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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??