Pediatric Board Review Course Pediatric Hematology/Oncology

1. Pediatric Board Review CoursePediatric Hematology/Oncology KusumViswanathan, MD Chair, Department of Pediatrics Director, Divn of Pediatric Hematology/Oncology BrookdaleUniv Hospital and Medical Center

2. Question • 6 week old term infant referred for anemia. Hb 7.5, Retic 2 %. Mother O+, Baby A -, Direct Coombs + Cord blood Hb 14.2 g/dL. Jaundice of 15mg/dL at 48 hours of life, recd photo Rx and discharged at 5 days. No complaints, pale, Bili 3.5, Direct 0.5. • Blood smear shows spherocytes

3. Most likely explanation for the anemia • G 6 PD deficiency • Hereditary spherocytosis • Physiologic anemia • ABO incompatibilty • Rh hemolytic disease 6

4. Newborn –anemia- important • Hemoglobin at birth is 17 g/dl, MCV over 100. • Falls to 11-12 by 6 weeks of age- nadir of physiologic anemia • Anemia at birth could be : • Hemorrhage, may not have had time to mount a retic response • Acute hemorrhage- pallor and tachypnea • Look at MCV- low MCV-suggestive of • chronic feto-maternal hemorrhage • Alpha Thalassemia trait. • Kleihauer-Betke- Hb F resistance to acid elution

5. The treatment of choice for alloimune neonatal thrombocytopenia is • random platelet transfusion • IVIG • Steroids • Exchange transfusion • Washed maternal platelets 6

6. Immune thrombocytopenia • Auto-immune: Pregnant women with ITP/Hx of ITP • Passive transfer of antibodies (IgG) from mother. • Even when mother has a normal platelet count (Splenectomy) • Nadir-few days; Platelets < 50,00 have 1% risk of ICH. • IVIG to mother, Fetal platelet counts, C sec, US, IVGG to baby • Allo or Iso-Immune: Normal platelet count in mother • Similar to Rh disease; PL A1 antigen/ Zw-a negative mother. • 97% of population is PL A1 positive • Sensitization early in pregnancy • Plt function defect because Anti-PL-A1 interferes w/aggregation. • Severe bleeding more likely; first born affected • Recovery in 2-3 weeks • Mother’s washed (PLA1 neg) platelets; IVIG; Ultrasound; Steroids

7. Kasabach- Merritt, TAR

8. 15 months old girl presented in ER with h/o URI, and scattered petechiae and ecchymoses over the body and lower extremities. Physical exam normal, no hepatosplenomegaly. WBC-14,000, Hb 12.8, Plts-5,000, Diff: Normal - Next step • perform a bone marrow aspirate to confirm the diagnosis • Non-accidental injury; skeletal survey to rule out bony fractures • treatment with either IVIG or anti-D • Administer platelet transfusion 6

9. Acute ITP • Usually acute onset; immune mediated; post viral • Peak 2-5 years of age, • PE –no lymphadenopathy (LN), hepatosplenomegaly. • CBC- other cell lines normal, large plts on smear • Treat if plt< 10,000 or wet ITP, • Treat- IVIG best response, 48-72 hours; blocks Fc receptors,SE • Anti-D (WInRho)- Rh+ ,hemolysis, quick response • Steroids good response, block phagocytosis, reduces antibodies, SE, inexpensive, need BM • BM- Increased megakaryocytes, otherwise normal • Chronic- If >6 months, F>M, older, unpredictable prognosis

10. Petechiae, HSP

11. A 2 year old boy presents for evaluation of a chronic pruritic eruption. H/o recurrent epistaxis, otitis media, and pneumonia P/E reveals erythematous, slightly scaling patches on the trunk and in the antecubital and popliteal fossae. Petechiae too- most suggestive of • Acrodermatitisenteropathica • Ataxia telangiectasia • Atopic dermatitis • Langerhans cell histiocytosis • Wiskott-Aldrich syndrome 6

12. Normal platelet 7-10 days Large platelets: ITP May Hegglin (Dohle bodies in neutrophils, Plt function normal). Bernard Soulier syndrome (AR, Plat function disorder). Small platelets: Wiskott Aldrich syndrome( X-linked, recurrent infections, eczematoid rash, platelet dysfunction) Large platelets

13. Platelet function defects • Normal platelet number • Abnormal aggregation • Glanzmannthrombasthenia--- AR, Bleeding disorder, check h/o consanguinity • afibrinogenemia • Abnormal adhesion- Bernard-Soulier, VWD • Ineffective Thrombopoiesis • MayHegglin Anomaly (Large platelets) • Disorders of Secretion: Storage pool, gray platelet syndrome • HermanskyPudlak Syndrome: • AR, Decreased dense granules, In Puerto Ricans • Oculocutaneous albinism

14. Thrombocytosis • H- Hemorrhage, Hereditary Asplenia, Down myeloprol. • I- Infections, Kawasaki, Immune:GVH, Nephrotic syndrome • P- Polycythemia vera, Myeloproliferative, Essential • L- Leukemia (CML) • A- Anemia,- Iron, Vit E deficiency, Sideroblastic • T- Tumors • E- Epinephrine, Steroids • L- Lymphoma, Hodgkins • E- Exercise • T- Trauma, Fractures • S- Splenectomy

15. Anemia • An 18 month old girl brought in for pallor. Normal diet and PMH. She is alert, interactive, only pallor, normal vital signs, No hepatosplenomegaly, lymph nodes or bruises. • CBC- Normal WBC, Plt, Hb 4.5g/dl, MCV 74, • Anemia • Reduced production • Increased destruction • Loss • What else do you want??

16. Reticulocyte count • Normal/Low- reduced production • Iron deficiency anemia- MCV will be low • ALL (leukemia)- other findings, LN, HSM • Diamond Blackfan anemia- • TEC: Over 1 year of age, Pallor, transient rbc production failure, recovers, MCV and Hb F high during recovery, rbc transfusion, rbc ADA normal .

17. Normal smear

18. A 2 month old girl with a history of ventricular septal defect and horseshoe kidney presents for a health maintenance visit. Her parents are concerned that she is not feeding well, appearing to become “tired” soon after beginning to breastfeed. She is tachycardic and appears pale. Her hemoglobin level is 3.8 g/dL. Peripheral smear reveals macrocytic red blood cells. The bone marrow aspirate shows normal cellularity of the marrow with markedly decreased erythroid precursors. • Which of the following findings is most likely to be identified during additional physical examination of this patient? • Multiple superficial hemangiomas • Cutis aplasia • Bifid thumbs • Speckled white rings in the periphery of the iris • Posterior parietal hair whorl

19. Microcytic anemia is a characteristic laboratory abnormality of all listed diseases except • Iron deficiency • Lead poisoning • Sickle cell disease • Thalassemia trait 6

20. Microcytic anemia

21. Question A blood smear taken from a toddler shows microcytic hypochromic anemia. Iron supplementation therapy is started. When will the reticulocyte response be at maximum? • a. 1-2 days • b. 5-7 days • c. 14-21 days • d. 3-4 weeks • e. about 6 weeks

22. Iron deficiency questions • Low MCV, low MCHC, low retic, RDW can be normal, Low Iron, Incr TIBC, Transferrin low, Ferritin low • Causes: Inadequate dietary intake • Toddlers, too much milk, less solids, Breast fed need iron supplements • Blood loss: Menstrual, GI tract, Meckels, Epistaxis • D/D: Thalassemia trait- MCV much lower in prop to anemia Anemia of chronic disease- low Fe, low TIBC, normal /high Ferritin.

23. Question- Beta Thalassemia 3 year old comes for a routine check and found to be anemic. P/E Normal. CBC Hb 8.9, MCV 58, Iron levels are normal. Hemoglobin electrophoresis is done and shows Beta Thalassemia trait. All are true except: • The MCV is always low • Fetal hemoglobin is < 2% • Hemoglobin A 2 is > 3.5% • Does not respond to Iron • RDW is usually normal

24. Quantitative defect in globin chains Reduced production of Beta chains Hb electrophoresis Hb A- 2 Alpha, 2 Beta Hb F- 2 Alpha, 2 Gamma Hb A2- 2 Alpha, 2 Delta Excess Alpha combines with Gamma or Delta- Increased Hb F and A2. Smear abnormalities significant even with MILD anemia. Anemia Low MCV, normal RDW, normal retic Smear shows aniso and poikulocytosis, target cells, microcytes, misshapen cells, basophilic stippling Hb Electrophoresis: Increased Hb A2 and/or F. Normal iron studies, no response to iron Beta Thalassemia Minor

25. Beta Thalassemia Major • No production of Beta chains- Chromosome 11 • Autosomal recessive • 25 % chance with each pregnancy • Pre-natal testing for carriers • Chorionic villous sampling for diagnosis • Transfusion dependent-allows for normal development • Pen Prophylaxis, Anti oxidants • Splenectomy after age 5 • Iron overload- inherent and transfusion • Need chelators

26. Question 4 year old male with no complaints. Routine CBC showed a Hb9.8, MCV 62, RDW 12.5 , Retic 0.2%, Normal Iron studies, Hemoglobin electrophoresis was normal with normal Hb A2 and Hb F. You suspect Alpha Thalassemia. All of the statements are true except: • It is carried on 4 alleles • The severe form is Hydropsfetalis • Hemoglobin H disease occurs when 3 alleles are affected • Diagnosed by newborn screening when a “fast moving” hemoglobin is noted. • Fast moving hemoglobin is made up of a hemoglobin with 4 beta chains

27. Thalassemia- Alpha • Reduced Alpha chains • 4 types- carried on 4 allelles. (xx/xx) • One absent- Silent carrier (x-/xx) • 2 absent- Alpha Thal trait (xx/- - or x-/x-) • 3 absent- Hb H disease (x-/- -) Has 4 excess Beta chains) • 4 absent- Hydrops fetalis (- -/- -) • NB period: Excess Gamma chains form Hb Barts- FAST moving Hb on Newborn screening

28. Case • 3 year old patient is brought to the ER with complaints of feeling very tired over the past 3 days. • Patient is pale, jaundiced with the spleen tip palpable. • CBC Hb 5, Retic 5 %, LDH Increased, • What does this sound like??

29. Question • A previously well African-American child visited Africa and was given malarial prophylaxis. He experienced pallor, fatigue, and dark urine. His hemoglobin level decreased from 14.8 to 9 g/dL. • SMEAR

30. An African-Am child visited Africa & received malaria prophylaxis. He has • Hereditary spherocytosis • Sickle cell disease • Hepatitis • G6PD deficiency 6

31. Reticulocyte count- Increased • Hemolysis • Intrinsic- • Membrane defects-Hereditary spherocytosis (HS) • Enzyme-G 6 PD deficiency • Hemoglobinopathies • Extrinsic- AIHA (Auto-immune hemolytic anemia), DIC, Intravascular hemolysis • Loss • Blood loss

32. Children with hereditary spherocytosis have all of the listed conditions except: • positive Direct Coombs • splenomegaly, gallbladder stones • abnormalities in spectrin and /or ankyrin • increased MCHC • abnormal osmotic fragility test. 6

33. Spherocytes Nucleated rbc Coombs-AIHA Osmotic fragility-HS Spherocytes

34. HS- with severe anemia • A 6 year old girl who has hereditary spherocytosis presents with a 1 week history of fever. Physical examination reveals abdominal pain, vomiting, fatigue and pallor. Her hemoglobin is typically about 10 g/dL with a reticulocyte count of 9%, but now, her hemoglobin is 4 g/dL and the reticulocyte count is 1%. Her bilirubin is 1 mg/dL. Of the following, the MOST likely cause for this girl’s present illness is infection with • Coxsackie virus • Parvovirus B19 • Epstein-Barr virus • Hepatitis A virus • Influenza A virus

35. HS- with severe anemia • Coxsackie virus • Parvovirus B19 • Epstein-Barr virus • Hepatitis A virus • Influenza A virus 6

36. Newborn Screening Questions • You get a call from a frantic parent because she received a letter from the State regarding her baby’s test results on NBS. • FS- SS disease, S-B0 Thal, Sickle cell w/ HPFH. • FSA- Sickle B+ thal, Sickle cell trait • FSC- SC disease • FAS- Sickle cell trait • FAC- Hb C trait • FAE- Hb E trait • FE - Hb EE disease, E-Thal

37. Hemolysis- life span 20-50 days. Abnormal cell shape, abnormal adherence to endothelium, decreased oxygenation, Increased polymerization. Symptoms start by 2-4 months of age. Hb electrophoresis, S >75 %. Penicillin daily until age 5. Prevention of pneumococcal infections-asplenic. PPV (Pnu-23) age 2, 5 Meningococcal vaccine early two doses and every 5 years. Folic acid daily Sickle cell Questions

38. Sickle cell questions • Vaso-occlusive crisis New infant born in another country presenting with swollen hands---Dactylitis • Aplastic crisis: • low Hb, low retic, Secondary to Parvovirus B 19 infection. • Splenic sequestration crisis: • Sudden enlargement of the spleen in SS or older SC patient • Rx- Transfuse • Teach spleen palpation • Splenectomy

39. The mother of a 10 month old baby with SS disease asks you about prognostic indicators. All of the following indicate likelihood of more severe disease except: • High WBC • Associated alpha thalassemia trait • Low hemoglobin • Repeated episodes of dactylitis 6

40. Sickle cell Acute Chest Syndrome • True statements include all except: 1. Presents with a new infiltrate on X-ray 2. Due to infarction, infection, BM fat embolism 3. Treat with antibiotics to cover pneumococcus, Mycoplasma, Chlamydia 4. Treat with bronchodilator, Incentive spirometry, transfusion, Steroids (controversial). 5. Intensive hydration is important

41. A routine TCD on a 4 year old patient with SS disease shows a Cerebral blood flow (CBF) of 210 cm/second. What is the next step? STOP studies- STOP I and II TCD- Transcranial Doppler

42. According to the STOP protocol all children with abnormal TCD require enrollment in hypertransfusion protocol till (choose one) • Repeat TCD is normal • Continue indefinitely • the child reaches 18 years • MRA/MRI are reported normal 6

43. Sickle cell and Stroke Questions • Affects 10 % of patients • Infarctive stroke (younger patients) • Hemorrhagic stroke (older) • STOP I study established the role of yearly TCD (transcranialdoppler) to measure cerebral blood flow velocity as a tool for determining stroke risk. • Transfusion therapy as current therapy for high risk patients (CBF> 200cm/sec) • Reversal of CBF velocity is not sufficient to stop transfusion therapy. (STOP II)

44. Sickle cell and Hydroxyurea • FDA approved for adults • Studies in children demonstrated efficacy and safety • Increases hemoglobin F level • Increases hemoglobin • Decreases WBC – ancillary effect • Reduces number of ACS, VOC • Hydroxyurea is recommended by the hematologist for patients who have recurrent vaso-occlusive crises, acute chest syndrome.

45. A healthy 5 year old boy- 2 day hx of fever, P/E normal No hepatosplenomegaly, LN, no focus of infection. CBC WBC 3, Neutrophils 25 %, Hb 12, Platelet 200X109/L, ANC 750. Most appropriate step is • Amoxicillin for 10 days • G- CSF for 10 days. • BM aspirate • Refer to a hematologist • Repeat CBC in 1-2 weeks 6

46. Case • A 2-year-old boy has had several 10-day-long episodes of fever, mouth ulcerations, stomatitis, and pharyngitis. These episodes have occurred at about monthly intervals. Absolute neutrophil counts have been 50/mm³on day 1 of each illness, 500/mm³ on day 10, and 1,500/mm³ on day 14. • Among the following, the MOST likely cause for the findings in this patient is • A. chronic benign neutropenia • B. cyclic neutropenia • C. Schwachman-Diamond syndrome • D. severe congenital neutropenia • E.. transient viral bone marrow suppression

47. Abnormal Bleeding • Epistaxis unrelieved by 15 minutes of pressure, both nostrils, requiring an ER visit, documented drop of hemoglobin. • Menstrual periods( amount, pads, duration) • Bleeding after procedures (circumcision, dental extractions, T and A-delayed bleed) • Ecchymoses/bruising inconsistent with the degree of trauma

48. Bleeding patient • Physical Examination: Type of bleeding: Superficial or deep • Bruises, Petechiae • Epistaxis, Gum bleeding, Excessive menstrual bleeding • Site of bleeding • Bleeding into the joints and soft tissues • Look for evidence of shock • Medication history (Aspirin, NSAIDS)

49. Lab studies(What do they measure?) • CBC and Peripheral smear • PT, INR and PTT • PT - Factor VII, common pathway • PTT- Factor VIII, IX, XI, XII, common pathway • Mixing studies (Inhibitors and deficiency) • Specific coagulation factor assays

50. Coagulation cascade