approach to anemia in children: IDA , MEGALOBLASTIC ANEMIA AND APLASTIC ANEMIA

lecture to undergraduates on anemia causes types and treatment in children

1. Approach to the child with anemia DR SUMERA AKRAM FCPS (PEDIATRCIS). CHPE, MRCPCH 1a SR DEPARTMENT OF PEDIATRIC MEDICINE SMC

2. LEARNING OBJECTIVES

3. DEFINITION OF ANEMIA A nemia is HGB or HCT at or below the 2.5 th  percentile for age and sex ●Reference ranges for HGB and HCT vary with age and sex. Anemia is one of the commonest disorders in children Anemia is seen in 53.7 % of children in Pakistan (NNS 2018)

4. Erythropoiesis (RBC production) In fetal life, erythropoiesis occurs in liver and spleen After birth, RBCs are produced in Bone marrow Active Bone marrow in small children is present in all skeleton Active Bone marrow in adults is present in axial skeleton

5. Normal values for hematologic parameters in children

6. PATIENT CHARACTERISTICS: Age of patien t   Birth to three months Physiological anemia Pathological anemia Anemia of prematurity 6-9 wks age Most common at this age Physiological nadir of 10-11 gm/dl at 6-9 wks age Anemia (HGB <13.5 g/dL) within the first month of life. Anemia with lower HGB level than is typically seen with physiologic anemia ( ie , <9 g/dL). Signs of hemolysis ( eg , jaundice, scleral icterus, or dark urine) or symptoms of anemia ( eg , irritability or poor feeding). Causes: blood loss, immune hemolytic disease ( ie , Rh or ABO incompatibility), congenital infection, twin-twin transfusion, congenital hemolytic anemia ( eg , hereditary spherocytosis, glucose-6-phosphate dehydrogenase [G6PD] deficiency). Compared with term infants, preterm infants are born with lower HCT and HGB, have shorter red blood cell (RBC) life span, and have impaired erythropoietin production due to immature liver function. Hence, the decline in RBC production occurs earlier after birth and is more severe than the anemia seen in term infants. This is referred to as "anemia of prematurity”   6 to 7 Gm. per dl at 3 to 7 weeks of age.

7. PATIENT CHARACTERISTICS : Age of patient   ● Infants three to six months  – hemoglobinopathy. Nutritional iron deficiency is an unlikely cause of anemia before the age of six months in term infants. ● Toddlers, children, and adolescents  – acquired causes: iron deficiency anemia. children who are exclusively breastfed or breastfed without sufficient iron supplementation are at highest risk for iron deficiency , and folate and B12 def. excessive cow milk intake in toddlers 12 to 36 months of age, onset of menarche in adolescent females

8. PATIENT CHARACTERISTICS: gender

9. PATIENT CHARACTERISTICS: Ethnicity/ancestry   ●HGB S and C : African or Hispanic descent, and Middle Eastern populations ●Thalassemia syndromes: Mediterranean and Southeast Asian descent. ●G6PD deficiency: Sephardic Jewish individuals; Black individuals from sub-Saharan Africa or Brazil; African Americans; and people from Thailand, Sardinia, Greece, South China, and India (areas where malaria was once endemic)

10. EVALUATION

11. 3 basic questions Is the child anemic ? What is the cause and type of anemia? How sever is anemia ?

12. Is the child anemic ?

13. History   : ● Symptoms  

14. History ● Past medical history  -previous hospitalization with anemia and blood transfusions. • Birth history  – gestational age, duration of birth hospitalization, history of jaundice (including onset and need for phototherapy) anemia in the newborn period.. ● Drug and toxin exposure  – G6PD deficiency ( eg , drugs such as fluoroquinolones,  dapsone ,  nitrofurantoin , and sulfonylureas; foods such as fava beans ) Possible environmental toxin exposure should be explored, including lead exposure and nitrates in well water ● Family history  – Family members with anemia, jaundice, gallstones, or splenomegaly should be identified. Asking if family members have undergone cholecystectomy or splenectomy for hemolytic anemias ● Dietary history  – The dietary history is focused on assessing iron intake and, to a lesser degree, folate and  vitamin B12  content. For infants and toddlers, the type of diet, type of formula (if iron fortified), and age of infant at the time of discontinuation of formula or breast milk. amount and type of milk the patient is drinking. Infants and children who are exclusively fed goat milk can develop anemia due to folate deficiency Pica special dietary practices ( eg , vegetarian or vegan diet), junk food intake, and picky eating habits. ● Developmental history  -Developmental delay can be associated with iron deficiency, lead toxicity,  vitamin B12 / folic acid  deficiency, and Fanconi anemia.

15. Physical examination   Pallor is assessed by examining sites where capillary beds are visible ( eg , conjunctiva, palm, and nail beds). Dysmorphic features – Congenital hypoplastic anemia(Fanconi anemia) Chronic hemolytic anemia Jaundice – Hemolysis Glossitis, angular stomatitis- iron def anemia Tongue (atrophy of papillae) – severe Iron deficiency Red beefy tongue- vit B12 def Brusing and petechiae- aplastic anemia Koilonychia – severe Iron deficiency Flow murmur – Heart Failure due to anemia Lymphadenopathy – leukemia, lymphoma Splenomegaly – Hemolysis, leukemia, lymphoma

16. Physical findings as clues to the etiology of anemia in children

17. What is the cause and type of anemia ?

18. Laboratory evaluation   : CBC with red blood cell (RBC) indices and review of the peripheral blood smear and reticulocyte count Hemoglobin and hematocrit

19. RED BLOOD CELL INDICES :   The RBC indices are an integral part of the evaluation of the anemic child. These include: MCV, MCHC, RDW Mean corpuscular volume (MCV)   : A useful rule of thumb to remember approximate age-appropriate lower reference limits for MCV values is 70 + age in years. Because reticulocytes have a greater MCV than do mature cells, patients with significant degrees of reticulocytosis may have elevated MCV values in the face of otherwise normocytic RBCs

20. types of anemia according to morphology Normocytic anemia Microcytic anemia Macrocytic anemia MCV = 75 - 105 fl ) MCV < 75 fl ) MCV > 105 fl ) hemolytic anemias, blood loss, infection, medication, anemia of chronic disease. Hypothyroidism chronic kidney disease. Transient erythroblastopenia of childhood is an acquired red cell aplasia that typically presents with a progressive normocytic anemia in otherwise healthy children and is a diagnosis of exclusion iron deficiency thalassemia exposure to certain medications ( eg , anticonvulsants,  zidovudine , and immunosuppressive agents).   vitamin B12  or folate deficiency, liver disease, Diamond- Blackfan anemia, hypothyroidism aplastic anemia . Isolated macrocytosis is also commonly seen in children with Down syndrome.

21. Laboratory evaluation : Blood smear ● RBC size  – A normal RBC should have the same diameter as the nucleus of a small lymphocyte. ● Central pallor  – The normal mature RBC is a biconcave disc with an area of central pallor, in normochromic RBCs , is approximately one-third of the diameter of the cell. Increased central pallor indicates hypochromic cells- iron deficiency and thalassemia. Anisocytosis – variation in size Poikilocytosis – variation in shapes

22. Laboratory evaluation : Blood smear ● Fragmented cells  –indicating a microangiopathic process: • Sickle cells- sickle cell disease• Spherocytes - hereditary spherocytosis and acute hemolysis, or elliptocytes , as seen in congenital elliptocytosis • Stomatocytes - hereditary or acquired stomatocytosis • Pencil poikilocytes - iron deficiency anemia or thalassemia • Target cells - hemoglobinopathies, including thalassemia, as well as in liver disease and post-splenectomy ) • Bite cells and Heinz bodies -hemolytic anemia due to oxidant sensitivity, such as G6PD deficiency • N ucleated RBCs indicates rapid bone marrow turnover and is seen with hemolytic processes (•RBC agglutination is seen in cold agglutinin hemolytic anemia ) • Howell-Jolly bodies- absence or hypofunction of the spleen • Basophilic stippling is classically seen in lead poisoning and may also be present in thalassemia, sickle cell anemia, and sideroblastic anemia)

23. Laboratory evaluation   White blood count and platelet count  — Leukocytosis: infectious etiology , acute leukemia. Hypersegmented neutrophils suggest  vitamin B12 deficiency. Thrombocytosis is a common finding in iron deficiency, Leukopenia, neutropenia, and/or thrombocytopenia bone marrow suppression/failure include: transient suppression due to viral infection, drugs or toxins, nutritional deficiency ( eg ,  folic acid  or  vitamin B12 deficiency) acute leukemia, or aplastic anemia. Blast cells - leukemia Increased peripheral destruction of blood cells: splenic hyperfunction ("hypersplenism"), microangiopathic hemolytic anemia ( eg , hemolytic uremic syndrome), or an autoimmune process ( eg , systemic lupus erythematosus, Evans syndrome, autoimmune lymphoproliferative disease)

24. Laboratory evaluation   Reticulocyte count  — The reticulocyte count is an indication of bone marrow erythropoietic activity and is used to classify the bone marrow response to anemia • Anemia with a high reticulocyte count reflects an increased erythropoietic response to hemolysis or blood loss • Anemia with a low or normal reticulocyte count reflects deficient production of RBCs Reticulocyte percentage  – The reticulocyte is reported as a percentage of the RBC population. After the first few months of life, the reference reticulocyte percentage is the same as that of the adult: approximately 1.5 percent [ 3 ]. ● Absolute reticulocyte count (ARC)  – The ARC is the product of the total RBC count multiplied by the reticulocyte count percentage: ARC = Percent reticulocytes × RBC count/L ● Corrected reticulocyte count  – Estimating the corrected reticulocyte count can be a useful method to determine whether the bone marrow response to anemia is appropriate. The calculation is based on the measured reticulocyte count, measured hematocrit, and normal hematocrit for the patient's age and sex: Corrected reticulocyte count = Measured reticulocyte count [percent] × (measured hematocrit ÷ normal hematocrit for age) A corrected reticulocyte count <2 percent is inappropriately low in the setting of anemia.

25. Laboratory evaluation: specific tests

26. DIAGNOSTIC Algorithm

27. Approach to microctic hypochromic anemia

28. Approach to macrocytic anemia

29. Approach to normocytic normochromic anemia

30. Case scenario

31. How severe is anemia ?

32. treatment

33. Approach to the child with anemia DR SUMERA AKRAM FCPS (PEDIATRCIS). CHPE, MRCPCH 1a SR DEPARTMENT OF PEDIATRIC MEDICINE SMC

34. CASE 1 • A 14 year old girl came to the physician complaining of weakness, lethargy and easy fatigibility . Upon questioning she revealed that she just had her first menstrual cycle (menarche) last month and it lasted for 20 days. Also this month she is having heavy periods . She has breathlessness and palpitations while climbing stairs. Also she had episodes of dizziness . • Vitals: BP= 110/ 74; HR= 115; RR= 16; Temp= 36.8 • Examination showed overall pallor, pale nail bed , pale conjunctiva and pale gums. No yellow discoloration of the sclera or skin. • CVS= Heart murmur present. • Respiratory – Normal breath sound • Abdomen- Soft lax and non- tender. What is the next step?

35. CBC: WBC- 6000 Hb - 5g/dl RBC count: 3 million/ mm3 Hct = 18% MCV- 56 fl MCH- 20 pg MCHC- 26 g/dl Platelet- 200,000/mm Reticulocyte-1.2% Inference ? What additional tests you want to do? Serum Iron- 30mcg/ dL TIBC- 450 Ferritin-9 ng /ml Transferrin saturation- 7% What kind of anemia is this?

36. Case 2 6 year old child presented to opd with loose stools. This is her 3 rd time presenting with loose motions. According to her mother she has alternating bowel habits . Her stools are foul smelling and contains undigested food particles. She is on average family diet. On examination she has marked pallor with protuberant abdomen. No visceromegaly. Her height is below 5 th centile . Diagnosis ?

37. Case 3 A 7 month old child came to emergency with history of blood streaks in diaper. His pst histroiry is suggestive of recurrent diarrhea. He was a playful child. His weight and height are on 25th centile. Systemic examination is unremarkable except pallor. He is on top feed since birth and weaning started on 6 month of age consisting of rice based cereals. Mother noticed this blood streak for the 3rd time since last 1 month. Diagnosis?

38. Iron Deficiency Anemia • Most common type of anemia worldwide. Pakistan 30 % Causes: Nutritional- poor weaning(milk being a poor soure of iron) dietary deficiency : lack of iron rich foods, Worm infestation( round worm and tap worm) Recurrent infections(poor oral intake) Cow milk protein allergy • Blood loss- overt/ occult • malabsorption: Celiac disease, Clinical Presentation- pallor, lethargy, headache, irritability, easy fatigue, exercise intolerance and pica

39. Workup of iron deficiency anemia peripheral smear: Microcytic hypochromic anemia with high RDW and low reticulocytes Low ferritin, low transferrin saturation High TIBC. Stool for ova and cyst Hb electrophoresis and Celiac screening: consider in case of poor response to iron therapy, severe anemia, failure to thrive, strong symptoms of disease.

40. Treatment: Oral Iron Therapy: better to give empty stomach • The recommended dose for IDA in children is 3-5mg/kg/day. • Three forms are available: Ferrous fumarate, Ferrous Sulfate , Ferrous gluconate. Ferrous polymaltose. Parenteral Iron therapy: oral iron intolerance, or refractory to oral therapy. Deworm Blood Transfusion :Hemodynamically unstable Reticulocytes- starts to rise in 3 -4 days, Hbg- after 4- 5 days After Hgb normalisation – continue Fe therapy 1-2 months to replace Fe stores *Iron- rich foods: animal protein, green vegetables, iron fortified cereales Encourage breast milk Folate, vit C ?

41. CASE 4 2 year old boy on goat milk comes to opd with irritability and failure to thrive. No weaning has been started . Physical exam reveals pallor of the skin and mucosa and slight jaundiced discoloration of the sclera and a red and a shiny tongue. He denies paresthesia and sensation is normal on neurological exam.

42. CBC Hb - 8.5g/ dL Hct = 28% MCV= 130fl MCH- 35 WBC- 4800/mm3 Platelets- 140,000/mm3 Reticulocyte - 0.2% Bilirubin Total- 2.0mg/ dL Direct- 0.3 mg/ dL Peripheral Blood Smear Macrocytes , ovalocytes and hypersegmented neutrophil LDH- 600U/L Additional test: Folate level- 1ng/ml (220ng/ml) Vitamin B12 level- 300pg/ml (200pg -500pg/ml) Most likely Diagnosis? Folate Deficiency Anemia

43. Case 5 7-year-old boy presented to your clinic with recent complaints of experiencing a decline in energy levels and is often irritable. He also has frequent headaches and has started to have difficulty concentrating in school. His family follows a strict vegetarian diet. No history of any past disease or medication use. His physical examination was unremarkable except pale sclera and slight numbness of toes. Labs : hb % 7.5 gm/dl Peripherasl film has macrocytic picture with tear drop cells. Any other test ? Folate level- 200ng/ml (220ng/ml) Vitamin B12 level- 95pg/ml (200pg -500pg/ml) B12 deficiency anemia

44. Megaloblastic anemia Folate and B 12 def Causes: Underlying cause Vitamin B 12 deficiency Folate deficiency Inadequate dietary intake Malnutrition Vegetarian diet Infant on breast milk with maternal deficiency Malnutrition Overcooking of food Goat milk in infancy Defective absorption Failure to secrete intrinsic factor Congenital IF def Pernicious anemia Gastrectomy Failure of absorption in small intestine- coeliac disease Crohn disease Intestinal resection’fish tape worm Jejunal resection Tropical sprue Intestinal lymphoma Broad spectrum antibiotics Defective transport Cong transcobalamine deficiency Defective metabolism Congenital Acquired ( liver diseases, drugs) Folate antagonists( methotrexate, trimethoprim) Liver diseases Increased demand Rapid growth ( prematurity, pregnancy) Chronic hemolytic anemia( thalassemia, hereditary spherocytosis) Infections hyperthyroidism

45. pathophysiology Vitamin B 12 ( cobalamin) and folate are required for DNA synthesis in cells. Vitamin B 12 def so folate cannot be utilized. Defective DNA synthesis in erythroid precursors –nucleus continue to increase in size without maturation-nuclear cytoplasmic asynchrony-megaloblasts-destroyed in BM-ineffective erythropoiesis

46. CLINICAL FEATURE OF MEGALOBLASTIC ANEMIA

47. investoigations

48. treatment Folate supplementation 1-5 mg/day for 3-4 weeks Parenteral B12: cobalamine 1mg IM daily for 2 weeks then weekly until hematocrit value is normaland then monthly for life. Can be continued orally if there is no mal absorption Dietary conselling RCC transfusion

49. CASE 6 An 5 year old boy comes to the clinic for evaluation of weakness and fatigue lasting for 6 weeks. Before the past 6 weeks he reports being fairly healthy. He did how ever had a recent case of ‘flu’. Before this illness, he has been healthy, takes no medication and has no family history of any disease. No history of blood transfusion Physical examination revealed marked pallor and a 2/6 non-radiating systolic murmur heard best at the right upper sternal border. Abdominal examination reveals few scattered petichae but no hepato splenomegaly

50. Labs: Hb-5.0g /dL WBC- 4000 Platlets : 90 x 10 Differentials normal Reticulocytes - 0.5% What do you infer from the results? Pancytopenia Other chemistries and liver function was normal. What is the next most important test you would do? Bone marrow biopsy- It showed cellularity of < 5% with normal cellular morphology and no organism on gram stain. Diagnosis: Aplastic Anemia

51. APLASTIC ANEMIA Aplastic anemia is characterized by diminished or absent hematopoietic precursors in the bone marrow, most often due to injury to the pluripotent stem cell.

52. Acquired aplastic anemia Usually result of immune mediated injury to hematopoietic system Idiopathic 70% Secondary causes: infections( hep C HIV EBV CMV PARVO ) Sever mal nutrition Drugs (chloramphenicol, methotrexate, cyclophosphamide) Chemicals( benzene, carbon tetrachloride) Ionizing radiation Paroxysmal nocturnal hemoglobinuria Clinical presentation: fatigue, palpitations infections, fever, petichae , pallor, easy bruising, gum bleed , epistaxis, increased susceptibility to infection, oral ulcersetc .

53. Diagnostic approach History and examination : Cause Liver and spleen and lymph nodes Congenital anomalies CBC and peripheral film: Low hb % Normocytic normochromic ( macrocytic in FA ans DBA) Low retics Low WBC and low ANC LOW platelets Viral serologies Autoimmune profile ( ANA and Anti ds DNA ) Serum B 12 and folic acid levels Bone marrow aspirate and trephine biopsy Cytogenetics, flow cytometry and mutational analysis

54. TREATMENT SUPPORTIVE CARE- Infection: prophylactic antibiotics, isolation and good hygiene, mouth care Control of bleeding if present: platlet transfusion oral and IV tranexamic acid Anemia: Replacement with blood and blood products SPECIFIC TREATMENT- Immunosuppressive agents: cyclosporin alone or in combination ) Anti thymocyte globulin ( ATG) Anabolic steroids Hematopietic stem cell transplant/Bone marrow transplantation: fully HLA matched or haplo matched donor

55. Congenital aplastic anemia Inherited bone marrow failure syndrome Types: Fanconi syndrome ( most common ) Diamond blackfan anemia * congenital pure red cell aplasia) Dyskeratosis congenita Schwachman diamond syndrome Transient erythroblastopenia of childhood

56. Fanconi anemia Autosomal recessive ( 20% -30% cases of aplastic anemia ) Congenital anomalies+ progressive bone marrow failure+predisposition to develop malignanacy Clinical features : short stature, Fanconi facies, skeletal malformation, skin menifectations , kidney, heart , anorectal, hydrocephalous, Lab : pancytopenia ( b/w 5-10 yr age) Increased risk of myelodysplastic syndrome and AML / solid tumors ( SCC) Confirmatory test : chromosomal breakage study, bone marrow examination and genetic mutational study Management : supportive and specific

57. CASE 7 A 9 year old male presented to the clinic in tertiary care due to fatigue, abdominal pain, joint pain and a general feeling of being unwell since 2-3 months. He says that he was diagnosed to have a blood disorder at the age of 1 year. Since then he has received several blood transfusion. Upon examination, he is a thin built with relatively short stature ,sitting comfortably, not in distress. He is vitally stable. General Exam showed pallor, hyperpigmentation of the skin and yellowish discoloration of the sclera Head and neck examination reveal depressed cranial vault, frontal bossing, maxillary expansion and exposure of upper teeth. Abdominal examination shows hepatomegaly and splenomegaly . What to do next?

58. CBC: Hb - 8.4 g/ dL MCV- 90.1 fl/ WBC-11.6x 109/L Platelets- 161x 10 6/L Reticulocytes - 5% PBS- microcytic , hypochromic , polychromasia , nucleated RBCs target cells, poikilocytosis and anisocytosis Bilirubin (Indirect)-1.9 What is the additional test that will help you to reach diagnosis? Hb Electropheresis - HbA - 87.5%; Hb A2-2.2%; Hb F- 10.3%

59. What is diagnosis? What other tests would you do? Iron Studies: Serum Iron-219 mcg/ dL Ferritin-1000ng/ml TIBC- 250mcg/ dL LFTs: ALT- 90 U/L AST- 75 U/L What do you infer from above tests? Iron overload Beta thalassemia major

60. HEMOLYTIC ANEMIA Definition: Anemias which result from an increase in RBC destruction in the body with increased erythropoiesis in Bone Marrow

61. Pathophysiology of Hemolytic Anemia In Hemolytic Anemia, life span of RBCs is shortened - Anemia. RBCs destruction is increased - Blood Unconjugated bilirubin. Hemoglobin and RBC count in blood is reduced . Cellular hypoxia stimulates erythropoietin production - Reticulocytes (immature RBCs) in blood. Bone marrow becomes hyperplastic and increases its output of erythrocytes but ineffectively .- Skeletal deformities (Bone marrow expansion, Hepatosplenomegaly (RE hyperplasia) .

62. Cellular Defects : (hereditary diseases) when RBCs are abnormal : RBC membrane defects: Hereditary spherocytosis RBC enzyme deficiency: G 6- PD Deficiency Hemoglobin abnormalities Thalassemia Sickle cell anemia Extra- cellular Defects : (acquired diseases) with defects in environment of RBCs : Immune Hemolysis (due to antibodies) - - Hemolytic disease of newborn (Rh- incompatibility) - - Auto- immune Hemolytic Anemia Non Immune Hemolysis: Physical Damage to RBCs – DIC, Burns Infections – malaria, bacterial sepsis Etiological classification of Hemolytic Anemia

63. Hemolytic anemia

64. Clinical Features Anemia (mild to severe, may be masked by blood transfusion) Jaundice (unconjugated, in some cases) Splenomegaly (in all cases) Bony deformities (in severe chronic cases especially Thalassemia) Gall stones (bilirubin stones usually in Hereditary Spherocytosis)

65. Diagnostic algorithm for Hemolytic Anemia

66. Lab Diagnosis Hemoglobinuria (dark brown color urine containing Hemoglobin seen in intravascular hemolysis) Bone Marrow exam (rarely needed) shows Erythroid Hyperplasia

67. Laboratory evaluation   : hb electrophoresis

68. Beta Thalassemia Major Most common Hemolytic anemia in Pakistan Autosomal recessive Thalassemia gene carrier rate in Pakistan is 6 % Hemoglobin in blood is mainly Hb F Severe hemolysis Anemia starts in first six months of life Very large spleen Significant bony changes Peripheral blood film shows Target cells

69. Beta Thalassemia Major Diagnosed by : Hb electrophoresis Thalassemia Gene tests in peripheral blood Frequent Blood Transfusions and Iron chelation are needed Hydroxyurea may reduce need of blood transfusions Life span shortened due to multiple complications Bone Marrow Transplant can cure the patient

70. BETA- THALASSEMIA Autosomal recessive. Defective hemoglobin structure 2 beta and 2 alpha chains. Types: beta thalassemia major, minor , intermedia Alpha thalassemia, HbH BARTS, HbE , HbD Heterozygous:HbE , HbD , HbS thalassemia Clinical presentation: fatigue, weakness, palpitation, short stature, frontal bossing, maxillary expansion, abnormal teeth, hepatomegaly, splenomegaly etc. If Iron overload: joint pain, abdominal pain, bronze skin, palpitations, depression.

71. Diagnosis: Microcytic hypochromic anemia. Peripheral blood film shows- microcytosis , hypochromia , polychromasia , target cells and nucleated RBCs Hb Electropheresis - decreased amount of hbA , variable amount of Hb A2 and increased HbF Complications- Iron overload ( cirrhosis, cardiomyopathy ), Endocrinopathies . Ineffective erythropoisis - thalassemic facies Cortical destruction and impaired bone function- osteoporosis Arterial venous thromboembolism- leg ulcers

72. Management: Transfusion: Blood transfusion has become the accepted regimen for BTM patients in order to maintain a Hb 0f 9-10 g/ dL packed red cells 10-15 ml\kg every three to five weeks. Chelation therapy: Initiated usually after 10 transfusions. Or if ferritin is above 1000. Desferoxamine Deferiprone deferasirox

73. Endocrine therapy- Administration of deficient hormones ( thyroid hormones) Treatment of Diabetes Supportive care- cardiac monitoring, monitoring for osteoporosis and osteopenia , folic acid , zinc replacement etc. Splenectomy - Indicated in patients with beta- thalassemia major and intermedia requiring an increase of 50 percent or more in the red cell transfusion over a one-year. bone marrow transplant: definitive treatment for appropriately selected patients Genetic counselling

74. Comparison of Iron deficiency Anemia and Thalassemia Iron deficiency Anemia Thalassemia Onset in late infancy Slow developing anemia No splenomegaly Serum Ferritin low Reticulocyte count < 2 % Hb electrophoresis shows Hb A Onset in early infancy Rapidly developing anemia Splenomegaly Serum Ferritin raised Reticulocyte count > 2 % Hb electrophoresis shows raised Hb F

75. Hereditary Spherocytosis Autosomal dominant Mild to moderate hemolysis Newborns may have anemia and hyperbilirubinemia Children have mild anemia Gall stones (Calcium bilirubinate) are common Spleen is enlarged

76. Hereditary Spherocytosis Hb normal to low Retic Count > 2 % MCHC increased Blood film shows spherocytes In severe disease, splenectomy is indicated

77. Blood film in Hereditary Spherocytosis

78. CASE 8 A 11 year old male presented to the ER with acute onset of Left hemiparesis that started 3 hours ago. The patient has no history of thromboembolic disease, no family history of venous or arterial thrombosis. But he says he has a blood disease where he gets frequent pains in legs, joints, chest and needs to come to hospital for IV pain medication. Physical Exam shows scleral jaundice, no splenomegaly

79. CBC- Hb - 8.0g/ dL MCV- 82.3 WBC- 9800/mm3 ANC- 8500 Platelets- 465000/mm3 Reticulocyte - 7% Indirect Bilirubin - 84mg/ dL PBS- Numerous Sickle cell Non- contrast CT brain showed acute RT MCA infarct What is the most likely diagnosis? Sickle Cell anemia

80. How to manage this patient? Admit the patient Pain medication- opioid Good hydration Red Cell exchange transfusion to maintain HBS at <50% Hydroxyurea -decreases the painful episodes,raises the HB level,raises the HBF level.

81. SICKLE CELL ANEMIA AR disease where there is a substitution of valine for glutamic acid in the beta globin chain of Hb which produces Hb tetramer which poorly soluble when deoxygenated. Clinical presentation- anemia, jaundice and painful episodes, delayed growth and puberty, neurocognitive impairment, osteonecrosis , infections. Laboratory findings- Mild to moderate anemia, reticulocytosis , unconjugated hyperbilirubinemia , increased level of LDH and decreased level of Haptoglobin . Peripheral Blood Smear reveal normocytic normochromic red cells sickled red cells, polychromasia and Howell jolly bodies reflecting asplenia .

82. Treatment Includes Management of pain and anemia. Management of sicklecell crisis. Management of complications. Prevention of infections by capsulated organisms

83. Sickle Cell Anemia Seen in Baluchistan, Middle East Autosomal recessive Hemoglobin in blood is mainly Hb S RBCs become sickle- shaped with reduced Oxygen Sickled RBCs block capillaries resulting in tissue hypoxia Severe vaso- occlusive pain in bones and limbs starts at an early age Anemia mild to moderate Bacteremic infections are common

84. Sickle Cell Anemia Diagnosed by: sickling test Hb electrophoresis Blood Transfusions may be needed during acute complications Management of Painful crisis needs hydration analgesics and blood transfusion Hydoxyurea increases Hb F and reduces hypoxic, painful episodes

85. Glucose 6- Phosphate Dehydrogenase Deficiency (G6PD) X- linked recessive, seen in males G6PD enzyme is deficient in RBCs Glucose 6- Phosphate Dehydrogenase enzyme protects against Oxidative reactions in RBCs G6PD Usually produces episodic severe hemolysis after exposure to certain drugs or infections Severe intravascular hemolysis results in sudden severe anemia and hemoglobinuria (cola- colored urine) Blood Transfusion is needed urgently

86. Glucose 6- Phosphate Dehydrogenase Deficiency (G6PD) Diagnosis: Blood G6PD levels are low Life long avoidance of specific drugs is important for prevention

87. CASE 9 A 12 year old girl presented to the Emergency Department with fever (38.6 C) headache, abdominal pain, vomiting and yellowish discoloration of eyes of 5 days duration. Physical examination revealed marked pallor, fever, tachycardia, tachypnea and icterus . There was no lymphadenopathy , edema, rash, petichae or bruises. Cardio vascular examination revealed a 3/6 systolic murmur along the left sternal border. A non tender soft hepatomegaly with a span of 14 cm and a soft spleen 3 cm below the left costal margin was noted. Lung fields were clear and neurological examination was normal.

88. CBC WBC- 9000/mm3 Hb - 3g/ dL MCV- 128 fl MCH- 50.9pg MCHC- 39.7g/ dL Platelets- 170,000/mm3 Reticulocyte - 10% Total Bilirubin - 4.5mg/ dL Indirect Bilirubin - 3.2 mg/ dL PBS- Agglutination of RBCs noted. Smear showed anisopikilocytosis with predominant macrocytes , hypochromia and nucleated red blood cells. DcT - strongly positive

89. AUTOIMMUNE HEMOLYTIC ANEMIA Hemolytic anemias which results from the development of auto antibodies directed against antigens on the surface of patient’s own red blood cells. Causes- associated with infections, malignancy and other autoimmune disease Clinical manifestation- anemia, jaundice, splenomegaly Diagnosis: Reticulocytosis , raised serum bilirubin and positive DCT.

90. Treatment: Transfusion of red cell if Hb is considerably low. It is complicated because of cross matching problems and rapid in vivo destruction of transfused cells due to the presence of auto antibodies Corticosteroid is the main stay of therapy for AIHA. Immunosuppressive agent including monoclonal Anti- CD20 ( Rituximab ) proves useful in refractory AIHA. Splenectomy benefit in refractory cases of AIHA.

91. Autoimmune Hemolytic Anemia Seen in older children Anti RBC antibodies develop in the body Progressive anemia Spleen is enlarged Direct Coombs test is positive Blood Transfusions may be needed Management includes steroids and other immunosuppresants Disease may last for months to years

92. THANK YOU