PEDIATRIC HEMATOLOGY

1. PEDIATRIC HEMATOLOGY Unit 4: Part 3 Module 3

2. REFERENCES C290- Nelson�s Essentials of Pediatrics C306- Toronto Sick Kids Manual C277- Toronto Notes C291- Primary care for PA�s Class Handout

3. OUTLINE Normal Pediatric Hematology Values Physical Signs of Anemia in Children Iron Deficiency Anemia Hemolytic Anemias Major Hemaglobinopathies Bleeding Disorders White Cell Disorders -

4. NORMAL PEDIATRIC HEMATOLOGY VALUES Birth - Hbg - mean 16.8 (13.7-20.1) - HCT �mean 55% (45-65) - Wbc -mean 18,000( 9000-30,000 - Retics - mean 5.0% 3mos - Hbg - mean 12.0 - HCT �mean 36% - Wbc -mean 12,000 - Retics - mean 1.0 Hbg relatively higher in utero ( > 170 g/L) hypoxic environment Immediately after birth starts to decline , due to increased RBC destruction( shorter lifespan than adult 70 vs 120 days), and increased blood volume secondary to growth Very little erythropoesis after birth for 6-8 weeks due to new O2 rich environment The increased RBC destruction in the early newborn period, leads to physiologic jaundiceHbg relatively higher in utero ( > 170 g/L) hypoxic environment Immediately after birth starts to decline , due to increased RBC destruction( shorter lifespan than adult 70 vs 120 days), and increased blood volume secondary to growth Very little erythropoesis after birth for 6-8 weeks due to new O2 rich environment The increased RBC destruction in the early newborn period, leads to physiologic jaundice

5. NORMAL PEDIATRIC HEMATOLOGY VALUES 6mos - 6 years - Hbg - mean - 12.0 - HCT �mean - 37% - Wbc -mean - 10,000 - Retics - mean -1.0% 7-12 yrs - Hbg - mean - 13.0 - HCT �mean - 38% - Wbc -mean - 8,000 - Retics - mean -1.0%

6. PHYSICAL SIGNS OF ANEMIA Skin - Jaundice- hemolytic anemia - Petechiae - purpura- autoimmune hemolysis with autoimmune thrombocytopenia, bone marrow infiltration, hemolytic uremic syndrome - Vitiligo - Vitamin B12 deficiency - Hyperpigmentation/caf�-au-lait spots - Franconi anemia - Butterfly rash- SLE antibodies - Erythematous rash- Epstein barr virus

7. PHYSICAL SIGNS OF ANEMIA Head - Frontal bossing of cranium- severe iron deficiency anemia, Thalassemia major - Microcephaly - Franconi anemia Eyes - Microphthalmia - Franconi anemia - Blue sclera - iron deficiency

8. PHYSICAL SIGNS OF ANEMIA Mouth - Glossitis- iron deficiency, B12 deficiency - Stomatitis - iron deficiency Chest - Heart murmur- severe anemia

9. PHYSICAL SIGNS OF ANEMIA Abdomen - Hepatomegaly - hemolytic anemia, anemia of chronic disease, - Splenomegaly- hemolytic anemia, sickle cell, thalessemia, lymphoma, Epstein barr virus - Enlarged kidneys- Franconi anemia

10. PHYSICAL SIGNS OF ANEMIA Extremities - Spoon nails - iron deficiency - Beau lines in nails- heavy metal intoxication, severe illness - Mees lines in nails- heavy metals, severe illness, sickle cell

11. PHYSICAL SIGNS OF ANEMIA Neurological - Irritability, apathy, poor concentration - iron deficiency - Peripheral neuropathy- B1, B12 deficiency, lead poisoning - Ataxia, loss of vibration/position sense- B12 deficiency - Stroke- sickle cell anemia Small stature - Anemia of malnutrition, HIV, Franconi anemia

12. IRON DEFICENCY ANEMIA A microcytic, hypochromic anemia Decreased ferritin, decreased TIBC, marrow deplete of stainable Fe2+ Most common cause of childhood anemia worldwide Full-term infants exhaust Fe 2+ reserves by 5-6 months age Preterm infants have lower reserves � exhaust by 2-3 months of age

13. IRON DEFICENCY ANEMIA Commonly presents: - Between 6 months � 3 years - Ages 11-17 years: periods of rapid growth and increased Fe 2+ requirements - Adolescents at risk - poor diets, menstrual losses - Can cause irreversible effects on development if untreated

14. IRON DEFICENCY ANEMIA Etiology - Vegan diet - Secondary to poor intake of iron-rich foods ( typically in bottle-fed infants (6-24 months) receiving large volumes of cow�s milk) GIT blood loss - Cow�s milk allergy: occult bleeding & protein-losing enteropathy secondary to inflammation enteropathy; secondary to inflammatory bowel disease

15. IRON DEFICENCY ANEMIA Management - CBC, diff, smear, Iron, TIBC, Ferritin - Determine underlying cause - Encourage diverse, balanced diet - iron rich foods /formula - Oral iron therapy � ferrous sulfate 3mg/kg/day BID-TID for 3 months - Close follow up to monitor dietary intake,Hbg , ferritn for response to RX increased reticulocyte count in 48-72 hours increased hemoglobin in 4-30 days repletion of iron stores in 1-3 months Apoor response to oral Fe2+ therapy: think non-compliance, ongoing blood loss, insufficient duration of therapy, high gastric pH, incorrect diagnosis increased reticulocyte count in 48-72 hours increased hemoglobin in 4-30 days repletion of iron stores in 1-3 months Apoor response to oral Fe2+ therapy: think non-compliance, ongoing blood loss, insufficient duration of therapy, high gastric pH, incorrect diagnosis

16. IRON DEFICENCY ANEMIA Prevention - Breast-fed infants: after 6 months, give iron-fortified cereals and iron-rich foods - Non-breast fed infants: give iron-fortified formula from birth - Premature infants: start iron supplements at 6-8 weeks of age and continue until 1 year old

17. HEMOLYTIC ANEMIAS Intrinsic RBC disorders - Hereditary spherocytosis - G6PD( glucose-6-phosphate dehydrogenase deficiency) Extrinsic RBC disorders - ABO, Rh incompatibility

18. INTRINSIC RBC DISORDERS Spherocytosis - Red cell membrane disorder, causes a sphering of red blood cells which are removed by the spleen - Genetic base- autosomal dominant (positive family history) - High spontaneous mutation rate (no family history) - Clinical presentation variable from well-compensated, mild hemolytic anemia to severe hemolytic anemia with growth failure, splenomegaly, and chronic transfusion requirements especially in infancy Abnormality of spectrin a compound in the RBC membrane) Management transfusions and splenectomy as needed genetic counseling Abnormality of spectrin a compound in the RBC membrane) Management transfusions and splenectomy as needed genetic counseling

19. INTRINSIC RBC DISORDERS Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency - X-lined recessive, different variants of the disease - Enzyme deficient red blood cells - Higher prevalence in Mediterranean's, Blacks, Orientals - Presents with acute hemolytic anemia with jaundice and dark urine - Diagnosis- G6PD assay, Blood film- Heinz bodies enzyme deficient red blood cells are unable to defend against oxidant stress (infection, drugs) and form Heinz bodies (denatured hemoglobin) which are phagocytosed by splenic macrophages, creating �bites� on cells Heinz bodies appear as granules in RBC�s G6PD assay best done when not in acute crisis as retic count is highenzyme deficient red blood cells are unable to defend against oxidant stress (infection, drugs) and form Heinz bodies (denatured hemoglobin) which are phagocytosed by splenic macrophages, creating �bites� on cells Heinz bodies appear as granules in RBC�s G6PD assay best done when not in acute crisis as retic count is high

20. INTRINSIC RBC DISORDERS Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency - Management is supportive: hydration, transfusion, phototherapy - Prevention of acute episodes: Avoid known oxidants (e.g. fava beans, ASA, antimalarials, sulfonamides

21. EXTRINSIC RBC DISORDERS ABO Blood Group Incompatibility - Commonest cause of iso-immune hemolysis in the newborn - Results from blood group differences between an sensitized mother and fetus - Sensitized mother produces IgG antibodies that cross the placenta by active transport and hemolyze fetal RBC,s - Mother is sensitized by prior exposure to A or B antigens - ABO incompatibility rarely produces significant anemia in utero but may cause more significant anemia and hyperbilirubinemia in the newborn Immunologically mediated hemolysis of the fetal RBC in utero may lead to erythroblastosis fetalis or the fetus may be spared in utero and develop hemolytic disease in the newborn period ABO Sensitization of the mother may have occurred by conditions of pregnancy such as first trimester abortions, ectopic pregnancy, amniocentesis that results in mixing of fetal RBC with maternal blood Because many mother with O type blood have IgG antibodies to A&B before pregnancy the first born infant may be affected In contrast Rh incompatibility ABO hemolytic disease does not get worse with subsequent pregnancies and generally causes less severe diseaseImmunologically mediated hemolysis of the fetal RBC in utero may lead to erythroblastosis fetalis or the fetus may be spared in utero and develop hemolytic disease in the newborn period ABO Sensitization of the mother may have occurred by conditions of pregnancy such as first trimester abortions, ectopic pregnancy, amniocentesis that results in mixing of fetal RBC with maternal blood Because many mother with O type blood have IgG antibodies to A&B before pregnancy the first born infant may be affected In contrast Rh incompatibility ABO hemolytic disease does not get worse with subsequent pregnancies and generally causes less severe disease

22. EXTRINSIC RBC DISORDERS Rh factor Incompatibility - Rh system consists of 5 antigens- C,D,E, c, e, - In most cases of Rh sensitization it is the �D� antigen of the fetus which sensitizes the Rh negative mother resulting in IgG antibody production during the first pregnancy - The first affected infant in the1st pregnancy may not manifest any disease in utero but may manifest hemolytic disease in the newborn period ( anemia+ hyperbilirubinemia)

23. EXTRINSIC RBC DISORDERS Rh factor Incompatibility - Subsequent pregnancies are affected by earlier onset of hemolysis in utero - Leads to fetal anemia, heart failure, elevated venous pressure, portal vein obstruction and hypoalbuminemia -->fetal hydrops - Fetal hydrops- ascites , pleural/pericardial effusions - Risk of fetal death high

24. EXTRINSIC RBC DISORDERS Rh factor Incompatibility - Severity of hemolysis in utero is detected by assessing the quantity of bilirubin in amniotic fluid - Treatment depends on severity of disease and gestational age of infant - Intrauterine transfusions of O negative blood until lungs mature then deliver - Prevention - screen all mother prenatally - Rh -, mothers given anti-Rh-positive immune globulin at 28 weeks, post -partum ( 72 hours) Test is called spectrophotometric analysis of the optical density of amniotic fluid 3 zones of optical densities with decreasing slopes toward a term gestation have been developed to predict severity of illness The highest zone is associated with severs disease Other antigens that can cause disease in the fetus, newborn include Rh C, E, Kell, and Duffy. Rh immune globulin will not prevent these.That is why we repeat antibodies screening in later pregnancy ( 32-34wks)in Rh + and _ women in case they become sensitized and develop these antibodies later Test is called spectrophotometric analysis of the optical density of amniotic fluid 3 zones of optical densities with decreasing slopes toward a term gestation have been developed to predict severity of illness The highest zone is associated with severs disease Other antigens that can cause disease in the fetus, newborn include Rh C, E, Kell, and Duffy. Rh immune globulin will not prevent these.That is why we repeat antibodies screening in later pregnancy ( 32-34wks)in Rh + and _ women in case they become sensitized and develop these antibodies later

25. SICKLE CELL ANEMIA Describes syndrome of hemoglobin SS, S-C, sickle cell thalassemia Identification of specific hemaglobin phenotypes important due to differences in frequency, type and severity of clinical complications (most severe is SS, least severe SD) SCA results from a single amino acid substitution valine for glutamic acid on the hemaglobin molecule

26. SICKLE CELL ANEMIA Red blood cells sickle with low pO2, dehydration, fever, acidosis Acute intravascular sickling results in infarction of tissue Hemolysis causes chronic, well-compensated anemia (Hb 60-90 g/L) More common in Blacks and Mediterranean's

27. SICKLE CELL ANEMIA Clinical Presentation - SC trait: asymptomatic + microscopic hematuria - SC disease; after 10-12 weeks - fall in fetal Hb, anemia, jaundice, splenomegaly - Chronic compensated anemia - Recurrent crises

28. SICKLE CELL ANEMIA Types of Crises Vaso-occlusive crises - Most common presentation - Due to obstruction of blood vessels by rigid, sickled cells ? tissue hypoxia ? cell death; presents as pain and fever - Affects in any organ - Commonly in long bones of arms and legs, chest, abdomen, CNS (stroke), dactylitis (in young children

29. SICKLE CELL ANEMIA Types of Crises Aplastic crisis - Depression of erythropoiesis, generally associated with infection (Parvovirus B19) Splenic sequestration - Sudden massive pooling of red cells in spleen, acute fall in hemoglobin, shock (increased reticulocyte count, decreased Hb)

30. SICKLE CELL ANEMIA Functional Asplenia - Splenic dysfunction usually by 5 years secondary to autoinfarction - Susceptible to infection by encapsulated organisms (especially S. pneumoniae) requires prophylactic antibiotics, pneumococcal vaccine, and immediate evaluation of fever requires prophylactic antibiotics, pneumococcal vaccine, and immediate evaluation of fever

31. SICKLE CELL ANEMIA Other Manifestations - Growth delay - Bony abnormalities - Avascular necrosis (AVN) of femoral head - Priapism (often results in permanent impotence in adults) - Stones - Acute chest crisis: fever, chest pain, increased WBC count, pulmonary infiltrates

32. SICKLE CELL ANEMIA Management - Acute crises - Supportive and symptomatic - Fluids (1 � maintenance) - Analgesia - Exchange/straight transfusions - Antibiotics - O2

33. SICKLE CELL ANEMIA Management - Chronic ongoing care - Early aggressive treatment of infections, prophylactic antibiotics (daily oral penicillin) - Pneumococcal, meningococcal, Hepatitis B, Hib and influenza vaccines - Folate supplementation if macrocytic - Hydroxyurea if have frequent crises - Recurrent transfusion program if history of stroke - Genetic counseling

34. BETA-THALASSEMIA MAJOR Defect in production of � Hbg Leading to ineffective production and hemolysis of RBC�s Increase in Hbg F Autosomal recessive inheritance Affects Asian and Mediterranean people

35. BETA-THALASSEMIA MAJOR Clinical Presentation - Child 3-6 months - Severe anemia - Jaundice - delayed growth /development( hypogonadal dwarfism) - Hepatosplenomegaly - Expanded bone marrow cavity - Pathological fractures common

36. BETA-THALASSEMIA MAJOR Investigations - CBC, smear, Hbg electrophoresis Treatment - Transfusions - Iron chelation to prevent overload - Bone marrow transplant Hbg decreased 9 4.0-6.0g/dl Smear shows: hypochromic microcytosis increased retics basophilic stiplling/target cells Hbg eletrophoresis show a low Hbg A, increased Hbg F Antenatal screening of at risk people with Hbg electrophoresisHbg decreased 9 4.0-6.0g/dl Smear shows: hypochromic microcytosis increased retics basophilic stiplling/target cells Hbg eletrophoresis show a low Hbg A, increased Hbg F Antenatal screening of at risk people with Hbg electrophoresis

37. IDIOPATHIC THROMBOCYTOPENIC PURPURA Peak age: 2-6 M=F Caused by antibodies IgG or IgM that bind to platelet membranes ? splenic destruction of antibody-coated platelets Typically presents after viral illness or immunization 1-3 weeks prior to presentation

38. IDIOPATHIC THROMBOCYTOPENIC PURPURA Clinical Presentation - Occurs in an otherwise well child - Sudden onset of :petechiae, purpura, epistaxis, hematuria or GI hemorrhage - Usually no lymphadenopathy - Usually no hepatosplenomegaly - Rarely ITP may a presenting symptom of autoimmune disease (e.g. SLE) Self-limited in children: spontaneous recovery in 80% of cases but usually treat because spontaneous recovery takes a few months If atypical presentation (more than one cell line abnormal, hepatosplenomegaly), do bone marrow to rule out leukemia Self-limited in children: spontaneous recovery in 80% of cases but usually treat because spontaneous recovery takes a few months If atypical presentation (more than one cell line abnormal, hepatosplenomegaly), do bone marrow to rule out leukemia

39. IDIOPATHIC THROMBOCYTOPENIC PURPURA Differential diagnosis: - Leukemia - Drug-induced thrombocytopenia - HIV, infection (viral) - SLE

40. IDIOPATHIC THROMBOCYTOPENIC PURPURA Lab work : CBC - Thrombocytopenia with normal RBC, WBC Management: - IVIG - 1g/kg/24 hr for 2 days - Prednisone 2-4 mg/kg/24 hr x 2 weeks - Must rule out leukemia before using prednisone - Splenectomy (only for life-threatening bleeding)

41. NEONATAL THROMBOCYTOPENIA Neonatal alloimmune thrombocytopenia (NAIT) Mother mounts immune response against antigens on fetal platelets Diagnosis: maternal serum (with immunoglobulins) reacts with father�s or child�s platelets Treatment: transfusion of infant with washed maternal platelets Suspect in thrombocytopenic newborn who is otherwise well, normal maternal platelets, no history of maternal autoimmune disease or ITPSuspect in thrombocytopenic newborn who is otherwise well, normal maternal platelets, no history of maternal autoimmune disease or ITP

42. HEMORRHAGIC DISEASE OF THE NEWBORN Caused by vitamin K deficiency Factors II, VII, IX, X are vitamin K-dependent, therefore both PT and PTT are abnormal Presents at 2-7 days of life with GI hemorrhage, intracranial hemorrhage bleeding from a circumcision or umbilical stump Prophylaxis: IM vitamin K administration at birth to all newborns

43. HEMOPHILIA A X-linked recessive, 1/5000 males 5 times more common than Hemophilia B Factor VIII deficiency Severity determined by level of factor VIII, severity of bleeds, and presence of antibodies to factor VIII Mild (>5% factor VIII): - Bleeding with significant trauma (e.g. surgery) - May go undiagnosed for many years delayed formation of thrombin which is crucial to forming a normal, functional fibrin clot and solidifying the platelet plug to areas of vascular injurydelayed formation of thrombin which is crucial to forming a normal, functional fibrin clot and solidifying the platelet plug to areas of vascular injury

44. HEMOPHILIA A Moderate( 1-5%) - Moderate trauma to induce bleeding Severe (<1% factor VIII): - Spontaneous bleeding or bleeding from minor trauma, - Manifests in infancy, - Hallmark: hemarthrosis Treatment: Factor VIII replacement DDAVP for mild disease

45. HEMOPHILIA B (Christmas Disease) Factor IX deficiency X-linked recessive genetic disorder Treated with factor IX replacement or plasma Presentation same as Hemophilia A

46. von WILLEBRAND�S DISEASE Common disorder affecting 1% of population Abnormality in von Willebrand factor (vWF) Autosomal dominant (mild presentation more common ( 80%) Autosomal recessive (rarer, more severe) S&S - mucocutaneous bleeding, epistaxis, bleeding gums, heavy menstrual bleeding, DDAVP Rx of choice, also Humate P( vWB containing concentrate) vWF is an adhesive protein that bridges subendothelial collagen and platelets, and protects factor VIII from rapid clearance vWF is an adhesive protein that bridges subendothelial collagen and platelets, and protects factor VIII from rapid clearance

47. LEUKEMIA Affects children ages 1-10 typically ALL type commonest (80%) AML second commonest form ( 15%) CML ( 5%) Etiology is unknown

48. LEUKEMIA S&S - Fever, pallor, lethargy - Malaise, anorexia - Bone /joint pain - Petechiae, ecchymosis - Lymphadenopath, hepatosplenomeglay, - Anemia, neutropenia, thrombocytopenia CNS involvement is rare but possibleCNS involvement is rare but possible

49. LEUKEMIA Dx based on finding immature blast cells on either the peripheral blood smear, bone marrow or both Rx is with chemotherapy Prognosis ( in 2000) - Cure rate 50% with ALL except in the very young infant and 50% with AML ( Nelson�s) Low risk subtype- ALL - 90% long term remission High risk subtype 70% long term remissionLow risk subtype- ALL - 90% long term remission High risk subtype 70% long term remission

50. LYMPHOMA Two types- Hodgkins, Non- Hodgkins Hodgkins - Etiology is unknown - Incidence increases during childhood and peaks late adolescence - Males > Females (3:1) in early childhood, after puberty ratio 1:4 Third most common malignant tumors in childhood Malignant proliferation of lymphoid cells with Reed-Steinberg cells Suggested association with EBV Third most common malignant tumors in childhood Malignant proliferation of lymphoid cells with Reed-Steinberg cells Suggested association with EBV

51. LYMPHOMA Hodgkins (continued) - Presents as persistent painless lymphadenopathy ( cervical and supraclavicular , axillary nodes) - Persistent cough, SOB( mediastinal mass) - B symptoms- high spiking fevers, night sweats, weight loss - Pruritis

52. LYMPHOMA Hodgkins (continued) Diagnosis - CBC, RFT�s, LFT�s, uric acid, ESR, Ca+, aLP, phosphate for bone metastases - CXR - CT of chest, abdomen, pelvis - Biopsy of nodes - Bone marrow biopsy CBC- normocytic , nomochromic anemai leukocytosisin 1/3 of patients Eosinophilia platelets may be normal or increased in early disease, decreased in advanced diseaseCBC- normocytic , nomochromic anemai leukocytosisin 1/3 of patients Eosinophilia platelets may be normal or increased in early disease, decreased in advanced disease

53. LYMPHOMA Hodgkins (continued) Treatment - High cure rate - Stage I-II - radiation or chemo+ local field radiation - Stage III-IV- combination chemotherapy - Relapse Rx - higher dose chemo + bone marrow transplant Complications of RX infertility, hypotyroidism, secondary malignancy, accelerated cardiovascular diseaseComplications of RX infertility, hypotyroidism, secondary malignancy, accelerated cardiovascular disease