Sickle Cell Disease




    • 1 in 600 black people in US
    • 8% are heterozygous for HbAS (Sickle trait), and 40% of their Hb is HbS.
      •  Most heterozygotes are asymptomatic except:
        • They usually have periodic asymptomatic gross hematuria due to papillary necrosis (deoxyhemoglobin polymerizes due to rapid exchange at the papilla - deep medullary part of kidney, and they "pee out necrotic papillas").
        • Other things reported: renal medullary carcinoma, risk of splenic rupture at high altitudes, venous thromboembolism, and sudden death during extreme conditions have been reported.
        • Screening performed in military (controversial - due to low risk of sudden death).
    • Characterized by having HbS gene instead of the hemoglobin β-globulin.
      • (Generally RBCs have 4 hemoglobins in a tetramer, 2 α and 2 β, and sickle cell involves β component .
    • Terms:
      • Hemoglobin A --> normal hemoglobin
      • Hemoglobin F --> fetal hemoglobin (different Hb saturation curve)
      • Hemoglobin S --> Sickle cell hemoglobin with a point mutation (Glu-6-Val)
      • Hemoglobin C --> (Glu-6-Lys) point mutation  (Target cells, microspherocytes, and HbC crystals found on smear)
    • Types of Sickle Disease
      • Hb AS --> Heterozygous sickle trait (Asymptomatic)
      • Hb SS --> Homozygous, sickle cell (Sickle Cell Disease)
      • Hb Sβ --> Sickle Cell with β-Thalassemia trait (but thalassemia trait is such that some β-globulins are produced - such that 18-25% is HbA)
      • Hb Sβ0 --> Sickle Cell with Severe β-Thalassemia triat (NO β-Globulin production= phenotypically equivalent to HbSS, there are no HbA red cells?)


    • Sickle cell disease is characterized by having the HbS gene (heterozygous vs. homozygous)
      • HbS is prone to polymerization, and the polymerization depends on three things:
          1.   Cell's degree of deoxygenation
          2.   Intracellular Hb concentration  (heterozygotes have 40% HbS --> less likely to polymerize)
          3.   Presence of absence of hemoglobin F - fetal hemoglobin (inhibits HbS polymerization)
      • These three variables determine time to polymerise (Td).
      • Time to polymerize is important --> if there is a delay in deoxygenated transit through microcirculation that is longer than Td, rapid co-operative HbS polymerization occurs --> leading to sickling --> vaso-occlusive crisis.
    • Dehydration of cells causes HbS polymerization:
      • Rate of polymerization of deoxygenated HbS is dependent on Hb concentration (dehydration).
        • Dehydrated dense SS cells --> distorted, rigid RBC --> vaso-occlusion and hemolysis.
      • Most important dehydration contributor is theHbS dehydrationB.jpg        
        1. K+/Cl- cotransporter
                            Activated by acidification or cell swelling
                            Inhibited by Mg+ ions
        Ca++ activated K+ efflux pump (Gardos Channel)
                            Inhibited by Clotrimazole
        • In normal AA cells K+/Cl- transport only active in reticulocytes, but transport rate higher in CC and SS RBCs.  This transporter is induced by cell swelling and acidification.
        • Acidification occurs in vivo at sites of stagnant circulation.
        • This process is important in dehydration of SS, CC, and SC cells (latter two cause target cells)
        • Sickling causes membrane distortion --> disrupts Ca++ rich vesicles --> releases Ca++ --> activates K+ efflux pump --> dehydration --> further sickling.
    • SS Red Cells Interact with Vascular Endothelium
      • It is mysterious why vaso-occlusive events are episodic and unpredictable temporally and spacially.
      • If the capillary transit time is increased past the polymerization time (Td) --> vaso-occlusive crisis ensues.
        • Hence, many studies are interested in how SS RBCs interact with endothelium.
        • SS RBCs have stickly membranes and readily attach to endothelium in culture. (correlates disease severity)
        • This process involves released cytokines, tumor necrosis alpha, fibronectin, and thrombosporin secreted by activated platelets.
      • HbS polymerizes --> damages cellular membrane --> sickle cells perturb endothelium --> vasoconstrictor release --> decreased blood flow --> deoxygenation --> further polymerization
      • Granulocytes interact with endothelial cells and sickle cells --> release cytokines --> activate platelets --> promote adhesion of sickle cells to endothelium.
        • Granulocytes are marker of death in sickle cell anemia.
        • Stress reticulocytes are released.



           HbS Polymerization.jpg     RBC Endothelium Intraction.jpg

    Pictures from NEJM article (see document attachments)


    • Hemoglobin electropheresis:

    Characteristics of Adult Sickle Cell Syndromes


    Disease Type



    Hb S (%)

    Hb A (%)

    Hb A2 (%)

    Peripheral Blood

    Smear Findings

    Clinical Severity

    0 to +++

    Sickle trait (AS)








    Hb SS






    Sickle cells








    Rare sickle cells

    Target cells

    + to ++







    Sickle cells

    Target cells







    Hb A2 = 0

    Hb C = 50a

    Fat sickle cells

    Target cells

    + to ++

    Created using data from MKSAP 16 - ACP


    • No reliable blood work marker for a vaso-occlusive crisis

    Clinical Features

    • Vaso-Occlusive crises: risk is 60% yearly:
      • Symptoms: Acute episodes of severe pain in chest, back, abdomen, or extremities.
        • Possible triggers:
          • Infection
          • Extreme Temperatures
          • Physical or Emotional Stress
      • Some have persistent pain.
    • See "Approach to Therapy" for different syndromes.


    • Older kids develop splenic atrophy and dysfunction, predisposing to pneumococcal sepsis.
    • Sickle Cell HbSC:
      • People with HbSC have milder disease
      • HbC does not polymerize as readily as HbS, and there is less sickling.  Peripheral smear demonstrates mostly target cells and few sickle cells. 
      • There are fewer vaso-occlusive events.
      • There are more frequent retinopathy, ischemic necrosis of bone, and priapism compared to pure SS disease.


    Prevention Care

    • Hepatitis C screen
    • Retinal exam q1-2 years
    • Penicillin BID <5yo
    • Immunizations for encapsulated organisms (esp. S. pneumo)

    Sickle Cell Syndromes

    • All Acute Crises:
      • 1. Hydration
      • 2. Pain Control (Opioids)
      • 3. Incentive spirometry (to avoid chest syndrome).
    Crisis Details Treatments
    Pain Crisis

    - Uncomplicated painful episodes
    (no marker of organ injury?)   

    - Hydration!!!

    - Analgesia (opioids)

    - Incentive Spirometry (avoid chest crisis)

    - NO transfusions, if uncomplicated.

       (risk of iron overload)

    Acute Chest


    - Features: Dyspnea, fever, hypoxia, new infiltrate.

    - 40% of SC people, most common but 
       least severe in children.

    - Can be caused by pneumonia (hard to distinguish)

    - Other causes: Lung infarction, bone fat emboli

    - Broad spectrum abx

    - Supplemental oxygen

    - Pain management (diminish chest splinting)

    - Incentive spirometry, bronchodilators.

    - NEED ERYTHROCYTES (if hypoxic

     despite supplemental O2)

      Require RBC transfusion.

      (Exchange vs. pRBC transfusion 

       controversial, not answered in RCT)

    - Hydroxyurea - not acutely, but to prevent


    - COMMON, esp in young.

    - Prolongued and recurrent priapism = impotence.

    - Requires 

    - Support: Pain Control, O2, IV fluids

    - URGENT urology consultation if >2h

       (local aspiration, irrigation)

    (ephedrine, alpha-blockers, hormones

    can decrease currence, but not studied)

    Aplastic Crisis


       - Pavrovirus B19 infection

       - Failure to take folate (megaloblastic crisis)

       - Renal Failure

    - Sickle patients have RBC lifespan < 120 days, 

      Pavrovirus can cause profound anemia. 

    - Self-limited

    - May require transfusion

    Multi-Organ Failure    

    - High risk of stroke.

    - Etiology: circulating activated endothelial cells,
      Nitric Oxide consumption.

    - 70% liklihood of recurrent stroke (reduced to 50% with

      chronic transfusions)

         - Careful with: Iron overload, alloimmunization

    - In stroke:

      RBC exchange transfusion

    (reduce HbS concentration to < 30%)

    Pulmonary HTN

    - Recently recognized (thought 2ndary to Nitric Oxyde

      depletion by free heme). 

    - Unknown how to treat. 

    - Sildenafil tried in RCTs, but stopped early

      due to higher incidence of pain crises.

    (Bocentin sometimes used)

    - Hydroxyurea DOES NOT help pulmHTN

    - Chronic Transfusions --> unclear.

    Infection - Functionally asplenic: if come in, treat!

    - Abx to cover encapsulated organisms,

      gram negatives, atypical community 




    Sickle Cell Disease

    • Annual optho exam (neovascularization)

    • Encapsulated org. vaccinations


    • Screen for pulmonary HTN (free heme removes nitric oxide)


    1. Prophylaxis
      • Penicillin
        • Pneumococcal sepsis leading cause of death (spleen cannot clear bactermias)
        • 84% reduction of pneumococcal sepsis with 125mg BID penicillin for 2-3 mo to 3 years, then 250mg BID until 5 years.
        • Older kids and those with HbSC disease who have normal spleens do not need prophylaxis.
      • Pneumococcal vaccination (23 valent vaccine, conjugate even more immunogenic).
      • Folic Acid
        • Prevent megaloblastic erythropoiesis from rapid RBC turnover.
      • Retinal Eye exams q1-2 years (high risk retinopathy)
      • Pulmonary HTN Echo screen q1y
    2. Acute Episodes
      • Analgesia --> opioid medications likely needed.
      • Antibiotics
        • Only if fever or chest syndrome.
      • Supportive care
        • Hydration - > increases RBC volume, dilutes HbS, decrease
        • Transfusion / exchange transfusion. 
          • Usually not for strict anemia
          • Indications:
            • Symptomatic acute anemia
            • Chest crises with hypoxia
            • Acute anemia from splenic sequestration or Parvovirus B19-related aplastic crisis.
            • Surgery, general anesthesia, eye surgery.
            • Generally done to decrease stroke risk.
              • Transfusion decreases stroke (50% of children with stroke get another one in 3y, and 10% if transfusions, another study 16% --> 2%).
                • Target conc of HbS is 30% total.
          • Often become alloimmunized --> need to deplete leukocytes and match common antigens.
    3. Preventing future episodes
      • Hydroxyurea
        • boosts HbF (potent inhibitor of HbS polymerization), alters RBC-endothelium interactions, and alters interplay with neutrophils, retics, etc.
          • Slightly raises total CBC Hb.
          • Decreases mortality, reduces frequency of painful crises.
        • Indication:
          • Recurrent painful episodes
          • acute chest syndrome
          • symptomatic anemia
        • USE the right dose: RCTs used 35mg/kg, many underdosed.
        • Contraception should be undertaken (very terratogenic)
        • Monitoring:
          • Causes macrocytosis (high MCV can be used to check compliance)
          • Have to check CBC q2weeks and tirate to monitor for:
            • Toxicity (decrease in granulocytes and platelets)
            • Benefit (Increase in MCV or MCH? - as surrogates for HbF concentration).
        • 10-25% of patients have no response, and should discontinue hydroxyurea.
    4. Experimental Therapy (1999):
      • Clotrimazole (see below)
      • Magnesium
      • Nitric oxide.
      • Short-chain fatty acids (Butyrate)
    5. Transplant
      • If healthy donor, 

    Erythrocyte Transfusion Guidelines

    • Type of Transfusion   Indications Notes

      Exchange Transfusion


      Give non-sickle RBCs

      take away sickle RBCs)

      - Acute Stroke

      - Acute Chest Syndrome

      - ICU

      - Multi-Organ failure

      - Raise Hb >100 g/L 

      (Higher = viscocity problems)

      Simple Transfusion Simple pRBC transfusion - Symptomatic Anemia  


      (Chronic Transfusion)

      Give blood on chronic

      basis (i.q. qMonthly)

      - Secondary prevention 

        of stroke.

      - Prevent recurrent

        priapism or non-healing




    • DO NOT Give blood:
      • DO NOT give blood in the following instances:

        • DO NOT give blood during a routine painful crisis!
        • DO NOT give blood for a minor surgery that doesn't require anesthesia!
        • DO NOT give blood for uncomplicated pregnancies!
        • DO NOT give blood for asymptomatic anemia!


    • Blood should be leuko-reduced, hemoglobin S negative, and phenotypically matched for minor antigens (including E, C, and Kell) as well as any known allo-antibodies.
    • Hb targets should be < 100. (hyperviscocity)


    Mechanistic Approach

    1. Inhibit HbS Polymerization
      • HbS polymerization inhibitor has not yet been found.
    2. Reduction of Intracellular Hb Concentration
      • (Rate of polymerization of HbS depends on its concentration)
        • Anything that decreases the mean corpuscular hemoglobin concentration (MCH) has a sound rationale.
      • Simplest approach is induction of hyponatremia. (osmotic swelling of RBC).
        • Works, but dangerous, needs close monitoring.
      • At the very least, Hydrate!
      • Stop RBC dehydration = Lower Mean Corpuscular Hemoglobin --> Inhibit K+ and water loss from SS cells.
        • Gardos channel is inhibited by clotrimazole.
          • Efficacy demonstrated in-vitro experiments, transgenic mice, and observed in SS patients.
          • Clotrimazole tx (much lower dose than antifugal therapy) in 5 patients with SS --> reduction in dense and irreversibly sickled cells + increased intracellular K+ + increase in CBC Hb concentration + decrease in unconjugated bilirubin (less hemolysis). 
        • Inhibit K+/Cl- cotransport
          • Mg++ is an inhibitor, and stops K+ loss from cells.
          • Mg++ supplements in 11 pts with SS --> 50% inhibition of K+/Cl-, increase in CBC  Hb conc.
    3. Induce Hemoglobin F
      • Inhibits deoxy-HbS polymerization
      • Drugs tested:
        • 5-sazacytidine
          • Oldest one
          • Anti-neoplastic, inhibits maintenance demethylation of DNA, increased HbF in baboons.
        • Hydroxyurea
          • The only drug with widespread use.
          • Non-toxic, myelosuppressive effects reversible, not known to induce tumors.
          • Effects: HbF increase, CBC Hb increase, decrease in hemolysis, decrease in sickling, decrease hospitalizations, need for transfusions, and frequency/intensity of episodes.
          • Evidence:
            • Multicenter 299 adults: nontoxic, decreases frequency+severity of crises, decreases acute chest syndrome, decreases transfusion need.
            • Crossover study 22 children: substation reduction of SC hospitaliation.
          • Mechanism:
            • Unknown, thought due to HbF induction, but benefits show prior to HbF rise, so other mechanisms:
              • neutropenia (Neutrophils enhance fibronectin binding, correlation of neutraphil count to painful crises)
              • Decreases adhesion of RBC to cultured endothelial cells.
          • Long-term tx risk unknown: concern over tumors, no chromosomal changes in BM so far in 32 pts.
          • Can predict response.  Predictors of good response:
            • Adults with higher granulocyte and retic counts, and larger tx-associated decrease in counts had higher HbF conc. 
          • In studies hydroxyurea:
            • Increases in MCV
            • Increases in Hb
            • Decreases retic count, "Stress" retic count, and serum bilirubin.
            • RBC density was reduced.
        • Recombinant Human Erythropoietin?
          • Stimulated HbF production, but conflicting results.
        • Butyric acid?
          • Increased butyric acid in babies delays HbF clearance.
        • Bone marrow transplant
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