know • Toxicities of hydroxyurea include neutropenia, which is transient and reversible with holding or dose adjustment. – Periodic (every 1 to 3 month) assessment of CBC is essential. • Malignancy has occurred in some patients taking hydroxyurea, but not at a rate that appears to be significantly increased over that in the general population.
12. Required Reading • https://www.nhlbi.nih.gov/sites/www.nhlbi.nih.gov/files/sickle-cell-disease-report.pdf. • Yawn BP, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312:1033-48. doi: 10.1001/jama.2014.10517. • Al Hosani H, Salah M, Osman HM, Farag HM, Anvery SM. Incidence of hemoglobinopathies detected through neonatal screening in the United Arab Emirates. East Mediterr Health J. 2005;11:300-7. • Pai SY, et al. Transplantation outcomes for severe combined immunodeficiency, 2000- 2009. N Engl J Med. 2014;371:434-46. doi: 10.1056/NEJMoa1401177. • Estcourt LJ, Fortin PM, Hopewell S, Trivella M, Wang WC. Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease. Cochrane Database Syst Rev. 2017 Jan 17;1:CD003146. doi: 10.1002/14651858. • Bourzac K. Gene therapy: Erasing sickle-cell disease. Nature 2017;549:S28-S30. doi: 10.1038/549S28a. PubMed PMID: 28953858. 9/26/2018 12