TOC |
HEME
Sickle Cell Anemia
Ref: Outlines in Clinical Medicine on Physician Online 2002
A. Introduction
See outline
Hemoglobin
SC Disease
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Sickle cell anemia ccurs in ~1 per 600 black persons in USA
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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)
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About 8% of black persons in USA are carriers of one copy of sickle hemogloblin
(HbS) - the "sickle trait"
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About 40% of their Hb is in the sickle form & the remaining 60% of Hb
is in the normal (HbA) or variant (HbA2) form
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These persons are essentially asymptomatic
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Life Expectancy
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Average lifespan: 42 years for men, 48 years for women
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Most common cause of death related to renal failure; 33% died from sickle
crisis (pain/chest syndrome or stroke)
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High level of HbF predicts improved survival
B. Pathophysiology
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Vaso-occlusion is responsible for most of the major symptoms of the
disease
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Other symptoms are due to hemolysis of red cells leading to anemia
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Genetic Disease
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Normal Hemoglobin (Hb) consists of two alpha and two beta protein chains
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Normal adult Hb is called Hb A
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Sickle cell Hb, or Hb S, is due to mutation of the sixth residue of beta
chain
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Mutation of ß6 glutamic acid to valine (ß6 glu-->val or ß6
E/V)
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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
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D. Summary of Complications of Sickle Cell Disease
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Vaso-Occlusive Complications:
Painful Episodes, Stroke, Acute Chest Syndrome,
Priapism, Liver Disease, Splenic Sequestration, Spontaneous Abortion, Leg
Ulcers, Osteonecrosis, Proliferative Retinopathy, Renal Insufficiency
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Complications of Hemolysis: Anemia -
hemolytic type, Cholelithiasis, Acute aplastic episodes (due to parvovirus
B19)
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Infectious Complications: Mainly related
to functional asplenia, Pneumococcal sepsis, E. coli sepsis, Osteomyelitis
- salmonella or Staphylococcus aureus
E. Symptoms and Signs
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Painful Episodes
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Often acute, usually due to bone ischemia and/or infarction
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PAINFUL Crisis (Vaso-occlusion)
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Infarction of femoral head is not uncommon
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Occur in ~70% of patients with HbSS disease
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Anemias
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Chronic Hemolytic
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Hyperhemolytic (below)
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Painful Crises (increased Reticulocytosis)
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Pancyotopenia: APLASTIC Crisis (decreased Reticulocytosis)
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Megaloblastic Crises (Folate Deficiency)
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Iron Deficiency
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Hyperhemolytic Anemias
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Infection
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Delayed hemolytic Transfusion
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Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
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Spleen Related Problems
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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
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Cerebral Hemorrhage
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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
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Shortness of Breath
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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)
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Large Vessel Disease
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Vascular abnormalities similar to HTN; Renal vascular disease and intrinsic
renal disease, papillary necrosis (see below); Associated problems: cardiac
murmur, rheumatic fever, jaundice
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Other complications
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Gallstones (cholesterol) - cholecystectomy usually only recommended if
symptomatic
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Renal Insufficiency (see below)
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Proteinuria
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Hypertension in minority of patients - often with renal disease; evaluate
carefully
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Avascular necrosis of femoral head
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Leg Ulcers, Strokes, Seizures
F. Acute Chest Syndrome (ACS)
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Occurs at least once in >50% of all patients with SCA; About 13 cases
per 100 patient-years
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Definition of ACS
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Presence of new pulmonary intiltrate infvolving at least one complete lung
segment
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Chest Pain
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Temperature >38.5°C
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Tachypnea, wheezing or cough
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Laboratory
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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
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Initiating Factors
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Fat embolism was most common cause
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Fat likely broken away from bone marrow to venous system and lodged in lung
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Infectious agents with or without fat embolism
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Chlamydia pneumonia, Mycoplasma pneumoniae, and respiratory syncytial virus
most common
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Streptotoccous pneumonia and Staphylococci also found less frequently
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Fat emboli or infection induce local hypoxia in the lung
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Hypoxia induced vasoconstriction and sickling initiate ACS
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Pathophysiology
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Related to multiple mechanisms of pulmonary capillary injury
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Sickle RBC are "stickier" to endothelium due to increased adhesion molecule
expression
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Enhanced VCAM-1 expression on vascular endothelium to alpha4ß1 and
CD36 on RBCs
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Atelectasis exacerbates slowed sickle blood flow through lung
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Complications
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Patients >20 years have more severe course than younger patients
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Multilobar progressive pneumonia
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Mechanical ventilation (13%)
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Neurologic events (11%)
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Death (3%)
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Treatment
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Supportive care in intensive care unit
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High dose oxygen, transfusions and/or fluid to reduce blood viscosity
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Must treat for infection and sickle crisis
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Antibiotics - broad spectrum including atypicals, concern for functional
asplenia
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Bronchodilators - effective in ~20% of patients
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Nitric Oxide
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Nitric oxide reduces RBC-endothelial adhesion and dilates blood vessels
-
Inhaled nitric oxide should be considered experimental for treatment of ACS
G. Management
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No specific HbS polymerization inhibitors to date
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Reduction of intracellular HbS concentration
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Additional Folate Supplementation - 1-4mg po folate per day
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Blood Transfusions to maintain Hb > 8.0 g/dL
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Induction of HbF (fetal hemoglobin; see below)
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Hydroxyurea induces HbF form, replaces partially Hb SS
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Erythropoietin may potentiate effects of hydroxyurea, though this is
controversial
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Short term use of butyrate may also increase HbF but not in long term
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Thus, 10 weeks of intravenous arginine butyrate in severe HbSS or thalassemia
did not increase HbF fraction
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Bolus glucocorticoids can precipitate and/or exacerbate disease due to elevated
HCT
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Vaccinations
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As for surgical or traumatic splenectomy
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Pneumococcus, HIB, Meningococcus
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Painful Crises
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No particular type of pain
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Mild to moderate pain treated with Tylenol, NSAID, Percocet
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Severe Pain: Dilaudid (4mg im), Demerol (100-125mg im), Morphine (10mg im
or iv)
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Oral controlled (slow) release morphine is reliable in children with painful
crisis
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Add diphenhydramine (Benadryl®) or hydroxizine (Vistaril®) im
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Maintain bowel motility wth senekot, magnesium citrate
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Intravenous fluids
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Consider pentoxifylline (Trental®) to increase red cell deformability
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Transfusions are not needed to specifically treat pain
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Renal Disease
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Enalapril 5-10mg po qd decreases proteinuria in 2 week and 6 month trials
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ACE Inhibitors likely protect kidney by decreasing glomerular filtration
pressures
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Effects of 6 months of enalapril occasionally last even after drug is stopped
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Captopril reduces microalbuminuria >50% in normotensive sickle cell patients
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Renal tubular acidosis also occurs
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RTA should be treated with bicarbonate or citrate replacement therapy
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Papillary necrosis can occur during cris due to renal hypoxia
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Treatment of Anemia
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Blood replacement required mainly for sudden severe anemia
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Occurs with splenic sequestration and with parvovirus induced aplastic crisis
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Hypoxia with acute chest syndrome can also be treated with transfusion
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Also for prevention of recurrent strokes in children (maintain HbS fraction
<30%)
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If anesthesia is required, recommend maintaining HCT >30%
H. Hydroxyurea (Hydrea®)
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Mechanisms of Action
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Reduces bone marrow cellularity
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Increases proportion of nucleated RBC's making hemoglobin F (HbF)
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Increases blood levels of fetal hemoglobin (HbF = alpha2 gamma2)
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HbF lacks ß-globin chains and so there is no sickling
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Macrocytosis and increased cell hydration occurs
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Reduces peripheral reticulocytes
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Also reduces RBC adherance to endothelial cells
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Improves endothelial cell function in HbSS patients
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Very effective in reducing number of painful crises in adults with HbSS
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Study done on adults with >2 painful crises per year
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Mean number of crises per year was 2.5 with hydroxyurea and 4.5 with placebo
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Dose is 15mg/kg/day for 12 weeks, increase as tolerated by 5mg/kg/day
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Main side effect is bone marrow suppression
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Folate, 1mg per day, can reduce some of these effects
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Monitor CBC every two weeks
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Stop agent for the following until counts return to normal:
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neutrophils <2000/µL
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reticulocytes or platelets <80,000/µL
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Hb level <4.5gm/dL
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Resume hydroxyurea at 2.5mg/kg/day less than original dose once counts normalize
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Drug may be discontinued in up to ~30% of patients
I. Bone Marrow Transplantation
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May be considered in severe disease
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Criteria for Severe Disease
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History of stroke
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Recurrent acute chest syndrome
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Recurrent painful crises
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HLA-identical sibling allogeneic BMT performed in 22 person <16 years
of age
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Survival
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91% (20/22) survived the initial BMT
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16/20 (75%) had engraftment of donor hematopoietic cells
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Two deaths due to CNS hemorrhage or graft versus host disease (GVHD)
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Overall, ~100 patients with sickle cell disease have undergone transplantation
J. Experimental Therapies
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Induction of HbF by short-chain fatty acids (arginine butyrate)
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Reversing cellular dehydration using cation transporter blockers
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Clotrimazole - antifungal azole which also blocks cation channels
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Combination of clotrimazole, erythropoietin, and hydroxyurea under study
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Magnesium
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Nitric oxide induction may increase HbS affinity for O2, decrease sickling
References