Sickle Cell DiseaseSickle Cell Disease

Gerald M. Woods, MDGerald M. Woods, MDProfessor of PediatricsProfessor of Pediatrics

Division Director, Hematology/Oncology/BMTDivision Director, Hematology/Oncology/BMTDirector of Sickle Cell ProgramDirector of Sickle Cell Program

Children’s Mercy Hospitals and ClinicsChildren’s Mercy Hospitals and Clinics

DisclaimerDisclaimer

Member of DSMB for MASTMember of DSMB for MAST Member of DSMB for MASTMember of DSMB for MAST

ObjectivesObjectives

To become acquainted with sickle cellTo become acquainted with sickle cellTo become acquainted with sickle cell To become acquainted with sickle cell center expertise in caring for patients with center expertise in caring for patients with sickle cell diseasesickle cell disease

To become familiar with the Newborn To become familiar with the Newborn screening resultsscreening results

To understand the role of the primary To understand the role of the primary care provider in the care of patients with care provider in the care of patients with Si kl C ll DiSi kl C ll DiSickle Cell DiseaseSickle Cell Disease

To become familiar with clinical To become familiar with clinical complications in sickle cell children and complications in sickle cell children and adolescentsadolescents

Sickle Cell DiseaseSickle Cell Disease

How Common is it?How Common is it? How Common is it?How Common is it? In the US Pediatric population the In the US Pediatric population the

prevalence ofprevalence of Diabetes Mellitus 1:2,500Diabetes Mellitus 1:2,500 Acute Leukemia 1:2,880Acute Leukemia 1:2,880 Cystic Fibrosis 1:2 940Cystic Fibrosis 1:2 940 Cystic Fibrosis 1:2,940Cystic Fibrosis 1:2,940 Muscular Dystrophy 1:5,000Muscular Dystrophy 1:5,000 Phenylketonuria (PKU) 1:10,000Phenylketonuria (PKU) 1:10,000 Galactosemia 1:17,000Galactosemia 1:17,000

SCD IncidenceSCD Incidence

In the US Sickle Cell DiseaseIn the US Sickle Cell Disease In the US, Sickle Cell Disease In the US, Sickle Cell Disease affectsaffects 1 in every 400 African Americans1 in every 400 African Americans 1 in 1,0001 in 1,000--1,400 Hispanics1,400 Hispanics 1 in 3,000 Native Americans1 in 3,000 Native Americans 1 in 60,000 Whites1 in 60,000 Whites

(1993, AFHCPR data)(1993, AFHCPR data)

SCD IncidenceSCD Incidence

Disease Impact in our CountryDisease Impact in our Country Disease Impact in our CountryDisease Impact in our Country Most common genetic defect in the US Most common genetic defect in the US

(autosomal recessive)(autosomal recessive) 100,000 people with SCD in the US100,000 people with SCD in the US 5,000 affected infants born in US each 5,000 affected infants born in US each

yearyear HbHb SS 65%SS 65% HbHb SC 25%SC 25% HbHb SSββ++ Thalassemia 8%Thalassemia 8% HbHb SSββ00 Thalassemia 2%Thalassemia 2%

World-Wide Distribution of Hemoglobin S

World-Wide Distribution of Hemoglobin S

Geographic distribution of hemoglobin S in the world

Why Do Cells Sickle?Why Do Cells Sickle?

Point of mutationPoint of mutationPoint of mutation Point of mutation on on ββ--globin chain globin chain of hemoglobin: of hemoglobin: Glutamic acid is Glutamic acid is substituted for substituted for valinevaline

Allowing the Allowing the l i ti fl i ti fpolymerization of polymerization of

sickle hemoglobin sickle hemoglobin when when deoxygenateddeoxygenated

Normal vs. Sickle Red CellsNormal vs. Sickle Red Cells

NormalNormal SickleSickleNormalNormal DiscDisc--shapedshaped DeformableDeformable Life span of 120 Life span of 120

daysdays

SickleSickle SickleSickle--shapedshaped RigidRigid Life span of 20 days Life span of 20 days

or lessor less

Hemoloysis and Vaso-occlusionHemoloysis and Vaso-occlusion

HemoloysisHemoloysis:: VasoVaso--occlusion:occlusion:HemoloysisHemoloysis::The anemia in SCD is The anemia in SCD is caused by hemolysis, and caused by hemolysis, and the degree of anemia the degree of anemia varies widely between varies widely between patients.patients.

The production of red cells The production of red cells by the bone marrow by the bone marrow

VasoVaso occlusion:occlusion:Occurs when the rigid Occurs when the rigid sickle shaped cells fail to sickle shaped cells fail to move through the small move through the small blood vessels, blocking blood vessels, blocking local blood flow to a local blood flow to a microscopic region of microscopic region of tissue.tissue.

yyincreases dramatically, but increases dramatically, but is unable to keep pace with is unable to keep pace with the destruction.the destruction.

Amplified many times, Amplified many times, these episodes produce these episodes produce tissue hypoxia. The result tissue hypoxia. The result is pain, and often damage is pain, and often damage to organs.to organs.

Sickle Cell ManifestationsSickle Cell Manifestations

Acute ManifestationsAcute Manifestations Chronic ManifestationsChronic Manifestations Bacterial sepsis or meningitis*Bacterial sepsis or meningitis* Recurrent vasoRecurrent vaso--occlusive pain occlusive pain

(dactylitis, musculoskeletal or (dactylitis, musculoskeletal or abdominal pain)abdominal pain)

Splenic sequestration*Splenic sequestration* Aplastic crisis*Aplastic crisis* Acute chest syndrome*Acute chest syndrome* Stroke*Stroke* PriapismPriapism Hematuria, including papillary Hematuria, including papillary

Anemia Anemia JaundiceJaundice SplenomegalySplenomegaly Functional aspleniaFunctional asplenia Cardiomegaly and functional Cardiomegaly and functional

murmursmurmurs Hyposthenuria and enuresisHyposthenuria and enuresis ProteinemiaProteinemia CholelithiasisCholelithiasis Delayed grown and sexualDelayed grown and sexualg p p yg p p y

necrosisnecrosis

*Potential cause of mortality

Delayed grown and sexual Delayed grown and sexual maturationmaturation

Restrictive lung disease*Restrictive lung disease* Pulmonary hypertension*Pulmonary hypertension* Avascular necrosisAvascular necrosis Proliferative retinopathyProliferative retinopathy Leg ulcersLeg ulcers Transfusional hemosiderosis*Transfusional hemosiderosis*

SCD IncidenceSCD Incidence

Is Newborn ScreeningIs Newborn Screening Is Newborn Screening Is Newborn Screening Necessary?Necessary? All 50 states have a newborn All 50 states have a newborn

screening program to detect sickle screening program to detect sickle cell disease!cell disease!1 i 10 Af i A i1 i 10 Af i A i 1 in 10 African Americans carry one 1 in 10 African Americans carry one gene (sickle trait)gene (sickle trait)

Constituents of HemoglobinConstituents of Hemoglobin

Hemoglobin has 2 Alpha and 2 Beta chainsHemoglobin has 2 Alpha and 2 Beta chainsg pg p Normal hemoglobin in the red cell consists of Normal hemoglobin in the red cell consists of

HbHb A, A, HbHb F, and F, and HbHb A2A2 Chromosome 11 encodes DNA sequences Chromosome 11 encodes DNA sequences

for for beta (beta (ββ), delta (), delta (δδ) and gamma () and gamma (λλ) ) chainschains Chromosome 16 encodes DNA sequences of Chromosome 16 encodes DNA sequences of

alpha (alpha (αα)) chainschains The beta variants such asThe beta variants such as HbHb SS HbHb C andC and The beta variants such as The beta variants such as HbHb S, S, HbHb C, and C, and

HbHb D all occur from a mutation on D all occur from a mutation on Chromosome 11 causing a defective beta Chromosome 11 causing a defective beta globin geneglobin gene

Normal Newborn ScreeningNormal Newborn Screening

FAFAF = Fetal hemoglobin 80F = Fetal hemoglobin 80--90%90%

A = Normal A hemoglobin 10A = Normal A hemoglobin 10--20%20%

Hemoglobin SHemoglobin S

Valine substitutes for glutamic acidValine substitutes for glutamic acid Valine substitutes for glutamic acid Valine substitutes for glutamic acid on position 6 of Beta globin chainon position 6 of Beta globin chain Sickle Sickle HbHb polymerizes with polymerizes with

deoxygenation causing distortion of deoxygenation causing distortion of RBC, leading to vasoocclusion and RBC, leading to vasoocclusion and ggeventual hemolysiseventual hemolysis

Newborn (NBS) Screening Results

Newborn (NBS) Screening Results

Hemoglobins are listed in order ofHemoglobins are listed in order of Hemoglobins are listed in order of Hemoglobins are listed in order of percentagepercentage

Sickle Cell TraitSickle Cell Trait FASFAS

Sickle Cell DiseaseSickle Cell Disease FSFS Electrophoresis shows absence of Electrophoresis shows absence of αα1, 1,

normal normal αα2 and F; and presence of 2 and F; and presence of HbHb SS

Newborn Screening in MissouriNewborn Screening in Missouri

All significant hemoglobinopathies are All significant hemoglobinopathies are g g pg g pscreened in Missouriscreened in Missouri

Greater responsibility is placed on the Greater responsibility is placed on the physician of recordphysician of record Inform and educate parentsInform and educate parents Recommend additional appointments to a sickle Recommend additional appointments to a sickle

cell expertcell expert All SCA infants should be started onAll SCA infants should be started onAll SCA infants should be started on All SCA infants should be started on

prophylactic penicillin by the age of 2 monthsprophylactic penicillin by the age of 2 months All parents are instructed to seek medical All parents are instructed to seek medical

attention when there is a fever of attention when there is a fever of >> 101.5101.5°° FF

Hemoglobin CHemoglobin C

Lysine substitutes for glutamic acid inLysine substitutes for glutamic acid in Lysine substitutes for glutamic acid in Lysine substitutes for glutamic acid in position 6 of Beta globin chain position 6 of Beta globin chain (Chromosome 11)(Chromosome 11)

Higher frequency among Western Higher frequency among Western Africa, Italy, Greece, Turkey, and the Africa, Italy, Greece, Turkey, and the Middle EastMiddle EastMiddle EastMiddle East

HbHb C crystalizes within the red cellC crystalizes within the red cell The presence of The presence of HbHb C results in C results in

increase viscosity of the bloodincrease viscosity of the blood

NBS ResultsNBS Results

C traitC trait C traitC trait FACFAC

CC hemoglobinCC hemoglobin FCFC Shortened red cell survival (hemolysis) in Shortened red cell survival (hemolysis) in

HbCCHbCC

SC diseaseSC disease FSCFSC Sickling complicationsSickling complications

Beta ThalassemiaBeta Thalassemia

Absence or decrease of one orAbsence or decrease of one or Absence or decrease of one or Absence or decrease of one or more beta globin genesmore beta globin genes Decreased production of normal Decreased production of normal

Hemoglobin A (Chromosome 11)Hemoglobin A (Chromosome 11) MicrocytosisMicrocytosis Unbalance synthesis of alpha andUnbalance synthesis of alpha andUnbalance synthesis of alpha and Unbalance synthesis of alpha and

beta globin chainsbeta globin chains Ineffective erythropoiesis and a Ineffective erythropoiesis and a

hemolytic anemiahemolytic anemia

NBS ResultsNBS Results

Beta Beta thalthal major: fatal in early childhood w/o PRBC major: fatal in early childhood w/o PRBC j yj ytransfusionstransfusions SplenomegalySplenomegaly Significant red cell dyscrasiaSignificant red cell dyscrasia

Beta Beta thalthal intermedia: severe microcytosis; +/intermedia: severe microcytosis; +/--PRBCPRBC HEP: HEP: HbHb F, F, HbHb AA22, , HbHb A is absent (BetaA is absent (Beta00) or ) or

markedly markedly (Beta(Beta++))B t Th l i Mi /T it h t t fB t Th l i Mi /T it h t t f Beta Thalassemia Minor/Trait: heterozygotes for Beta Thalassemia Minor/Trait: heterozygotes for one abnormal beta globin geneone abnormal beta globin gene Mild microcytic anemiaMild microcytic anemia HEP: + HEP: + HbHb A, slight A, slight HbHb A2, normal or slightly A2, normal or slightly HbHb F and F and RBC countRBC count

Alpha ThalassemiaAlpha Thalassemia

Loss of Loss of >> one alpha globin genes one alpha globin genes p g gp g g(Chromosome 16)(Chromosome 16)

A normal person has four alpha genes A normal person has four alpha genes ((αααα//αααα))

Alpha Alpha thalthal major: lack of all four alpha genesmajor: lack of all four alpha genes Hydrops fetalis; usually fatal in utero (Hydrops fetalis; usually fatal in utero (----//----))

Hemoglobin H disease: loss of three alpha Hemoglobin H disease: loss of three alpha genesgenesgenesgenes Moderately severe hemolytic anemia (Moderately severe hemolytic anemia (--αα//----))

Alpha Alpha thalthal trait: two alpha genes losttrait: two alpha genes lost Mild anemia with microcytosis; resembles Fe Mild anemia with microcytosis; resembles Fe

deficiency; normal A2 (deficiency; normal A2 (αα--//αα--) or () or (----//αααα))

Hemoglobin Bart’sHemoglobin Bart’s

Silent carrier alpha Silent carrier alpha thalthal: one alpha gene lost: one alpha gene lostpp p gp g Not clinically significantNot clinically significant HbHb Bart’s on newborn screen (Bart’s on newborn screen (αα--//αααα))

HbHb Bart’s in cord blood sample may indicate Bart’s in cord blood sample may indicate the number of alpha genes lostthe number of alpha genes lost <5% = most likely one gene deletion; silent <5% = most likely one gene deletion; silent

carrier alpha carrier alpha thalthal, (, (--αα//αααα)) 55--10% = alpha10% = alpha thalthal minor, loss of two alphaminor, loss of two alpha55 10% alpha 10% alpha thalthal minor, loss of two alpha minor, loss of two alpha

genes (genes (--αα//--αα) or () or (----//αααα)) >10% (usually 15>10% (usually 15--20%) = more severe form of 20%) = more severe form of

alpha alpha thalthal; further testing is indicated (; further testing is indicated (----//--αα))

Newborn Screening ResultsNewborn Screening Results

Confirmation of NBS by HEP must beConfirmation of NBS by HEP must beConfirmation of NBS by HEP must be Confirmation of NBS by HEP must be donedone

Genetic counseling for “traits” by PCP, Genetic counseling for “traits” by PCP, Sickle Cell Foundation or hematologistSickle Cell Foundation or hematologist

Absence of Hemoglobin A1 confirms it is Absence of Hemoglobin A1 confirms it is NOT sickle cell traitNOT sickle cell trait

www.SCInfo.orgwww.SCInfo.org : info on NBS results: info on NBS resultsgg HbHb F modifies severity of SCDF modifies severity of SCD Alpha thalassemia trait modifies SCA Alpha thalassemia trait modifies SCA

severityseverity

Newborn Screening ResultsNewborn Screening Results

FS (Sickle Cell Anemia FS (Sickle Cell Anemia HbHb SS)SS) FS (Sickle betaFS (Sickle beta--0 Thalassemia, no beta globin)0 Thalassemia, no beta globin) FS (Sickle Hereditary Persistence of Fetal Hemoglobin FS (Sickle Hereditary Persistence of Fetal Hemoglobin

HPFH)HPFH) FSC (Hemoglobin SC Disease, FSC (Hemoglobin SC Disease, HbHb SC)SC) FSA or FS (Sickle beta FSA or FS (Sickle beta --+ Thalassemia, reduced beta+ Thalassemia, reduced beta--

globin)globin) FC (Hemoglobin C Disease, may have hemolysis)FC (Hemoglobin C Disease, may have hemolysis) FAS (Sickle Cell Trait, must do genetic counseling)FAS (Sickle Cell Trait, must do genetic counseling)( , g g)( , g g) FA (Normal newborn screen)FA (Normal newborn screen) FAX or FX (Abnormal hemoglobin present, MUST have FAX or FX (Abnormal hemoglobin present, MUST have

confirmatory testing done)confirmatory testing done) F (Homozygous beta Thalassemia)F (Homozygous beta Thalassemia)

Significant Causes of Morbidity/Mortality in Children with

Sickle Cell Disease

Significant Causes of Morbidity/Mortality in Children with

Sickle Cell DiseaseA l i C i iA l i C i i Aplastic CrisisAplastic Crisis Splenic SequestrationSplenic Sequestration StrokeStroke Acute Chest SyndromeAcute Chest Syndrome Painful EpisodesPainful Episodes Serious InfectionSerious Infection

Role of the Primary Care Physician

Role of the Primary Care Physician

ENCOURAGE COMPREHENSIVE CAREENCOURAGE COMPREHENSIVE CAREENCOURAGE COMPREHENSIVE CARE ENCOURAGE COMPREHENSIVE CARE AND MEDICAL HOMEAND MEDICAL HOME

Check the Newborn Screen Results!!!Check the Newborn Screen Results!!! Start PCN 125mg BID Start PCN 125mg BID if suspectif suspect SCASCA Refer to hematologyRefer to hematology

Offer genetic counseling for AS, AC, ADOffer genetic counseling for AS, AC, AD Impaired urine concentration Impaired urine concentration –– ASASpp Gross Hematuria Gross Hematuria –– ASAS Splenic infarct at high altitudes Splenic infarct at high altitudes –– ASAS Rhabdomyolysis during prolonged Rhabdomyolysis during prolonged

strenuous exercise strenuous exercise -- ASAS

Fever and InfectionFever and Infection

Fever > 38.5Fever > 38.5°° C C Indications for Indications for (101.5(101.5°° F) is an F) is an EMERGENCYEMERGENCY

33% <5y 33% <5y HbHb SS will SS will become septic become septic without PCN without PCN prophylaxisprophylaxis

Basic laboratory Basic laboratory evaluation (consider):evaluation (consider):

hospitalization & IV hospitalization & IV antibioticsantibiotics Child appears illChild appears ill Any temperature > 40 Any temperature > 40

CC Abnormal laboratory Abnormal laboratory

valuesvalues Start IV antibiotics Start IV antibiotics evaluation (consider):evaluation (consider):

CBC with differential CBC with differential and reticulocyte and reticulocyte count, blood, urine, count, blood, urine, and throat cultures, and throat cultures, urinalysis, chest xurinalysis, chest x--rayray

Sta t a t b ot csSta t a t b ot csIMMEDIATELY IMMEDIATELY if if child appears ill or child appears ill or temperature > 40temperature > 40°° C C (DO NOT WAIT FOR (DO NOT WAIT FOR LABS)LABS)

HyposplenismHyposplenism

Functional reduction of splenic activityFunctional reduction of splenic activityp yp y Intrasplenic sickling Intrasplenic sickling altered circulation altered circulation

splenomegaly splenomegaly progressive fibrosis progressive fibrosis autosplenectomyautosplenectomy May see HowellMay see Howell--Jolly bodies on smearJolly bodies on smear

Infection riskInfection risk 300300--600x more likely to develop overwhelming 600x more likely to develop overwhelming

pneumococcal and pneumococcal and H. influenzaeH. influenzaesepsis/meningitissepsis/meningitissepsis/meningitissepsis/meningitis

Also linked to increased risk of gramAlso linked to increased risk of gram--negative negative enteric organisms and Salmonellaenteric organisms and Salmonella

Greatest risk is during the first 5 years of life!!Greatest risk is during the first 5 years of life!!

Current RecommendationsCurrent Recommendations

Antibiotic prophylaxisAntibiotic prophylaxisAntibiotic prophylaxisAntibiotic prophylaxis Hgb SS and Hgb SHgb SS and Hgb Sββ°° thalassemia thalassemia

patientspatients Pen VKPen VK

00--3 yo:3 yo: 125mg PO BID125mg PO BID 33--11 yo:11 yo: 250mg PO BID250mg PO BID >> 12 yo:12 yo: 500mg PO BIX500mg PO BIX

Alternative = ErythromycinAlternative = ErythromycinAlternative ErythromycinAlternative Erythromycin Typically stop at 5 yo @ CMH (other centers Typically stop at 5 yo @ CMH (other centers

may vary)may vary) Longer if surgical splenectomy or Longer if surgical splenectomy or

pneumococcal sepsispneumococcal sepsis

Splenic SequestrationSplenic Sequestration

Hemoglobin SSHemoglobin SS Hemoglobin SSHemoglobin SS Incidence increased: 6 and 36 Incidence increased: 6 and 36

monthsmonths Overall incidence about 16%Overall incidence about 16%

Hemoglobin SCHemoglobin SC Incidence increased: 2 and 17 yearsIncidence increased: 2 and 17 years Incidence increased: 2 and 17 yearsIncidence increased: 2 and 17 years Mean age 8.9 yearsMean age 8.9 years Can occur in adolescence and adulthoodCan occur in adolescence and adulthood Incidence about 5%Incidence about 5%

Splenic SequestrationSplenic Sequestration

Splenic Sequestration CrisisSplenic Sequestration CrisisSplenic Sequestration CrisisSplenic Sequestration Crisis Rapid splenic enlargementRapid splenic enlargement Rapid fall in hemoglobin levelRapid fall in hemoglobin level Fall in Platelet countsFall in Platelet counts Presence of Nucleated Red Blood CellsPresence of Nucleated Red Blood Cells Usually febrile and sometimes listlessUsually febrile and sometimes listless

TreatmentTreatment Close monitor VS, Close monitor VS, HbHb Hydration and transfusion acute and chronicHydration and transfusion acute and chronic Teach spleen palpation Teach spleen palpation

Pneumonias and Acute Chest Syndrome

Pneumonias and Acute Chest Syndrome

Acute Chest SyndromeAcute Chest Syndrome May be associated with May be associated with yy New pulmonary New pulmonary

infiltrate on chest infiltrate on chest radiographradiograph

+/+/-- chest painchest pain + low oxygen level+ low oxygen level 22ndnd cause for cause for

hospitalizationhospitalization 25% of all deaths in 25% of all deaths in

SCDSCD

yyemerging pulmonary emerging pulmonary hypertensionhypertension

TreatmentTreatment AntibioticsAntibiotics Bronchodilator/bedsidBronchodilator/bedsid

e incentive spirometrye incentive spirometry Respiratory toiletRespiratory toilet Careful pain controlCareful pain controlSCDSCD

Increased association Increased association with asthma/atopywith asthma/atopy

Occurs frequently Occurs frequently during or after painful during or after painful episodeepisode

Transfusions Transfusions

Acute Chest SyndromeA leading cause of death in sickle cell disease

Acute Chest SyndromeA leading cause of death in sickle cell disease

Clinically:Clinically: Clinically:Clinically: Acute onset of fever, Acute onset of fever,

respiratory symptoms, new respiratory symptoms, new infiltrate on chest xinfiltrate on chest x--rayray

Definition:Definition: Acute onset chest symptoms Acute onset chest symptoms

ANDAND new infiltratenew infiltrate on CXR,on CXR,AND AND new infiltrate new infiltrate on CXR, on CXR, fever, tachypnea, cough, fever, tachypnea, cough, new new onset hypoxiaonset hypoxia, increased , increased WOB, chest painWOB, chest pain

Since you cannot distinguish between acute chest syndrome and pneumonia clinically there is no change in treatment.

StrokesStrokes

10% of children with10% of children with HbHb SSSS10% of children with 10% of children with HbHb SSSS 300 x risk of normal children300 x risk of normal children Mostly between ages 3Mostly between ages 3--12 years12 years 70% risk of reoccurrence without 70% risk of reoccurrence without

chronic transfusion therapychronic transfusion therapy Treatment is chronic transfusionsTreatment is chronic transfusions May be “silent” manifesting only as May be “silent” manifesting only as

learning difficulties or headaches learning difficulties or headaches (22%)(22%)

StrokeStroke

Peak incidence b/w 5Peak incidence b/w 5--10 yo10 yo Peak incidence b/w 5Peak incidence b/w 5--10 yo10 yo Underlying arterial stenosis or Underlying arterial stenosis or

obstructionobstruction Internal carotid, MCA or ACAInternal carotid, MCA or ACA

Diagnosis: diffusionDiagnosis: diffusion--weighted MRI, weighted MRI, FLAIR MRAFLAIR MRAFLAIR, MRAFLAIR, MRA

Treatment: exchange transfusion Treatment: exchange transfusion therapy to maintain sickle hemoglobin therapy to maintain sickle hemoglobin at or below 30%at or below 30%

Transcranial Doppler Ultrasonography

Transcranial Doppler Ultrasonography

Transcranial Doppler (TCD) uses ultrasound to examine the arteries, measure blood Transcranial Doppler (TCD) uses ultrasound to examine the arteries, measure blood flow, and look for signs of vasospasm.flow, and look for signs of vasospasm.

Courtesy of Mayfield Clinic / University of Cincinnati Department of Neurosurgery, Ohio

Transcranial Doppler Ultrasonography

Transcranial Doppler Ultrasonography

Indications for Simple/Acute Transfusion

Indications for Simple/Acute Transfusion

PrePre--operatively (Goal tooperatively (Goal to PrePre operatively (Goal to operatively (Goal to hemoglobin hemoglobin >> 10gm/dL10gm/dL

Stroke (initial presentation)Stroke (initial presentation) Acute Chest Syndrome (initial Acute Chest Syndrome (initial

presentation)presentation) Aplastic AnemiaAplastic Anemia Splenic sequestrationSplenic sequestration Symptomatic anemiaSymptomatic anemia PriapismPriapism

Indications for Chronic Transfusions

Indications for Chronic Transfusions

Cerebral Vascular Events (stroke)Cerebral Vascular Events (stroke) Cerebral Vascular Events (stroke) Cerebral Vascular Events (stroke) Secondary Stroke PreventionSecondary Stroke Prevention

Abnormal Transcranial Doppler Abnormal Transcranial Doppler (TCD) (TCD) Primary Stroke PreventionPrimary Stroke Prevention

?? Silent Infarct?? Silent Infarct Recurrent Splenic SequestrationRecurrent Splenic Sequestration Recurrent Splenic SequestrationRecurrent Splenic Sequestration Recurrent Acute Chest SyndromeRecurrent Acute Chest Syndrome Recurrent Intractable PainRecurrent Intractable Pain

Pain GuidelinesPain Guidelines

Still the hallmark ofStill the hallmark of Painful episodePainful episodeStill the hallmark of Still the hallmark of sickle cell diseasesickle cell disease

All pain is not sickle All pain is not sickle cell pain episodecell pain episode

20% 20% -- frequent painfrequent pain 30% 30% -- rarely have rarely have

Painful episode Painful episode (vasoocclusion (vasoocclusion episode)episode) Hydration andHydration and AntiAnti--inflammatoryinflammatory

NSAIDNSAID Narcotics Narcotics

O l lO l lpainpain 50% 50% -- one pain one pain

episode per yearepisode per year

Oral or parenteralOral or parenteral

Observe for Observe for respiratory respiratory compromisecompromise

Pain ManagementPain Management

Pain is an emergencyPain is an emergency Pain is an emergencyPain is an emergency Hospital evaluation:Hospital evaluation: Hydration: 1.5 times maintenance unless Hydration: 1.5 times maintenance unless

acute chest syndrome suspectedacute chest syndrome suspected Assess pain level and treatAssess pain level and treat

D t ithh ld i idD t ithh ld i id Do not withhold opioidsDo not withhold opioids Frequently reassess pain controlFrequently reassess pain control

Assess for cause of pain/complicationsAssess for cause of pain/complications

Pain ManagementPain Management

MildMild moderate painmoderate painMild Mild –– moderate painmoderate pain AcetaminophenAcetaminophen Hepatotoxic Hepatotoxic

NonNon--steroidal antisteroidal anti--inflammatory inflammatory agents (NSAIDs)agents (NSAIDs)

CC Contraindicated in patients with Contraindicated in patients with gastritis/ulcers and renal failuregastritis/ulcers and renal failure Monitor renal function if used chronicallyMonitor renal function if used chronically

Pain ManagementPain Management

Moderate or less severe painModerate or less severe painpp Opioids are firstOpioids are first--line treatmentline treatment Morphine sulfate or hydromorphoneMorphine sulfate or hydromorphone Meperidine NOT recommendedMeperidine NOT recommended

(Metabolite causes seizures & renal toxicity)(Metabolite causes seizures & renal toxicity)

Moderate Moderate –– severe painsevere pain Acetaminophen or NSAIDs in combination withAcetaminophen or NSAIDs in combination with Acetaminophen or NSAIDs in combination with Acetaminophen or NSAIDs in combination with

opioidsopioids Other adjuvant medications (sedatives, Other adjuvant medications (sedatives,

anxiolytics)anxiolytics) May increase efficacy of analgesicsMay increase efficacy of analgesics

Parenteral Opioids in SCDParenteral Opioids in SCD

Other Complications of Sickle Cell Disease

Other Complications of Sickle Cell Disease

Aplastic crisisAplastic crisispp PriapismPriapism RetinopathyRetinopathy Pulmonary hypertensionPulmonary hypertension Sleep apneaSleep apnea Cardiomyopathy, heart failureCardiomyopathy, heart failure Gall stones, CholecystitisGall stones, Cholecystitis EnuresisEnuresisEnuresisEnuresis Avascular necrosis, early osteoarthritisAvascular necrosis, early osteoarthritis Infarcts Infarcts –– bone, organsbone, organs Skin ulcersSkin ulcers Increased fetal lossIncreased fetal loss

HydroxyureaHydroxyurea

Promotes production of Promotes production of HbHb FFpp Even a small increase in Even a small increase in HbHb F can retard sicklingF can retard sickling inflammation, inflammation, hemolysishemolysis metabolic ratemetabolic rate Few side effects (mild neutropenia, Few side effects (mild neutropenia,

thrombocytopenia, hair loss)thrombocytopenia, hair loss) Treatment with Hydroxyurea has been shown to Treatment with Hydroxyurea has been shown to

reduce pain events, hospital admissions and the reduce pain events, hospital admissions and the d f bl d t f i b 50%d f bl d t f i b 50%need for blood transfusions by 50%need for blood transfusions by 50%

15 years experience in adults, not experimental15 years experience in adults, not experimental

Multicenter Study of Hydroxyurea in Sickle Cell Disease

Multicenter Study of Hydroxyurea in Sickle Cell Disease

Hydroxyurea PlaceboEvent Hydroxyurea(n = 152)

Placebo(n-147) P value

Pain events/year 2.5 4.6 .001Hospitalizations/year for pain 1.0 2.5 .0027

Episodes of ACS 56 101 .003Patients 55 79 .002transfusedTransfusion units 423 670 .003

Hydroxyurea EffectPeripheral Smear

Hydroxyurea EffectPeripheral Smear

Pictures courtesy of Dr. Russell Ware, St. Jude Children’s Research Hospital. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood. 2010; 115(26):5306.

Sickle Cell Disease and BMTSickle Cell Disease and BMT

Bone Marrow TransplantBone Marrow TransplantBone Marrow TransplantBone Marrow Transplant Substitutes normal red blood cell Substitutes normal red blood cell

progenitors from ‘donor’progenitors from ‘donor’ Requires high dose chemotherapy to Requires high dose chemotherapy to

prevent rejectionprevent rejection Donor source either BM or CBDonor source either BM or CB Mixed chimera enough to modify course Mixed chimera enough to modify course g yg y

of disease, full ablation may not be of disease, full ablation may not be neededneeded Success 90% cure, 5% relapse and 5% Success 90% cure, 5% relapse and 5%

risk of death risk of death

Myeloablative Matched Sibling BMT for Sickle Cell Disease

Myeloablative Matched Sibling BMT for Sickle Cell Disease

Worldwide Walters Atlanta

n 175 55 25

Survival 93% 95% 96%

DFS 85% 85% 96%

Rejection 12% 9% 0%

aGVHD 10% 15% 4%

cGVHD 12% 11% 8%

Recent and Current StudiesRecent and Current Studies

BABY HUG (Prospective HU in <18mo)BABY HUG (Prospective HU in <18mo)BABY HUG (Prospective HU in <18mo)BABY HUG (Prospective HU in <18mo) SWITCH (Transfusion to HU for CVA)SWITCH (Transfusion to HU for CVA) SITTSITT TWITCHTWITCH GlutamineGlutamine AntiAnti--Platelet DrugsPlatelet DrugsAntiAnti Platelet DrugsPlatelet Drugs Neuroprotective StudyNeuroprotective Study Vasodilators for Pulmonary HypertensionVasodilators for Pulmonary Hypertension

QuestionsQuestions

Case ScenariosCase Scenarios