Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 13-13: Sickle Cell Anemia & Related Syndromes + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Irreversibly sickled cells on peripheral blood smear Positive family history and lifelong personal history of hemolytic anemia Recurrent pain episodes Hemoglobin S is the major hemoglobin seen on electrophoresis +++ General Considerations ++ Autosomal recessive disorder in which abnormal hemoglobin leads to chronic hemolytic anemia with numerous clinical consequences Single DNA base change leads to amino acid substitution of valine for glutamate in the sixth position on beta-globin chain Sickling is caused by increased red blood cell (RBC) hemoglobin S concentration, RBC dehydration, acidosis, and hypoxemia Acute painful episodes as a result of vaso-occlusion by sickled RBCs occur spontaneously or they are provoked by infection, dehydration, or hypoxia Sickling is retarded markedly by hemoglobin F; high hemoglobin F levels are associated with more benign course Patients with S-beta+-thalassemia and SS alpha-thalassemia also have a benign clinical course Patients with heterozygous genotype (hemoglobin AS) have sickle cell trait +++ Demographics ++ BetaS gene is carried in 8% of American blacks Sickle cell anemia occurs in 1 birth in 400 in American blacks Onset during first year of life, when hemoglobin F levels fall + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Chronic hemolytic anemia produces Jaundice Pigment (calcium bilirubinate) gallstones Splenomegaly (early in life) Poorly healing skin ulcers over the lower tibia Anemia may be life-threatening during Hemolytic or aplastic crises Aplastic crises are generally associated with viral or other infection caused by Immunoincompetence from hyposplenism or Folic acid deficiency causing reduced erythropoiesis Hemolytic crises result from splenic sequestration of sickled cells (primarily in childhood, before spleen has infarcted) or with coexistent disorders such as glucose-6-phosphate dehydrogenase deficiency Aplastic crises occur when bone marrow compensation is reduced by infection or folate deficiency Acute painful episodes Include spine long appendicular bones Can last hours to days and produce low-grade fever Acute vaso-occlusion may cause priapism and strokes Repeated vaso-occlusion affects Heart (cardiomegaly, hyperdynamic precordium, systolic murmurs) Lungs Liver Bone (ischemic necrosis, staphylococcal or salmonella osteomyelitis) Spleen (infarction, asplenia) Kidney (infarction of renal medullary papillae, renal tubular concentrating defects, and gross hematuria) Acute chest syndrome Characterized by acute chest pain, hypoxemia and pulmonary infiltrates on a chest radiograph Must be distinguished from an infectious pneumonia Pulmonary hypertension is associated with decreased survival Increased susceptibility to infection occurs as a result of hyposplenism and complement defects Sickle cell trait Asymptomatic most often Acute vaso-occlusion occurs only under extreme conditions Gross hematuria or renal tubular defect causing inability to concentrate urine may occur +++ Differential Diagnosis ++ Other sickle cell syndromes Sickle cell trait Sickle thalassemia Hemoglobin SC disease Osteomyelitis Hematuria from other cause Acute rheumatic fever + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ Hematocrit usually 20–30% Peripheral blood smear: sickled cells comprise 5–50% of RBCs; reticulocytosis (10–25%); nucleated RBCs; Howell-Jolly bodies and target cells White blood cell count characteristically elevated to 12,000–15,000/mcL; reactive thrombocytosis may occur Elevated serum indirect bilirubin Screening test for sickle hemoglobin positive Hemoglobin electrophoresis confirms diagnosis Sickle cell anemia (homozygous S) Hemoglobin S usually comprises 85–98% of hemoglobin and no hemoglobin A is present Hemoglobin F levels sometimes increased Sickle cell trait Complete blood count and peripheral blood smear normal Hemoglobin electrophoresis shows that hemoglobin S comprises ~40% of hemoglobin + Treatment Download Section PDF Listen +++ +++ General Measures ++ Supportive care is mainstay of treatment Prenatal diagnosis and genetic counseling should be made available to those with personal or family history Omega-3 (n-3) fatty acid supplementation may reduce vaso-occlusive episodes and transfusion needs L-glutamine has been shown to favorably modulate sickle pain crises and acute chest syndrome Sickle cell trait No treatment necessary Genetic counseling appropriate Acute painful episodes Identify precipitating factors Treat infections if present Maintain good hydration Provide adequate analgesics Administer oxygen if hypoxic +++ Medications ++ Folic acid, 1 mg orally once daily Hydroxyurea, 500–750 mg orally once daily Increases hemoglobin F levels Reduces frequency of painful crises in patients whose quality of life is disrupted by frequent vaso-occlusive pain crises (3 or more per year) Concern exists about potential for secondary malignancies Long-term follow-up demonstrates improved overall survival with little evidence for secondary malignancy Crizanlizumab-tmca (a monoclonal antibody) Reduces vaso-occlusive episodes by one-half Blocks P-selectin on activated endothelial cells Disrupts the adverse interactions of platelets, red blood cells, and leukocytes with the endothelial wall Angiotensin-converting enzyme inhibitors are recommended in those with microalbuminuria +++ Therapeutic Procedures ++ Exchange transfusions are indicated for the treatment of severe or intractable acute vaso-occlusive crises, acute chest syndrome, priapism, and stroke Long-term transfusion therapy has been shown to be effective in reducing the risk of recurrent stroke in children Phenotypically-matched transfused red blood cells are recommended to reduce the risk of red blood cell alloimmunization Iron chelation is needed for those on chronic transfusion therapy Transfusions given for aplastic or hemolytic crises Exchange transfusion primarily indicated for treatment of severe acute vaso-occlusive crises, intractable pain crises, acute chest syndrome, priapism, and stroke Long-term transfusion therapy shown to reduce risk of recurrent stroke in children Iron chelation is needed for those patients receiving long-term transfusion therapy When allogeneic hematopoietic stem cell transplantation is performed before onset of significant end-organ damage, it can cure more than 80% of children with sickle cell anemia who have suitable HLA-matched donors + Outcome Download Section PDF Listen +++ +++ Follow-Up ++ Annual transcranial ultrasound Indicated for children with SS who are aged 2–16 years If the Doppler velocity is abnormal (200 cm/s or greater), the clinician should strongly consider beginning transfusions to prevent stroke +++ Prevention ++ Pneumococcal vaccination reduces incidence of infections +++ Complications ++ Sickle cell anemia becomes a chronic multisystem disease, with death from organ failure Acute chest syndrome +++ Prognosis ++ With improved supportive care, average life expectancy is between ages 40 and 50 +++ When to Refer ++ Patients should have their care coordinated with a hematologist and should be referred to a Comprehensive Sickle Cell Center if one is available +++ When to Admit ++ Patients should be admitted for management of acute chest syndrome or for painful episodes that do not respond to outpatient intervention + References Download Section PDF Listen +++ + +Bauer DE et al. Curative approaches for sickle cell disease: a review of allogeneic and autologous strategies. Blood Cells Mol Dis. 2017 Sep;67:155–68. [PubMed: 28893518] + +Kutlar A et al. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: a SUSTAIN study analysis. Am J Hematol. 2019 Jan;94(1):55–61. [PubMed: 30295335] + +Niihara Y et al. A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med. 2018 Jul 19;379(3):226–35. [PubMed: 30021096] + +Rees DC et al. How I manage red cell transfusions in patients with sickle cell disease. Br J Haematol. 2018 Feb;180(4):607–17. [PubMed: 29377071] + +Thein SL et al. How I treat the older adult with sickle cell disease. Blood. 2018 Oct 25;132(17):1750–60. [PubMed: 30206116]