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Introduction and Anemia 2007

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Introduction and Anemia 2007

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Introduction and Anemia 2007

  1. 1. UNE HEMATOLOGY SECTION CLINICAL PEDIATRIC HEMATOLOGY December, 2008
  2. 2. An Introduction <ul><li>Pediatric Hematology-Oncology, 1984-98 </li></ul><ul><li>Hospice & Palliative Care Medicine </li></ul><ul><li>Medical Director, The Jason Program, 1998 - 2008 </li></ul>Gary Allegretta, MD
  3. 3. Pediatric Hematology Outline <ul><li>Section 1: The Red Cell </li></ul><ul><li>Section 2: Leukocytes & Marrow Failure </li></ul><ul><li>Section 3: Coagulation </li></ul><ul><li>Section 4: Hematopoietic Malignancies </li></ul><ul><li>Section 5: Hematologic Manifestations of Systemic Disease </li></ul>Take-Home point
  4. 4. The Evaluation Process Understand the System Where is it Broken? How is it Broken? Infection Toxic Trauma Metabolic Neoplastic Congenital Endocrine Immune Example
  5. 5. Physiology of Nausea <ul><li>CTZ </li></ul><ul><li>All transmitters </li></ul>Cortical Anticipation <ul><li>GI Tract </li></ul><ul><li>Serotonin -- vagal </li></ul><ul><li>ACH - peristalsis </li></ul><ul><li>? Dopamine </li></ul><ul><li>Other CNS </li></ul><ul><li>Vestibular ACH, histamine </li></ul><ul><li>ICP </li></ul>Vagal • acetylcholine
  6. 6. CTZ Cortical Other CNS Vagal GI Infection - Abscess Meningitis UTI Salmonella Toxic Chemo Mercury Lead - Pizza Trauma - CHI Subdural Chest Abdomen Metabolic - - DKA -  Thyroid Neoplastic - Metastasis  ICP; Mets Bladder Mass Obstruction Congenital - Anxiety Chiari - Dysmotility Endocrine -  Thyroid Addison ’ s - Diabetes Immune - ADEM ADEM - IBD
  7. 7. RBC DEVELOPMENT [OxyHgb] & O 2 Delivery EPO RBC #
  8. 8. Section I : The Red Cell <ul><li>General Physiology </li></ul><ul><li>Developmental Physiology </li></ul><ul><li>Definition & Effects of Anemia </li></ul><ul><li>Formulating a Differential Dx </li></ul><ul><li>Specific Conditions </li></ul><ul><ul><li>Newborns </li></ul></ul><ul><ul><li>Children & Adolescents </li></ul></ul>
  9. 9. UNDERSTANDING THE SYSTEM -- IT ALL STARTS HERE
  10. 10. Marrow Components Microenvironment Red Cells Leukocytes Platelets
  11. 11. Structural Microenvironment
  12. 12. Cells of the Microenvironment Foam Cell – Fat-laden Macrophage Osteoblast Normal Macrophage
  13. 13. Cellular Development Deliver O 2 Clotting Infection Allergy & Infection
  14. 14. Hematopoietic Growth Factors Factor Age of Onset Production Site Target Cells Medication EPO 1 st & 2nd Trimester Liver  Kidney CFU-E Epogen G-CSF 24 weeks  Environment Cells CFU-G + GMM; Polys Neupogen GM-CSF 24 weeks  Environment Cells Myeloid, Mono, RBC Leukine SCF 24 weeks  Environment Cells Myeloid, Mono, RBC, Mast Cells -- IL-3 T-Cells Broad -- IL-11  Environment Cells Mature Platelets Neumega Thrombopoietin (TPO) Liver~platelet count All Platelets --
  15. 15. RBC FUNCTION [OxyHgb] & O 2 Delivery EPO
  16. 16. RBC Morphologic Development
  17. 17. In Developmental Order
  18. 18. HEMOGLOBIN PRODUCTION <ul><li>Globin : Protein Formation </li></ul><ul><li>Heme : Heme + Iron Acquisition </li></ul><ul><li>Hemoglobin : O 2 delivery to tissues </li></ul>
  19. 19. Globin Formation The Hemoglobin Tetramer
  20. 20. IRON PROCESSING Iron Processing Factors That Modify Iron Absorption Copper Development Fe Deficiency
  21. 21. Heme +Fe + Globin = Hemoglobin <ul><li>Incorporation of Iron into Globin </li></ul><ul><ul><li>Blocked by Lead </li></ul></ul><ul><ul><li>Requires 5 ’ Nucleotidase </li></ul></ul><ul><li>Final Common Result: </li></ul>Poor Hgb Production MCV
  22. 22. Hemoglobin Function Hgb-Oxygen Dissociation Curve % O 2 Saturation Lung & Circulation Tissues Fetal Hgb High Altitude
  23. 23. RED CELL SURVIVAL ~ 120 DAYS <ul><li>Mechanisms of Survival </li></ul><ul><li>Intravascular Hemolysis </li></ul><ul><li>Extravascular Hemolysis </li></ul>
  24. 24. RBC Survival in the Circulation <ul><li>RBC must deform to traverse the spleen </li></ul><ul><ul><li>Intrinsic defects </li></ul></ul><ul><ul><li>Extrinsic defects </li></ul></ul><ul><li>Must stay mechanically intact </li></ul>
  25. 25. Red Blood Cells - Shape
  26. 26. Normal vs. Sickle red cells
  27. 27. RBC Hemoglobin Integrity <ul><li>Hemoglobin Variants </li></ul><ul><ul><li>Sickle Cell </li></ul></ul><ul><ul><li>Sickle variants </li></ul></ul><ul><ul><li>Unstable hemoglobin </li></ul></ul>Valine replaces glutamine
  28. 28. RBC MEMBRANE INTEGRITY RBC Membrane
  29. 29. RBC HYDRATION NEEDS RBC Cation Transporters
  30. 30. RBC Metabolic Needs <ul><li>Pentose Phosphate Pathway </li></ul><ul><ul><li>Produces NADPH to prevent O2 Damage </li></ul></ul><ul><ul><li>G6PD + Glucose 6PG NADPH </li></ul></ul><ul><li>Glycolosis </li></ul><ul><ul><li>Produces ATP </li></ul></ul><ul><ul><li>G6PD + Glucose F6P ATP </li></ul></ul>
  31. 31. External Threats <ul><li>Antigen-Antibody complexes </li></ul><ul><li>Sepsis (DIC) </li></ul><ul><li>Heat </li></ul><ul><li>Cardiac Valves </li></ul><ul><li>Exercise </li></ul>
  32. 32. Cellular Antigens <ul><li>Red Cells </li></ul><ul><ul><li>Major antigens = A,B,D (Rh) </li></ul></ul><ul><ul><li>Two genes per antigen </li></ul></ul><ul><ul><ul><li>Mother O,A </li></ul></ul></ul><ul><ul><ul><li>Father A,B </li></ul></ul></ul><ul><ul><li>Isohemaglutinin antibodies made naturally </li></ul></ul><ul><li>Platelets - PLA1 System </li></ul><ul><li>Leukocytes - NA1 System </li></ul>Child: A, B, or AB
  33. 33. Bilirubin Metabolism Intravascular Extravascular Free Hgb + Haptoglobin Fe + Transferrin Free Hgb Red cells contain SGOT & LDH All Fe is recycled
  34. 34. <ul><li>Effects on Health & Disease </li></ul>Developmental RBC Physiology
  35. 35. Newborn Blood Values Age Hgb g/dl Hct% MCV Retic WBC Plts EPO Term 14.5-22.5 48-69 95-121 0.4-6 9-30 84-478 35.6 mU/ml 3 days Same 44-72 Gradual Change Gradual Change 150-400 2 weeks Gradual Change Gradual Change 1-1.2 No Change 1 month 1-2.4 5-19 2 months 9-14 28-42 0.1-2.9 Gradual Change 11.5 mU/ml 6 months 70-86 0.1-1.3 18.8 mU/ml
  36. 36. Fetal Marrow Development Primitive megaloblastic blood formation starts at 18th day - recurs with illness
  37. 37. Kleihauer-Betke Smear Adult (Maternal) RBC Fetal type RBC Acid removes adult hemoglobin, but not fetal hemoglobin
  38. 38. Megaloblastic Condition <ul><li>Primary cause: results from inhibition of DNA synthesis in red blood cell production </li></ul><ul><ul><li>B12 and/ or Folate deficiency </li></ul></ul><ul><ul><li>Pernicious Anemia </li></ul></ul><ul><li>Hematological findings </li></ul><ul><ul><li>Increased MCV </li></ul></ul><ul><ul><li>Multi-segmented Neutrophils </li></ul></ul><ul><ul><li>Howell-Jolly bodies </li></ul></ul>
  39. 39. Megaloblastic Disease <ul><li>Pre-Leukemia: Myelodysplastic Disease – Elevated MCV </li></ul><ul><li>Fanconi Anemia </li></ul><ul><ul><li>People with FA may also have physical findings, which are highly variable, and may include short stature, upper limb differences, kidney, cardiac, and gastrointestinal problems, brown-pigmented spots on the skin, hearing loss, and developmental delay. </li></ul></ul>
  40. 40. Fetal Marrow Development <ul><li>Normoblastic = 90% @ 10 th week </li></ul><ul><li>Liver is 1 o site from 3 rd -6 th month </li></ul><ul><li>Marrow is 1 o site from 6 th month </li></ul><ul><li>Myeloid development starts ~4 th month </li></ul><ul><li>Blood is rich in progenitors – Cord blood transplants </li></ul>
  41. 41. Human Hemoglobins
  42. 42. Hgb Chain Production Gestational Age 0 3 6 Birth 3 ß- Adult γ- Fetal (high O 2 affinity) є- Embryonic ά- Adult
  43. 43. Fetal Hemoglobin Oxygenated placental blood Lower extremity blood Fetal Brain Perfusion
  44. 44. Fetal Circulation Prenatal Fetal Circulation Video Postnatal
  45. 45.  - Thalassemia Genetics <ul><li> -thal affects 1-4 alpha chains </li></ul><ul><ul><li>Normal (   /   ) </li></ul></ul><ul><ul><li>1 gene (-  /  ) = carrier </li></ul></ul><ul><ul><li>2 genes (- - /  or -  /-  ) =  -thal trait </li></ul></ul><ul><ul><li>3 genes (- - / -  ) = hgb H disease </li></ul></ul><ul><ul><li>4 genes (- - /- -) = hgb Barts </li></ul></ul>
  46. 46. Severe Newborn  - Thalassemia <ul><li>Hgb Bart = γ tetromer (fetal Hgb): no O 2 delivery </li></ul><ul><li>Infants usually die in utero. </li></ul><ul><li>Massive total body edema (hydrops fetalis) due to high output heart failure, with massive hepatomegaly due to extramedullary hematopoiesis. </li></ul><ul><li>Few infants with Hgb Bart's have survived for variable amounts of time, but many have developmental abnormalities, and all have required regular blood transfusion and chelation therapy. </li></ul>
  47. 47. Severe anemia - Parvovirus
  48. 48. Blood Vessel Vascular Wall Cardiac Compensation to Hypoxia Hypoxia: Damaged RBC; Less RBC; Less Oxygen Delivery O 2
  49. 49. High Output Heart Failure <ul><li>Cardiac Output = SV X HR </li></ul><ul><li>Hypoxia requires increased cardiac output </li></ul><ul><ul><li>HR increases first </li></ul></ul><ul><ul><li>SV increases by Starling ’ s Law </li></ul></ul>Intravascular Volume <ul><ul><li>Contractility </li></ul></ul>Better Worse
  50. 50. Pleural Effusion Normal Lung Cardiomegaly Hydrops Fetalis Radiograph
  51. 51. Infant with Hydrops Fetalis
  52. 52. Malignancy until proven otherwise after first week of life Leukoerythroblastic Blood Smear
  53. 53. “ Unusual ” Definition of Normal <ul><li>Possible Sepsis </li></ul><ul><li>Day of Birth: WBC 30K </li></ul><ul><li>Next Day: WBC 34 K </li></ul><ul><li>Peripheral Smear: Leukoerythroblastic </li></ul><ul><li>Dx: Normal </li></ul>
  54. 54. Newborn Iron Acquisition <ul><li>Physiology Review </li></ul><ul><li>Fetus rapidly accumulates Hgb & Fe </li></ul><ul><ul><li>Newborn will have normal Hgb & ferritin even if mother has mild-moderate iron deficiency - May cause of prematurity, LBW </li></ul></ul><ul><li>Fe content at birth = ~ 75 mg/kg </li></ul><ul><li>Varies with cord clamping technique </li></ul><ul><li>Fe deficiency rare before 4 mos of age </li></ul><ul><li>Neither human nor cow ’ s milk has iron </li></ul><ul><li>Fe absorption better with human (lactoferrin) </li></ul>
  55. 55. Umbilical Cord Management <ul><li>Placental vessels contain 75-125 ml of blood, ~ 25-30% fetal blood volume </li></ul><ul><li>Umbilical arteries constrict after birth </li></ul><ul><li>Umbilical veins remain open  gravity flow </li></ul><ul><li>Vaginal birth: ~ ½ placental volume transfused 1 minute </li></ul><ul><li>C-Section: keep infant below placenta 20 seconds prior to clamping the cord </li></ul>
  56. 56. Postnatal Erythropoiesis <ul><li>RBC production  10X during 1 st week </li></ul><ul><li>Mechanism unknown -- EPO level = 0 </li></ul><ul><li>Increases from wk 2 - 3 months </li></ul><ul><li>Consequence = “ physiologic anemia ” </li></ul><ul><li>Marked increase from 4 mos - 12 mos due to body mass growth </li></ul>
  57. 57. Normal Infant Hgb Values Lower Normal - Term Lower Normal - Preterm
  58. 58. RBC-Related Conditions of the Infant <ul><li>Fetal Blood Loss (rare) </li></ul><ul><li>Jaundice (very common) </li></ul><ul><li>Newborn Immune Hemolysis (occasional) </li></ul><ul><li>Congenital RBC Aplasia (rare) </li></ul>
  59. 59. Fetal-Maternal Blood Loss <ul><li>Occurs through the placenta </li></ul><ul><li>Causes: trauma, iatrogenic, idiopathic </li></ul><ul><li>Cause of fetal death if >20% fetal blood volume is lost </li></ul><ul><li>Dx: Test maternal blood for fetal cells </li></ul><ul><ul><li>Kleihauer-Betke Smear </li></ul></ul>
  60. 60. Fetal-Fetal Blood Loss <ul><li>Occurs in 70% of identical twins </li></ul><ul><li>Significant if  Hgb > 5 g/dl </li></ul><ul><li>Chronic – </li></ul><ul><ul><li> weight > 20% of larger twin </li></ul></ul><ul><ul><li>Donor: SGA </li></ul></ul><ul><li>Acute – </li></ul><ul><ul><li> weight < 20% of larger twin </li></ul></ul><ul><ul><li>Donor: volume & rbc depleted </li></ul></ul>
  61. 61. Fetal-Placental Loss <ul><li>Placental Accidents </li></ul><ul><ul><li>Abruption </li></ul></ul><ul><ul><li>Previa </li></ul></ul><ul><ul><li>Multilobar placenta </li></ul></ul><ul><ul><li>Rupture of a cord aneurysm </li></ul></ul><ul><ul><li>Iatrogenic during C-section </li></ul></ul>
  62. 62. Jaundice in the Newborn <ul><li>Fundamentals of physiology </li></ul><ul><ul><li>Bilirubin produced by rbc breakdown </li></ul></ul><ul><ul><li>Newborn liver conjugates poorly </li></ul></ul><ul><ul><li>Lab: T/D </li></ul></ul><ul><ul><li>Direct bili = conjugated </li></ul></ul><ul><ul><li>Indirect bili = unconjugated </li></ul></ul><ul><li>Common:  indirect bilirubin (1/0.2) </li></ul><ul><ul><li>Physiologic; breast milk; rbc destruction; </li></ul></ul><ul><li>Uncommon:  direct bilirubin </li></ul><ul><ul><li>Cholestasis (abnormal ducts; sepsis; mass) </li></ul></ul>
  63. 63. Potential Consequences <ul><li>Bilirubin toxicity </li></ul><ul><ul><li>Kernicterus – </li></ul></ul><ul><ul><ul><li>deafness, retardation </li></ul></ul></ul><ul><ul><ul><li>Caused by staining of basal ganglia </li></ul></ul></ul><ul><ul><li>Risk level: > 20 if hemolysis </li></ul></ul>
  64. 64. Jaundice Evaluation <ul><li>Clinical – sick vs. well / normal color vs. orange </li></ul>
  65. 65. Jaundice Evaluation - Continued <ul><li>Examination for hepatomegaly </li></ul><ul><li>Labs : </li></ul><ul><ul><li>Bili T/D </li></ul></ul><ul><ul><li>?Hemolysis - </li></ul></ul><ul><ul><li>SGOT, SGPT, LDH, Retic, CO-Hgb </li></ul></ul><ul><ul><li>Maternal ABO </li></ul></ul><ul><ul><li>Liver Function Studies </li></ul></ul>
  66. 68. Management <ul><ul><li>Hydration </li></ul></ul><ul><ul><li>Phototherapy </li></ul></ul><ul><ul><ul><li>Isomerize unconjugated bilirubin </li></ul></ul></ul><ul><ul><ul><li>Degrades bilirubin to biliverdin </li></ul></ul></ul><ul><ul><li>Exchange transfusion </li></ul></ul>
  67. 70. Newborn Isoimmune Hemolysis - Rh <ul><li>Anti-D (Rh) </li></ul><ul><li>Setup - </li></ul><ul><ul><li>mother Rh-, IgG Antibody + </li></ul></ul><ul><ul><li>infant is Rh+ </li></ul></ul><ul><li>Mechanism – </li></ul><ul><ul><li>Maternal anti-D IgG crosses placenta, binds fetal rbcs, fetal macrophages destroy rbcs </li></ul></ul><ul><li>Consequences – </li></ul><ul><ul><li>jaundice, anemia, CHF </li></ul></ul>Rh- Rh+ Maternal Anti-D Mother Baby
  68. 71. Prevention and Treatment <ul><li>Prevention </li></ul><ul><ul><li>Administer Rhogam (IM anti-D antibody) at 28 weeks & at delivery </li></ul></ul><ul><li>Treatment (anti-D + mother) </li></ul><ul><ul><li>Follow anti-D levels </li></ul></ul><ul><ul><li>Amniocentesis (bilirubin) </li></ul></ul><ul><ul><li>Fetal ultrasound – scalp edema  transfusion </li></ul></ul><ul><ul><li>Infant – Exchange transfusions </li></ul></ul>
  69. 72. Isoimmune Hemolysis - ABO <ul><li>ABO Incompatibility </li></ul><ul><li>Setup: mother type O </li></ul><ul><li>Mechanism: </li></ul><ul><ul><li>Same </li></ul></ul><ul><ul><li>Antibody is usually anti-A isohemaglutinnin </li></ul></ul><ul><li>Infant: </li></ul><ul><ul><li>Jaundice before anemia </li></ul></ul><ul><ul><li>Spherocytes – rbc membrane destruction </li></ul></ul>O +/- A+ Anti A & B Mother Baby
  70. 73. Congenital Hypoplastic Anemia <ul><li>Blackfan-Diamond Anemia </li></ul><ul><ul><li>Fault in one of the early steps of red blood cell production </li></ul></ul><ul><ul><li>25% have a gene called RPS19 (short for 'small ribosomal protein 19') </li></ul></ul><ul><li>Symptoms </li></ul><ul><ul><li>Fatigue, pallor, “ open mouth ” facies, protruding scapulae,web neck, cardiac abnormalities </li></ul></ul>
  71. 74. Congenital Hypoplastic Anemia <ul><li>Dx: </li></ul><ul><ul><li>Infantile normochromic, macrocytic anemia </li></ul></ul><ul><ul><li>Reticulocytopenia </li></ul></ul><ul><ul><li>Normocellular marrow with deficiency of rbc precursors </li></ul></ul><ul><ul><li>Nl or sl  wbc </li></ul></ul><ul><ul><li>Nl or sl  platelets </li></ul></ul><ul><li>Rx: </li></ul><ul><ul><li>Transfusions, steroids, marrow transplant </li></ul></ul>
  72. 75. Common Anemias - Children & Adolescents <ul><li>Iron Deficiency </li></ul><ul><li>Lead poisoning </li></ul><ul><li>Destructive Anemias </li></ul>
  73. 76. All Ages Anemia Definition <ul><li>Numerical -- Reduction in Hgb Level > 2 S.D. Below the Population Mean </li></ul>
  74. 77. Clinical Definition <ul><li>Generic </li></ul><ul><ul><li>Multisystem failure; Global CNS depression </li></ul></ul><ul><li>Infants </li></ul><ul><ul><li>Poor Feeding; Tachypnea; Apnea; Irritability </li></ul></ul><ul><li>Children </li></ul><ul><ul><li>Poor Growth; Learning difficulties; Fatigue </li></ul></ul><ul><li>Teens </li></ul><ul><ul><li>Headache; Fatigue; Poor school and athletic performance </li></ul></ul>Tissue O 2
  75. 78. Reasons for Investigating <ul><li>General Health -- </li></ul><ul><ul><li>Sxs: Fatigue, headache, cardiac failure </li></ul></ul><ul><li>Sign of Underlying Illness </li></ul><ul><ul><li>Malnutrition; Lead poisoning; Marrow disease; Hypothyroid </li></ul></ul><ul><li>Genetic Counseling </li></ul>
  76. 79. Evaluating an Anemia Destruction Production Loss Immune Not Immune GI Marrow Disease Marrow Invasion
  77. 80. Increased Destruction Immune Not Immune ABO Rh AIHA EBV SLE Intrinsic Extrinsic Enzyme Membrane HGB DIC & Sepsis Burns & Heat Toxins Heart Valve
  78. 81. Decreased Production Marrow Disease Marrow Invasion Nutritional Iron; Copper; Folate Metabolic Thyroid; B-12; Failure Aplastic Anemia Myelodysplasia Infection Congenital Fanconi; BFD Malignant Leukemia Neuroblastoma Lymphoma Solid Tumor Non-Malignant Histiocytosis Storage Disease
  79. 82. Anemia Toolkit <ul><li>First Step – History, family history, ROS </li></ul><ul><li>Labs: </li></ul><ul><ul><ul><li>CBC – define anemia; rbc morphology; </li></ul></ul></ul><ul><ul><ul><li>Retic – Helps with RBC destruction/production </li></ul></ul></ul><ul><ul><ul><li>RBC Destruction – LDH, ALT(normal),AST( ), CO, Haptoglobin ( in intravascular hemolysis) </li></ul></ul></ul><ul><ul><ul><li>Urtinalysis – Hematuria </li></ul></ul></ul><ul><ul><ul><li>Detailed tests then based on mechanism/sxs </li></ul></ul></ul>
  80. 83. Iron Deficiency <ul><li>Physical Performance & Growth </li></ul><ul><ul><li>Restless Leg Syndrome </li></ul></ul><ul><ul><li>Weakness, Dyspnea, Sexual dysfunctions </li></ul></ul><ul><ul><li>Headaches </li></ul></ul><ul><li>Intellectual Performance & Growth </li></ul><ul><ul><li>Attention Deficit Disorder, Cognitive or behavioral dysfunction, fatigue, depression </li></ul></ul><ul><li>GI: pica, anorexia, headache, burning tongue, </li></ul><ul><li>Endocrine: increased menstrual blood </li></ul><ul><li>Immune: Increased severity of infections </li></ul><ul><li>Skin: pruritis, paresthesias, pallor </li></ul>
  81. 84. Glossitis
  82. 85. Angular Chelitis
  83. 86. Koilonychia
  84. 87. Stages of Iron Deficiency <ul><li>Decreased stores (  ferritin) </li></ul><ul><li> Transferrin saturation </li></ul><ul><li>Morphologic Changes </li></ul><ul><ul><li>Anisocytosis </li></ul></ul><ul><ul><li>Normochromic, normocytic anemia </li></ul></ul><ul><ul><li> Hgb,  MCV,  MCHC; thrombocytosis </li></ul></ul><ul><li>Bone marrow depletion </li></ul>
  85. 88. Causes <ul><li>Blood loss </li></ul><ul><ul><li>GI: Cow ’ s milk in infants, Celiac disease </li></ul></ul><ul><ul><li>Menses: 20% teenage girls are deficient </li></ul></ul><ul><ul><li>Respiratory loss is rare </li></ul></ul><ul><li>Dietary </li></ul><ul><ul><li>Nursing: 1 mg/kg/day required for term infants starting at 4 months of age </li></ul></ul><ul><ul><li>Children who drink a lot of milk </li></ul></ul><ul><ul><li>Age 1-2 years; Female 14-30; Pregnancy; </li></ul></ul><ul><ul><li>Males > 12 are OK (low requirement; carnivorous) </li></ul></ul>
  86. 89. Laboratory Dx <ul><li>CBC terminology </li></ul><ul><li>Peripheral Smear </li></ul><ul><li>Iron Studies </li></ul>
  87. 90. Normal Blood Smear
  88. 91. Iron Deficiency Smear
  89. 92. Iron Studies Iron Iron Iron Varies TIBC NL  TIBC TIBC Varies Normal Fe Deficient Chronic Disease <ul><li>Iron </li></ul><ul><li>TIBC (transferrin) </li></ul><ul><li>Ferritin </li></ul>Normal Fe Deficient ??? Chronic disease
  90. 93. Serum Ferritin <ul><li>Generally correlates with iron stores </li></ul><ul><li>Nl ferritin @ 6 mos-15 years lower than other ages </li></ul><ul><li>Taking Fe increases ferritin </li></ul><ul><li>Normal Ferritin </li></ul><ul><ul><li>Newborn: 25-200 ng/ml or SI units </li></ul></ul><ul><ul><li>1 st month: 200-600 </li></ul></ul><ul><ul><li>2-5 months: 50-200 </li></ul></ul><ul><ul><li>> 5 months: 7-140 </li></ul></ul><ul><ul><li>Adult Male: 20-250 </li></ul></ul><ul><ul><li>Adult female: 10-120 </li></ul></ul>
  91. 94. Soluble Transferrin Receptor
  92. 95. Using TF Receptor <ul><li>The concentration of cell surface transferrin receptor is regulated according to the internal iron content of the cell and its iron requirements. </li></ul><ul><li>Iron-deficient cells contain increased numbers of receptors, while receptor numbers are downregulated in iron-replete cells </li></ul><ul><li>Reference intervals: 3.5 – 8.5 mg/L </li></ul>
  93. 96. Diagnoses with TR <ul><li>Serum concentrations of transferrin receptor increase in iron-deficiency anemia </li></ul><ul><li>Transferrin receptor concentrations do not increase in anemia secondary to inflammatory disorders </li></ul>
  94. 97. Treatment <ul><li>Iron replacement </li></ul><ul><ul><li>3mg/kg elemental Fe daily X 3 months </li></ul></ul><ul><ul><li>Poor compliance is main reason for failure </li></ul></ul><ul><ul><li>Retics increase after 3 days; Hgb by 1 week </li></ul></ul><ul><ul><li>GI absorptive defect very rare - use intravenous Fe (not IM) </li></ul></ul><ul><ul><li>Transfusion needed only if anemia is hemodynamically very significant </li></ul></ul>
  95. 98. Lead Poisoning <ul><li>Physiology </li></ul><ul><ul><li>Absorbed like iron from air, paint, dirt, dust </li></ul></ul><ul><ul><li>Inhibits 1 st and last steps in Hgb production </li></ul></ul><ul><ul><li> -ala and EPP basal ganglia damage </li></ul></ul><ul><ul><li>Disrupt CNS heme synthesis </li></ul></ul>
  96. 99. Sources <ul><li>Homes built before 1960 </li></ul><ul><li>Ongoing home renovation </li></ul><ul><li>Lead in water pipes </li></ul><ul><li>Nearby industry </li></ul><ul><li>Old furniture, toys, art supplies </li></ul>
  97. 100. <ul><ul><li>Acute </li></ul></ul><ul><ul><ul><li>Neurological: hyperactivity or lethargy; increased sleep; ataxia; coma, seizures, respiratory arrest </li></ul></ul></ul><ul><ul><ul><li>Renal: Fanconi nephropathy </li></ul></ul></ul><ul><ul><li>Chronic </li></ul></ul><ul><ul><ul><li>Neurological: behavioral changes, peripheral neuropathy with pain & weakness of extensors, deteriorating cognitive function - even with mildly elevated Lead levels of ~ 20 mcg/dl </li></ul></ul></ul><ul><ul><ul><li>GI: abdominal pain, vomiting, malaise, constipation </li></ul></ul></ul><ul><ul><ul><li>Skeletal: Lead lines </li></ul></ul></ul>Symptoms
  98. 101. Diagnosis <ul><li>Increased serum lead level (veinipuncture) </li></ul><ul><li>CBC with microcytosis and basophilic stippling </li></ul><ul><li>X-ray: dense metaphyseal bands </li></ul>
  99. 102. Basophilic Stippling
  100. 103. Dense Metaphyseal Bands
  101. 104. <ul><li>Treatment </li></ul><ul><li>Asymptomatic: </li></ul><ul><ul><ul><li>level 20-44 - consider chelation </li></ul></ul></ul><ul><ul><ul><li>Level 45-69 - urgent chelation </li></ul></ul></ul><ul><ul><ul><li>Level > 70 - emergency chelation </li></ul></ul></ul><ul><ul><li>Symptomatic children require immediate supportive care and aggressive chelation </li></ul></ul><ul><ul><li>Identify the Source of Lead </li></ul></ul><ul><ul><li>Quarantine the house </li></ul></ul><ul><ul><li>Follow-up closely </li></ul></ul><ul><ul><li>The state of Maine will help with all of this </li></ul></ul>
  102. 105. Anemia of Increased Destruction <ul><li>Intrinsic </li></ul><ul><ul><li>Hemoglobin disorders </li></ul></ul><ul><ul><ul><li>Hgb SS </li></ul></ul></ul><ul><ul><ul><li>Thalassemia </li></ul></ul></ul><ul><ul><li>Membrane </li></ul></ul><ul><ul><ul><li>HS -- Stiff membrane </li></ul></ul></ul><ul><ul><li>Metabolic </li></ul></ul><ul><ul><ul><li>PK </li></ul></ul></ul><ul><li>Extrinsic </li></ul><ul><ul><li>Autoimmune, mechanical, DIC </li></ul></ul>
  103. 106. Laboratory Findings <ul><li>Heme:  retics; anemia; abnl smear </li></ul><ul><li>Chem:  LDH, AST (SGPT);  haptoglobin </li></ul><ul><li>Urine: Hgb (vs. myoglobin) </li></ul>
  104. 107. Sickle Cell Anemia <ul><li>Pathophysiology </li></ul><ul><li>Clinical </li></ul><ul><ul><li>Autosplenectomy & OPSI </li></ul></ul><ul><ul><li>Acute splenic sequestration </li></ul></ul><ul><ul><li>Aplastic Crisis </li></ul></ul><ul><ul><li>Vaso-occlusive crisis </li></ul></ul><ul><ul><li>Stroke </li></ul></ul><ul><ul><li>Endocrinopathies </li></ul></ul>
  105. 108. Pain with Sickle Cell Disease <ul><li>The most common symptom is pain </li></ul><ul><li>Pain crises – people go to the emergency room to get treated </li></ul><ul><ul><li>Pains seem to come from the bones, usually in the arms, hands, legs, feet, or back </li></ul></ul><ul><ul><li>acute chest syndrome </li></ul></ul><ul><ul><li>Some have been accused of being addicted to pain meds </li></ul></ul><ul><li>Prevention – avoid dehydration, excess exercise </li></ul><ul><li>Rx – pain meds; hydration; steroids </li></ul>
  106. 109.  -Thalassemia <ul><li>1 o problem is ineffective hematopoiesis </li></ul><ul><li> -thal trait </li></ul><ul><ul><li>Asymptomatic </li></ul></ul><ul><ul><li>Low MCV, +/- mild anemia </li></ul></ul><ul><li> -thal major </li></ul><ul><ul><li>Severe disease-some recommend BMT </li></ul></ul><ul><ul><li>Severe anemia (hgb ~ 5) </li></ul></ul><ul><ul><li>Progressive Fe overload causes morbidity & mortality - cardiac, endocrine, liver </li></ul></ul><ul><ul><li>Rx: Support; BMT </li></ul></ul>
  107. 110. Hereditary Sphereocytosis <ul><li>Defective membrane (stiff) </li></ul><ul><li>Intrasplenic hemolysis </li></ul><ul><li>Clinical </li></ul><ul><ul><li>Varying degrees of severity </li></ul></ul><ul><ul><li>Aplastic crises </li></ul></ul><ul><ul><li>Anemia </li></ul></ul><ul><ul><li>Increased MCHC </li></ul></ul><ul><ul><li>Cholelithiasis WHY? </li></ul></ul><ul><ul><li>Folate deficiency </li></ul></ul>
  108. 111. Blood Smear Spherocytes
  109. 112. Osmotic Fragility [NaCl] % Lysis % Lysis 1.0% NS (plasma) 0 0 .75% NS 10 20 .50% NS 30 60 .25% NS 70 90 .00% NS (water) 100 100 • Normal •HS
  110. 114. Management <ul><li>Follow infant Hgb & bilirubin closely </li></ul><ul><li>Follow reticulocyte counts when well </li></ul><ul><li>Follow growth & “ wellness ” </li></ul><ul><li>Folic acid supplementation </li></ul><ul><li>Rx aplastic crises with patience and transfusion or steroids if necessary </li></ul><ul><li>Splenectomy based on clinical course </li></ul>Case Studies End
  111. 115. Spherocytosis Case <ul><li>7 year old boy, + OF and family history </li></ul><ul><li>Taking folic acid daily </li></ul><ul><li>2 years of difficulty keeping up with peers </li></ul><ul><li>Retics ~ 15%, Hgb 9 mg/dl </li></ul><ul><li>PE: Thin, short; spleen 8 cm below LCM </li></ul>
  112. 117. What needs to be done? <ul><li>New labs show normal thyroid, celiac, growth hormone. </li></ul><ul><li>Options? …… </li></ul>
  113. 118. Childhood Hemolytic Anemia <ul><li>Autoimmune - antibody mediated </li></ul><ul><ul><li>Idiopathic </li></ul></ul><ul><ul><li>Drug-Induced </li></ul></ul><ul><ul><li>Disease-related </li></ul></ul><ul><ul><ul><li>Infections - Viral (EBV, HIV), mycoplasma </li></ul></ul></ul><ul><ul><ul><li>Autoimmune - SLE, RA, Thyroid, UC </li></ul></ul></ul><ul><ul><ul><li>Immunodeficiency - all of them </li></ul></ul></ul><ul><ul><ul><li>Cancer - Hodgkin ’ s, ALL, NHL, etc. </li></ul></ul></ul>
  114. 119. Clinical Course <ul><li>Age usually < 4 yrs </li></ul><ul><li>Acute onset - rapid Hgb fall 0-4 days </li></ul><ul><li>Course can be acute (3-6 mos) or chronic </li></ul><ul><li>Mortality 9-19% </li></ul><ul><li>Clinical: pallor, jaundice, dark urine, fever, abdominal pain, hepatosplenomegaly, CHF </li></ul>
  115. 120. Diagnosis <ul><li>Evidence of hemolysis </li></ul><ul><li>Blood Smear: spherocytes; retics </li></ul><ul><li>DAT - Direct antibody test </li></ul><ul><ul><li>Macro (> 1000 IgG molecules/rbc) </li></ul></ul><ul><ul><li>Micro (detects > 100 molecules/rbc) </li></ul></ul>
  116. 121. Treatment <ul><li>Observation </li></ul><ul><li>Corticosteroids </li></ul><ul><li>Intravenous Immunoglobulin (IVIG) </li></ul><ul><li>Transfusion -- need a good lab </li></ul><ul><li>Exchange transfusion - severe CHF </li></ul><ul><li>Plasmapheresis </li></ul><ul><li>Splenectomy </li></ul><ul><li>Rituximab: anti-CD20 (new & cool) </li></ul>
  117. 122. Mechanical Destruction <ul><li>DIC </li></ul><ul><ul><li>Sepsis, coagulopathy, tissue necrosis </li></ul></ul><ul><li>Thermal </li></ul><ul><ul><li>burns, heatstroke </li></ul></ul><ul><li>Infection </li></ul><ul><li>Hardware </li></ul><ul><ul><li>heart valve, thrombosed CVL </li></ul></ul><ul><li>Surgery - cardiac </li></ul>
  118. 123. Case Studies
  119. 124. Case 1 <ul><li>12 hr old black male term infant with jaundice </li></ul><ul><li>Mother is 25 yrs. Old, G2P1001, O-, serology -, uncomplicated pregnancy, received Rhogam @ 28 weeks </li></ul><ul><li>Infant is clinically well, has not voided or stooled </li></ul><ul><li>Labs: </li></ul><ul><ul><li>Bilirubin 16/0.5 </li></ul></ul><ul><ul><li>CBC: WBC 21,000 60p/5b/27lymphs </li></ul></ul><ul><ul><li>Hgb 16/ Hct 50; Platelets 165 K </li></ul></ul><ul><ul><li>Peripheral Smear </li></ul></ul><ul><ul><li>Type & Coombs: A+; DAT +; IAT + (anti-A) </li></ul></ul>
  120. 125. Blood Smear
  121. 126. Case 2 <ul><li>5 yr old white male with a 4 mo. hx of irritability and inattention at school </li></ul><ul><li>Social hx: Lives with parents and 2 siblings in an old apartment that is under repair. </li></ul><ul><li>Family hx: “ We all fed our babies whole milk, and nobody ever had a problem! ” </li></ul><ul><li>Past hx: mild developmental delay. </li></ul><ul><li>PE: hyperactivity; pale conjunctivae; hyperreflexia; </li></ul>
  122. 127. Case 2 Labs <ul><li>CBC- </li></ul><ul><ul><li>WBC 9,000, normal differential </li></ul></ul><ul><ul><li>Hgb 9.0/Hct 27, MCV 72, </li></ul></ul><ul><ul><li>Platelets 220 K </li></ul></ul><ul><ul><li>Smear </li></ul></ul><ul><li>Retics: 1% </li></ul><ul><li>Lead: 21 mcg/dl </li></ul><ul><li>Ferritin: 5 </li></ul><ul><li>Fe low; TIBC elevated </li></ul>
  123. 128. High Power Low Power
  124. 129. A Different Scenario <ul><li>PE: grade II systolic murmur; no CHF </li></ul><ul><li>Hgb: 4.9 </li></ul><ul><li>MCV: 63 </li></ul><ul><li>Retics: 0.5% </li></ul><ul><li>WBC 6000, 10 polys, 90 lymphs </li></ul><ul><li>Platelets: 1,300,000 </li></ul>
  125. 130. Management Options Dx: Fe Deficiency Consider Hospitalization Rx: Fe, 3-6 mg/kg/day Folate, 1 mg/day Retic in 3 Day Hgb in 1 Week ? Transfusion Continue Fe & Folate X 3 mos
  126. 131. Case 8 <ul><li>3 year old child presents for WCC. Parents note 2 months of increasing pallor & fatigue. No medical care since 4 months of age. Several recent colds. </li></ul><ul><li>Both parents are of Italian descent. Apartment is 80 years old & under repair. </li></ul><ul><li>PE: slightly pale. No dysmorphic features. Grade III SEM, no gallop. Liver down 2 cm. </li></ul>
  127. 132. Case 8 Labs <ul><li>CBC: </li></ul><ul><ul><li>WBC 8,000 40 polys, 60 lymphs </li></ul></ul><ul><ul><li>Hgb 3.8 Hct 11.9 </li></ul></ul><ul><ul><li>MCV 80 </li></ul></ul><ul><ul><li>Platelets 190 K </li></ul></ul><ul><ul><li>Smear </li></ul></ul><ul><ul><li>Retics: 0.5% </li></ul></ul><ul><ul><li>Lead: 15 mcg/dl </li></ul></ul><ul><ul><li>Ferritin: 50 </li></ul></ul><ul><ul><li>Hgb Electrophoresis: A 1 = 97%; A 2 = 2%; F=1% </li></ul></ul><ul><ul><li>Bone marrow: decreased rbc precursors </li></ul></ul>
  128. 133. Another Scenario <ul><li>CBC- </li></ul><ul><ul><li>WBC 8,000 with a normal differential </li></ul></ul><ul><ul><li>Hgb 3.8 Hct 11.9 </li></ul></ul><ul><ul><li>MCV 100 </li></ul></ul><ul><ul><li>Platelets 400,000 </li></ul></ul><ul><ul><li>Smear: 2+ polychromasia, 1+ nrbcs </li></ul></ul><ul><ul><li>Retics: 5% </li></ul></ul><ul><ul><li>Bone marrow: increased RBC precursors </li></ul></ul>
  129. 134. Case 12 <ul><li>CC: 4 yr. old girl, 1 week of pallor & jaundice </li></ul><ul><li>HX: Started with fever, malaise, congestion </li></ul><ul><li>Progressive pallor, fatigue, abdominal pain </li></ul><ul><li>PE: Vitals : HR 130; RR 27; obvious pallor </li></ul><ul><li>HEENT : Scleral icterus </li></ul><ul><li>Cardiac : Grade II systolic murmur </li></ul><ul><li>Abdomen: Spleen 5 cm below RCM </li></ul>
  130. 135. More History <ul><li>Neonatal jaundice </li></ul><ul><li>Transfused once in infancy </li></ul><ul><li>Several similar episodes in past </li></ul>
  131. 136. Family History <ul><li>Mother “ always ” anemic </li></ul><ul><li>Mother and her sister with cholecystectomy in early 20 ’ s </li></ul><ul><li>Mother ’ s Father had splenectomy “ many years ago ” </li></ul>
  132. 137. Lab Tests <ul><li>Hgb: 5.5 gm/dl </li></ul><ul><li>MCHC: 32 </li></ul><ul><li>Retic: 0.1% </li></ul><ul><li>WBC & Platelets: Normal </li></ul><ul><li>Coombs: Negative </li></ul><ul><li>Smear </li></ul>
  133. 138. Break Time! Grazing Horse, Freeport
  134. 139. Bilirubin Metabolism Intravascular Extravascular Free Hgb + Haptoglobin Fe + Transferrin Free Hgb Red cells contain SGOT & LDH All Fe is recycled
  135. 140. The CBC - Definitions <ul><li>WBC : Total leukocytes per mm 3 </li></ul><ul><li>ANC: Total # neutrophils per mm 3 </li></ul><ul><li>Hgb: Grams Hgb/dl </li></ul><ul><li>Hct: % rbcs in a spun tube of blood </li></ul><ul><li>MCV: mean rbc volume </li></ul><ul><li>MCHC: mean Hgb concentration </li></ul><ul><li>Platelets: # per </li></ul><ul><li>MPV: mean platelet volume </li></ul>Spun Capillary Tube
  136. 141. Blood Smear Normal

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