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Sickle Cell Anemia JFK Pediatric Core Curriculum Edited by Venée Tubman, MD HEARTT Department of Pediatrics Children’s Hospital Boston.

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Presentation on theme: "Sickle Cell Anemia JFK Pediatric Core Curriculum Edited by Venée Tubman, MD HEARTT Department of Pediatrics Children’s Hospital Boston."— Presentation transcript:

1 Sickle Cell Anemia JFK Pediatric Core Curriculum Edited by Venée Tubman, MD HEARTT Department of Pediatrics Children’s Hospital Boston

2 Definition and Molecular Basis of Disease Sickle cell disease (SCD): a recessively inherited chronic hemolytic anemia Sickle cell disease (SCD): a recessively inherited chronic hemolytic anemia Caused by a single nucleotide substitution in the β globin gene on chromosome 11 Caused by a single nucleotide substitution in the β globin gene on chromosome 11 –Hemoglobin S (most common): GTG  GAG results in substitution of valine (hydrophobic) for glutamate (hydrophilic) –Many other variant hemoglobins are described Mutant hemoglobin polymerizes under low oxygen conditions and form bundles that distort red cells into the classic sickle shape Mutant hemoglobin polymerizes under low oxygen conditions and form bundles that distort red cells into the classic sickle shape

3 3 Pathophysiology Deoxygenation polymerization of hemoglobin sickling of red cells endothelial damage/activation RBC and leukocyte adhesion to endothelium, vasoconstriction vascular occlusion, organ ischemia and end-organ damage

4 Pathophysiology Severity of disease varies widely among individuals and disease type: Severity of disease varies widely among individuals and disease type: SS disease is most severe SS disease is most severe SC and S-beta thal 0 disease portend intermediate severity SC and S-beta thal 0 disease portend intermediate severity SA (one normal allele=trait) is generally asymptomatic SA (one normal allele=trait) is generally asymptomatic

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

6 Epidemiology Hb S, thalassemia, G6PD, HPHF all confer malaria survival advantage Hb S, thalassemia, G6PD, HPHF all confer malaria survival advantage Up to 30% of population carriers for Hb S allele in many parts of West Africa Up to 30% of population carriers for Hb S allele in many parts of West Africa Hb S carrier estimate for Liberia: 15% Hb S carrier estimate for Liberia: 15%

7 Prognosis Over the past 30 years in US/Europe, median survival has increased from 14yrs to 45-55yrs for SS disease Over the past 30 years in US/Europe, median survival has increased from 14yrs to 45-55yrs for SS disease Figures not available for Africa but estimated 50% of affected die before 5yrs Figures not available for Africa but estimated 50% of affected die before 5yrs WHO estimates that SCD complicates up to 9% of under 5 deaths in West Africa WHO estimates that SCD complicates up to 9% of under 5 deaths in West Africa

8 Initial Clinical Presentation Typically presents in infancy after 6 months of age, when Hb F is waning Typically presents in infancy after 6 months of age, when Hb F is waning –Birth hemoglobin F: α2γ2 –Hemoglobin A: α2β2 –Hemoglobin S: α2S2 Pain and anemia are hallmarks of disease Pain and anemia are hallmarks of disease

9 Initial Clinical Presentation Suggestive historical findings: Suggestive historical findings: –Family history of known SCD –Family history of sudden death in young child –Frequent pain –Frequent chest infections –Failure to gain weight despite good nutrition –Persistent jaundice –Classic sequelae (hand/foot syndrome, priapism)

10 Initial Clinical Presentation Physical Exam findings are nonspecific: Physical Exam findings are nonspecific: –scleral icterus –pale mucous membranes –systolic murmur throughout precordium –splenomegaly

11 Initial Clinical Presentation Predictors of adverse outcome at presentation: Predictors of adverse outcome at presentation: –dactylitis in infant <1y/o –Hb<7g/dL –leukocytosis absent infection –priapism

12 Laboratory Findings and Diagnosis Hemolytic anemia: low hemoglobin, high reticulocyte count, elevated LDH and decreased haptoglobin Hemolytic anemia: low hemoglobin, high reticulocyte count, elevated LDH and decreased haptoglobin Peripheral blood smear: Peripheral blood smear:

13 Diagnosis: Sodium metabisulfite Screening for SCD with sodium metabisulfite Screening for SCD with sodium metabisulfite –Add Na metabisulfite to blood –Seal mixed sample in airtight container or under coverslip –Look for sickling under microscope Does not differentiate trait from disease Does not differentiate trait from disease

14 Diagnosis: Hemoglobin Electrophoresis

15 Sequelae: Vaso-occlusive/pain crisis Occurs in 60% of SS patients when vaso- occlusion  tissue ischemia Occurs in 60% of SS patients when vaso- occlusion  tissue ischemia May be triggered by infection, temperature extremes, dehydration or stress but usually w/o identifiable cause. May be triggered by infection, temperature extremes, dehydration or stress but usually w/o identifiable cause. Characterized by severe pain often in extremities, involving the long bones, or the abdomen. May last hours to days. Characterized by severe pain often in extremities, involving the long bones, or the abdomen. May last hours to days. Number of pain crises/year varies widely between individuals with some patients w/ constant low level pain. Number of pain crises/year varies widely between individuals with some patients w/ constant low level pain.

16 Sequelae: Vaso-occlusive/pain crisis Management: Hydration: 20cc/kg NS bolus, then PO/IV hydration at 1.5 x maintenance (not for acute chest) Hydration: 20cc/kg NS bolus, then PO/IV hydration at 1.5 x maintenance (not for acute chest) Pain ladder: Pain ladder: Paracetamol 15mg/kg PO q4hr ADD Ibuprofen 10 mg/kg PO q6hr ADD Codeine 1mg/kg PO q4hr CHANGE Codeine to Tramadol (need dose) CHANGE Tramadol to Morphine 0.1mg/kg q4hr Ambulation to prevent acute chest Ambulation to prevent acute chest Oxygen to maintain O2 sat > 95% Oxygen to maintain O2 sat > 95%

17 Sequelae: Infection By age 1 30% of Hb SS pts are asplenic, by age 6, 90% are asplenic due to microinfarcts. By age 1 30% of Hb SS pts are asplenic, by age 6, 90% are asplenic due to microinfarcts. This makes children especially vulnerable to infection/sepsis with encapsulated organisms, esp. Strep pneumoniae (400x higher risk vs. general population) This makes children especially vulnerable to infection/sepsis with encapsulated organisms, esp. Strep pneumoniae (400x higher risk vs. general population) Sickle Cell patients are also more susceptible to osteomyelitis (Salmonella and Staph spp.) Sickle Cell patients are also more susceptible to osteomyelitis (Salmonella and Staph spp.)

18 Sequelae: Infection(cont’d) Management of fever: For T ≥38, send: Hb, malaria smear, CXR, UA (under 2 years or symptoms) For T ≥38, send: Hb, malaria smear, CXR, UA (under 2 years or symptoms) Administer Ceftriaxone 50 mg/kg QD until clinically improving OR 3 days Administer Ceftriaxone 50 mg/kg QD until clinically improving OR 3 days Change to amoxclav or ampicillin to complete 14 days Change to amoxclav or ampicillin to complete 14 days

19 Sequelae: Acute Chest Syndrome Characterized by new respiratory distress, CXR infiltrate, hypoxia(O2<95%) and/or chest pain Characterized by new respiratory distress, CXR infiltrate, hypoxia(O2<95%) and/or chest pain Occurs in 40% of patients with SS disease Occurs in 40% of patients with SS disease Can progress rapidly to ARDS Can progress rapidly to ARDS May be caused by viral or bacterial infection, fat embolism(2/2 bone marrow infarction), cause unknown in most cases May be caused by viral or bacterial infection, fat embolism(2/2 bone marrow infarction), cause unknown in most cases

20 Sequelae: Acute Chest Syndrome Management : Ceftriaxone 50mg/kg IV daily, then when pain improving ampicillin or amoxclav Ceftriaxone 50mg/kg IV daily, then when pain improving ampicillin or amoxclav If O2<94 and Hb < 6 g/dL, consider transfusion If O2<94 and Hb < 6 g/dL, consider transfusion Do not hydrate > 1x maintenance (furosemide with transfusion) Do not hydrate > 1x maintenance (furosemide with transfusion)

21 Sequelae: Stroke 11% of SS patients have a stroke by age 20 with peak incidence between 2 and 10 11% of SS patients have a stroke by age 20 with peak incidence between 2 and 10 Presents as focal neurologic deficit or seizure Presents as focal neurologic deficit or seizure Management: Transfusion Management: Transfusion

22 Sequelae: Acute Splenic Sequestration Sudden enlargement of the spleen accompanied by a >2g/dL decrease in Hb from baseline, often w/ thrombocytopenia Sudden enlargement of the spleen accompanied by a >2g/dL decrease in Hb from baseline, often w/ thrombocytopenia Occurs in children <3y/o Occurs in children <3y/o Can cause sudden circulatory collapse Can cause sudden circulatory collapseManagement: Immediate volume expansion with crystalloid Immediate volume expansion with crystalloid Transfusion Transfusion If >2 episodes  splenectomy If >2 episodes  splenectomy

23 Sequelae: Aplastic Crisis Caused by infection with Parvovirus B19 (fifth disease) which invades young erythroblasts in bone marrow Caused by infection with Parvovirus B19 (fifth disease) which invades young erythroblasts in bone marrow Often presents with fever, URI sx and drop in Hb Often presents with fever, URI sx and drop in Hb RBC life expectancy in SS disease is 10-20 days, thus decrease in RBC production has profound effect. RBC life expectancy in SS disease is 10-20 days, thus decrease in RBC production has profound effect. Bone marrow recovery typically within 7-10 days Bone marrow recovery typically within 7-10 daysManagement: Transfusion if symptomatic with Hb drop. Transfusion if symptomatic with Hb drop.

24 Sequelae: Anemia Compensated anemia at baseline Compensated anemia at baseline Baseline Hb normally 8-9 g/dl Baseline Hb normally 8-9 g/dl Overtransfusion can predispose to transfusion transmitted infections and iron overload Overtransfusion can predispose to transfusion transmitted infections and iron overloadManagement Transfuse for Hb < 5g/dL or <6g/dL with cardiac decompensation Transfuse for Hb < 5g/dL or <6g/dL with cardiac decompensation

25 Indications for Simple Transfusion Final hematocrit after transfusion <30%. Final hematocrit after transfusion <30%. Simple Transfusion for: Simple Transfusion for: –aplastic crises –splenic sequestration –Acute chest syndrome –Before surgery –Priapism resistant to medical management –Stroke –Persistent pain despite proper pain management

26 Indications for Exchange Transfusion For stroke, severe ACS For stroke, severe ACS

27 Other Sequelae Priapism: May require surgical drainage, phenylephrine injection, exchange transfusion Priapism: May require surgical drainage, phenylephrine injection, exchange transfusion Dactylitis (hand-foot syndrome): painful swelling of hands and feet which occurs in infants. Dactylitis (hand-foot syndrome): painful swelling of hands and feet which occurs in infants. Avascular necrosis of the humeral/femoral head Avascular necrosis of the humeral/femoral head Cholelithiasis Cholelithiasis Retinopathy Retinopathy Chronic leg ulcers Chronic leg ulcers

28 Preventive Care: Daily Penicillin VK 125mg BID from time of diagnosis (ideally<3mos) through 5 years of age (increase dose to 250mg BID at age 3yrs.) Daily Penicillin VK 125mg BID from time of diagnosis (ideally<3mos) through 5 years of age (increase dose to 250mg BID at age 3yrs.) May use erythromycin in penicillin allergic patients May use erythromycin in penicillin allergic patients Folic Acid 1mg daily started by 1y/o Folic Acid 1mg daily started by 1y/o Pneumococcal Vaccine (if available) Pneumococcal Vaccine (if available) All standard vaccines All standard vaccines

29 Preventive Care: Stroke Prevention Trial in SCD (STOP): A two year trial of children 2-16y/o screened with transcranial Doppler ultrasonography and found to be high risk (flow velocity>200cm/sec) A two year trial of children 2-16y/o screened with transcranial Doppler ultrasonography and found to be high risk (flow velocity>200cm/sec) The children then randomly assigned to receive either standard care or prophylactic transfusions to keep their HbS concentrations<30% The children then randomly assigned to receive either standard care or prophylactic transfusions to keep their HbS concentrations<30% In the group that received prophylactic transfusions, 2% had strokes, compared with 16% in the control group. In the group that received prophylactic transfusions, 2% had strokes, compared with 16% in the control group. Therefore, current recommendations are to screen all children >2y/o with transcranial doppler ultrasound and offer prophylactic transfusion to children with a flow velocity>200cm/sec (high risk of stroke) Therefore, current recommendations are to screen all children >2y/o with transcranial doppler ultrasound and offer prophylactic transfusion to children with a flow velocity>200cm/sec (high risk of stroke) Adams RJ, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. NEJM 1998;339:5-11 Adams RJ, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. NEJM 1998;339:5-11

30 Definitive Treatment: 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

31 Definitive Treatment: Bone Marrow Transplant Definitive cure for SCD Definitive cure for SCD Only 14% of SCD patients have a human- leukocyte antigen matched donor Only 14% of SCD patients have a human- leukocyte antigen matched donor Associated with a peri-transplant morbidity of ~10% Associated with a peri-transplant morbidity of ~10%

32 References Driscoll, C. Sickle Cell Disease. Pediatrics in Review 2007;28:259-267 Driscoll, C. Sickle Cell Disease. Pediatrics in Review 2007;28:259-267 Steinberg, M Management of Sickle Cell Disease. New England Journal of Medicine 1999; 340: 1021-1030 Steinberg, M Management of Sickle Cell Disease. New England Journal of Medicine 1999; 340: 1021-1030 Claster, S Managing Sickle Cell Disease. British Medical Journal 2003; 327:1151-1155 Claster, S Managing Sickle Cell Disease. British Medical Journal 2003; 327:1151-1155 Serjeant, G Mortality from sickle cell disease in Africa. British Medical Journal 2005; 330:432-433 Serjeant, G Mortality from sickle cell disease in Africa. British Medical Journal 2005; 330:432-433 Distenfeld, A Sickle Cell Anemia. eMedicine.com Distenfeld, A Sickle Cell Anemia. eMedicine.com Paediatric Treatment Protocols in Island Hospital, 2007 Paediatric Treatment Protocols in Island Hospital, 2007 Adapted from a lecture by: Kevin Schwartz, MD


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