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Sickle Cell Anemia –An OverviewVictoria Price
Blood Matters HalifaxBlood Matters, Halifax28 November 2014
Conflict of InterestsConflict of Interests
• NoneNone
ObjectivesObjectives
• Epidemiology• PathophysiologyPathophysiology• Diagnosis• Complications of SCD• Complications of SCD• Current therapies• Future therapies• Future therapies
HistoryHistory
• 1910 - described by Herrick (Chicago)
• First patient - Dr Walter Clement N l (1884 1916 G d )Noel (1884-1916, Grenada)
• 1920s - named sickle cell disease• 1949 – Linus Pauling refers to “the
first molecular disease” 1949, Science
1956 V I d ib• 1956 – Vernon Ingram describes qualitative defect Hb S: β6
G→V
1956 Nature1956, Nature
Geographic DistributionGeographic Distribution
www.ox.ac.uk
InheritanceInheritance
EpidemiologyEpidemiology
African Americans:African Americans:• Hb S Carriers 1/12• HbSS: 1/425HbSS: 1/425• Hb SC: 1/1000• HbSβ+thal: 1/3000• HbSβ+thal: 1/3000Prevalence in Nova Scotia?
Pathophysiologyy gy
Lancet 2010;376:2018
Diagnosis
Screening – NewbornsScreening Newborns
• Universal screening: Ontario, BC, NS 2014
• Rationale: early therapy prevents M&M
• HPLC• Identifies carriersde t es ca e s• False negative: transfusion,
prematurity (<30 wks)p y ( )
Screening - In ERScreening In ER
Kit test • Sickle solubility test– Kit test– Red cells are
hemolysed
• Sickle solubility test
y– Reducing buffer is
added and HbS precipitatesprecipitates
– Requires >20% HbS– Positive in carriersPositive in carriers
ConfirmationConfirmation
• Peripheral smear review
• HPLC• ElectrophoresisElectrophoresis• IEF• Capillarys• Capillarys
ComplicationsComplications
• Hemolysis
• Vaso-occlusionVaso occlusion
HemolysisHemolysis
• Anemia• CholelithiasisCholelithiasis• Retarded growth• Delayed sexual maturation• Delayed sexual maturation• Pulmonary hypertension
Vaso-occlusionVaso occlusion
• Recurrent painful crises• Recurrent painful crises• Functional asplenia• Stroke• Splenic sequestration• Acute chest syndrome• Avascular necrosis of femoral and
humeral heads• Chronic organ damageChronic organ damage• Priapism• Leg ulcersg
FeverFever
41/2 ld i l• 41/2 yr old girl• HPI: cough 5 days
fever vomitingfever, vomiting, abdominal pain
• PMH: HbSS• PMH: HbSSSplenectomyPneumovax PenVPneumovax, PenV
• ED: 22h00• Died that morning of pneumococcalDied that morning of pneumococcal
sepsis.
FeverFever
• Functional asplenia 3-5 years• Encapsulated organismsp g
• Prevention of infections– Immunizations– Penicillin prophylaxis
• Give antibiotics within 30 i t f t timinutes of presentation.
PainPain
• 5 years male5 years, male• Abdominal and right hip pain • PMH: episodic abdo pain,PMH: episodic abdo pain,
constipation• Sickle screen positive• Uncle HbSC• Diagnosis: HbSC, recurrent
i f l ipainful crises• MRI: bone infarcts
Acute Pain Episodes
InfectionF
HbS polymerizationTissue hypoxiaFever
DehydrationC ld
Hypoxemia
ColdHeat
Hypoxemiaacidosis Veno-occlusion
Management in ERManagement in ER
• EmergentMild-moderate pain:• acetaminophen + ibuprofen• 30-60 min, no relief give
morphinemorphine
Severe pain:Severe pain:• Morphine infusion• HospitalizationHospitalization
TreatmentTreatment
Hydroxyurea
Ware R E Blood 2010;115:5300-5311
©2010 by American Society of Hematology
HydroxyureaHydroxyurea
Green, Pediatric Research (2014) 75, 196–204
TransfusionTransfusion
Sept 2014, JAMA
TransfusionTransfusion
Goals:Goals: 1. Increase oxygen-carrying
capacity p y2. Replace rigid sickle RBCs with
deformable RBCs, to restore ,blood flow
Transfusion- IndicationsTransfusion Indications
• Episodic vs chronic• Always consider :Always consider :
– Benefits vs risks of transfusionAlternatives– Alternatives
– Clinical status of the patientBaseline Hb– Baseline Hb
• Some indications per experience/clinical judgementexperience/clinical judgement
Transfusion MethodsTransfusion Methods
Simple Manual exchange ErythrocytapheresispTransfusion
gTransfusion
y y p
Easy to perform venous access (1)
Time-consuming Manual
ExpensiveSpecialized equipmentvenous access (1) Manual
Trained personnelSpecialized equipment Trained personnel Venous accesses (2)↑Exposure RBC units↑Exposure RBC units
Iron Overload +++ Iron Overload + No iron overload
www.sicklecellsociety.org/carebook.pdf
TransfusionAcute Complications
• Acute chest syndrome• Acute chest syndrome• Splenic sequestration• Stroke• Hepatic sequestration• Hepatic sequestration• Intrahepatic cholestasis• Multi-organ failure• Aplastic crises• Aplastic crises
Sept 2014, JAMA
Transfusion-SurgeryTransfusion Surgery
• Transfuse to Hb 100g/L prior to GA (simple)prior to GA (simple)
• NEJM 1995, Lancet 2013
E h i l f• Exchange vs simple for HbSS with Hb > 85g/Lg HbSβthal and HbSC
Sept 2014,JAMA
Chronic TransfusionsChronic Transfusions
• Child TCD > 200mm/secSTOP I, NEJM 1998
• Previous overt stroke SWITCH, Blood 2012
• Previous silent strokeSIT, NEJM August 2014
Sept 2014, JAMA
Risks of TransfusionsRisks of Transfusions
ACUTE• Acute hemolytic
transfusion reaction
DELAYED• Bloodborne pathogens• Delayed hemolytic
• Bacterial contamination• Allergic reaction• Hypotension
Delayed hemolytic transfusion reaction (DHTR)
• HyperhemolysisHypotension• TRALI
yp y• Alloimmunization• Iron overlaod• PTPPTP• TA-GvHD
Alloimmunization in SCD
• Historical data (1980-1990):( 980 990)– Alloimmunization rate varied from 7.5% to 36% in SCD
patients compared to 5% in -thalassemia patients.Rate of alloimmunization increases exponentially with– Rate of alloimmunization increases exponentially with increasing number of transfusions
– Alloimmunization usually occurs with less than 15 transfusions– Specificity of alloantibodies (% of patients sensitized):
Anti-E Anti-C Anti-K Anti-Fya Anti-Jkb Anti-S
42.3% 30.2% 28.1% 18.3% 10.7% 9.2%
Rosse WF et al. Blood. 1990:76:1431-1437
Alloimmunization: Rh variants
• ↑Frequency Rh variants in African descent.
Eg:Hybrid RHD CE D allele → altered C: 25%Eg:Hybrid RHD-CE-D allele → altered C: 25% • Alloimmunization occurs despite
conventional antigen-matching.g g• Many of the antibodies present as
autoantibodies, but they can cause serious hemolytic reactionsserious hemolytic reactions.
• Samples should be sent to a reference lab.
Prevention of AlloimmunizationPrevention of Alloimmunization1. Transfuse when clinically indicated2 Perform phenotypic matching for C E and Kell antigens2. Perform phenotypic matching for C, E and Kell antigens
for non-alloimmunized SCD patients.– Vichinksy et al. Transfusion 2001
↓ ll i i ti t f 3% t 0 5%/ it• ↓ alloimmunization rate from 3% to 0.5%/unit• ↓ in hemolytic transfusion reactions by 90%
– Reproduced in other studiesSIT t i l ll i i ti t 0 278%/ it• SIT trial: allo-immunisation rate 0.278%/unit
– Castro et al. Transfusion 2002• Limited phenotyping (C, c, E, e, K) would prevent 53,3% of
ll ll tib di d t 70 8% f t d dall alloantibodies compared to 70.8% for a more extended phenotyping (C, c, E, e, K, S, Fya and Jkb ).
• However, finding compatible blood would be problematic (13 6% vs 0 6% of random white blood donors)(13.6% vs 0,6% of random white blood donors)
Prevention of Alloimmunization
3 Communication between transfusion services in order to know the3. Communication between transfusion services in order to know the patient’s transfusion history
4. Recruit and supply RBCs from African-American donors – Blue Tag Program, ARC, Philadelphia
5. Genotype SCD patients and blood donors.
HSCTHSCT
• Only curative intervention• HLA matched unaffected sibHLA matched unaffected sib
(18%)• Unrelated donor: experimentalUnrelated donor: experimental• Graft loss and GVHD• Reduced intensity conditioning• Reduced intensity conditioning
(NIH, ACH) JAMA, July 2014
Future ConsiderationsFuture Considerations
• Excessive cellular adhesion• Ischaemic reperfusion injuryIschaemic reperfusion injury• Hb modifiers that ↑O2 affinity• New generation HbF inducers• New generation HbF inducers• Inflammation-vasculopathy• Gene therapy• Gene therapy
Hematology/Oncology Clinics of NA, April 2014
Take Home PointsTake Home Points
• SCD rare in MaritimesSCD rare in Maritimes• Increasing due to immigrant population• Early diagnosis to prevent complicationsEarly diagnosis to prevent complications• Emergent management of complications to
prevent morbidity and mortalityprevent morbidity and mortality• Requires a multidisciplinary team approach
ResourcesResources
apphon rohppa com• www.apphon-rohppa.com• http://www.nhlbi.nih.gov/health/prof
/blood/sickle/sc mngt pdf/blood/sickle/sc_mngt.pdf• http://www.sickleandthal.org.uk
htt // i kl lldi /• http://www.sicklecelldisease.org/
Questions??Questions??