A. Introduction

1. Epidemiology
   1. Occurs in ~1 per 600 black persons in USA
   2. Over 50,000 patients total in USA
   3. About 2000 babies with SCA born annually in USA
   4. About 113,000 hospitalizations annually
2. Other sickle cell syndromes occur in ~1 per 1000 blacks in USA (see table below)
   1. Sickle cell - hemogloblin C disease (HbSC)
   2. Sickle cell - ß-thalassemia (HbS-ßthal)
3. About 7% of black persons in USA are carriers of one copy of sickle hemogloblin (HbS)
   1. About 40% of their Hb is in the sickle form
   2. The remaining 60% of Hb is in the normal (HbA) or variant (HbA2) form
   3. These persons are essentially asymptomatic
   4. Carriers of HbS on one of their Hb alleles are said to have the "sickle trait"
   5. Sickle cell trait (HbS) associated with marked reduction (~90%) in severe falciparum malaria; no effect of HbC or alpha thalassemia [2]
   6. About 1 in 700 newborns of African heritage have HbSS
4. Life Expectancy
   1. Average lifespan: 42 years for men, 48 years for women
   2. Most common cause of death related to renal failure
   3. 33% died from sickle crisis: pain/chest syndrome or stroke
   4. High level of HbF predicts improved survival

B. Pathophysiology [3]

1. Vascular 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")
4. Biochemical properties of Hb S
   1. Hb S polymerizes into long fibers when in the deoxygenated form
   2. Most polymers form sort of stick-in-hole molecular conformation
   3. The polymers form because a hydrophobic interaction occurs with new Valine (V) residue
   4. The long fibers and Hb tetramers exist in a simple 2 phase equilibrium
   5. Thus, there are essentially no "intermediate" oligomers in a solution of Hb S
5. Deformed ("Sickled") Red Blood Cells (RBC)
   1. Abnormal or sickled RBC due to polymerization of HbS inside of sickle patient RBC
   2. In addition to banana-shaped sickled cells, other rigid bizarre RBC forms occur
   3. All of these abnormalities are due to the long HbS polymers
   4. Two copies of abnormal Hb are required for disease (single copy is benign)
6. Sickle RBC Occlude Blood Vessels
   1. The "hard" sickle cells do not pass through capillaries well (non-deformable)
   2. Also cause physical endothelial damage by smashing against arterial intima
   3. Cells tend to stick to endothelial cells
   4. All of these factors contribute to intimal thickening and vessel dysplasia
   5. Sickle RBC are also "dehydrated" due to abnormal ion channel function
7. Inhibitors of Sickling
   1. Reduced blood viscosity in HbS due to the decreased hematocrit
   2. Fetal hemoglobin (Hb F) inhibits HbS polymerization
   3. Increased RBC volume reduces HbS polymerization (reduced HbS concentration)
   4. High oxygen content inhibits HbS polymerization
8. Endothelial - Sickle Cell Interactions
   1. Increased "stickiness" of sickle cells to endothelium due to specific interactions
   2. Reticulocyte counts are elevated in HbSS due to chronic anemia
   3. Reticulocytes express VLA-4 (Integrin a4b1), which binds endothelial cell VCAM-1
   4. High levels of vascular adhesion molecules induced by hypoxia contribute to occlusion [15]
   5. Activated platelet thrombospondin bridges CD36 proteins on endothelium and RBC
   6. Endotheium in SCD is characterized by nitric oxide resistance, reduced L-arginine
   7. Increased arginase activity and dysregulated arginine metabolism found in SCD [16]
   8. Increased hemolysis in SCD may lead to reduced nitric oxide bioavailability as well [16]
9. Hypercoagulability and Platelet Activation [10]
   1. Widespread activation of platelets and pro-coagulant factor increases
   2. Prothrombin fragments and antithrombin/thrombin complexes increased
   3. Elevated plasma D-dimers
   4. Factor V levels reduced (consumption)
   5. Increases in plasmin-antiplasmin complexes
   6. Elevated CD62P (P-selectin) and CD40 ligand expression on platelets
   7. Increased tissue factor expression
   8. Elevated platelet factor 4
   9. Likely that these changes increase vaso-occlusion in SSA and other HbSS syndromes
10. Affected Organs [4]
    1. Many organs are affected, but the following contribute to HbSS polymerization
    2. Sluggish circulation
    3. High level oxygen extraction
    4. Low pH are most
    5. Spleen and bone marrow are particularly vulnerable to chronic damage in SCA
    6. Pulmonary vascular disease: pulmonary hypertension (see below)
    7. Stroke: ~11% of patients <20 years old; important cause of morbidity and mortality [20]
11. Hemoglobin Jamaica Plain (Hb JP) [11]
    1. Double mutant sickling Hb
    2. ß6 E/V and ß68 L/F (leucine to phenylalanine)
    3. More benign course after splenectomy than pure HbS

C. Sickle Cell Syndromes

1. Vaso-Occlusive Complications
   1. Painful Episodes and Chronic Pain [7]
   2. Stroke
   3. Acute Chest Syndrome
   4. Priapism
   5. Liver Disease
   6. Splenic Sequestration
   7. Spontaneous Abortion
   8. Leg Ulcers
   9. Osteonecrosis
   10. Proliferative Retinopathy
   11. Renal Insufficiency
2. Cerebrovascular Disease [20,21]
   1. Stroke ~11% of HbSS patients <20 years
   2. ~10% of children with SSA without neurologic symptoms/signs have cerebral stenosis
   3. Risk of stroke in children with cerebral arterial stenosis is ~40X those without stenosis
   4. Likely due to damage that sickled cells cause to endothelium
   5. Regular blood transfusions to maintain <30% HbSS cells reduces stroke risk >90%
3. Complications of Hemolysis
   1. Anemia - hemolytic type
   2. Cholelithiasis
   3. Acute aplastic episodes (due to parvovirus B19)
   4. Pulmonary Hypertension
4. Pulmonary Hypertension (P-HTN) [17,18,19]
   1. Clinically significant P-HTN present in 10-20% of SCA patients [17]
   2. Symptoms develop when mean pulmonary artery pressure reaches 30-40mm
   3. Severity of P-HTN correlates with degree of hemolysis
   4. P-HTN in SCA increases risk for early death [18]
   5. Hypoxia and vaso-occlusion likely contribute
   6. Right ventricular (RV) dysfunction occurs and leads eventually to Cor Pulmonale
   7. N-terminal pro-B-natriuretic peptide levels correlate with RV dysfunction, progression to frank congestive heart failure, and death in SCA patients [19]
   8. Focus on therapies that increase nitric oxide
   9. Sildenafil (Revatio®, Viagra®) reduces pulmonary pressures and improves exercise tolerance (6 minute walk distance)
   10. Sildenafil also reduced BNP levels
5. Infectious Complications
   1. Mainly related to functional asplenia
   2. Pneumococcal sepsis
   3. E. coli sepsis
   4. Osteomyelitis - salmonella or Staphylococcus aureus
6. Prognostic Factors [5]
   1. In infants <2 years of age, the following are risk factors for poor outcomes:
   2. Dactylytis - pain in hands or feet
   3. Hemoglobin level <7gm/dL
   4. Leukocytosis in the absence of infection

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 [6]
   4. Occur in ~70% of patients with HbSS disease
   5. Chronic pain occurs in ~55% of adults with SS disease; ~30% have daily pain [7]
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
   2. Splenic Infarction
   3. Risk of infection by encapsulated organisms
   4. Howell-Jolly Bodies
   5. By age ~6 years, nearly all patients with SCA have functional asplenia
5. Cerebral Hemorrhage
   1. Common
   2. Complete occlusion of all collateral circulation serving one region
   3. Vaso-Occlusive Crisis
   4. Transfusion therapy for stroke: can prevent vaso-occlusive crises in some people
   5. Note, however, that transfusions increased blood viscosity
6. Shortness of Breath [6]
   1. Often due to problem called "Chest Syndrome" (see below)
   2. Consider bronchoalveolar lavage in patients with unclear etiology or infectious agent
   3. Differential: Rib / Sternal infarction, pulmonary infarction (thrombotic or fat embolus)
   4. Assess for congestive heart failure (usually RV dysfunction initially)
   5. May be complicated / exacerbated by P-HTN (see above)
7. Large Vessel Disease
   1. Vascular abnormalities similar to HTN
   2. Cerebrovascular disease (see above)
   3. Renal vascular disease and intrinsic renal disease, papillary necrosis (see below)
   4. 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
   7. P-HTN - as above

F. Acute Chest Syndrome (ACS) [4,6]

1. Occurs at least once in >50% of all patients with SCA
   1. Second most common cause of hospitalization in SCA (after painful crises)
   2. Leading cause of death in SCA
2. About 13 cases per 100 patient-years
3. Definition of ACS
   1. Presence of new pulmonary intiltrate involving at least one complete lung segment
   2. Chest Pain
   3. Temperature >38.5°C
   4. Tachypnea, dyspnea, wheezing or cough
4. Laboratory
   1. Hemoglobin and hematocrit levels are usually reduced
   2. Leukocytosis is prominant
   3. Chest radiograph with pulmonary infiltrates - usually multilobar
   4. Ventilation-Perfusion Scan may be useful to rule out larger embolism
5. Initiating Factors [8]
   1. Four major precipitants: bone marrow (fat) embolism, infection, venous thromboembolism, atelectasis
   2. Fat embolism is most common cause
   3. Fat usually broken away from (infarcted) bone marrow to venous system, lodges in lung
   4. Infectious agents with or without fat embolism
   5. Chlamydia pneumonia, Mycoplasma pneumoniae, respiratory syncytial virus most common
   6. Streptotoccous pneumonia and Staphylococci less frequently
   7. Fat or thrombotic emboli or infection and/or atelectasis induce local hypoxia in the lung
   8. Hypoxia induced vasoconstriction and sickling initiate ACS
6. 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
7. Complications [8]
   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%)
8. Treatment
   1. Supportive care in intensive care unit
   2. Primary goal is to reduce the percentage of HbSS in the blood
   3. Acutely, packed RBC transfusion or RBC exchange
   4. Transfusion reduces HbSS but increases blood volume and viscosity
   5. RBC exchange replaces a large portion of HbSS with HbA without increasing volume
   6. Most centers perform RBC exchange in patients who deteriorate with RBC transfusion
   7. High dose oxygen reduces sickling
   8. Must treat for infection and sickle crisis
   9. Antibiotics - broad spectrum including atypicals, concern for functional asplenia
   10. Bronchodilators - effective in ~20% of patients [8]
9. Nitric Oxide [9,16]
   1. Nitric oxide bioavailability is reduced in SCD, likely due to hemolysis, endothelial dysfunction
   2. Nitric oxide reduces RBC-endothelial adhesion and dilates blood vessels
   3. Inhaled nitric oxide should be considered experimental for treatment of ACS (see below)

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. Blood transfusions critical for patients with carotid stenosis on Doppler screening [20,21]
   4. Blood transfusions to maintain <30% sickle cells (HbSS) reduces stroke risk [21]
3. Induction of HbF (fetal hemoglobin; see below) [1]
   1. Hydroxyurea induces HbF form, partially replaces Hb SS
   2. Erythropoietin may potentiate effects of hydroxyurea, though this is controversial [1]
   3. Intravenous arginine butyrate in severe HbSS or thalassemia did not increase HbF fraction
   4. 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 and Vaso-Occlusive Crises
   1. Pain control, oxygenation and hydration are critical
   2. Oxygen is always given
   3. Mild to moderate pain treated with Tylenol, NSAID, Percocet
   4. Severe Pain: Dilaudid (4mg im), Demerol (100-125mg im), Morphine (10mg im or iv)
   5. Oral controlled (slow) release morphine is reliable in children with painful crisis
   6. Add diphenhydramine (Benadryl®) or hydroxizine (Vistaril®) im
   7. Preliminary data suggest inhaled nitric oxide reduces pain, morphine use; may reduce duration of hospitalization [9]
   8. Maintain bowel motility wth senekot, magnesium citrate
   9. Intravenous fluids to maintain good hydration
   10. Consider pentoxifylline (Trental®) to increase red cell deformability
   11. Poloxamer 188 is nonionic block copolymer surfactant, antithrombotic, hemorheologic
   12. Treatment of painful crises with poloxamer 188 for 48 hours reduced symptoms, particularly in patients receiving hydroxyurea [12]
   13. Transfusions are not needed to specifically treat pain
   14. Hydroxyurea reduces painful episodes and improves mortality [13]
6. Blood Pressure
   1. Appears to be reduced in most patients with sickle cell disease
   2. Higher values of BP correlated with increased risk of stroke and death (expected)
   3. Blood pressures above 140/90mm Hg should be evaluated and usually treated
   4. ACE inhibitors may be preferred, as they reduce microalbuminuria
7. Renal Disease [14]
   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
8. 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®) [1,24,25,26]

1. Clear Benefits on Several Disease Endpoints [13,25,26]
   1. Improves Hb level, HbF %, MCV of RBCs, leukocyte counts
   2. Reduces pain crises, hospitalizations, transfusions required, acute chest syndrome
   3. No difference in incidence of leg ulcers
   4. Mortality reduced >30% with hydroxyurea in adults with HbSS after 9 years' followup [13]
   5. FDA approved for treatment of SCA and clearly modifies disease progression
2. 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 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
3. 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
4. Dosing [24]
   1. Given once daily as single oral dose
   2. Starting dose is 15mg/kg/day if creatinine clearance is >60mL/min
   3. Starting dose is 7.5mg/kg/day if creatinine clearance is <60mL/min
   4. Assess Hb level and blood counts at 2 weeks
   5. Expect significant reduction in white cell and platelet count and increase in mean RBC volume
   6. Peripheral counts monitored every 2 weeks to determine if dose adjustment needed
   7. HbF level should be evaluated q3-4 months
5. Stopping Hydroxyurea
   1. Stop if the following until counts return to normal: b Neutrophils <2000/µL
   2. Reticulocytes or platelets <80,000/µL
   3. Hb level <4.5gm/dL
   4. Restart at a lower dose once values have returned to acceptable range
   5. Do not allow counts to go into very low range more than twice
6. Dose Escalation
   1. If after 12 weeks counts are in acceptable range, increase as tolerated by 5mg/kg/day
   2. Maximum dose of 35mg/kg/day or when counts fall into very low range
   3. Do not allow counts to go into very low range more than twice
   4. Stable dose is usually defined within 6 months
7. Main side effect is bone marrow suppression [25,26]
   1. Folate, 1mg per day, can reduce some of these effects
   2. Once on a stable dose, monitor counts monthly x 4 months, then q3 months for a year
   3. After 1 year on stable dose, monitoring every 3-6 months is acceptable
   4. HbF level should be evaluated q3-4 months
   5. May also impair spermatogenesis
   6. No association with leukemia (which is seen with various other chemotherapies)

I. Bone Marrow Transplantation [22,23]

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]

1. Nitric oxide (as above)
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

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