Hemoglobin

Sickle Cell Anemia

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

  • See Also
  1. Transient Red Cell Aplasia
  2. Acute Chest Syndrome
  3. Acute Vaso-Occlusive Episode in Sickle Cell Anemia
  4. Aplastic Crisis in Sickle Cell Anemia
  5. Cerebrovascular Accident in Sickle Cell Anemia
  6. Dactylitis in Sickle Cell Anemia (Hand Foot Syndrome in Sickle Cell Anemia)
  7. Hematuria in Sickle Cell Anemia
  8. Osteomyelitis in Sickle Cell Anemia
  9. Priapism in Sickle Cell Anemia
  10. Pulmonary Hypertension in Sickle Cell Anemia
  11. Septic Arthritis in Sickle Cell Anemia
  12. Sickle Cell Anemia Related Pulmonary Hypertension
  13. Sickle Cell Anemia with Splenic Sequestration
  14. Sickle Cell Hemolytic Crisis
  15. Fever in Sickle Cell Disease
  • 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 (4.9 per 10,000) 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, hispanic patients, and those from India
  • Pathophysiology
  1. Normal Hemoglobin A replaced by Hemoglobin S (Hb S)
    1. Deoxygenated Hemoglobin-S assumes a sickle shape deforming Red Blood Cells
    2. Sickling Red Blood Cells first identified in 1910 (James Herrick), and named SCA in 1922 (Verne Mason)
    3. Hemoglobin S first identified as cause of Sickle Cell Anemia by electrophoresis in 1949 (Linus Pauling)
  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
      2. Sickle Cell Trait is protective against Malaria, resulting in up to 40% trait Prevalence in some African regions
  3. Sickling Mechanism
    1. Deoxygenated HbS aggregates under low oxygen tension
      1. Molecules polymerize into a gelatinous network
      2. Deforms Red Blood Cells into a sickle shape
    2. Red cells with sickle shape are less deformable
      1. Results in microvascular Occlusion, ischemia and acidosis from sludging within arterioles
      2. Results in Hemolysis due to red cell fragility
  4. 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
  5. 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
  • 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 or HbS)
    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 Cell Anemia with Hemoglobin C (HbC)
    1. Lysine is substituted for Glutamic Acid at position 6 of the Beta chain (contrast with Valine in HbS)
    2. Similar complications as with Sickle Cell Anemia, but with a less severe course
  4. Sickle - Beta Thalassemia
    1. One HgbS and one HgbB0 (no beta chain) or HgbB+ (reduced beta chain)
  • Labs
  1. Newborn Screening identifies Hemoglobinopathies including Sickle Cell Trait and Sickle Cell Anemia
  2. Monitoring
    1. Hemoglobin
    2. Reticulocyte Count
    3. Liver Function Tests
    4. Renal Function tests
  3. Hemoglobin
    1. Chronic Anemia is due to decreased Red Blood Cell lifespan (10-20 days compared with normal 120 days)
      1. Sickle Cell Anemia patients have typically adapted to low Hemoglobin levels
      2. HgbSS or HgbSb0: 6-8 g/dl Hgb
      3. HgbSB+: 9-12 g/dl Hgb
      4. HgbSC: 10-15 g/dl Hgb
    2. Acutely worsened Anemia has several potential causes (see below)
      1. Levels below baseline frequently require Blood Transfusion
  4. Serum Creatinine
    1. Frequently lower in Sickle Cell Anemia and may underestimate renal dysfunction
    2. See screening protocol below under prevention
  5. Precautions
    1. White Blood Cell Count (WBC)
      1. Infection may cause increased WBC Count
      2. However, WBCs also increased with stress Demargination and Anemia-induced Bone Marrow hyperactivity
    2. Maintain a low threshold for infection evaluation
      1. See Infectious Disease in Sickle Cell Disease
      2. Urinalysis
      3. Blood Cultures
      4. Lumbar Puncture (if CNS findings)
  • Imaging
  1. Chest XRay Indications
    1. Respiratory symptoms (Hypoxia, cough, respiratory distress)
    2. Fever, Leukocytosis or increased inflammatory markers
    3. Evaluate for Pneumonia, Lung Infarction, Acute Chest Syndrome
  2. 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
  • 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
  3. Disposition in acute illness
    1. Uncomplicated Sickle Cell Crisis with adequate Oral Analgesic control may be discharged home
    2. Low threshold for hospital admission
      1. Infection or Sepsis
      2. Acute on chronic Anemia
      3. Acute Chest Syndrome (all patients are admitted)
  • Management
  • Acute Presentations
  1. General
    1. See Complications as below
    2. Sickle Cell Crisis (VOC) accounts for 86% of pediatric SCD emergency department visits
    3. Children with SCD average 2-3 emergency department visits per year
      1. Most visits occur at pediatric hospitals with comprehensive Sickle Cell centers
      2. Pediatric SCD patients are more likely than adults to present with life-threatening complications
  2. Most important initial labs in acute Sickle Cell Anemia presentations (however these do not dictate disposition)
    1. Complete Blood Count or Hemoglobin
    2. Reticulocyte Count
  3. Low Hemoglobin (>2 g/dl below baseline, see labs above)
    1. Normal to High Reticulocyte Count
      1. Reticulocyte Count is typically >5% at baseline in SCA
      2. Splenic Sequestration in Sickle Cell Anemia
        1. Age <4 years old
        2. Spleen enlarged on Bedside Ultrasound
      3. Sickle Cell Hemolytic Crisis
        1. Increased Serum Bilirubin, LDH and transaminases (AST, ALT)
      4. Gastrointestinal Bleeding
    2. Low Reticulocyte Count (<5%)
      1. See below
      2. Reticulocyte Count 2 to 5%
        1. Hypoplastic Anemia
      3. Reticulocyte Count <2%
        1. Transient Red Cell Aplasia (Parvovirus B19)
  4. Hemoglobin near baseline
    1. Cardiopulmonary signs or symptoms
      1. Obtain Chest XRay in acute chest complaints (cough, fever, Shortness of Breath)
      2. 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. Leukocytosis has low Test Sensitivity and Test Specificity in acute presentations
    1. Acute infection
    2. Stress induced Demargination
    3. Hematopoiesis in acute Anemia
  6. Reticulocyte Count
    1. Reticulocyte Count is normally increased to >5% in Sickle Cell Anemia
    2. Bone Marrow hypoactivity (<5%) is a red flag
      1. Reticulocyte Count 2-5%: Hypoplastic Anemia
      2. Reticulocyte Count <1%: Aplastic Crisis in Sickle Cell Anemia
  7. References
    1. Jhun, Raam and Mallemat in Herbert (2016) EM:Rap 16(6): 9-11
  1. Simple transfusion or exchange transfusion
  2. Acute indications
    1. Anemia with severe cardiopulmonary compromise (e.g. Severe Tachycardia, Hypotension)
    2. Multi-organ failure syndrome (exchange transfusion)
    3. Major surgical procedures (including Tonsillectomy)
    4. Cerebrovascular Accident in Sickle Cell Anemia (exchange transfusion)
    5. Intrahepatic cholestasis (exchange transfusion)
    6. Acute Splenic Sequestration or hepatic sequestration and severe Anemia (exchange transfusion)
      1. Transient Red Cell Aplasia
    7. Progressive or severe Acute Chest Syndrome (exchange transfusion)
      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)
  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
  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)
  • 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. Prophylaxis Indications
      1. Sickle Cell Anemia ages 2 months to 5 years old AND
      2. Splenectomy OR Genotype HbSS or HbS Thalassemia Beta Zero
    3. Prophylaxis Course
      1. Ages 2 months to 5 years old
      2. Extend course if complications (until Pneumococcal Vaccine series completion)
        1. Splenectomy
        2. Invasive pneumococcal infection
    4. Prophylactic Agents
      1. Penicillin V Suspension (Preferred, strongest evidence)
        1. Age <3 years: 125 mg orally twice daily
        2. Age 3 to 5 years: 250 mg orally twice daily
        3. Penicillin tablets may be split or crushed as an alternative
      2. Alternatives if Penicillin not tolerated
        1. Amoxicillin 10 mg/kg/dose (up to 250 mg) orally twice daily
        2. Bicillin LA every 3 weeks
      3. Alternatives for true Penicillin Allergy
        1. Erythromycin at same dose as Penicillin V Suspension
    5. References
      1. (2024) Presc Lett 31(12): 71
  5. Immunizations (In addition to standard CDC)
    1. See Asplenic
    2. Haemophilus influenzae B Vaccine
    3. Hepatitis B Vaccine
    4. Influenza Vaccine annually (6 months or older)
    5. Meningococcal Vaccine
      1. Menveo series starting at 2 months of age
      2. Meningococcal Vaccine booster Immunizations every 5 years
    6. Pneumococcal Vaccine
      1. Newer Protocol: Pneumococcal Conjugate Vaccine Only
        1. PCV20 (children) or PCV21 (adults)
      2. Older protocol (combination Vaccines)
        1. PCV13 (13-Valent Conjugate Vaccine, Prevnar 13, 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
  • Complications
  1. Musculoskeletal pain
    1. Acute Vaso-Occlusive Episode in Sickle Cell Anemia (Sickle Cell Crisis)
      1. Most common pediatric Sickle Cell Disease ED presentation (86% of cases)
    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 (Hyperhemolytic Crisis)
  3. Fever and Sepsis
    1. See Fever in Sickle Cell Disease
  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
      1. Emergency in Sickle Cell Anemia
      2. Risk of Aqueous Humor obstruction and acute Narrow Angle Glaucoma
      3. If IOP >25 mmHg, start ophthalmic medications (e.g. Timolol, Pilocarpine)
        1. See Acute Angle-Closure Glaucoma for acute protocol
        2. Avoid Carbonic Anhydrase Inhibitors (e.g. Acetazolamide)
          1. May worsen Glaucoma via decreased Blood Pressure and ocular pH
    2. Proliferative Retinopathy
    3. Central Retinal Artery Occlusion (Retinal Infarcts)
    4. Retinal Detachment
    5. Vitreous Hemorrhage
  10. Biliary disorders
    1. See Hepatic Crisis in Sickle Cell Anemia
    2. Intrahepatic cholestasis
      1. See Sickle Cell Intrahepatic Cholestasis
      2. RBC sickling within liver sinusoids results in hepatic ischemia and Unconjugated Hyperbilirubinemia accumulation
      3. Contrast with benign cholestasis presenting only with Jaundice and Pruritus
      4. Intrahepatic cholestasis is a life threatening condition associated with a high mortality rate
        1. Presents with RUQ Abdominal Pain, fever, Vomiting and Jaundice
        2. Risk of Hemorrhage (due to Coagulopathy), encephalopathy and Renal Failure
    3. Cholelithiasis or biliary sludge
      1. Onset in childhood and affects up to 75 to 85% of adults
      2. Hemolysis episodes generate higher Red Blood Cell turn-over, resulting in higher Unconjugated Bilirubin
      3. Increased Incidence of Gallstones, sludging, Cholecystitis, Cholelithiasis, Choledocholithiasis, Gallstone Pancreatitis
      4. Asymptomatic Cholelithiasis may be observed as with non-Sickle Cell Anemia patients
      5. Emergent Antibiotics and surgical management for Acute Cholecystitis or Choledocholithiasis
        1. Consult hematology regarding preoperative transfusion
    4. Acute hepatic sequestration
      1. Abnormal Red Blood Cells may be sequestered within the liver
  11. Abdominal Pain
    1. See Hepatic Crisis in Sickle Cell Anemia
    2. Biliary disorders (see above)
    3. Vaso-occlusive crisis
    4. Splenic Sequestration (life threatening)
    5. Intrahepatic sickling (first year of life)
    6. Consider common other intraabdominal conditions
      1. Constipation
      2. Appendicitis
      3. Ovarian Torsion
      4. Ectopic Pregnancy
  • 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
  • Prognosis
  1. Sickle Cell Anemia is associated with an overall lifespan 2-3 decades shorter than non-Sickle Cell Anemia patients
  • References
  1. (2015) Presc Lett 22(2): 11
  2. Claudius, Behar and Sadowitz in Herbert (2018) EM:Rap 18(4): 10-2
  3. Dwyer, Kleinmann, Goswami and Lopez (2025) Crit Dec Emerg Med 39(1): 26-35
  4. Glassberg and Weingart in Majoewsky (2012) EM: Rap 12(8): 5-6
  5. Lopez, Kleinmann, Chandra and Lopez (2025) Crit Dec Emerg Med 30(3): 4-12
  6. Lowe and Wang (2018) Crit Dec Emerg Med 32(11): 17-25
  7. Welsh and Welsh (2016) Crit Dec Emerg Med 30(11): 15-23
  8. (2002) Pediatrics 109:526-35 [PubMed]
  9. Mehta (2006) Am Fam Physician 74:303-14 [PubMed]
  10. Steinberg (1999) N Engl J Med 340:1021-30 [PubMed]
  11. Yawn (2015) Am Fam Physician 92(12): 1069-76 [PubMed]