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Sickle Cell Anemia    
Ref: Outlines in Clinical Medicine on Physician Online 2002  

A. Introduction                                                                                                          See outline Hemoglobin SC Disease

  1. Sickle cell anemia ccurs in ~1 per 600 black persons in USA
  2. Other sickle cell syndromes as Sickle cell - hemogloblin C disease (HbSC) & Sickle cell - ß-thalassemia (HbS-ßthal) occur in ~1 per 1000 blacks in USA (see table below)
  3. About 8% of black persons in USA are carriers of one copy of sickle hemogloblin (HbS) - the "sickle trait"
    1. About 40% of their Hb is in the sickle form & the remaining 60% of Hb is in the normal (HbA) or variant (HbA2) form
    2. These persons are essentially asymptomatic
  4. Life Expectancy
    1. Average lifespan: 42 years for men, 48 years for women
    2. Most common cause of death related to renal failure; 33% died from sickle crisis (pain/chest syndrome or stroke)
    3. High level of HbF predicts improved survival

B. Pathophysiology

  1. Vaso-occlusion is responsible for most of the major symptoms of the disease
  2. Other symptoms are due to hemolysis of red cells leading to anemia
  3. Genetic Disease       
    1. Normal Hemoglobin (Hb) consists of two alpha and two beta protein chains
    2. Normal adult Hb is called Hb A
    3. Sickle cell Hb, or Hb S, is due to mutation of the sixth residue of beta chain
    4. Mutation of ß6 glutamic acid to valine (ß6 glu-->val or ß6 E/V)
    5. Having one copy of Hb S and one of Hb A is benign (called "sickle trait")

C. Sickle Cell Syndromes
Type             Genotype      HCT      Retic      MCV        
1. HbSS Disease ßs ßsaa/aa 20-22% 15% 85-110 fL
2. Sickle-a-Thal ßs ßsa-/a- 26-28% 6-12% 75
3. Sickle ßo Thal ßs ßoaa/aa 20-30% 65
4. Sickle ß+ Thal ßs ß+aa/aa > 30% 65
5. HbSC Disease ßs ßCaa/aa 20-30% 80
6. Sickle Trait ßs ßAaa/aa > 36% >82

D. Summary of Complications of Sickle Cell Disease

  1. Vaso-Occlusive Complications: Painful Episodes, Stroke, Acute Chest Syndrome, Priapism, Liver Disease, Splenic Sequestration, Spontaneous Abortion, Leg Ulcers, Osteonecrosis, Proliferative Retinopathy, Renal Insufficiency
  2. Complications of Hemolysis: Anemia - hemolytic type, Cholelithiasis, Acute aplastic episodes (due to parvovirus B19)
  3. Infectious Complications: Mainly related to functional asplenia, Pneumococcal sepsis, E. coli sepsis, Osteomyelitis - salmonella or Staphylococcus aureus

E. Symptoms and Signs

  1. Painful Episodes
    1. Often acute, usually due to bone ischemia and/or infarction
    2. PAINFUL Crisis (Vaso-occlusion)
    3. Infarction of femoral head is not uncommon
    4. Occur in ~70% of patients with HbSS disease
  2. Anemias       
    1. Chronic Hemolytic
    2. Hyperhemolytic (below)
    3. Painful Crises (increased Reticulocytosis)
    4. Pancyotopenia: APLASTIC Crisis (decreased Reticulocytosis)
    5. Megaloblastic Crises (Folate Deficiency)
    6. Iron Deficiency
  3. Hyperhemolytic Anemias
    1. Infection
    2. Delayed hemolytic Transfusion
    3. Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
  4. Spleen Related Problems      
    1. SEQUESTRATION Crisis; Splenic Infarction; Risk of infection by encapsulated organisms; Howell-Jolly Bodies; By age ~6 years, nearly all patients with SCA have functional asplenia
  5. Cerebral Hemorrhage
    1. Common; Complete occlusion of all collateral circulation serving one region; VASO-OCCLUSIVE Crisis; Transfusion therapy for stroke: can prevent vaso-occlusive crises in some people; Note, however, that transfusions increased blood viscosity
  6. Shortness of Breath
    1. Often due to problem called "Chest Syndrome" (see below); Consider bronchoalveolar lavage in patients with unclear etiology or infectious agent; Differential: Rib / Sternal infarction, pulmonary infarction (thrombotic or fat embolus)
  7. Large Vessel Disease
    1. Vascular abnormalities similar to HTN; Renal vascular disease and intrinsic renal disease, papillary necrosis (see below); Associated problems: cardiac murmur, rheumatic fever, jaundice
  8. Other complications
    1. Gallstones (cholesterol) - cholecystectomy usually only recommended if symptomatic
    2. Renal Insufficiency (see below)    
    3. Proteinuria      
    4. Hypertension in minority of patients - often with renal disease; evaluate carefully
    5. Avascular necrosis of femoral head       
    6. Leg Ulcers, Strokes, Seizures

F. Acute Chest Syndrome (ACS)

  1. Occurs at least once in >50% of all patients with SCA; About 13 cases per 100 patient-years
  2. Definition of ACS
    1. Presence of new pulmonary intiltrate infvolving at least one complete lung segment
    2. Chest Pain
    3. Temperature >38.5°C
    4. Tachypnea, wheezing or cough
  3. Laboratory
    1. Hemoglobin and hematocrit levels are usually reduced; Leukocytosis is prominant; Chest radiograph with pulmonary infiltrates - usually multilobar; Ventilation-Perfusion Scan may be useful to rule out larger embolism
  4. Initiating Factors
    1. Fat embolism was most common cause
    2. Fat likely broken away from bone marrow to venous system and lodged in lung
    3. Infectious agents with or without fat embolism
    4. Chlamydia pneumonia, Mycoplasma pneumoniae, and respiratory syncytial virus most common
    5. Streptotoccous pneumonia and Staphylococci also found less frequently
    6. Fat emboli or infection induce local hypoxia in the lung
    7. Hypoxia induced vasoconstriction and sickling initiate ACS
  5. Pathophysiology
    1. Related to multiple mechanisms of pulmonary capillary injury
    2. Sickle RBC are "stickier" to endothelium due to increased adhesion molecule expression
    3. Enhanced VCAM-1 expression on vascular endothelium to alpha4ß1 and CD36 on RBCs
    4. Atelectasis exacerbates slowed sickle blood flow through lung
  6. Complications
    1. Patients >20 years have more severe course than younger patients
    2. Multilobar progressive pneumonia
    3. Mechanical ventilation (13%)
    4. Neurologic events (11%)
    5. Death (3%)
  7. Treatment
    1. Supportive care in intensive care unit
    2. High dose oxygen, transfusions and/or fluid to reduce blood viscosity
    3. Must treat for infection and sickle crisis
    4. Antibiotics - broad spectrum including atypicals, concern for functional asplenia
    5. Bronchodilators - effective in ~20% of patients
  8. Nitric Oxide
    1. Nitric oxide reduces RBC-endothelial adhesion and dilates blood vessels
    2. Inhaled nitric oxide should be considered experimental for treatment of ACS

G. Management

  1. No specific HbS polymerization inhibitors to date
  2. Reduction of intracellular HbS concentration
    1. Additional Folate Supplementation - 1-4mg po folate per day
    2. Blood Transfusions to maintain Hb > 8.0 g/dL
  3. Induction of HbF (fetal hemoglobin; see below)
    1. Hydroxyurea induces HbF form, replaces partially Hb SS
    2. Erythropoietin may potentiate effects of hydroxyurea, though this is controversial
    3. Short term use of butyrate may also increase HbF but not in long term
    4. Thus, 10 weeks of intravenous arginine butyrate in severe HbSS or thalassemia did not increase HbF fraction
    5. Bolus glucocorticoids can precipitate and/or exacerbate disease due to elevated HCT
  4. Vaccinations       
    1. As for surgical or traumatic splenectomy
    2. Pneumococcus, HIB, Meningococcus
  5. Painful Crises
    1. No particular type of pain
    2. Mild to moderate pain treated with Tylenol, NSAID, Percocet
    3. Severe Pain: Dilaudid (4mg im), Demerol (100-125mg im), Morphine (10mg im or iv)
    4. Oral controlled (slow) release morphine is reliable in children with painful crisis
    5. Add diphenhydramine (Benadryl®) or hydroxizine (Vistaril®) im
    6. Maintain bowel motility wth senekot, magnesium citrate
    7. Intravenous fluids
    8. Consider pentoxifylline (Trental®) to increase red cell deformability
    9. Transfusions are not needed to specifically treat pain
  6. Renal Disease       
    1. Enalapril 5-10mg po qd decreases proteinuria in 2 week and 6 month trials
    2. ACE Inhibitors likely protect kidney by decreasing glomerular filtration pressures
    3. Effects of 6 months of enalapril occasionally last even after drug is stopped
    4. Captopril reduces microalbuminuria >50% in normotensive sickle cell patients
    5. Renal tubular acidosis also occurs       
    6. RTA should be treated with bicarbonate or citrate replacement therapy
    7. Papillary necrosis can occur during cris due to renal hypoxia
  7. Treatment of Anemia
    1. Blood replacement required mainly for sudden severe anemia
    2. Occurs with splenic sequestration and with parvovirus induced aplastic crisis
    3. Hypoxia with acute chest syndrome can also be treated with transfusion
    4. Also for prevention of recurrent strokes in children (maintain HbS fraction <30%)
    5. If anesthesia is required, recommend maintaining HCT >30%

H. Hydroxyurea (Hydrea®)

  1. Mechanisms of Action
    1. Reduces bone marrow cellularity
    2. Increases proportion of nucleated RBC's making hemoglobin F (HbF)
    3. Increases blood levels of fetal hemoglobin (HbF = alpha2 gamma2)
    4. HbF lacks ß-globin chains and so there is no sickling
    5. Macrocytosis and increased cell hydration occurs
    6. Reduces peripheral reticulocytes
    7. Also reduces RBC adherance to endothelial cells
    8. Improves endothelial cell function in HbSS patients
  2. Very effective in reducing number of painful crises in adults with HbSS
    1. Study done on adults with >2 painful crises per year
    2. Mean number of crises per year was 2.5 with hydroxyurea and 4.5 with placebo
    3. Dose is 15mg/kg/day for 12 weeks, increase as tolerated by 5mg/kg/day
  3. Main side effect is bone marrow suppression
    1. Folate, 1mg per day, can reduce some of these effects
    2. Monitor CBC every two weeks
    3. Stop agent for the following until counts return to normal:
    4. neutrophils <2000/µL
      1. reticulocytes or platelets <80,000/µL
      2. Hb level <4.5gm/dL
    5. Resume hydroxyurea at 2.5mg/kg/day less than original dose once counts normalize
    6. Drug may be discontinued in up to ~30% of patients

I. Bone Marrow Transplantation

  1. May be considered in severe disease
  2. Criteria for Severe Disease
    1. History of stroke
    2. Recurrent acute chest syndrome
    3. Recurrent painful crises
  3. HLA-identical sibling allogeneic BMT performed in 22 person <16 years of age
  4. Survival
    1. 91% (20/22) survived the initial BMT
    2. 16/20 (75%) had engraftment of donor hematopoietic cells
    3. Two deaths due to CNS hemorrhage or graft versus host disease (GVHD)
  5. Overall, ~100 patients with sickle cell disease have undergone transplantation

J. Experimental Therapies

  1. Induction of HbF by short-chain fatty acids (arginine butyrate)
  2. Reversing cellular dehydration using cation transporter blockers
    1. Clotrimazole - antifungal azole which also blocks cation channels
    2. Combination of clotrimazole, erythropoietin, and hydroxyurea under study
    3. Magnesium
  3. Nitric oxide induction may increase HbS affinity for O2, decrease sickling