Sickle Cell AnemiaSickle Cell AnemiaJFK Pediatric Core JFK Pediatric Core

CurriculumCurriculum

Edited byEdited by

Venée Tubman, MDVenée Tubman, MD

HEARTTHEARTT

Department of PediatricsDepartment of Pediatrics

Children’s Hospital BostonChildren’s Hospital Boston

Definition and Molecular Basis Definition and Molecular Basis of Diseaseof Disease

Sickle cell disease (SCD): a recessively Sickle cell disease (SCD): a recessively inherited chronic hemolytic anemiainherited chronic hemolytic anemia

Caused by a single nucleotide substitution Caused by a single nucleotide substitution in the in the ββ globin gene on chromosome 11 globin gene on chromosome 11 – Hemoglobin S (most common): GTG Hemoglobin S (most common): GTG GAG GAG

results in substitution of valine (hydrophobic) results in substitution of valine (hydrophobic) for glutamate (hydrophilic)for glutamate (hydrophilic)

– Many other variant hemoglobins are describedMany other variant hemoglobins are described

Mutant hemoglobin polymerizes under low Mutant hemoglobin polymerizes under low oxygen conditions and form bundles that oxygen conditions and form bundles that distort red cells into the classic sickle distort red cells into the classic sickle shape shape

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PathophysioloPathophysiologygy

DeoxygenationDeoxygenation

polymerization of hemoglobin polymerization of hemoglobin

sickling of red cells sickling of red cells

endothelial damage/activationendothelial damage/activation

RBC and leukocyte adhesion RBC and leukocyte adhesion to endothelium, to endothelium, vasoconstrictionvasoconstriction

vascular occlusion, organ vascular occlusion, organ ischemia and end-organ ischemia and end-organ

damagedamage

PathophysiologyPathophysiology

Severity of disease varies widely Severity of disease varies widely among individuals and disease type:among individuals and disease type:

SS disease is most severeSS disease is most severe SC and S-beta thalSC and S-beta thal00 disease portend disease portend

intermediate severityintermediate severity SA (one normal allele=trait) is SA (one normal allele=trait) is

generally asymptomaticgenerally asymptomatic

Sickle Cell Anemia and Sickle Cell Anemia and MalariaMalaria

Children with sickle trait (heterozygotes) have a milder Children with sickle trait (heterozygotes) have a milder course of P. falciparum. However, children with SS course of P. falciparum. However, children with SS disease have more severe courses with a very high disease have more severe courses with a very high mortality rate. mortality rate.

EpidemiologyEpidemiology

Hb S, thalassemia, G6PD, HPHF all Hb S, thalassemia, G6PD, HPHF all confer malaria survival advantageconfer malaria survival advantage

Up to 30% of population carriers for Up to 30% of population carriers for Hb S allele in many parts of West Hb S allele in many parts of West AfricaAfrica

Hb S carrier estimate for Liberia: 15%Hb S carrier estimate for Liberia: 15%

PrognosisPrognosis

Over the past 30 years in US/Europe, Over the past 30 years in US/Europe, median survival has increased from median survival has increased from 14yrs to 45-55yrs for SS disease14yrs to 45-55yrs for SS disease

Figures not available for Africa but Figures not available for Africa but estimated 50% of affected die before estimated 50% of affected die before 5yrs5yrs

WHO estimates that SCD complicates WHO estimates that SCD complicates up to 9% of under 5 deaths in West up to 9% of under 5 deaths in West AfricaAfrica

Initial Clinical PresentationInitial Clinical Presentation

Typically presents in infancy after 6 Typically presents in infancy after 6 months of age, when Hb F is waningmonths of age, when Hb F is waning

– Birth hemoglobin F: Birth hemoglobin F: αα22γγ22– Hemoglobin A: Hemoglobin A: αα22ββ22– Hemoglobin S: Hemoglobin S: αα2S22S2

Pain and anemia are hallmarks of diseasePain and anemia are hallmarks of disease

Initial Clinical PresentationInitial Clinical Presentation

Suggestive historical findings:Suggestive historical findings:

– Family history of known SCDFamily history of known SCD– Family history of sudden death in young childFamily history of sudden death in young child– Frequent painFrequent pain– Frequent chest infectionsFrequent chest infections– Failure to gain weight despite good nutritionFailure to gain weight despite good nutrition– Persistent jaundicePersistent jaundice– Classic sequelae (hand/foot syndrome, Classic sequelae (hand/foot syndrome,

priapism)priapism)

Initial Clinical PresentationInitial Clinical Presentation

Physical Exam findings are nonspecific:Physical Exam findings are nonspecific:

– scleral icterusscleral icterus– pale mucous membranespale mucous membranes– systolic murmur throughout precordiumsystolic murmur throughout precordium– splenomegalysplenomegaly

Initial Clinical PresentationInitial Clinical Presentation

Predictors of adverse outcome at presentation:Predictors of adverse outcome at presentation:

– dactylitis in infant <1y/odactylitis in infant <1y/o

– Hb<7g/dLHb<7g/dL

– leukocytosis absent infectionleukocytosis absent infection

– priapismpriapism

Laboratory Findings and Laboratory Findings and DiagnosisDiagnosis

Hemolytic anemia: low hemoglobin, Hemolytic anemia: low hemoglobin, high reticulocyte count, elevated LDH high reticulocyte count, elevated LDH and decreased haptoglobinand decreased haptoglobin

Peripheral blood smear: Peripheral blood smear:

Diagnosis: Sodium Diagnosis: Sodium metabisulfitemetabisulfite

Screening for SCD with sodium Screening for SCD with sodium metabisulfite metabisulfite – Add Na metabisulfite to bloodAdd Na metabisulfite to blood– Seal mixed sample in airtight container Seal mixed sample in airtight container

or under coverslipor under coverslip– Look for sickling under microscopeLook for sickling under microscope

Does not differentiate trait from Does not differentiate trait from diseasedisease

Diagnosis: Hemoglobin Diagnosis: Hemoglobin ElectrophoresisElectrophoresis

Sequelae: Vaso-occlusive/pain Sequelae: Vaso-occlusive/pain crisiscrisis

Occurs in 60% of SS patients when vaso-Occurs in 60% of SS patients when vaso-occlusion occlusion tissue ischemia tissue ischemia

May be triggered by infection, temperature May be triggered by infection, temperature extremes, dehydration or stress but extremes, dehydration or stress but usually w/o identifiable cause.usually w/o identifiable cause.

Characterized by severe pain often in Characterized by severe pain often in extremities, involving the long bones, or extremities, involving the long bones, or the abdomen. May last hours to days.the abdomen. May last hours to days.

Number of pain crises/year varies widely Number of pain crises/year varies widely between individuals with some patients w/ between individuals with some patients w/ constant low level pain.constant low level pain.

Sequelae: Vaso-occlusive/pain Sequelae: Vaso-occlusive/pain crisiscrisis

Management:Management: Hydration: 20cc/kg NS bolus, then PO/IV Hydration: 20cc/kg NS bolus, then PO/IV

hydration at 1.5 x maintenance (hydration at 1.5 x maintenance (notnot for for acute chest)acute chest)

Pain ladder: Pain ladder: Paracetamol 15mg/kg PO q4hr ADDParacetamol 15mg/kg PO q4hr ADDIbuprofen 10 mg/kg PO q6hr ADDIbuprofen 10 mg/kg PO q6hr ADDCodeine 1mg/kg PO q4hrCodeine 1mg/kg PO q4hrCHANGE Codeine to Tramadol (need dose) CHANGE Codeine to Tramadol (need dose) CHANGE Tramadol to Morphine 0.1mg/kg q4hrCHANGE Tramadol to Morphine 0.1mg/kg q4hr

Ambulation to prevent acute chestAmbulation to prevent acute chest Oxygen to maintain O2 sat > 95%Oxygen to maintain O2 sat > 95%

Sequelae: InfectionSequelae: Infection

By age 1 30% of Hb SS pts are By age 1 30% of Hb SS pts are asplenic, by age 6, 90% are asplenic asplenic, by age 6, 90% are asplenic due to microinfarcts.due to microinfarcts.

This makes children especially This makes children especially vulnerable to infection/sepsis with vulnerable to infection/sepsis with encapsulated organisms, esp. Strep encapsulated organisms, esp. Strep pneumoniae (400x higher risk vs. pneumoniae (400x higher risk vs. general population)general population)

Sickle Cell patients are also more Sickle Cell patients are also more susceptible to osteomyelitis susceptible to osteomyelitis (Salmonella and Staph spp.)(Salmonella and Staph spp.)

Sequelae: Infection(cont’d)Sequelae: Infection(cont’d)

Management of fever:Management of fever: For T For T ≥38, send: Hb, malaria smear, ≥38, send: Hb, malaria smear,

CXR, UA (under 2 years or CXR, UA (under 2 years or symptoms)symptoms)

Administer Ceftriaxone 50 mg/kg QD Administer Ceftriaxone 50 mg/kg QD until clinically improving OR 3 daysuntil clinically improving OR 3 days

Change to amoxclav or ampicillin to Change to amoxclav or ampicillin to complete 14 dayscomplete 14 days

Sequelae: Acute Chest Sequelae: Acute Chest SyndromeSyndrome

Characterized by new respiratory Characterized by new respiratory distress, CXR infiltrate, distress, CXR infiltrate, hypoxia(O2<95%) and/or chest painhypoxia(O2<95%) and/or chest pain

Occurs in 40% of patients with SS Occurs in 40% of patients with SS diseasedisease

Can progress rapidly to ARDSCan progress rapidly to ARDS May be caused by viral or bacterial May be caused by viral or bacterial

infection, fat embolism(2/2 bone marrow infection, fat embolism(2/2 bone marrow infarction), cause unknown in most casesinfarction), cause unknown in most cases

Sequelae: Acute Chest Sequelae: Acute Chest SyndromeSyndrome

Management :Management :

CeftriaxoneCeftriaxone 50mg/kg IV daily, then 50mg/kg IV daily, then when pain improving ampicillin or when pain improving ampicillin or amoxclavamoxclav

If O2<94 and Hb < 6 g/dL, consider If O2<94 and Hb < 6 g/dL, consider transfusiontransfusion

Do not hydrate > 1x maintenance Do not hydrate > 1x maintenance (furosemide with transfusion)(furosemide with transfusion)

Sequelae: StrokeSequelae: Stroke

11% of SS patients have a stroke by 11% of SS patients have a stroke by age 20 with peak incidence between age 20 with peak incidence between 2 and 102 and 10

Presents as focal neurologic deficit or Presents as focal neurologic deficit or seizureseizure

Management: Management: TransfusionTransfusion

Sequelae: Acute Splenic Sequelae: Acute Splenic SequestrationSequestration

Sudden enlargement of the spleen Sudden enlargement of the spleen accompanied by a >2g/dL decrease in Hb from accompanied by a >2g/dL decrease in Hb from baseline, often w/ thrombocytopeniabaseline, often w/ thrombocytopenia

Occurs in children <3y/oOccurs in children <3y/o Can cause sudden circulatory collapseCan cause sudden circulatory collapse

Management:Management: Immediate volume expansion with crystalloidImmediate volume expansion with crystalloid TransfusionTransfusion If >2 episodes If >2 episodes splenectomysplenectomy

Sequelae: Aplastic CrisisSequelae: Aplastic Crisis Caused by infection with Parvovirus B19 (fifth Caused by infection with Parvovirus B19 (fifth

disease) which invades young erythroblasts in disease) which invades young erythroblasts in bone marrowbone marrow

Often presents with fever, URI sx and drop in Often presents with fever, URI sx and drop in HbHb

RBC life expectancy in SS disease is 10-20 RBC life expectancy in SS disease is 10-20 days, thus decrease in RBC production has days, thus decrease in RBC production has profound effect.profound effect.

Bone marrow recovery typically within 7-10 Bone marrow recovery typically within 7-10 daysdays

Management:Management: Transfusion if symptomatic with Hb drop.Transfusion if symptomatic with Hb drop.

Sequelae: AnemiaSequelae: Anemia

Compensated anemia at baselineCompensated anemia at baseline Baseline Hb normally 8-9 g/dlBaseline Hb normally 8-9 g/dl Overtransfusion can predispose to Overtransfusion can predispose to

transfusion transmitted infections transfusion transmitted infections and iron overloadand iron overload

ManagementManagement Transfuse for Hb < 5g/dL or <6g/dL Transfuse for Hb < 5g/dL or <6g/dL

with cardiac decompensationwith cardiac decompensation

Indications for Simple Indications for Simple TransfusionTransfusion

Final hematocrit after transfusion <30%.Final hematocrit after transfusion <30%. Simple Transfusion for: Simple Transfusion for:

– aplastic crisesaplastic crises– splenic sequestrationsplenic sequestration– Acute chest syndromeAcute chest syndrome– Before surgeryBefore surgery– Priapism resistant to medical managementPriapism resistant to medical management– StrokeStroke– Persistent pain despite proper pain Persistent pain despite proper pain

managementmanagement

Indications for Exchange Indications for Exchange TransfusionTransfusion

For stroke, severe ACSFor stroke, severe ACS

Other SequelaeOther Sequelae

Priapism: May require surgical drainage, Priapism: May require surgical drainage, phenylephrine injection, exchange transfusionphenylephrine injection, exchange transfusion

Dactylitis (hand-foot syndrome): painful Dactylitis (hand-foot syndrome): painful swelling of hands and feet which occurs in swelling of hands and feet which occurs in infants.infants.

Avascular necrosis of the humeral/femoral Avascular necrosis of the humeral/femoral headhead

CholelithiasisCholelithiasis RetinopathyRetinopathy Chronic leg ulcers Chronic leg ulcers

Preventive Care:Preventive Care:

Daily Penicillin VK 125mg BID from Daily Penicillin VK 125mg BID from time of diagnosis (ideally<3mos) time of diagnosis (ideally<3mos) through 5 years of age (increase through 5 years of age (increase dose to 250mg BID at age 3yrs.)dose to 250mg BID at age 3yrs.)

May use erythromycin in penicillin May use erythromycin in penicillin allergic patientsallergic patients

Folic Acid 1mg daily started by 1y/oFolic Acid 1mg daily started by 1y/o Pneumococcal Vaccine (if available) Pneumococcal Vaccine (if available) All standard vaccinesAll standard vaccines

Preventive Care:Preventive Care:Stroke Prevention Trial in SCD (STOP):Stroke Prevention Trial in SCD (STOP): A two year trial of children 2-16y/o screened with transcranial A two year trial of children 2-16y/o screened with transcranial

Doppler ultrasonography and found to be high risk (flow Doppler ultrasonography and found to be high risk (flow velocity>200cm/sec)velocity>200cm/sec)

The children then randomly assigned to receive either The children then randomly assigned to receive either standard care or prophylactic transfusions to keep their HbS standard care or prophylactic transfusions to keep their HbS concentrations<30%concentrations<30%

In the group that received prophylactic transfusions, 2% had In the group that received prophylactic transfusions, 2% had strokes, compared with 16% in the control group.strokes, compared with 16% in the control group.

Therefore, current recommendations are to screen all Therefore, current recommendations are to screen all children >2y/o with transcranial doppler ultrasound and offer children >2y/o with transcranial doppler ultrasound and offer prophylactic transfusion to children with a flow prophylactic transfusion to children with a flow velocity>200cm/sec (high risk of stroke)velocity>200cm/sec (high risk of stroke)

Adams RJ, et al. Prevention of a first stroke by transfusions in children with Adams RJ, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. NEJM 1998;339:5-11ultrasonography. NEJM 1998;339:5-11

Definitive Treatment:Definitive Treatment: Hydroxyurea therapy Hydroxyurea therapy

• Indicated for children >5y/o who have severe complications of SCD

• Effective because increases HbF, decreases leukocytes, platelets and reticulocytes

• CBC must be monitored regularly when on therapy for leukopenia

Definitive Treatment: Definitive Treatment: Bone Marrow TransplantBone Marrow Transplant

Definitive cure for SCDDefinitive cure for SCD Only 14% of SCD patients have a Only 14% of SCD patients have a

human-leukocyte antigen matched human-leukocyte antigen matched donordonor

Associated with a peri-transplant Associated with a peri-transplant morbidity of ~10%morbidity of ~10%

ReferencesReferences Driscoll, C. Driscoll, C. Sickle Cell Disease. Pediatrics in Review Sickle Cell Disease. Pediatrics in Review

2007;28:259-2672007;28:259-267 Steinberg, Steinberg, M M Management of Sickle Cell Disease. Management of Sickle Cell Disease.

New England Journal of Medicine 1999; 340: 1021-New England Journal of Medicine 1999; 340: 1021-10301030

Claster, S Claster, S Managing Sickle Cell DiseaseManaging Sickle Cell Disease. British . British Medical Journal 2003; 327:1151-1155Medical Journal 2003; 327:1151-1155

Serjeant, G Serjeant, G Mortality from sickle cell disease in Mortality from sickle cell disease in AfricaAfrica. British Medical Journal 2005; 330:432-433. British Medical Journal 2005; 330:432-433

Distenfeld, A Distenfeld, A Sickle Cell Anemia.Sickle Cell Anemia. eMedicine.com eMedicine.com Paediatric Treatment Protocols in Island Hospital, Paediatric Treatment Protocols in Island Hospital,

20072007

Adapted from a lecture by: Kevin Schwartz, MDAdapted from a lecture by: Kevin Schwartz, MD