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Sickle Cell Disease

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Title: Sickle Cell Disease


1
Sickle Cell Disease
  • Douglas E. Laux
  • 2/06/08 and 2/08/08

2
Suggested Websites
  • www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mng
    t.pdf -- NIH guidelines for management
  • of all aspects of sickle cell disease (2002)
  • http//www.gfmer.ch/Guidelines/Anemia_and_hemoglo
    binopathies/Sickle_cell_anemia.htm
  • Excellent website list of guidelines, papers,
    WHO info, Cochrane systematic reviews
  • http//www.scinfo.org -- Grady Memorial Hospital
    (Atlanta, GA) comprehensive website
  • for patient and health care providers.lots of
    good stuff
  • http//sickle.bwh.harvard.edu/menu_sickle.html
    -- Brigham and Womens Hospitals
  • comprehensive center for sickle cell disease
    information website
  • http//www.nslc.wustl.edu/sicklecell/sicklecell.h
    tml -- Washingon Universitys center
  • for sickle cell disease information website

3
Definition
  • Sickle Cell Disease
  • A genetic hemoglobinopathy
  • Results in deformation, increased
  • rigidity, and destruction of RBCs
  • Vasocclusive and pro-inflammatory
  • disease process
  • Chronic multiorgan system disease
  • Severe morbidity and early mortality

http//UpToDateonline.com
Madigan and Malik, Expert Rev in Mol Med 8 (9)
1-18, 2006
4
Definition
  • Autosomal recessive genetic disease
  • ß-globin gene (chromosome 11q) mutation GAG?GTG
    at 6th codon
  • Glutamic Acid ? Valine at the 6th amino acid
    along the ß-globin chain
  • a2ß2 normal hemoglobin
  • a2ßS heterozygote Sickle trait
  • a2S2 homozygous recessive Sickle cell
    disease

5
History of Sickle Cell Disease
  • Known by many African tribes for centuries
  • Earliest historical report -- 1670 in Ghana
  • African cultures often named illness to describe
    the sounds of moaning made by the victims
  • Tribal names
  • Ahututua Twi tribe
  • Chwecheechwe Ga tribe
  • Nuidudui Ewe tribe
  • Obanje Children who come and go

6
History of Sickle Cell Disease
  • 1846 US Case of Absence of Spleen Southern
    Journal of Pharmacology ? likely first paper
    describing pathology of sickle cell disease at
    autopsy of an executed runaway slave
  • 1870 Disease first described in African medical
    literature
  • 1904 peculiar elongated and sickle shaped cells
    described by Dr. James Herrick, cardiologist, and
    intern Dr. Ernest Irons at Presbyterian Hospital,
    Chicago. Pt was Walter Clement Noel, a 1st-year
    dental student and native of Grenada

7
History of Sickle Cell Disease
  • 1917 Washington Univ A woman was identified
    having a father with sickling blood and 3 sisters
    who had died from severe anemia
  • 1923 Taliaferro and Huck described sickling as an
    inheritable Mendelian autosomal characteristic
  • 1932 Diggs et al. distinguished latent sicklers
    (having sickle cell trait) from symptomatic
    sicklers (as having sickle cell anemia)
  • 1947-1949 Neel clarified genetics, associating
    sickle cell trait with heterozygosity and sickle
    cell disease with homozygousity for the S allele

8
History of Sickle Cell Disease
  • 1927 Hahn and Gillespie ? SaO2 and ? pH ?
    sickling
  • 1949 Linus Pauling Applied Gel Electrophoresis
    to separate Hgb A, Hgb AS, Hgb SS, and Hgb F
  • Disease ?? Molecular Defect
  • 1st-ever demonstration
  • 1956-1959 Hunt and Ingram identified B6 Glu?Val
  • 1950s Xray diffraction (Perutz and Mitchison) and
    1960s electron microscopy (Dobler and Bertles)
  • deoxygenation hemoglobin ? Hgb S
    polymerization ? sickling

9
History of Sickle Cell Disease
  • 1950s Concept of Balanced Polymorphism
  • Observation Equatorial Africa ? high frequency
    of Hgb AS was incompatible with high death rate
    of homozygotes and hence high rate of loss of Hgb
    S alleles
  • Drs. Alan Raper (East Africa), Hermann Lehmann
    (Uganda) and Anthony Allison (Kenya)
  • Sickle cell trait malaria survival advantage
  • 1956 Colbourne Edington, 1957 Edington and
    Laing Sickle cell trait confers protection vs
    malaria during early childhood between stages of
    loss of passive immunity and acquirement of
    active immunity

10
Epidemiology
  • Worldwide
  • 5 of world population harbor alleles for
    hemoglobinopathies
  • 300,000 children born each year with
    hemoglobinopathy
  • 200,000 children born yearly in Africa with
    Sickle Cell Disease
  • Areas of Prevalence
  • Sub-Saharan Africa
  • S.C. trait frequency 10-40
  • Highest rates in Ghana,
  • Nigeria, Uganda
  • S.C. disease freq lt/ 2
  • http//www.nslc.wustl.edu/sicklecell/part3/biogeog
    raphy.html

11
Epidemiology
  • Other Areas of Prevalence
  • India
  • Saudi Arabia
  • Mediterranean region (Turkey, Greece, Italy)
  • South and Central America (especially Panama
  • Caribbean Islands

12
Epidemiology
  • Hemoglobin B-globin chain polymorphisms and
    worldwide distribution of major haplotypes
  • http//www.nslc.wustl.edu/sicklecell/part3/biogeog
    raphy.html

13
Epidemiology
  • Hemoglobin B-globin chain polymorphisms and
    worldwide distribution of major haplotypes

http//sickle.bwh.harvard.edu
  • Haplotypes developed independently
  • 70,000 150,000 years ago
  • Each haplotype developed in endemic area
  • of Falciparum malaria

14
Epidemiology
  • USA
  • Sickle cell trait 2 .5 - 3 million (1 in 12)
    African Americans
  • Sickle cell disease 72,000 (1 / 500 African.
    Am. births)
  • Life expectancy (SCD) 42 years (males) and 48
    years (females)
  • Annual cost 475 million (1996)

15
Pathophysiology
Normal Adult Blood a2ß2 Hgb A (97) a2d2
Hgb A2 (2) a2?2 Hgb F (lt1)
http//sickle.bwh.harvard.edu/hbsynthesis.html
16
Pathophysiology
  • Inheritance of mutated hemoglobin ß-globin chain
  • Mutation GAG ? GTG at 6th codon
  • Glutamic acid ? Valine at 6th AA
  • a2ßS heterozygote Sickle trait
  • a2S2 homozygote recessive Sickle cell disease
  • Additional variants
  • Hgb S - ß thalassemia
  • Hgb S - ß0 thalassemia
  • Hgb S - a thalassemia
  • Hgb SC
  • Hgb SD
  • Hgb SE
  • Hgb S-HPFH (Hereditary Persistance of Fetal Hgb)

17
Pathophysiology
Sickling Mechanism
  • Deoxygenation HgbS ? protein conformational
    change
  • Hydrophobic Valine exposed at molecular surface
  • Val6 of B2 chain of 1st Hgb S chain forms
    hydrophobic bond with Phe85 and Leu88 of a 2nd
    Hgb S B1 chain
  • Pairing Hgb S monomers polymerize to form Hgb S
    chains
  • Hgb S polymers precipitate in RBCs as long, rigid
    fibers

Wood AJ. NEJM, 340(13) 1021-1030, 1999.
18
Pathophysiology
  • HgbS fibers are rigid
  • Hgb S fibers deform
  • RBC membranes
  • Membrane disruption
  • exposes transmembrane
  • proteins and lipids that
  • are pro-inflammatory
  • Progressive sickling
  • makes cells dense and
  • inflexible

Frenette et al., Journal of Clinical
Investigation 117(4) 850-858, 2007
19
Hallmarks of Sickle Cell Pathophysiology
  • Sickle Cell Formation
  • Microvascular vasoocclusion
  • Chronic Inflammation
  • Multiorgan System Disease

20
Pathophysiology
  • Factors that Promote Hgb S polymerization
  • Low pO2 / Hypoxia
  • Prolonged Delay Time time RBC spends in
    microcirculation
  • Low pH
  • High Hgb S concentration
  • Genotype-dependent
  • Cellular Dehydration
  • Volume depletion (total body)
  • Sickling ? Activation K / Cl- cotransporter and
  • Gardos Ca2- activated K efflux channels ?
    ion and water efflux
  • Low Hgb F concentration
  • a2?S gamma globin chains bind Hgb S chains and
    inhibit Hgb S
  • polymerization, thus countering sickling
    process

21
Pathophysiology
Vaso-occlusion A Multifactorial Process
  • Mechanical Obstruction
  • sickle cell aggregation
  • ? RBC - Endothelial Adherence
  • ? expression adhesion molecules
  • high pro-adhesive reticuloctes
  • Intimal thickening
  • Impaired vascular tone
  • ?responsiveness to NO

Madigan and Malik, Expert Rev in Mol Med 8(9)
1-18, 2006
22
Pathophysiology
Vaso-occlusion A Multifactorial Process
  • Inflammation
  • Chronic Leukocytosis -- characteristic of sickle
    cell disease
  • WBC gt 15,000 is independent risk factor for early
    death
  • Risk Factor for acute chest syndrome and stroke
  • Repetitive Vaso-occlusion episodes ? Chronic
    ischemia-reperfusion injury
  • ? granulocytic oxygen burst ? reactive oxygen
    species ? tissue damage
  • Up-regulation of pro-inflammatory cytokines
    (TNF-a, IL1-B)
  • Activation of PMNs and Monocytes ? release
    cytokines , chemotactic factors
  • ? PMN endothelium adhesion
  • ? extravasation of PMNs into interstitial tissues
    (? L-selectin / ? ß2-selectin)

23
Pathophysiology
Vaso-occlusion A Multifactorial Process
  • Endothelial Cell Activation
  • Endothelial Cell contraction ? exposure of
    pro-inflammatory subendothelial matrix
  • ? expression of adhesion molecules for RBCs and
    leukocytes
  • ICAM, VCAM, E-selectin
  • Expression of cytokines (IL-6) and chemotactic
    factors (IL-8)
  • Multiple Protrhrombotic Effects
  • Release of high-multimer Von-Willibrand Factor
  • Depletion of anticoagulants (thrombomodulin,
    heparan sulfate)
  • ? plasminogen activator inhibitor
  • ? platelet activating factor
  • ? expression of tissue factor

24
Pathophysiology
Vaso-occlusion A Multifactorial Process
  • Nitric Oxide and Dysregulation of Vascular Tone
  • NO is potent vasodilator
  • NO is produced from Arginine by Nitric Oxide
    Synthase
  • NO is consumed by hemoglobin
  • NO oxyhemoglobin ? methemoglobin and nitrate
  • NO deoxyhemoglobin ? iron nitrosylnitrate
  • SCD patients
  • High serum free oxy- and deoxyhemoglobin from RBC
    lysis
  • Decreased vascular responsiveness to NO
  • High serum arginase ? due to release by ruptured
    sickle RBCs
  • High levels of ROS ? consume NO
  • Low serum arginine ? due to excessive NO
    production and arginase activity

25
Pathophysiology
Redding-Lallinger et al., Curr Probl Pediatr
Adolesc Health Care 36 346-376, 2006.
26
Clinical Syndromes
Disease Severity is Genotype Dependent Genotype
Hgb SS Hgb S / ß0 thalassemia Hgb SC Hgb S /
a thalassemia Hgb S / D Hgb S / A Hgb S / E Hgb
S / ß thalassemia Hgb S / HPFH
Worsening Disease Severity
Asymptomatic / - Mild Anemia
27
Clinical Syndromes
  • Sickle Cell Trait
  • Prevalence 8-14 in African Americans
  • Usually asymptomatic and without anemia
  • Pathology usually limited to renal and splenic
    vascular beds
  • Increased risk of
  • UTI in women
  • Hematuria (4X risk)
  • Hyposthenuria
  • Splenic sequestration / infarction at high
    altitude (gt10,000 ft)
  • Exertional Heat Illness / Sudden Death (40 X
    increased risk)
  • Renal Medullary Carcinoma

28
Clinical Syndromes
  • Acute Vaso-occlusive Pain Crisis
  • Most frequent and recurrent manifestation
  • Age and Rate of Disease Onset (case series of 305
    children)
  • Bainbridge et al., J Pediatr
    106(6)881-885, 1985
  • 1yr old 32
  • 2 yrs 61
  • 6 yrs 92
  • 8yrs 96
  • Earliest Manifestations dactylitis 40, acute
    pain crisis 25,

  • splenic infarct 20
  • Adults gt 20 Average Risk in Hgb SS is 0.8 events
    / yr over 5 yrs
  • 39 pts have no episodes
  • 5.2 pts have 3 to 10 / yr, and account for 33
    of all episodes

29
Clinical Syndromes
  • Acute Vaso-occlusive Pain Crisis
  • Precipitating events weather, infection, asthma,
    exercise, dehydration, stress, menses, nocturnal
    hypoxia, OSA
  • Signs / Symptoms
  • Pain
  • Trivial to excruciating
  • Often multifocal, may affect any body area
  • Most common areas back, extremities, chest,
    abdomen
  • Accompanying Symptoms (50 of crises) fever,
    swelling, tenderness, tachypnea, hypertension,
    nausea, vomiting
  • Duration average 2-7 days

30
Clinical Syndromes
  • Anemia in Sickle Cell Disease
  • Chronic, usually well-compensated
  • Appropriate reticulocytosis
  • Mean Hgb 8, Hct 24
  • Mean RBC lifespan 17 days
  • Low folate
  • Iron Deficiency (20)
  • Low Erythropoietin (in cases w/ renal disease)

31
Clinical Syndromes
  • Anemia in Sickle Cell Disease
  • Chronic, usually well-compensated
  • Severity Hgb S and 1 / Hgb F
  • Appropriate reticulocytosis (absolute retics
    gt500,000)
  • Mean Hgb 8, Hct 24
  • Mean RBC lifespan 17 days
  • Low folate
  • Iron Deficiency (20)
  • Low Erythropoietin (in cases w/ renal disease)

32
Clinical Syndromes
  • Anemia Crises in Sickle Cell Disease
  • Splenic Sequestration Crisis
  • Splenic sinusoidal vaso-occlusion ? splenic
    trapping of blood ? acute splenomegaly, severe
    pain, sharp ? Hgb/Hct, hemodynamic shock
  • Affects 25 children with Hgb SS disease lt5 yrs
    old
  • Does not occur in patients post-splenic
    infarction
  • Aplastic Crisis
  • Destruction of erythroid precursurs in marrow
  • Low reticulocyte index (lt1) (abs count
    lt10,000/ul)
  • Mostly due to Parvo B19 viral infection
  • Also associated with Strept pneumo, Salmonella,
    EBV

33
Clinical Syndromes
  • Acute Chest Syndrome
  • Definition -- Presence of all of the following
    (NACSG)
  • New pulmonary infiltrate involving at least one
    complete lung segment (not atelectasis)
  • Chest pain
  • Temp gt 38.5C
  • Tachypnea, wheezing or cough
  • Epidemiology
  • 2nd most common complication of SCD
  • Occurs in 50 of all pts with SCD
  • Adults 8.7 events / 100 personyrs, 4 9
    mortality
  • Children 21 events / 100 personyrs, lt2
    mortality
  • Most common cause of acute death in adult patients

34
Clinical Syndromes
  • Results from the National Acute Chest Study
    Group
  • NEJM 342(25) 1855-65, 2000
  • Prospective, 30-center Study of 671 episodes of
    ACS involving 538
  • patients

35
Clinical Syndromes
  • Results from the National Acute Chest Study
    Group

Signs and Symptoms of ACS Fever 80 Cough
62 Tachypnea 45 Chest pain 44
Shortness of breath 41 Arm and leg pain
37 Abdominal pain 35 Rib or sternal pain
21 Wheezing 13
36
Clinical Syndromes
  • Results from the National Acute Chest Study
    Group
  • Clinical Outcomes
  • Mean hospitalization stay 10.5 days
  • Age gt20 yrs predictive of more severe course
  • 13 of patients required mechanical ventilation
  • 11 suffered CVA, 46 of these pts had
    respiratory failure
  • 3 of patients died
  • Most common causes of death pulmonary emboli
    and infectious
  • bronchopneumonia

37
Clinical Syndromes
  • Additional Pulmonary Complications of SCD
  • Asthma
  • Pneumonia
  • ? susceptibility to encapsulated organisms
    (Streptococcus, H. flu)
  • due to autosplenectomy
  • Mycoplamsa pneumoniae, Chlamydia pneumoniae
  • Polyvalent Pneumococcal vaccine recommended for
    all pts
  • Sickle Cell Chronic Lung Disease
  • Universally progressive, fatal lung disease
  • Mixed obstructive / restrictive features (low
    FVC, TLC)
  • Concomitant progressive chronic severe chest pain
  • Severe pulmonary fibrosis and pulmonary HTN ensue
  • Death occurs within 7 years

38
Clinical Syndromes
  • Pulmonary Hypertension
  • Defined as MPAP gt/ 25mmHg at rest, gt/ 30mm Hg
    w/
  • exerecise, PCWPlt/ 15mm Hg
  • Prevalence 20-40 in SCD
  • Mortality rate 20 at 2yrs following diagnosis
  • Mechanisms
  • consumption of NO by free hemoglobins and ROS in
  • pulmonary microvasculature
  • increased endothelin-1 expression by endothelium
    ? pulm
  • arterial intimal thickening

39
Clinical Syndromes
  • Pulmonary Hypertension as Risk Factor for Death
    in SCD
  • Galdwin MT et al., NEJM 2004
  • Screened 195 adult pts with SCD with
    Doppler-ECHO
  • Utilized Tricuspid Regurgitant Jet Velocity
    (TRV) to estimate MPAP
  • Pulmonary HTN was defined as TRV gt/ 2.5m/s,
    moderate-severe
  • pulm HTN as gt/ 3.0m/s
  • Right heart cath done to confirm pulm HTN

40
Clinical Syndromes
  • Pulmonary Hypertension as Risk Factor for Death
    in SCD
  • Galdwin MT et al., NEJM 2004
  • Findings
  • 32 pts w/ SCD had pulm HTN w/ TRV gt/ 2.5m/s
  • 9 had mod-severe pulm HTN w/ TRV gt/ 3.0m/s
  • Associated variables (univariate analysis)
  • low Hgb/Hct
  • high AST
  • high LDH
  • increasing age (TRV lt 2.5, age 34 /- 10 TRV gt
    2.5, age 39 /- 12)
  • Predictors of pulmonary HTN
  • assoicated renal and cardiovascular disease
  • systemic hypertension
  • elevated LDH
  • low transferrin levels

41
Clinical Syndromes
  • Pulmonary Hypertension as Risk Factor for Death
    in SCD
  • Galdwin MT et al., NEJM 2004
  • Findings
  • Increased risk of death if TRVgt2.5mm Hg, (RR
    10.1 CI 2.2-47 Plt0.001)
  • No association of pulm HTN with
  • Hgb F level
  • white cell count
  • platelet count

42
Clinical Syndromes
  • Renal Disease
  • Manifestations vary from mild proteinurea ? ESRD
  • 12 of pts with SCD develop CKD by 4th decade
  • SCD accounts for lt1 of ESRD
  • Pathogenesis
  • Repetitive sickling of RBCs in medullary vasa
    recta capillaries
  • Results in recurrent medullary microthrombotic
    infarctions
  • ischemic medullary and papillary necrosis and
    fibrosis
  • Effects ? Medulla, Glomeruli and cortical
    collecting tubules

43
Clinical Syndromes
  • Manifestations of Renal Disease
  • Glomeruli
  • Proteinuria (20-30)
  • Nephrotic syndrome (5)
  • FSGS / MPGN (without mesangial antibody/antigen
    deposits)
  • Medulla
  • Isothenuria 100 (max urine OsM 400-450
    mOsm/kg)
  • Papillary necrosis 15-36
  • Hematuria
  • Medullary Carcinoma (? risk in Sickle Cell Trait
    only!)
  • Distal Tubule
  • Incomplete distal RTA (only in setting of renal
    insufficiency)
  • Impaired potassium secretion

44
Clinical Syndromes
  • Neurologic Disease
  • Infarctive stroke, TIAs, ICH, spinal cord
    infarction
  • Overall incidence 25 in all forms of sickle
    cell anemia
  • Risk of CVA is 0.61 per 100 ptyrs
  • Risk of 1st CVA by age 20 (11) , 30 (15) ,
    40 (24)
  • Screen by transcranial doppler US in children ?
    Prophylaxis w/
  • transfusion therapy to keep Hgb S lt30 of
    total
  • Bone Disease
  • Bone infarction (40), hand-foot syndrome,
    dactylitis
  • Osteonecrosis (humeral and femoral heads)
  • Vertebral body collapse
  • Bone marrow infarction ? reticulocytopenia,
    anemia, pancytopenia

45
Clinical Syndromes
  • Hepatobilliary Disease
  • Acute sickle cell hepatic crisis (10)
  • S/S RUQ pain, nausea, vomiting, fever
  • AST and ALT rarely gt300 IU/L, Tbili usually
    lt15mg/dL
  • Intrahepatic cholestasis -- Severe variant of SC
    hepatic crisis
  • S/S per above profound jaundice, renal
    failure, bleeding diathesis
  • and encephalopathy
  • ALT/AST may range 3000, Tbili 50-200 (gt50
    conjugated)
  • Cholelithiasis / cholecystitis (pigmented
    gallstones in 70 pts)
  • Hepatic sequestration crisis
  • Iron Overload Syndrome

46
Clinical Syndromes
  • Infection
  • Susceptibility to encapsulated organisms due to
    functional asplenia
  • esp. Streptococcus pneumoniae and Haemophilus
    influenzae
  • Introduction of Pneumococcal conjugate vaccine
    ? ? 90 incidence of
  • Strep pneumo infections in children under 5
    yrs age
  • Specific infections of risk in SCD
  • Meningitis (mostly in children, and d/t Strept
    pneumo)
  • Bacterial pneumonia
  • Mycoplasma p. and Chlamydia p. 20 cases
  • Strept pneumo, H flu less common
  • All children 2 mos to 5 yrs ? prophylactic PCN
    VK daily
  • Legionella
  • Repiratory viruses
  • Osteomyelitis (mostly due to Salmonella, with
    Staph lt25)
  • Hepatitis A, B and C

47
Clinical Syndromes
  • Cardiac Disease
  • Increased cardiac output
  • Cardiomegaly, enlarged ventricular size
  • Cardiomyopathy unusual
  • Increased risk of non-atherogenic MI (10 in
    one autopsy series)
  • Priapism
  • Prevalence 6 - 42 of males with SCD
  • Bimodal onset 5-13 years and 21-29 years
  • Frequently recurrent, resulting in impotence
  • Affects Corpora cavernosa
  • Retinal Disease
  • Leg Ulcers
  • Growth Retardation
  • Delayed Cognitive Development

48
Diagnosis
  • Prenatal Testing
  • Offered to At-Risk couples at 10 to 12 weeks
    gestation
  • US At-Risk Pregnancies 4000 to 5000 / yr
  • Fetal DNA obtained via chorionic villus sampling
    or amniocentesis
  • PCR performed on fetal DNA (due to very small
    sample size)
  • If testing , confirmatory testing is done on
    parents
  • Newborn Screening
  • Universal screening is performed in almost all
    US states / territories
  • exceptions New Hampshire, Wash DC, Peurto
    Rico, Virgin Islands
  • Methods Hemoglobin Electrophoresis, Thin Layer
    Isoelectric Focusing,
  • HPLC
  • If testing , confirmatory testing is done on
    parents

49
Diagnosis
Embury SH et al. Diagnosis of sickle cell
syndromes. In UpToDate, Rose, BD(Ed), UpToDate,
Waltham, MA, 2008.
50
Diagnosis
Hemoglobin ElectrophoresisCellulose acetate, pH
8.4
Embury SH et al. Diagnosis of sickle cell
syndromes. In UpToDate, Rose, BD(Ed), UpToDate,
Waltham, MA, 2008.
51
Therapy
  • Acute Vaso-occlusive Pain Crisis
  • Identify Underlying Etiology of Crisis
  • Achieve Pain Control
  • IV Fluid Resuscitation
  • Identify and Treat Underlying Infections
  • Folic Acid Supplementation

52
Therapy
  • Assess Patient and Identify Etiology of Crisis
  • Identify all sources of pain
  • Assess oxygenation
  • Suppl O2 to keep SaO2 gt 92
  • Assess volume status
  • Consider reversible causes
  • Review previous pain crises
  • Look for signs / symptoms of infection
  • Assess for acute chest syndrome
  • Labs CBC, retic index, CMP, ABG
  • INR/aPTT
  • CXR

Yale SH et al., Am Fam Physician, 61(5)
1349-1356.
53
Therapy
  • Volume Repletion in Vaso-occlusive Crisis
  • Rationale Volume Depletion ? promotes sickling
  • ? plasma viscosity ? increases delay time
  • ? cell volume ? ? Hgb S
  • NIH guidelines Start D5 ½ NS 20 mEq KCl/L at
    1 1.5 X maintenance

54
Therapy
  • Fluid replacement therapy for acute episodes of
    pain in people with Sickle cell disease
  • Okomo U, Meremikwu MM. Cochrane Database of
    Systematic Reviews 2007, Issue 2.
  • Objectives
  • To determine the optimal route, quantity and type
    of fluid replacement for people with sickle cell
    disease with acute painful crises.
  • Selection criteria
  • Randomised and quasi-randomised controlled trials
    completed by 2/2002, comparing administration of
    supplemental fluids adjunctive to analgesics
    during acute pain crisis
  • Results Of 16 trials identified, 15 were
    declared not suitable for inclusion, the final
    study is awaiting further assessment.
  • Conclusions
  • Efficacy of any type, route, rate, or quantity of
    fluid repletion remains unknown.
  • A multicentre randomized controlled trial
    assessing efficacy and adverse effects is needed.

55
Therapy
  • Pain Management
  • Assessment
  • Rapid
  • Acute Crises
  • Focus on pain intensity, promt tx, and relief
  • Identify sources, quality, severity, related
    signs/symptoms
  • Comprehensive
  • Chronic pain assessment
  • Outpatient setting
  • Involves pt, family, health care team
  • Address physiologic, sensory, affective,
    cognitive, behavioral,
  • and sociocultural factors

56
Therapy
  • Acute Pain Management
  • Determine usual analgesics used during acute
    crises,
  • dosages, and side effects
  • Identify home maintenance regimen
  • Identify meds taken since onset of crisis

57
Therapy
  • Acute Pain Management NIH guidelines
  • Initiate analgesic therapy within 15 minutes
  • Pt with known crisis history ? use opioid and
    dose known to be effective
  • for that pt
  • Otherwise, give loading dose of IV morphine 5 to
    10mg or
  • IV hydromorphone 1.5mg
  • Reassess and Redose Q 15-30 min prn with ¼ to ½
    loading dose until pain
  • relieved
  • Start scheduled opioid dosing with breakthrough
    prn or PCA pump
  • Coadminister scheduled NSAIDs

Pain relief patient admits to moderate to
complete relief and has at least 50-60 pain
reduction from upper end of scale
58
Therapy
  • Pain management for sickle cell disease
  • Dunlop RJ, Bennett KCLB. Cochrane Database of
    Systematic Reviews 2007, Issue 4.
  • Objectives Assess effectiveness of pharmacologic
    analgesic treatment for management of acute and
    chronic pain in sickle cell disease.
  • Selection Criteria
  • RCTs (completed prior to 2/2002) investigating
    tx of acute or chronic pain in children and/or
    adults in sickle cell disease using pharmacologic
    analgesics.
  • Databases searched MEDLINE, EMBASE, Cochrane
    Controlled Trials Registry, Oxford Pain RCTs
    Citation Database.
  • 50 studies were selected for study.
  • Results 9 RCTs (of 50 retrieved for analysis)
    were included for analysis.

59
Therapy
  • Pain management for sickle cell disease
  • Dunlop RJ, Bennett KCLB. Cochrane Database of
    Systematic Reviews 2007, Issue 4.
  • Results
  • 6 studies children adults lt20 yo, 3 studies
    adults only
  • All studies focused on acute pain episodes
  • No study examined treatment of chronic pain
  • No study examined efficacy of weak analgesics
  • NSAIDS Opioids
  • 1 study oral NSAID provided no additional pain
    control
  • over placebo when coadministered with
    meperidine
  • 1 study scheduled IV ketorolac meperidine
    resulted in
  • 1/3 less meperidine used
  • lower daily pain intensity scores
  • shorter length of hospital stay (3.3d vs 7.2, p
    0.027)

60
Therapy
  • Pain management for sickle cell disease
  • Dunlop RJ, Bennett KCLB. Cochrane Database of
    Systematic Reviews 2007, Issue 4.
  • 1 study IV ketorolac vs meperidine for severe
    pain. Ketorolac
  • was superior in reducing pain in first 150
    minutes.
  • However, N 10 in each study arm.
  • 1 study Morphine SR po vs IV morphine. No
    significant
  • difference in pain scores, dosing frequency,
    adverse effects
  • 2 studies Adjunctive use of corticosteroids
  • single-dose methylprednisolone 15mg/kg vs
    placebo
  • 2 days dexamethasone 0.3mg/kg Q12h vs placebo
  • Result Both Steroid arms ?duration of analgesic
    tx
  • (41.3 vs 71.3 P 0.03 for single dose) and (36.2
    vs 48.4 P0.04
  • for multiple dose)

61
Therapy
  • Pain management in acute Vaso-occlusion crisis
  • Summary
  • Begin analgesic tx within 15 to 30 minutes
  • Titrate Q15 minutes until pain relieved
  • Convert to scheduled breakthrough vs PCA pump
  • Consider early conversion to po analgesics
  • Start concurrent NSAIDS (IV or PO)
  • Consider 2-day corticosteroid pulse
  • Convert to long-acting po meds
  • Consider addition of anxiolytics

62
Therapy
  • Acute Chest Syndrome
  • Oxygen supplementation, goal SaO2 gt 92 - 95
  • Aggressive pain management
  • IVF support
  • Serial ABGs, monitor A-a gradient
  • Daily CBC w/ diff, renal and liver function labs
  • Blood exchange or transfusion if PaO2 lt 70mm Hg
    or Hgb gt1 g/dL
  • below baseline
  • Exchange Txf
  • Multiple lobe involvement
  • Severe hypoxemia
  • Rapid progression
  • Blood / sputum / urine cultures
  • Empiric Broad-Spectrum Abx 3rd gen
    Cephalosporin and macrolide
  • Bronchodilator therapy
  • Incentive spirometry

63
Therapy
  • Hydroxyurea
  • S-phase cytotoxic, myelosuppressive drug
    inhibits ribonucleotide
  • reductase
  • Induces proliferation of early erythroid
    progenitors
  • Leads to ? Hgb F production (a2?2)
  • ? subunit production ? a2 ?S ? does not
    polymerize
  • Additional effects of hydroxyurea
  • ? Neutrophil numbers and neutrophil activation
  • ? stress reticulocytes, ? reticulocyte adhesion
  • ? endothelial adhesion properties (?VCAM-1, ?
    laminin, ?thrombospondin)
  • Improved RBC hydration and MCV
  • Increased Hgb

64
Therapy
  • Multicenter Study of Hydroxyurea (MSH)
  • Charache S et al., NEJM, 332(20) 1317-22, 1995
  • Double-blinded, 21-center, RCT examining effect
    of hydroxyurea in SCD
  • Enrolled 299 adult pts (Hgb SS) having 3 sickle
    cell crises per year
  • Study stopped after 24 months due to observed
    benefit of hydroxyurea
  • Compared to placebo, Tx w/ hydroxurea resulted
    in
  • fewer annual vaso-occlusive crises (2.5 vs 4.5,
    Plt0.001)
  • decreased incidence of acute chest syndrome (25
    vs 51, Plt0.001)
  • fewer pts requiring blood transfusions (48 vs
    73, Plt0.001)
  • increased time to first and second VOC

65
Therapy
  • Multicenter Study of Hydroxyurea (MSH)
  • 9-year follow-up study
  • Steinberg MH et al. JAMA 289(13) 1645-1651, 2003
  • 233 patients were longitudinally followed
  • Patients could chose to stop, start, or continue
    hydroxyurea
  • Results
  • Hydroxyurea led to 40 reduction in mortality at
    9 years
  • 75 patients died, 33 (28) from pulmonary
    disease
  • gt3 episodes VOC and ACS were risk factors for
    mortality
  • Mortality 28 when HbF lt0.5 g/dL, 15 when HbF
    gt0.5 g/dL
  • No pts developed leukemia
  • 3 pts developed cancer (cervical, breast,
    uterine), 1 died

66
Therapy
  • HUG-KIDS Trial
  • Ware RE et al., Blood 99(1) 10-14, 2002
  • Phase I/II pediatric safety trial
  • 53 school-aged children with SCD
  • Pts treated with Hydroxyurea for 2 yrs
  • Identified Predictors of Hgb F response
  • Hgb F increased from 6.8 to 19.8
  • Predictors of Response
  • Higher baseline Hgb F
  • Higher baseline reiculocyte count, WBC
  • Higher maximally tolerated dose of hydroxyurea
  • Better compliance

67
Therapy
  • Hydroxyurea Dosing NIH guidelines as defined by
    MSH
  • Initiation of Treatment
  • Hydroxyurea 10-15mg/kg/day in single daily dose
    X 6-8 weeks
  • Check CBC Q 2wks, Hgb F Q 6-8 wks, serum chem Q
    2-4 wks
  • Tx Continuation If no major toxicity,
    escalate dose Q 6-8wks
  • until desired
    endpoint reached
  • Treatment Endpoints
  • Decreased pain / pain crises
  • Hgb F 15-20
  • Acceptable myelotoxicity
  • lt2500 neutrophils / ul
  • lt 90,000 platelets / ul
  • Hgb lt 5.3 g/dL

68
Therapy
  • Hydroxyurea To Treat or not To Treat?
  • Very few randomized controlled trials
  • MSH is only large trial, and only included
    adults
  • Hydroxyurea only approved by FDA for adults with
    SCD
  • Pros
  • Promising benefits in reducing frequency of pain
    crises, ACS
  • Promising benefit in reducing mortality
  • Potential major cost benefits
  • Cons
  • Uncertain benefit in preventing other major
    complications of SCD
  • (stroke, avascular necrosis, priapism)
  • Uncertain effects on pregnancy
  • Application to other sickle cell variants?
  • Uncertain long-term toxicity risks Cancer?
    Leukemia?

69
Therapy
  • Other Hgb F inducing Agents
  • Short-chain fatty acids (sodium butyrate)
  • Mechanism Histone deacetylation
  • Baboons ? Hgb F
  • Phase II study (N15) 11 responders, Increased
    Hgb F 7 ?21
  • 5-Azacytidine and 5-Aza-2deoxycytidine
  • Mechanism Demethylation of DNA
  • 9-month Phase I/II study (N7) Increased Hgb F
    3.1 ? 13.9
  • Erythropoietin

70
Therapy
  • Allogeneic Stem Cell Transplantation
  • Only Therapy Offering Curative Potential for
    sickle cell disease
  • As of 2002, only 150 patients had undergone SCT
  • Patient recruitment hindered by
  • Difficult pt selection - Absence of early
    prognostic markers in SCD
  • Majority of patients do not have donor
  • High mortality risk of SCT
  • Risk of long-term treatment-induced malignancy
  • Risk of GVHD
  • Pts gt16 have demonstrated poor outcomes d/t
    comorbidities
  • Two multicentre series of allogeneic SCTs have
    been undertaken,
  • 1 in US, 1 in Europe

71
2002 NIH Guidelines for SCT Eligibility in Sickle
Cell Disease
72
Therapy
  • Allogeneic Stem Cell Transplantation
  • American Multicenter Series
  • 50 children received HCT allografts
  • All pts had severe disease, gt16yo, and had
    Allo-matched donor
  • At 39 months
  • 47 survived
  • Overall, event-free, and disease-free survival
    were
  • 90, 79, and 81
  • Of 26 pts with stable engraftment followed for
    gt2yrs
  • 22 pts had fully resolved SCD (no further pain,
    ACS, stroke)
  • All 10 pts w/ hx stroke exhibited improved
    cerebrovascular
  • patency on MRI
  • 5 of 7 females had impaired ovarian function d/t
    conditioning
  • regimen

73
Therapy
  • Allogeneic Stem Cell Transplantation
  • Remains experimental
  • High Rewards balanced with severe risks
  • Nonmyeloablative transplants
  • tried with limited success
  • require more severe immunosuppression
  • Related Umbilical cord transplantation ?

74
Therapy
  • Gene Therapy
  • Goal Transfer anti-sickling ß-globin genes
  • Obstacles
  • poor onco-retroviral vector stability
  • low viral titres and gene transfer efficiency
  • difficulty packaging large ß-globin gene and
    regulatory
  • elements
  • safety concerns
  • HIV Lentiviral vectors offer hope

75
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