Sickle Cell Anemia

Aka: Sickle Cell Anemia, Sickle Cell Trait, Sickle Cell Disease, Sickle Cell Disorder, Sickle Hemoglobin

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II. Epidemiology

  1. Sickle Cell Disease (Sickle Cell Anemia)
    1. Prevalence (U.S.): 100,000 (1 per 365 to 500 black or african american descent)
    2. From 2500 to 3000 children born per year with Sickle Cell Anemia in the United States
  2. Sickle Cell Trait (A/S) Incidence
    1. Americans of African Descent: 1 in 12
    2. Also seen in Greeks, Italians, Turks, Saudi Arabians, North Africans and hispanic patients

III. Pathophysiology

  1. Normal Hemoglobin A replaced by Hemoglobin S (Hb S)
    1. Deoxygenated Hemoglobin-S assumes a sickle shape
  2. Chromosome 11 Mutation: Substitution of Amino AcidValine for Glutamic Acid
    1. Occurs at the 6th position of the Hemoglobin beta-chain
    2. Results in a "sticky" Hemoglobin that forms a rigid chain when deoxygenated
    3. Sickle cell gene is inherited in Autosomal Recessive pattern
      1. Heterozygotes have Sickle Cell Trait and Homozygotes have Sickle Cell Anemia
  3. Mechanisms of dysfunction
    1. Hypercoagulable
      1. Sickle cells that do not reshape easily when passing through capillaries
        1. Results in decreased Blood Flow and local ischemia
      2. Clotting Cascade activation
      3. Inflammatory cascade activation
      4. Platelet activation
    2. Endothelial dysfunction
      1. Nitric oxide binds the free Hemoglobin in Sickle Cell Anemia
      2. Nitric oxide deficiency results in Vasoconstriction
    3. Decreased Red Blood Cell lifespan
      1. Fragile Red Blood Cells with decreased life span
  4. Sub-Phenotypes
    1. Vaso-occlusive Phenotype
      1. Presents with pain, increased Hemoglobin over baseline
      2. May present with Acute Chest Syndrome
    2. Hemolytic Phenotype
      1. Presents less with pain and more with profound Anemia (Hemoglobin < 6 g/dl)
      2. May present with Pulmonary Hypertension, leg ulcers and sudden death

IV. Types

  1. Sickle Cell Trait (A/S)
    1. No Anemia
    2. Hemoglobin S represents 25-40% of their Hemoglobin
    3. Under normal circumstances, RBCs do not hemolyze
  2. Sickle Cell Anemia (S/S)
    1. Initially infant's RBCs mainly contain fetal Hb F
    2. Within months the abnormal Hb S replaces the Hb F
    3. Similar manifestations with one Hb S and one Thalassemia gene (or other Hemoglobin Abnormality)
  3. Sickle - Beta Thalassemia
    1. One HgbS and one HgbB0 or HgbB+

V. Labs

  1. Newborn Screening identifies Hemoglobinopathies including Sickle Cell Trait and Sickle Cell Anemia
  2. Monitor liver function, Renal Function and blood counts
  3. Serum Creatinine
    1. Frequently lower in Sickle Cell Anemia and may underestimate renal dysfunction
    2. See screening protocol below under prevention
  4. Hemoglobin
    1. Chronic Anemia is due to decreased Red Blood Cell lifespan (10-20 days compared with normal 120 days)
    2. Acutely worsened Anemia has several potential causes (see below)
    3. HgbSS or HgbSb0: 6-8 g/dl Hgb
    4. HgbSB+: 9-12 g/dl Hgb
    5. HgbSC: 10-15 g/dl Hgb

VI. Imaging

  1. Transcranial Doppler Ultrasound (TCD)
    1. Evaluate transcranial blood-flow velocity
    2. Start screening at age 2 years until at least age 16 years old
    3. Abnormal if TCD >200 cm/s (and marginal if 170-199 cm/s )
      1. See Cerebrovascular Accident in Sickle Cell Anemia
      2. Annual CVA risk increases by 10%
      3. Consider for prophylactic transfusions

VII. Management: General

  1. Hematopoietic Cell Transplantation
    1. Curative in 85-90% of cases
    2. Mortality: 5-10% (related to rejection, infection)
  2. Mild Pain
    1. Start with Non-Opioid Analgesics (Acetaminophen, NSAIDS) for mild pain that is not Sickle Cell Crisis
    2. Caution with NSAIDs, especially if renal dysfunction

VIII. Management: Acute presentations

  1. See Complications as below
  2. Obtain Hemoglobin And Reticulocyte Count
  3. Low Hemoglobin (>2 g/dl below baseline)
    1. High Reticulocyte Count
      1. Splenic Sequestration in Sickle Cell Anemia
        1. Age <4 years old
        2. Spleen enlarged on Bedside Ultrasound
      2. Sickle Cell Hemolytic Crisis
        1. Increased Serum Bilirubin, LDH and transaminases (AST, ALT)
      3. Gastrointestinal Bleeding
    2. Low Reticulocyte Count
      1. Transient Red Cell Aplasia (Parvovirus B19)
  4. Hemoglobin near baseline
    1. Cardiopulmonary signs or symptoms
      1. Acute Chest Syndrome
        1. Presents with fever, Chest Pain, Hypoxia, rales and Pulmonary Infiltrates
        2. Most common cause of death in Sickle Cell Anemia
    2. No cardiopulmonary findings
      1. Acute Vaso-Occlusive Episode in Sickle Cell Anemia (Sickle Cell Crisis)
        1. Consider differential diagnosis (e.g. acute Septic Arthritis, Osteomyelitis)
  5. References
    1. Jhun, Raam and Mallemat in Herbert (2016) EM:Rap 16(6): 9-11

IX. Management: Blood Transfusion Indications

  1. Simple transfusion or exchange transfusion
  2. Acute indications
    1. Multi-organ failure syndrome
    2. Major surgical procedures (including Tonsillectomy)
    3. Cerebrovascular Accident in Sickle Cell Anemia
    4. Intrahepatic cholestasis
    5. Acute Splenic Sequestration (or hepatic sequestration) and severe Anemia
      1. Transient Red Cell Aplasia
    6. Progressive or severe Acute Chest Syndrome
      1. Hemoglobin 1 g/dl or more below baseline
      2. Hypoxia with Oxygen Saturation <90% despite Supplemental Oxygen
  3. Chronic indications (maintaining goal Hgb S at lower levels, <30%)
    1. Prevention in children at high risk of CVA
      1. See Cerebrovascular Accident in Sickle Cell Anemia
    2. Pulmonary Hypertension
    3. Chronic Heart Failure
  4. Contraindications
    1. Asymptomatic Anemia or uncomplicated pain crisis
    2. Priapism
  5. Precautions
    1. Blood matching should include C, E and Kell, Duffy Antigens to prevent sensitization (extended red cell Phenotype)
    2. Observe for delayed Transfusion Reaction (e.g. Jaundice, acute pain may occur weeks after transfusion)
    3. Monitor Ferritin for Iron Overload (and treat with chelation therapy if occurs)

X. Management: Hydroxyurea and Related Agents

  1. See Hydroxyurea for protocol
  2. Increases production of fetal Hemoglobin (HbF) which does not sickle
  3. Often managed in conjunction with Sickle Cell Disease specialist
  4. Indications in adults
    1. Sickle Cell Crisis 3 or more times in 12 months
    2. Severe or recurrent Acute Chest Syndrome
    3. Severe symptomatic chronic Anemia affecting functional status
    4. Sickle cell associated pain significantly impacting function or quality of life
  5. Indications in children over age 9 months
    1. All children over age 9 months should be offered Hydroxyurea to reduce complications
  6. Contraindications
    1. Pregnancy and Lactation
  7. Efficacy
    1. Full benefits may not be seen for the first 6 months after starting Hydroxyurea
    2. Reduces Sickle Cell Anemia mortality and hospitalizations (fewer episodes of crisis and Acute Chest Syndrome)
    3. Effective and underutilized in all age groups
    4. Steinberg (2003) JAMA 289:1645-51 [PubMed]
  8. Adjunctive Agents used in addition to Hydroxyurea
    1. Endari (L-Glutamine)
      1. Oral tablet twice daily for ages 5 years and older
      2. Reduces pain crises and and hospitalizations
      3. Costs $3500/month in 2020
    2. Adakveo (crizanlizumab)
      1. Monoclonal Antibody IV infusion given every 4 weeks in patients 16 years old and over
      2. Reduces vaso-Occlusion, and pain crises
      3. Costs $10,000/month in 2020
    3. Oxbryta (voxelotor)
      1. Oral tablet daily for ages 12 years and older
      2. Costs $10,000/month in 2020
    4. References
      1. (2020) presc lett 27(3): 17-8

XI. Management: Contraception

  1. Pregnancy in Sickle Cell Anemia is a high risk state
    1. Increased risk of thrombosis, Anemia, pain, infections as well as matermal death
    2. Also associated with preterm delivery, Stillbirth, Preeclampsia and severe fetal Anemia
  2. Depo Provera
    1. Preferred contraceptive option in women with Sickle Cell Anemia
    2. Lowers number of crises by 70%
    3. DeAbood (1997) Contraception [PubMed]
  3. Intrauterine Device (IUD)
    1. Levonorgestrel IUD (e.g. Mirena, Skyla) is preferred
    2. Avoid Copper-T IUD
      1. May increase risk of bleeding and worsening Anemia
  4. Oral Contraceptives
    1. Thrombosis risk is increased on Estrogen
    2. Avoid Oral Contraceptives with >20 mcg Ethinyl Estradiol (and avoid drospirenone, Desogestrel)
    3. Consider Progesteron only pills (e.g. Nor-QD)

XII. Prevention

  1. General Measures
    1. Maintain hydration
    2. Avoid Temperature extremes
    3. Sudden death risk at high altitude or with strenuous Exercise
  2. Periodic Evaluation
    1. Hematology
    2. Liver Function Tests
    3. Pulmonary Function Tests
    4. Ophthalmology with dilated exam of Retina (age 10 years and older)
      1. Repeat every 1-2 years (or more if positive findings)
    5. Renal Function tests yearly (age 10 years and older)
      1. Serum Creatinine
      2. Urine Microalbumin and Urine Protein (refer to nephrology for >Urine Protein 300 mg/24 h)
    6. Cerebrovascular Disease screening
      1. Transcranial Doppler Ultrasound (TCD) from age 2-16 years old (see above)
      2. See Cerebrovascular Accident in Sickle Cell Anemia
  3. Nutritional Supplements
    1. Folic Acid 1 mg/day
  4. Prophylactic Antibiotics
    1. See Asplenic
    2. Penicillin V
      1. Indicated for ages 2 months to 5 years old
      2. Dose 125 mg bid (age <3 years old) and 250 mg twice daily (ages 3-5 years)
      3. May substitute with Bicillin LA every 3 weeks
      4. Extend course if complications (until Pneumococcal Vaccine completion)
        1. Splenectomy
        2. Invasive pneumococcal infection
  5. Immunizations (In addition to standard CDC)
    1. See Asplenic
    2. Pneumococcal Vaccines
      1. 13-Valent Conjugate Vaccine (Prevnar, PCV)
        1. Give as per CDC Primary Series guidelines
        2. At least one dose in all children age 6 to 18 years with functional or anatomic Asplenia
        3. Has reduced Incidence of invasive Bacterial Infection from 13% to 4%
          1. Patel (2013) Pediatr Hematol Oncol 30(5): 432-6 [PubMed]
      2. 23-Valent Pneumococcal Vaccine (PPV)
        1. Give first dose at 2 years or older
        2. Repeat in 3-5 years if under age 10 years
    3. Haemophilus influenzae B Vaccine
    4. Hepatitis B Vaccine
    5. Influenza Vaccine annually (6 months or older)
    6. Meningococcal Vaccine
      1. Menveo series starting at 2 months of age
      2. Meningococcal Vaccine booster Immunizations every 5 years

XIII. Complications

  1. Musculoskeletal pain
    1. Acute Vaso-Occlusive Episode in Sickle Cell Anemia (Sickle Cell Crisis)
    2. Avascular Necrosis of the Femoral Head (or Shoulder)
      1. Peak Incidence age 5-15 years old
    3. Osteomyelitis in Sickle Cell Anemia
    4. Septic Arthritis in Sickle Cell Anemia
    5. Hand Foot Syndrome in Sickle Cell Anemia (Dactylitis in Sickle Cell Anemia)
      1. Acute Vaso-Occlusive Episode in Sickle Cell Anemia in age <4 years old
  2. Acute worsening Anemia (drop from baseline, see normal ranges under lab above)
    1. Low Reticulocyte Count indicates an RBC production disorder (contrasted with RBC destruction)
    2. Splenic Sequestration in Sickle Cell Anemia (ages 1 to 4 years old)
    3. Transient Red Cell Aplasia
    4. Sickle Cell Hemolytic Crisis
      1. Distinguish from more serious Anemia cause (Splenic Sequestration and Transient Red Cell Aplasia)
      2. Treated with routine Blood Transfusion (Leukocyte depleted, irradiated) in the ED or while admitted
        1. Risk of developing antibodies that make future transfusion matching much more difficult
        2. Request extended red cell phenotyping (includes minor Blood Groups, e.g. Kell, Duffy)
  3. Fever and Sepsis
    1. Evaluate fever >101 F (38.3 C) carefully even without localizing signs or symptoms
    2. Asplenia predisposes to overwhelming infection (esp. encapsulated Bacteria)
      1. Higher risk for pneumonococcus, HaemophilusInfluenzae, Salmonella typhi, Neisseria Meningitidis
    3. Obtain CBC, Reticulocyte Count, cultures (consider UA, CXR) and treat empirically (e.g. Ceftriaxone)
      1. Even when viral source is suspected, consider empiric Antibiotics until follow-up
    4. Unvaccinated children have a risk of serious Bacterial Infection in 10-15% (compared with 1-2% in vaccinated)
    5. Also consider other causes of fever
      1. Acute Chest Syndrome
      2. Severe Anemia
      3. Osteomyelitis
    6. Consider admitting even well appearing sickle cell children under age 2 years (highest bacteremia rate)
      1. Well appearing children over age 2 years with reassuring findings may be closely rechecked in <24 hours
    7. Admission criteria for Sickle Cell Anemia Patients (HgbSS or HgbSB0-Thal) with fever
      1. Ill appearance
      2. Fever >104 F (40 C)
      3. White Blood Cell Count >30k or <5k
      4. Central Line in place
      5. History of prior bacteremia
      6. Hemoglobin <5 g/dl OR >2 g/dl below baseline in HgbSS or HgbSB0-thal
      7. Unreliable follow-up
  4. Acute Dyspnea or Chest Pain
    1. Acute Chest Syndrome
    2. Pulmonary Hypertension (in up to 30% of patients)
    3. Pulmonary Embolism and Pulmonary Infarction
    4. Symptomatic severe Anemia (see above)
    5. Pulmonary parenchyma with Sickle Cell Crisis
    6. Other causes common to non-Sickle Cell Disease
      1. Pneumonia
      2. Acute Coronary Syndrome
      3. Asthma Exacerbation
      4. Congestive Heart Failure
  5. Neurologic conditions
    1. Cerebrovascular Accident in Sickle Cell Anemia (25% lifetime risk)
    2. Silent Cerebral Infarction in Sickle Cell Anemia (affects 25% of children by age 6 years old)
    3. Headaches
      1. Children with SCD have a 10 fold increased risk of serious underlying neurologic Headache cause
    4. Seizure Disorder (10x more common in SCD)
    5. Posterior Reversible Encephalopathy Syndrome (PRES)
      1. Presents with Headache, Seizure, Vision changes and Altered Level of Consciousness
      2. Associated with Acute Chest Syndrome in children
  6. Nephropathy
    1. Parenchymal destruction due to local chronic intermittent ischemia and infarction
    2. Starts with increased GFR, dilute urine, Dehydration and Proteinuria (present in 20% of SCA)
    3. Hematuria may be variably present (may also indicate renal papillary necrosis)
      1. See Hematuria in Sickle Cell Anemia
    4. Acute Renal Failure may accompany vaso-occlusive crisis, Acute Chest Syndrome
      1. May be provoked by NSAIDs
      2. Serum Creatinine is lower at baseline in Sickle Cell Anemia due to higher GFR
        1. Compare current Serum Creatinine to baseline Serum Creatinine levels
  7. Urologic conditions
    1. Priapism in Sickle Cell Anemia
    2. Hematuria in Sickle Cell Anemia
      1. Most common Sickle Cell Anemia complication
  8. Chronic organ damage
    1. Lung
    2. Kidney (Chronic Renal Failure)
    3. Liver
    4. Skin (Chronic Skin Ulcers)
  9. Eye complications
    1. Hyphema (emergency in Sickle Cell Anemia)
    2. Proliferative Retinopathy
    3. Central Retinal Artery Occlusion (Retinal Infarcts)
    4. Retinal Detachment
    5. Vitreous Hemorrhage
  10. Biliary disorders
    1. Cholelithiasis or biliary sludge (50% of 18 year olds, 75% of adults with Sickle Cell Disease)
      1. Higher Red Blood Cell turn-over results in higher Unconjugated Bilirubin
      2. Increased Incidence of Gallstones, sludging, Cholecystitis, Cholelithiasis, Choledocholithiasis
      3. Asymptomatic Cholelithiasis may be observed as with non-Sickle Cell Anemia patients
      4. Emergent Antibiotics and surgical management for Acute Cholecystitis or Choledocholithiasis
        1. Consult hematology regarding preoperative transfusion
    2. Intrahepatic cholestasis
      1. Jaundice (Unconjugated Hyperbilirubinemia)
  11. Abdominal Pain
    1. Biliary disorders (see above)
    2. Vaso-occlusive crisis
    3. Splenic Sequestration (life threatening)
    4. Intrahepatic sickling (first year of life)
    5. Consider common other intraabdominal conditions
      1. Constipation
      2. Appendicitis
      3. Ovarian Torsion
      4. Ectopic Pregnancy

XIV. Resources

  1. Sickle Cell Disease Association of America
    1. http://www.sicklecelldisease.org
    2. Phone: (800) 421-8453
  2. Sickle Centers
    1. http://www.rhofed.com/sickle
  3. Emory Sickle Cell Anemia Page
    1. http://www.scinfo.org

XV. Prognosis

  1. Sickle Cell Anemia is associated with an overall lifespan 2-3 decades shorter than non-Sickle Cell Anemia patients

XVI. References

  1. (2015) Presc Lett 22(2): 11
  2. Claudius, Behar and Sadowitz in Herbert (2018) EM:Rap 18(4): 10-2
  3. Glassberg and Weingart in Majoewsky (2012) EM: Rap 12(8): 5-6
  4. Lowe and Wang (2018) Crit Dec Emerg Med 32(11): 17-25
  5. Welsh and Welsh (2016) Crit Dec Emerg Med 30(11): 15-23
  6. (2002) Pediatrics 109:526-35 [PubMed]
  7. Mehta (2006) Am Fam Physician 74:303-14 [PubMed]
  8. Steinberg (1999) N Engl J Med 340:1021-30 [PubMed]
  9. Yawn (2015) Am Fam Physician 92(12): 1069-76 [PubMed]

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