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‘CURRICULUM CONTENT—CORE LECTURE SERIES Hematology Objectives The student will develop a reasonable differential diagnosis and basie evaluation scheme for new= bors with common clinical presentations of jaun- dice. ‘To successfully accomplish this competency the student will need the following skills oF knowl- edge base: Recognize predisposing factors to newborn jaundice. Interpret the results of CBC. The student will develop a reasonable differential diagnosis, diagnostic approach, and treatment plan for the common pediatric clinical problems (See Competency IV.) To successfully accom- plish this competeney the student will need the following skills or knowledge base: Interpret the results of commonly ordered laboratory tests such as CBC. The student will recognize the impact chronic illness has on the patient and the family. The stu- dent will demonstrate knowledge of common medications and treatment regimes used in the pediatric inpatient and non acute outpatient treat- ment of Sickle Cell Disease. (See Competency VL) Discuss common physical exam findings and implications associated with the diagnosis of Sickle Cell Disease See Table 2 1) Symptoms - Pallor/anemia ‘Common Conditions - [ron Deficiency anemia, lead poisoning Significant Other Condition Sickle Cell Content Developed by: Taru Hays, MD Disease 2). Symptoms - Bruising/petechiae Common Conditions - Readings Lane, P.A.; Nuss, R. & Ambruso, D.R ‘Hematologic Disorders." In W.W. Hay, Jr., A.R. Hayward, MJ. Levin, & JM. Sond- heimer’s Current Pediatric Diagnosis & Treatment, | 6th ed. Appleton & Lange, 2003. Case Study: Thrombocytopenia A six year old white female comes to the ER bruises, petechiae, and nose bleeds lasting for two hours. She had a URI three weeks ago which was treated with antibiotics. There is no fever or he- ‘maturia. Physical Ex ‘Active, alert Bruises all over body Petechiae ++ crusted nares, no active bleeding ‘no hepatosplenomegaly no lymphadenopathy CBC: Hemoglobin 13.9 g/dl Het 36.9% MCV 84 f1 WBC 9800/mel, segs 49%, lymph 49%, monocytes 2% Platelets 2,000/mel Smear: red cells and white cells morphology nor- ‘mal with decreased platelets and some platelets, very large. No pathological cells seen Questions: ‘CURRICULUM CONTENT—CORE LECTURE SERIES What is the differential diagnosis? 2. Any additional tests? 3. Management issues. Case Study: Newborn/Hemolytic Anemia Three day old full term healthy newborn is found to be jaundiced, and pale, No family history of anemia Physical Exam: ‘Active, alert, hyperbilirubinemic baby pale no hepatosplenomegaly chest is clear heart has no murmur, slightly tachycardiac CBC: Hemoglobin 11 g/dl Het 33% MCV 104 f1 WBC 15,000/mel with normal differential Platelet count 340,000/mel Reticulocyte Count 15% ‘Smear: normochromic, normocytic with many micro and macro spherocytes. Increase in poly- chromatophilic cells, some nucleated red cells seen. WBC and platelet morphology is normal. Special tests: mother’s blood type OF baby’s blood type B+ Direct Coombs test 1+ Indirect Coombs 2+ Questions: 1. What is the differential diagnosis? 2. Management? Case Study: Pancytopenia Five year old Hispanic male seen in ER with low trade fever, abdominal pain and leg pains of two weeks durat Physical Exam: Chronically ill looking child many bruises all over body pale but non-icteric liver 3 em below right costal margin spleen 6 cm below left costal margin anterior cervical lymph nodes ++ bilaterally CBC: Hemoglobin 6 g/dl Ht 18% WBC 2500/mel with 2% segs, 95% Iympho- eytes, 3% eosinophils Platelets 52,000/mel Reticuocyte count 1.5% Smear: Red cells: normochromiec, normoeytic with some teardrops and anisoeytosis; WBC: pre- dominantly lymphocytes with lymphoblasts seen: Platelets: decreased in number but normal in mor- phology, Questions: 1. What is the diagnosis? 2. Any differential diagnosis? 3. Any additional tests? 4. Management? Case Study: Epistaxis/Bruis Six year old Caucasian male was seen in pediatri- in’s office because of easy bruising and fre- ‘quent epistaxis since age four years. Epistaxis lasts for 20-30 minutes and happens once/weekly There was no other bleeding from any other site. Family History: Father with increased bruises and epistaxis, also increased bleeding post T&A. Fa- ther’s sister had menorrhagia, epistaxis, post- partum bleeding - need transfusion, Physical Exam: Active, alert ‘no hepatosplenomegaly bruises on the shins nares: crusting with dry bleed Screening test done: Bleeding time 12.5 minut (normal = 0-9.1 ‘CURRICULUM CONTENT—CORE LECTURE SERIES minutes) PT 12 seconds: PTT 36.4 seconds (PT, nor mal 12- 13.2 and PTT, normal 23-32) Platelet count 360,000/met Questions: I. What other laboratory tests need to be done? 2. What is your differential diagnosis? 3. When will you study the family members? Case Study: Microcytic Anemia ‘A one year old Caucasian boy comes to your of fice for the first time for a well child visit. He had previously received immunizations at a county health clinic. Past history includes a normal term delivery and neonatal course. Growth and devel- ‘opment are normal. Diet history includes formula until six months of age, with cow’s milk and baby foods (including some iron fortified cereals) since, Physical examination is normal. You order asereening CBC and blood lead level: Physical Exay pale, non-icterie no hepatosplenomegaly chest clear mild tachycardia Laboratory Evaluation: RBC 2.3 x 10"/ml Heb 6.8 mg/dl Het 22% MCV 60 f1 WBC 9,600 (21 segs, I band, 70 Iymphs, 8 mons) Platelet 486,000/me1 RDW 18.2 serum lead level = low Smear: microcytic hypochromie red cells with a few target cells Questions: 1. What is the most likely cause of the anemia? ‘And what is the differential diagnosis? 2. Will you order additional tests? Which ones? Case Study: Hemolytic Anemia Eleven month old black male with pufly hands and feet, Jaundice is observed on and off since birth. Baby is growing well. Physical Exam: Fussy but alert infant pale and ieteric Liver: 2 em below RCM and spleen tip palpa- ble No cardiomegaly Both hands and feet swollen and tender cBc Hgb 7.0 % Het 20.5% MCV 85 f1 WBC 12000/mel with 70 segs. 3 bands, 27 lymphs, 5 nucleated red cells Platelets normal in numbers and morphology Retic count 18% Questions: I. What is the differential diagnosis inthis case? 2. What additional tests should you order? 3. Management Case Study: Neutropenia Eighteen month old white female with chronic otitis media on Bactrim Physical Exam: Healthy, active child Serous otitis media No hepatosplenomegaly No nodes Chest clear CBC: WBC 3,200/mel, with 2% segs, 0% bands, CURRICULUM CONTENT—ConrE LECTURE SERIES 90% lymphocytes, 8% monocytes Hab 13.0 2% Het 38% Platelets 350,000/mel ‘Question: 1. How common is neutropenia in children? When should one work up neutropenia? What are the common causes of neutropenia? 4. Management of neutropenia Case Study: Red Cell Aplasia Three year old white male comes to the pediatri- ccian’s office for a well child check with pallor and history of upper respiratory infections/atitis, ‘media four weeks ago, which was treated with Amoxicillin, No family history of anemia, jaun- dice or splenectomy. Physical Exam: ‘Active, alert Pale, no icterus No hepatosplenomegaly No nodes palpable Pulse 115/m Systolic murmur without gallop cBe: Hab 5.0 gid Het 15.1% MCV 7811 WBC 10,000/mel with 46% segs, 51% lymphs, 3% monocytes Platelets 525,000/mel Retie Count 0.1% Smear: Normoeytic with normochromic with few spherocytes. No fragments. WBC: normal in ‘numbers and morphology. Platelets: normal in number Questions: 1. What is the differential diagnosis? 2. What additional tests do you want to order? 3. Should you ask for a bone marrow aspira- tion/biopsy? 4. Management Case Study: Microcytic Anemia You are called by a family practitioner for help in interpreting laboratory results for an 18 month old southeast Asian girl. A mild microcytic anemia hhad been discovered at one year of age and iron had been prescribed, Follow up studies showed tno improvement. The child’s growth and develop- ‘ment have been normal. There is no evidence of chronic disease. The caller is unsure about dietary history. The physical examination is normal. The children’s mother is three months pregnant. Physical Exam: RBC 5.05 x 10°%ml Hab 11.0 2% Het 32.8% MCV 65 f1 WBC 8,600/mel with 31% segs, 60% Iymphs, 8% monoeytes, 1% eosino- phils Platelets 386,000/mel RDW 14.0 Smear: 2+ micro, 2+ hypo, occasional targets se- rum iron: 78 mg/dl IBC: 312 mid] serum ferritin: 55 mg/L. Questions: 1. What else would you like to know about the history? 2. What is the most likely cause of the mild anemia? 3. Should you suggest additional tests? 4. Are there any genetic counseling issues for the family? CURRICULUM CONTENT—CoRE LECTURE SERIES Pediatric Hematology low as 9-10 g/dl and 28-30% respectively at about 2-3months (physiologic anemia). I. Normal Values Thereafter, the normal values for hemo- A. Red cells globin and hematocrit gradually increase n fe until adult values are reached after pu- The normal ranges for peripheral blood berty. Newborns have larger red cells ‘counts vary significantly with age. Nor than children and adults, sith MCV at ‘mal neonates show a relative polycythe- birth of more than 94 fl. The MCV cube ‘mia with a hematocrit of 45-65%. Within sequently falls to a nadir of 70:84 flat the first few days of life, erythrocyte pro- about 6 months of age. Thereafter, the duction decreases. and the levels of he- MCV gradually increases until it reaches moglobin and hematocrit fall to a nadir as adult normal values after puberty, Re MCV (A) MCH pe) MCHC (wid) = New [280 | Mean 390] Wen [250 em [3 en [a eT (ood plod) roid capil [ewe Ts [ea A A we Tess sf 9 a9 Tos [86 3 [re EC eT Tot [asf mo A A A a EE A 39 fom 1s} 95, 35 39a 310s 0 S2y [20 fos Jae as 0 sf 0 5 Bsus rf fa Bs a suns 3 [es a wo [ vo [a [ow | 46 vw [ow [ow fas Pow [ow i ae ee et uo [ vo [oa | ow | a6 w [3 ufos mas a a St I Hemoglobin (gal) | Hematoere ws [ous [os [2 [a [ao [oe [os | we fo | oo 7 ao ws [ous [ow fw [so ws fos foe fou [oo | 2 B. White Cells in the differential white count at birth and in the older child. There is a predomi- nance of lymphocytes (up to 80%) b tween about I month and 6 years of age. The normal number of white blood cells is higher in infancy and early childhood than later in life, Neutrophils predominate RCRD CURRICULUM CONTENT—CoRE LECTURE SERIES rus 1° a, ie ® 0 B 4 a POS eee ee op yes) ‘ae mar) Figure 1. Hemoglobin and red cell volume in infancy and childhood. (From Dallman PR, Siimes MA: Percentile curves for hemoglobin and red cell volume in infancy and childhood. J. Pediatr (1979;94:26.) TOTAL LEUKOCYTES NEUTROPHILS TyMPROorTES MONocYTES [ESONOPHIS Age [Mean] Range [Mean] Range [% [Mean] Range | _% [Mean] % [Mean] % [Binh_[18.1 | .0-30.0) | 11.0] 60-260) | 61 | 55 e011] 31] 11] 6 | 04] 2 2h [22.8] (13.0-38.0) | 15.5 | (6.0-28.0) | 68 | 5.5 | 20-11.) | 24} 12] 5 Jos] > th [89 [9.4340 [115] Gozo | or [se Teor [si fii] 6 fos] 2 wk [12.2 5.021.) [5.5 [C.s-10.0 [4s [5.0 Teor) [ 4 [it] 9 os] 4 Pwk [114] G.0-20.0) [45 40 [357 e017 [ae fio [9 fort 3 mo [10.8] (5.0-19.5) [3.8 35 [60 | 25165) | 36 [07 [7 [ost 3 mo [11.9 60-175) [3.8 | 1.085) [32 [73] ao-135)] 61 | 06] 5 Jos] 3 o a] 60-175) [35 | 585) [31 [70] 4.0-105)] 61 | 06] 5 fos] 3 b 10.6 | (6.0-17.0) | 3.5 | U5-85) | 33} 63 | 095 | 59 fos] 5 fos] 3 Hy [9.1 [s155) [3.8 [585) [2 [as [eos [x0 Posts fos] 3 8516.05) [431 0580 [51 3s, as7m [42 fost s [oz] 3 83 145-35) [44 [0580 [53 [33] 0568) | 39 Joa] 4 [02] 2 oy [8.1 [asi35) [aa [88.0 [sa [31] 1565) | 38 fos] 4 [02] 2 ley | 78 | 45-130) | 44 [ 880) | 37 [28] 1252) | 35 pos] 5 02] 3 bi 74 [aso [4s [87.7 [59 [25 [ 048) [34 [os] 4 foot 3 Table 2. Normal Leukocyte Counts ‘CURRICULUM CONTENT—CoRE LECTURE SERIES CC. Platelets Normal values for the platelet count are 150,000t0 400,000 mL. and vary little with age, IL. Anemia A. Overview Anemia helpful. B. Microcytic Anemia + Iron deficier y Dictary deficiency -6 to 36 months Chronic blood loss - any age Detrimental effects on cognitive & motor development Typical laboratory findings vMCV YMCH +RDW Figure 2. Anemia relatively common finding, with many potential etiologies. Oft correct diagnosis is suggested by the his- tory and physical findings and can be es- tablished with relatively little laboratory cost. MCV-dependent classification is serum ferritin serum iron AIBC (¥ % saturation) Alpha (a) Thalassemia Common in children of African and South and Southeast Asian ancestry Thalassemia trait most common (W MCV, 4 MCH, RBC, mild or no anemia) Often initially suspected by presence of Barts Hb (74) on neonatal sereening Hb electrophoresis in older children normal Beta (8) Thalassemia Common in Africans, Mediterrane- ans, Arabs, South and Southeast Asians Most heterozygotes have b thalas- semia minor (¥ MCV, % MCH, RBC, mild anemia) Neonatal sereening test normal Hb electrophoresis in older children shows Hb Asand /or 4 Hb F SISO LAE EHS RCR ELSIE ET PRESEN IS EET TOE ‘CURRICULUM CONTENT—Core LECTURE SERIES + Hemoglobin E (b Glu->Lys) disorders Very common in Southeast Asians, ‘especially from Thailand, Laos, Cambodia Heterozygote : normal CBC or slightly Y MCV Homozygote, 4 MCV. 4 MCH, may have mild anemia * Sickle- & thalassemia (see sickle cell disease) Microeytic, hypochromic anemia due to coexistent iron deficiency may be present Microcytic Anemia: Is it iron deficiency or ssemia? Ifthe history (e.g, inadequate die- tary iron, especially age 6-36 months, or known blood loss) and physical exam (no evidence of alternative diagnosis) suggest iron deficiency and if the CBC is consistent (see below), then itis ‘often appropriate to treat presumptively with oral C. Normoeytic Anemia + Decrease red cell production ‘Anemia of chronic disease (may have low MCV and low serum iron, but [in contrast to iron defi- ciency] IBC is normal or 4 and serum ferritin is normal or +) ‘Transient erythroblastopenia of child- hood (most common age 6 ‘months - 4 years) Aplastic crisis 2° parvovirus infection in patients with chronic hemoly- sis Aplastic anemia (usually pancyto- penia) Leukemia (usually pancytopenia with or without circulating blasts) ‘+ Hemolytic disease Acquired ‘Autoimmune (positive Coombs test) Microangiopathic (e.g. HUS, DIC) Congenital RBC membrane defects (e.g. he- reditary spherocytosis) RBC enzyme defects (e.g. G-6- PD deficiency) Hemoglobinopathies (e.g. sickle cell disease) mev | wac [mcvauc] epw | rertin | temoionm [spot a ee N Ys ‘tit | a} “a as ver [Ww Ne : : Tare oma fa [a a Nora [PR AEGPE yo Table 3, Tron Deficiency or Thalassemia IN = normal results, Hb ~ hemoglobin *Coexistent iron deficiency may Hb Az [+* Homozygous E or sickle b-thalassemia may eause mild tic anemia CURRICULUM CONTENT—CORE LECTURE SERIES I disease. All of the clinical manifesta- tions of the disease are due directly or indirectly to chronic hemolysis or to intermittent episodes of vascular occlusion that cause tissue ischemia and acute and chronic organ dysfunction. Important clinical manifestations include: Hemolysis Vaso-ocelusion Chronic anemia Recurrent acute pain Jaundice (ea, dactylitis, Aplastic crises musculoskeletal, Choletithiasis abdominal) Functional asplenia (bacterial infection)* Splenic sequestration Acute chest syndrome* Stroke* Hyposthenuria & enuresis Papillary necrosis, Chronic nephropathy Priapism Avascular necrosis Proliferative retinopathy Leg ulcers * Important cause of morality during childhood Delayed growth & sexual maturation Most states screen all newborns for sickle disease because presymptomatic diagnosis pro- Vides the opportunity for education and medical interventions that significantly reduce morbidity and mortality during childhood, For example, fa- tal episodes of bacterial infection can be pre- vented by the use of prophylactic penicillin, pneu- ‘mocoecal immunization, and prompt aggressive ‘evaluation and treatment (with parenteral antibiot ics) of al significant febrile illness. Death from splenic sequestration can be prevented by educat- ing parents about the signs, symptoms, and appro- priate interventions for that complication of the disease. Other interventions prevent or minimize other complications and/or their sequelae. Thus comprehensive medical care markedly prolongs life expectancy. The term sickle cell disease encompasses a num- ber of symptomatic disorders caused by homo: g0us inheritance of the sickle gene or by com- Pound heterozygous inheritance of Hb S with Hb C or with 6-thalassemia. The table below outlines the relative clinical severity and results of diag- nostic studies for the four common forms of sickle cell disease and contrasts them with chil- dren with sickle cell trait and with normal chil- dren, a a mC Syndrome | Genapne fot] V8 Meas Sti ing* (%) (%) () - (eo) eet mie we Pore {os | 0 | soa P 2a fas oo Ps ts) se tras J ose Jose [ose Pos [oo Paws | ous Paste] 0 | rm Sicisfe esa \ : freee se Foe Pow forse foo Passo fous fonar [asso ros bse) Sie - aE 8 | 50 | asa 560 vs Rasps [oo [oo [ms [om Poss ao pos | Pom om [aa | o [0 | mm [ow [op a pas} pa Table 4. Clini Severity & Diagnosis Testing for the Common Sickle Cell Syndromes Sains Penne TAL SSIES ENED NON PRON ‘CURRICULUM CONTENT—CoRE LECTURE SERIES D. Macrocytie Anemias © Drug therapy (e.g. AZT, anticonvul- sants) + Bone marrow failure syndromes (rare) Diamond-Blackfan anemia (congenital red cell aplasia) Fanconi’s anemia 9 congenital aplastic anemia) Down's syndrome Reticulocytosis, Chronic liver disease Hypothyroidism Megaloblastic anemia (rare in children) Cobalamine deficiency Folate deficiency Ill. Disorders of Leukocytes ‘A. Neutropenia = Congenital (rare) + Infection - especially viral + Drugs (e.g, sulfa, penicillins, cepha- losporins) ‘+ Autoimmune neutropenia (relatively common in toddlers, often benign) * Bone marrow failure Aplastic anemia (usually pancyto- penia) Leukemia (usually pancytopenia with or without circulating blasts) Leukemia. Acute lymphoblastic leukemia is the most common malignancy in childhood. It occurs in all age groups but is most common between ‘one and 10 years-of-age with a peak incidence at four years-of-age. Common presenting signs and symptoms inelude bone and joint pain, pallor and fatigue (anemia), fever and infection (leukopenia and neutropenia), petechiae, purpura, and bleed~ ing (thrombocytopenia), lymphadenopathy and. hepatosplenomegaly. 95% percent have two or more eytopenias and 80-90% have lymphoblasts ‘evident on the peripheral blood smear. The differ- ential diagnosis is extensive, but other possible diagnoses are readily excluded by bone marrow aspiration. Fever. Ivmphadenopathy and hepa- tosplenomegaly may suggest infections (EBV or CMV), storage diseases, or lymphoma. Fever, joint or bone pain may suggest juvenile rheuma- toid arthritis, rheumatic fever, or lupus. Anemia or thrombocytopenia may suggest transient eryth- roblastopenia of childhood or ITP or HUS. Pancytopenia may suggest aplastic anemia. Treat- ment with conventional chemotherapy is curative in over 70% of children with acute lymphoblastic leukemia, Acute non-lymphocytic leukemia is, less common and has a somewhat less favorable prognosis. B. Neutrophilia ‘+ Infections - especially bacterial ‘+ Myelodysplastic syndromes / Down's syndrome IV. Thrombocytopenia Immune thrombocytopenia (ITP) . HUS Consumptive coagulopathy (e.g. DIC, sep: E, Infections, especially viral (e.g. EBV, HIV) F, Bone marrow failure Congenital aplastic anemia (Fanconi’s) Acquired aplastic anemia (usually pancy- topenia) Leukemia (usually paneytopenia with or without circulatory blasts) A B, Other autoimmune (e.g. Lupus) c D. Immune Thromboeytopenic Purpura (ITP) is the most common cause of severe thrombocytopenia in children. ITP typically presents with wide- spread petechiae and purpura of skin and mucous membranes, often following a viral illness. The child is otherwise well, does not have fever, sys- temic toxicity, or history suggestive of chronic illness. The physical exam is normal except for petechiae, bruises, and sometimes epistaxis; there is no significant lymphadenopathy or hepa- tosplenomegaly. The CBC shows thrombocyto- penia (often severe with platelet count < 10,000) but normal Hb, Het, MCV, and WBC. Treatment options include observation, steroids (usually af- Curr ICULUM CONTENT—CORE LECTURE SERIES ter bone marrow aspirate to defini- yr tively 90% of children less than 10 years of age). ITP is more likely to be chronic and to be an [Pasmnopen Pas ing sys- temic disorder (e.g, lupus) in older children, Connon aco Fa Satan neta woeooen N diagnose Coagulopathies PET (normal PT) Hemophilia (VII, IX, or XI deficiency) Contact factor (HMWK, PK, XII) defi- ciencies -not associated with bleeding Von Willebrand’s disease (usually 4 bleeding time 2-platelet dysfunction) Lupus anticoagulant (predisposes to thrombosis) Heparin effect PL (normal PTT) Factor VII deficiency (rare) Liver disease (may have PTT) Mild vitamin K deficiency (4 PTT if more severe) Coumadin therapy mney (rae) Vitamin K deficiency Liver disease bic Heparin excess CURRICULUM CONTENT—CoRE LECTURE SERIES General References Lane, .PA., Nuss, R., Ambruso, D.R. "Hematologic Disorders." In W.W. Hay A.R. Hayward, MJ. Levin, & J.M. Sor heimer's Current Pediatric Diagnosis & Treatment, [4th ed. Appleton & Lange, 1998, p 732. Albano, E.A., Stork, L.C., Greffe, B.S. Odom, L.F., Forman, N, "Neoplastic Dis- ease.” In W.W. Hay, Jr, A.R, Hayward, MJ Levin, & J.M. Sondheimer’s Current Ped ric Diagnosis & Treatment, 14th ed. Appleton & Lange, 1998, p781. Jn, Hays, 7. "Hematologic Disorders." In Meren- stein, G.B., Kaplan, D.W., Rosenberg, A.A., editors. Handbook of Pediatrics, 18th edition. Stamford, CT, Appleton & Lange, 1997, p 601 Stork, L. "Neoplastic Diseases." In Meren- stein, G.B., Kaplan, D.W., Rosenberg, A.A., editors, Handbook of Pediatries, 18th edition. Stamford, CT, Appleton & Lange, 1997, p 791 Nathan, D.G., Oski, FLA. H faney and Childhood, 4th e% Phia, WB Saunders, 193, Lane, P.A., Nuss, R, Section on Hematologic Disorders. In Berman S. Pediatric Decision Making, 3rd edition, St. Louis, Mosby; 1996, Oski, F.A. "Iron deficiency in infancy and childhood." N Engl J Med 1993; 329:190, Abshire, T.C. "The anemia of inflammation: A common cause of childhood anemia." Pedi- atr Clin North Am 1996;43:639, Lan PA. "Sickle cell disease." Pediatr Clin North Am 1996:43:639, DiMichele D, Hemophilia 1996: " proach to an old disease." Pediatr C ‘Am 1996;43:709, tology of In- tion. Philadel- North

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