peds

1. HEMATOLOGY

2. Hematologic Markers: Hb: Is the concentration of oxygen carrying protein. Ht: Is the percentage of whole blood occupied by RBC MCV: measure average volume/size of RBC. Micro, Normo, Macrocytic MCHC: measure amount of Hb in the RBC. Normo, Hypo/Hyperchromic Reticulocytes: Measure circulating immature RBC. ↓ with iron deficiency. ↑ with blood loss Serum Ferritin: is a storage compound for iron. As total iron stores are depleted, Serum ferritin levels falls. ↑ levels: Hemolytic anemia, megaloblastic, hemochromatosis ↓ levels: Iron deficiency, Severe protein deficiency Transferrin: Iron absorbed in small intestine, and transported to plasma will be bound to a Globulin protein Total Iron Binding Capacity: Measures transferrin levels: ↑ serum iron concentration. ↓ malnutrition, infection

3. RBC: RBC exist in peripheral blood for 120 days. At the end of RBC life  hemolized and extracted from circulation by the spleen. Normal RBC values vary according to sex and age. If RBC ↓ more than 10%, the patient becomes anemic. Abnormal findings: Increased levels Decreased levels High altitude Hemorrhage (GI bleeding, trauma) Polycythemia Vera Hemolysis, Drugs Dehydration Anemias, Dietary deficiency (fe, B-12) Congenital heart Ds. Leukemia, Overhydration, Chronic Illness, Kidney failure (Epo)

4. The Child with Anemia Minimal level: Up to 18 months- Hb 11g% Ht 33% Over 18 months- Hb 12g% Ht 35% Types of Anemia: The RBC provide information about: the size or volume (MCV) weight (MCH) Hb concentration (MCHC) of the RBC. RBC distribution width (RDW) Also order Peripheral Smear: RBC, WBC, Platelets This microscopic examination can reveal variation in RBC size, shape, color, intracellular content

5. When checking for anemia: MCV (mean corpuscular volume or size of a single RBC): Microcitic - VCM less than 75-80% Fe def anemia, Thalassemia Macrocitic - VCM above 100% Megaloblastic: B-12/folic acid def. Normocitic - VCM between 75-100% MCH (mean corpuscular hemoglobin or weight within a RBC): Microcitic hypochromic: ↓ MCHC/MCV . Iron deficiency, Thalassemia, lead Macrocitic normochromic: ↑ MCV . No maturation factors (B12,folates, Etho Normocitic Normochromic: ↓ Hb, normal MCHC/MCV. Hemolitic, aplastic anemia Iron def., chronic illness, acute blood loss Microcytic Normochromic anemia: Renal disease (loss of erythropoietin) MCHC (mean corpuscular Hb concentration or % of Hb within a RBC): Hyperchromic: Spherocytosis Hypochromic : Fe def. anemia, Thalassemia Normochromic:

6. RBC Size (Anisocytosis): Microcytes (small RBC): Fe def., Hereditary spherocytosis, thalassemia Macrocytes (larger size): Vit-B12, folic acid def., occasional liver disease RBC Shape ( poikilocytosis): Ovalocytes: Megaloblastic anemia Spherocytosis: (Small and round)- Hereditary Spherocytosis Elliptocytosis: (Crescent or Sickled shaped)- Sickle cell anemia Hereditary Elliptocytosis Leptocytes (Target cells- thin and less hb): Thalassemia Hemoglobinopathies Spicule Cell: Uremia, Liver disease, Bleeding ulcer RBC Color: Hypochromic (pale): Fe def., Thalassemia, Cardiac disease Hyperchromasia: Concentrated Hb, usually caused by dehydration

7. RBC intracellular structures: Nucleus: RBC maturation process results in loss of nucleus, nucleated RBC (normoblasts) seen in the peripheral Smear, indicates increased RBC production Basophilic stippling: lead poisoning Howell-Jolly bodies: Megaloblastic anemia, Hemolitic anemia, Heinz Bodies: Hemoglobin Ds, Hemolitic anemia, G6PD WBC: Examined for total quantity, differential count and level of maturity Increased WBC may indicate Leukemia Decreased may indicate failure of marrow to produce WBC PLATELETS: Thrombocytosis: Polycytemia Vera, Leukemia, RA, Chirrosis, Trauma, Tu. Thrombocytopenia: Bleeding, ITP, Leukemia, DIC, SLE, Ca-Chemo, HA Drugs: acetoaminophen, H2 agents-Zantac, INH, etc..

8. Bone Marrow: Reveals the number, size, shape of RBC, WBC, megakaryocytes, as these cells evolve through several stages of development. Its microscopic exam reveals estimation of cellularity, determination of presence of fibrotic tissue or neoplasm, estimation of iron storage. Estimation of cellularity: Is a ratio between Myeloid (WBC) to Erythroid cells (RBC) (M:E ratio). Normal ratio is M3:E1 WBC: ↑: Leukemias , leukemoid drug reaction ↓ : leukemia, agranulocytosis, metastatic Tu,, chemo, aplastic RBC: Hyperplasia: polycythemia Vera, hemolitic anemia, Hypoplasia: Chemo/radiation Tx., iron def., toxic drugs, aplastic Megakaryocytes: ↑ - acute hemorrhage, CML ↓ - Radiation/chemo/drugs Tx, aplastic,infiltrative ds. Lymphocytes: ↑ - chronic or viral infections (Mono), CLL, lymphoma Megaloblastic: Def. of B-12, Folates

9. Reticulocyte Count: It is an immature RBC. Determine the bone marrow production of RBC and erythropoietic function. Increased level Decreased levels Hemolytic anemia Pernicious anemia Sickle cell anemia Folic acid def. Hemorrhage Aplastic anemia Pregnancy Bone marrow failure Leukemias Radiation therapy Chronic infection Fe def., Depletion of iron stores

10. WHITE CELL COUNT AND DIFFERENTIAL WBC: fight infection and react against foreign bodies. WBC has 2 components: WBC (leukocytes) and the Differential. Neutrophils and lymphocytes make up 75-90% of total leukocytes. Increased of WBC (leukocytocis)  infection, inflammation, leukemic neoplasia. Also trauma, stress Decreased of WBC  bone marrow failure (after radiation, chemo, or in agranulocytosis-drug), infections.

11. NEUTROPHILS (PMN): Produced every 7-14 days, lasts 6 hours. The function is phagocytosis. Acute bacterial infection ↑ neutrophil production  ↑ WBC. With neutrophils stimulation, immature forms enter the blood, called BAND cells  process called Shift to Left in WBC production  ongoing acute bacterial infection LYMPHOCYTES: Fight chronic bacterial infection and acute viral infection Divided in 2 types: T/B cells. T cells: involved with cellular type immune reaction B cells: involved in humoral immunity (antibody production ) MONOCYTES: Phagocytic cells that fight bacteria BASOPHILS / EOSINOPHILS: Are involved in allergic reaction. Parasitic infestations stimulate the production of those cells

15. Mild anemias are associated with few or no clinical symptoms or signs; and is detected from a screening measurement of Ht or Hb Obtain a complete blood count (CBC), reticulocyte count, measurements of the serum iron, total iron-binding capacity (TIBC) and serum ferritin. Patients with severe anemia and abnormalities in RBC morphology may require a bone-marrow aspirate If the MCV is suggestive of a megaloblastic anemia, consider testing for RBC and serum folate, serum vitamin B12, and obtain a peripheral blood smear and a bone-marrow evaluation.

16. NORMAL VALUES

17. Direct Coombs-DAT (direct antiglobulin test) : Detect autoantibodies against RBC’s, that cause cellular damage leading to hemolitic anemia. Mix the patients RBC’s with Coombs serum. Coombs serum is a solution that contains antibodies against human blood serum. If the patient RBC’s has autoantibodies against RBC’s, the Coombs antibodies will react with the autoantibodies on the RBC’s, causing agglutination of the RBC’s. Associated disease are: Erythroblastosis fetalis, Lymphomas, Lupus, EBV, , drugs (quinidine) Indirect Coombs : Detects circulating antibodies against RBC’s. Determines if the patient has serum antibodies (other than the ABO) in the RBC’s that the patient is about to receive by blood transfusion. If it has antibodies, it will cause agglutination. It can be present in a woman Rh- with a fetus who is Rh+ Associated disease: Erythroblastosis fetalis, Acquired hemolytic anemia, Anti-Rh antibodies, Incompatible cross-matched blood.

18. IRON DEFICIENCY ANEMIA Results in a ↓ production of Hb, with a small, pale and ↓ # of RBC Iron supply is insufficient to maintain normal levels of Hb. Epidemiology: Common in children from 6 months to 2 years, and teenage boys/girls. Common cause of anemia in developing countries Pathophysiology: Iron is necessary for oxygen transport by Hb. Iron is supplied by diet, absorbed in the GI tract (duodenum). Initially iron stores are depleted but the RBC are normal When all iron stores decrease, Hb synthesis decrease  gradual fall of RBC production in bone marrow  new RBC are smaller and paller  decrease tissue oxygenation.

20. Causes: -Decrease dietary intake of iron fortified formulas or meat -Excessive cow’s milk consumption -Decrease iron absorption -Blood loss: hemolysis (ABO incompatibility), parasites, cow’s milk enteropathy in infants, GI blood loss -Decreased production. -Socioeconomics status -Duration of breast feeding -Increased juice, soda pop intake

22. koilonychia : Spooning of the fingernails occurs in children with severe iron deficiency anemia. It refers to abnormally thin nails which have lost their convexity, becoming flat or even concave in shape.

25. TX: Iron supplement as ferrous sulfate orally for 6 months. 5-6mg/kg/day ferrous sulfate. ↑ Hb 1.0g/dl in 3-4 weeks. Should be given with orange juice to absorb better the iron. Should increase in one week after starting oral treatment. In case of iron toxicity, there is a new alternative to the efficient but painful IV iron chelator deferoxamine. It is an oral solution called deferasirox, name Exjade, taken once a day.

28. MEGALOBLASTIC ANEMIA Etiology: Milk products diet, Folic acid/B-12 deficiency, vegetarians, drugs that inhibit DNA synthesis (phenytoin) > folic acid. S/S: Onset of anemia associated with Pallor, Fatigue, Irritability. GI symptoms: Malabsorption/Diarrhea, Vegan diet, Glossitis (red beefy tongue), Atrophy of tongue papilla Neurological symptoms associated with vit-B12 def: Difficulty walking, numbness/tingling in hands and feet (paresthesia), ataxia, peripheral neuropathy, positive Babinski sign

29. Lab: Low Hb < 11g%, Ht, RBC Increased MCV (macrocitic) MCH / MCHC normal (normochronic) RDW elevated Reticulocytes- decrease. Peripheral Smear: Oval Macrocytes, hypersegmented neutrophils Increase aniso (size) / poikilocytosis (shape) Myelogram: Megaloblastic changes (large erythroblasts) Serum Folates / RBC Folates: low levels. Vit. B-12: low levels Schilling test: B-12 absorption, measuring urinary excretion Increase LDH Tx: Folic Acid- 1-5mg PO daily for 3 B-12 25-100mg IM daily Citrus fruits: Vit-C (transform folic acid in its active form) Diet rich in folates: green vegetables, meat (liver) Reticulocytes ↑ in 2 weeks of therapy. failing to ↑ in 2 months, check Dx.

30. A smooth, beefy red tongue may be observed in the physical examination of a patient with vitamin B12 deficiency.

31. APLASTIC ANEMIA: Failure of Bone Marrow to produce: RBC, WBC, Platelets Etiology: Drugs (chloramphenicol), Toxins, Virus, Radiation. S/S: Thrombocytopenia: Bruising, Gum/Nose bleed, Petecchia Anemia: Lethargy, Pallor Neutropenia: Infection, High fever, Trush, oral ulcerations Adenopathy / H-Smegaly: Leukemia, Cancer LAB: Normochromic/Normocytic Neutropenia < 500 cells Platelet count < 50.000 Reticulocyte count < 1% Bone marrow aspirate/biopsy: Hypocellularity. TX: Bone Marrow transplantation Immunosupppressive therapy (anti-thymocyte antigen/ Ciclosporine) Atb Antifungal oral Tx.

34. Basophilic stippling on peripheral smear

35. SICKLE CELL DISEASE Sickle cell is an inherited Autosomal recessive blood disorder affecting RBC, where Valine is subtituted for Glutamic acid at codon 6 on the B-globin chain of the Hb, and where in sickle patients, HbS predominates. Normal red blood cells contain hemoglobin A. These RBC become sickle-shaped (crescent-shaped), having difficulty passing through small blood vessels. The most common types of sickle cell disease are 3 forms of genotypes: HbSS Ds (sickle cell anemia) ds HbSC Ds (sickle-Hb C Ds) trait HbS-B Sickle Beta Thalassemia. Incidence: 1:500 ( in the Black population) live births.

36. Sickle cell trait is inherited from one’s parents, like hair or eye color. If one parent has sickle cell trait there is a 50% (one in two) chance with each pregnancy of having a child with sickle cell trait. If both parents have sickle cell trait there is a 25% (one in four) chance with each pregnancy of having a child with sickle cell disease. When affects one chromossome, the heterozygous condition  S.C. Trait When affects both chromossomes, the homozygous condition  S.C. Ds When one chromossome makes HbS and the other makes no hemoglobin (B-thalassemia trait)  HbS-B. Sickle cell Ds is a lifelong illness that result in serious health problems. For this reason, trait awareness is very important.

37. Hemoglobin A: Is a normal Hb that exist after birth. It is a tetramer with 2 alpha and 2 Beta chain (A2B2) Hemoglobin A2: Is a minor component of the Hb found in RBC after birth, and consist of 2 alpha and 2 Delta chains (A2d2). Less than 3% of total Hb Hemoglobin F: Is the predominant Hb during fetal development. The molecule is a tretamer of 2 alpha and 2 Gamma chains (a2g2). Production falls after birth, although some people produces small amounts of HbF during their entire lives. Hemoglobin S: Is the predominant Hb in people with sickle cell disease. The alpha chain is normal. The disease-producing mutation exists in the beta chain, giving the molecule the structure, a2bS2. People who have one sickle mutant gene and one normal beta gene have sickle cell trait which is benign. Hemoglobin C: Results from a mutation in the beta globin gene and is the predominant Hb found in people with Hb C disease (a2bC2). Hb C Ds. is relatively benign, producing a mild hemolytic anemia and splenomegaly.

39. S/S: Early signs are delayed growth and development, fever, infections Hallmark is Fever Hand/foot Syndrome- Dactylitis: -Most common age: 6 months to 3 years ( range 3 months – 5 years) -Often the first clinical manifestation -Symmetrical painful swelling of hands/feet. Refuses to bear weight. Fever Sudden and massive splenic sequestration: (acute blood trapping in spleen resulting in fall in Hb due to sickling). Leading cause of death in children under 5 years. S/S: spleen enlarged and tender, Hct ↓ by 25%, platelets under 100.000, ↑ in Reticulocytes, pallor, anemia (hemolysis), fatigue fever, jaundice, tachycardia Due to Splenic dysfunction by intravascular sickling of red cells, this is accentuated by: Hypoxia, Dehydration and Acidosis

40. Acute Chest Syndrome (Pneumonia): - Seen in more than 50% of Sickle cell patients. -Leading cause of mortality in sickle Cell disease Sepsis: Younger children: S. pneumoniae Older children: G-/Salmonella Symptoms : Fever, Cough, Chest/Back pain Tachypnea, ↑ RR, Flaring, Grunting, Hypoxemia Infiltrates in X-ray. Treat with antibiotics Painful Vaso-Occlusive crises: Pain in large joints, muscle, abd. pain, back pain, knee, shoulder, elbow. Priapism Seen in children after the age of 3-4 years Swelling, tenderness, decrease of ROM at site of pain. Pain triggers: stress, infection, menses, trauma, change of weather. Aplastic Crisis: Decrease of RBC production due to decrease of Hb/Retic Count. Parvovirus B-19 (mc) Anemia (hemolysis), Fatigue, pallor, decrease retic. Other Ds: Meningitis, Osteomyelitis (Salmonella), Sepsis (mcc-death)

41. LAB: Hemoglobin Electrophoresis is definitive diagnosis: Absence of hemoglobin A Presence of hemoglobin S with mild elevation of hemoglobin F Sickle cell anemia: Hgb-S 85-98% Hgb-F 2-20% Hgb A2 0-2% Sickle Cell trait has Hgb-S of 40% and Hgb-A of 60% CBC: low Hb (6-10gm/dL)/Ht presence of sickle cells/ Howell-Jolly Bodies on peripheral smear Increase WBC, Platelets Reticulocytes: elevated (5-15%) X-Ray: evidence of osteolysis, periostitis, bone reabsoption. Bone Scan: differentiate bone infarction from osteomyelitis Chemistry: LDH- ↑ , AST- ↑ Unconjugated bilirubin- ↑

42. TX: * Hydroxyurea- decrease number and severity of pain crises. *Pain: NSAID’S or narcotics (Demerol or Morphine Sulfate) *VOC ( vaso occlusive crisis)- fluids (Hydration), Oxygen, warmth. *Blood transfusion (packed RBC) during aplastic or sequestration crises (fall in hb) *Ceftriaxone, Cefuroxime: S. Pneumonia, H. influenza *Erythromycin: Mycoplasma Pneumonia * PCN prophylaxis: after 3 months: oral PCN 125mg BIDqd up to 2 years after 2 years: 250mg BID until 5-6 years *Pneumoccocal vaccine (after 2y), influenza virus vaccine, Hib/ Hep-B vaccine specially in patients with splenectomy *Bone marrow transplantation. *Genetic counseling

45. Peripheral blood smear of a child with hemoglobin SC disease. Sickle cells are seen less frequently in this disease, whereas target cells are more prominent.

49. Thalassemia Are hereditary anemias as a result of mutations affecting the synthesis of hemoglobin. Normal Hb is a tetramer of 2 alpha and 2 beta chains. - Alpha Thalassemia: decrease or total lack of alpha globin sysnthesis - Beta Thalassemia: Decrease or lack of beta globin sysnthesis. Pathophisiology: Several mutations in alpha and beta globin genes lead to various different phenotypes of alpha/beta Thalassemia, leading to varying levels of anemia depending on the gene defect Clinical Classification: Silent carrier (alpha/Beta): hematologically normal Thalassemia trait (alpha/beta): mild anemia w/ microcytosis, hypochromia Alpha Thalassemia Ds: severe hemolytic anemia, jaundice, splenomegaly B-Thalassemia Ds major (Cooley anemia): severe anemia, H/Smegaly, growth ↓

50. Epidemiology: Alpha Thalassemia: Asian, African, Afro-American people Beta Thalassemia: Mediterranean countries, Mideast, India, Pakistan S/S: Onset in first year of life May present with signs of CHF due to severe anemia Pallor, Hepatosplenomegaly, Jaundice Chipmunk facies in Beta thalassemia due to facial bone expansion by hyperthrophic marrow Growth retardation with FTT Prognosis: Life expectancy improved with regular transfusions and chelation therapy. Also a Bone Marrow transplant from a histocompatible sibling donor gives long term survival

51. LAB: CBC for anemia with low MCV, MCH, MCHC ( ↓ in ά / β ) Hb 9-10 g/dl – Thalassemia trait Hb 6-7g/dl - in alpha Thalassemia Hb less than 5 g/dl in thalassemia major Presence of Basophilic stiplings Peripheral Smear: Mycrocitosis, hypochromia Mild aniso/poikilocytosis in Thalassemia Trait Severe aniso/poikilocytosis in alpha and major (beta) Target cells, Teardrop cells, Polychromasia Reticulocytes: elevated in Thalassemia syndromes Indirect Bilirubin: Increased in severe Thalassemia Serum ferritin elevated in transfused Beta Thalassemia Hemoglobin Electrophoresis: Alpha Thalassemia Trait : 2 defective genes. 90% HbA Alpha Thalassemia Ds: 3 defective genes. 5-30% alpha thalassemia, remainder HbA Beta Thalassemia Trait: HbF 1%-5%, HbA2 3.5-8%, remainder HbA Beta Thalassemia Major: HbF 20-100%, HbA2 2-7%, HbA 0-80%. In most cases, HbA is not detected.

52. TX: Silent carriers alpha/beta: genetic counseling only Alpha disease: Folic acid Transfusions when necessary Splenectomy if evidence of hypersplenism Beta Thalassemia major: Transfusions of RBC every 3-4 weeks to maintain Hb at 9-10 g/dl Serum Ferritin, TIBC, Transferrin saturation, LFT: test every 3 months. Chelation therapy with Desferroxamine , avoiding iron overload Splenectomy if transfusion require more than 200 ml/kg/year Folic acid daily Penicillin prophylaxis to all splenectomised patients Pneumococcal/HIB vaccine prior to splenectomy Bone Marrow transplantation using sibling donor

53. Thalassemia major. A- This peripheral blood smear in a child with thalassemia major shows a hypochromic, microcytic anemia with prominent nucleated red blood cells surrounding the PMN cells and lymphocytes. B- Labeled schematic of peripheral blood smear.

54. A- Maxillary hyperplasia resulting from an increased marrow space in a child with thalassemia major. B- Skull R-X of the same patient demonstrates an increased marrow cavity of the skull and facial bones.

55. Idiopathic Thrombocytopenic Purpura (ITP) Thrombocytopenia 2ary to ↑ destruction of platelets by circulating anti-platelets antibody. ITP is the most common acquired platelet disorder Classified as : Acute- remission in less than 6 months Chronic- remission more than 6 months Etiology: Viral illness ( varicella, mumps, rubella, Mono) 65% Epidemiology: Incidence 4-8/100.000 under 15 years. Males=females Peak age: 2-5 years. Younger than 1 year or over 10 years are more likely to develop chronic ITP Pathophysiology: Immune mechanism- autoantibodies to foreign antigen SIGNS: Most cases is preceded by a viral infection 1-3 weeks before onset. Onset is acute in children, with overnight develop/ of petecchia, purpura. Presence of unusual bruises, urine/stool blood, epistaxis, gum bleeding Recent immunizations (MMR). Drug history affecting platelets: ASA, heparin, seizure meds.

56. S/S: Clusters of petecchia, or large bruises on skin Purpura in the oropharinx, dry blood or clots in the nares Fundoscopic exam is important LAB: CBC: Normal WBC/Hb with Thrombocytopenia PT/PTT: Normal Bleeding Time: prolonged Peripheral Smear: Normal, except Thrombocytopenia Bone Marrow: Normal or increased megakaryocytes. only if treating with Steroids and exclude leukemia TX: - IV Corticoids. Then oral steroids 2 mg/d for 2-4 weeks - IV Immunoglobulin (IVIG): 1g/kg/d

57. HEMOPHILIA Inherited bleeding disorder caused by the absence or severe deficiency functioning of plasma coagulation factor VIII or IX. Hemophilia A: deficiency of factor VIII Hemophilia B (Christmas disease): deficiency of factor IX Epidemiology: Distribution: Hemophilia A: 80-85% Hemophilia B: 15-20% Incidence: Hemophilia A: 1/5000 male births Hemophilia B: 1/25,000 male births Hemophilia A defective gene is carried on the X chromossome Inherited as sex-linked recessive disorder; males are affected, females are carriers Rarely, a girl is born with hemophilia. It happen if her father has hemophilia and her mother is a carrier. Males born to a woman that is a carrier, has 50% risk of having the Ds. Some males with the disorder are born to mothers who aren’t carriers. In these cases, a mutation occurs in the gene as it is passed to the child.

58. Pathophysiology: Thrombin generation delayed in patients with absent/reduced factor VIII/IX There is delayed formation of a fibrin clot, and severity of the disorder, is determined by the level of clotting factor def.: Mild hemophilia 5–30 percent of normal factor Moderate hemophilia 1–5 percent of normal factor Severe hemophilia Less than 1 percent of normal factor S/S: Neonatal period: Bleeding from circumcision site Hematoma after injections Infancy and Childhood: Bleeding spontaneously after trauma, GI, teeth eruption, epistaxis Deep soft tissue bleeding , easy bruising Hemarthrosis (knees, elbow, ankles) occuring after a trauma Joint examination: Acute Hemarthrosis: motion limitation of the joint, warmth, swelling, tenderness, decrease ROM, proximal muscle weakness

59. LAB: Hemophilia A: Factor VIII- Decreased Platelet count- Normal Bleeding Time, Prothrombin Time, Fibrinogen: Normal (A)PTT (activated partial thromboplastin Time): Prolonged 2-3 times normal Hemophilia B: Factor IX- Decreased (A)PTT- Prolonged Platelet Count, Bleeding Time, Fibrinogen- Normal

60. TX: Hemophilia A: - Factor VIII replacement products: * Recombinant non- plasma derived viral inactivated factor VIII concentrate * Monoclonal purified plasma derived viral inactivated factor VIII concentrate *Cryoprecipitate. Risk of Hep. B, C, D. Use in extreme cases - DDAVP (Desmopressin acetate): stimulates release of endogenous factor VIII Only for mild or moderate factor VIII deficiency. IV or intranasal spray - Antifibrinolytic Therapy: For oral mucosa bleeding, dental extractions *Epsilon aminocaproic acid 50 -100 mg/kg dose PO q6 or Tranexamic acid Adjuvant therapy for hemarthrosis: Immobilization, RICE, splints, casts

61. Inheritance Pattern for Hemophilia—Example 1 The diagram shows one example of how the hemophilia gene is inherited. In this example, the father doesn't have hemophillia (that is, he has two normal chromosomes—X and Y). The mother is a carrier of hemophilia (that is, she has one abnormal X chromosome and one normal X chromosome). Each daughter has a 50 percent chance of inheriting the abnormal gene from her mother and being a carrier. Each son has a 50 percent chance of inheriting the abnormal gene from his mother and having hemophilia.

62. Inheritance Pattern for Hemophilia—Example 2 The diagram shows one example of how the hemophilia gene is inherited. In this example, the father has hemophilia (that is, his X chromosome is abnormal). The mother isn’t a carrier of hemophilia (that is, she has two normal X chromosomes). Each daughter will inherit the abnormal gene from her father and be a carrier. None of the sons will inherit the abnormal gene from their father, and, therefore, none will have hemophilia.

63. TX: Hemophilia B: Factor IX concentrate infusion that also contains factors II,VII,X Viral inactivated factor IX concentrate Prophylaxis: Avoid trauma in sports, good dental hygiene, Immunizations Never give Aspirin, Nsaid’s- Interferes with platelet function

66. VON WILLEBRAND DISEASE Autosomal dominant disorder resulting from a defective Von Willebrand Factor, causing ineffective platelet adhesion. Decrease in vWF, will reduced Factor VIII-R Epidemiology: Affects Males/females same proportion. Occurs in 1/500 births Genetics: Type I: Follow a dominant inheritance pattern Type II: Heterozygous patients have been described Type III: Follow a recessive inheritance pattern S/S: Mucocutaneous bleeding, epistaxis, gum bleeding, menorrhagia, bruises In severe vWF, manifestations as Hemophilia A (hemarthrosis)- Type III Type I/II has mild symptoms, often are undetected

67. LAB: Bleeding Time: Prolonged vWF/VIII factor: Decreased PT, Platelet count: Normal aPTT: Mildly/moderately Prolonged Ristocetin cofactor activity: Decreased ( !!! ) induced vWF bind to platelets TX: Avoid heavy contact sports / Aspirin Type-I: DDAVP (Desmopressin acetate) IV/Intranasal. Release factor VIII Humate-P: viral attenuated vWF containing Factor VIII concentrate Avoid Cryoprecipitate- is not virally attenuated (inactivated) HIV/Hep-B infection risk Aminocaproic Acid: For oral cavity bleeding Hepatitis B vaccine given prior to exposure to plasma derived product

68. ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) Malignant disorder of lymphoblasts occurring in Bone Marrow as a result of clonal proliferation of a single lymphoblast that undergone malignant change Etiology: -Unknown -Exposure to ionizing radiation-Chemicals -Viral infections: HTLV I associated with adult T cell leukemia HTLV II associated with hairy cell leukemia -Immunodeficiencies -May be classified as B or T cell Epidemiology: -Most common Cancer of childhood. 75% is ALL -Incidence: peak incidence: 2-5 years old. Common in whites/boys.

69. S/S: Are due to infiltration of leukemic cells into normal tissues resulting in: - Bone Marrow failure (anemia, neutropenia, thrombocytopenia) - Specific tissue infiltration (lymph nodes, liver, spleen, brain, bone, gonads-testicular enlargement) Fever, Petecchia, weight loss, irritability, fatigue, pallor, bruising Bone pain, limp, tenderness, arthralgia - 90% long bones Lymph nodes enlargement, hepatosplenomegaly CNS involvement: Headache, vomiting, seizures, papilledema Sternal tenderness (bone marrow infiltration) Thrombocytopenia: Petecchia, ecchymosis, subconj/retina hemorrhage

71. LAB: CBC: WBC-Vary from 5000-100,000 average < 10,000 in 50% of cases 10,000-50,000 in 35% of cases Anemia: Hb < 7.5g/dL in 60% Neutropenia: < 500/mm3 Thrombocytopenia: < 100,000/mm3 in 75 % of cases < 20,000- 20% 20,000/100,000 - 55% Bone Marrow aspirate: > 25% leukemic lymphoblasts is diagnostic CFS fluid: Check for lymphoblats and increased PROTEIN, decreased GLUCOSE. X-Ray: Chest- check for anterior mediastinal mass Long Bones-multiple punctate osteolytic lesions Others: Coagulation panel: PT, PTT, fibrinogen Liver, renal and fluids panel, LDH Presence of Philadelphia chromossome is a bad prognostic sign Sudan Black stain- Negative

72. TX: Is according to risk groups: 4 phases of Therapy Induction: To achieve remission (< 5% of blasts in BM). Usually 3-4 drugs: Vincristine, Prednisone, L-asparaginase w/wo Doxorubicin, Intratecal metotrexate. Consolidation and CNS prophylaxis: To prevent CNS disease. Intrathecal metotrexate w/ oral 6-mercaptopurine (6MP)/MTX-standard risk Intrathecal metotrexate w/ cranial radiation, oral 6MP/MTX-High risk pt. Delayed intensification: To further decrease leukemic burden. Vincristine, Metotrexate, L-Asparaginase, Doxorubicin, Cyclophosphamide Cytosine Arabinoside (ARA-C), 6-Thioguanine (6-TG), Intrathecal MTX Maintenance: -Daily oral 6MP -Weekly MTX and monthly pulses of Vincristine and prednisone -Intrathecal metotrexate for 2,5-3 years

73. CNS Leukemia at diagnosis: -Cranial Radiation -Triple intrathecal (MXT, ARA-C, Hydrocortisone) in addition to Tx Bone Marrow transplant to be considered for relapsed patients. Supportive Care: Hydration, Avoid vigorous exercices Alkalization with NaHCO3 to keep urine pH 6.5 Blood/Platelet transfusions Broad spectrum ATB for fever and infections. Atb for Pneumocystis No live vaccine during treatment, Avoid vigorous exercises Prognosis: 70% with ALL achieve long term survival Risk factors for poor prognosis = age < 1 year or >10 years, WBC >100,000, CNS disease, Mediastinal mass

74. Swelling of the cervical lymph nodes

75. Disseminated Petecchya

76. Triad: Pallor-cutaneous hemorrhages- swelling of lymph nodes in a 3 year old girl Five days later: extensive cranial hemorrhage, and oral mucosa. Mickulicz syndrome: swelling on infiltration of the lacrimal, salivary and parotid gland

77. Bone Marrow aspirate in ALL child

78. ACUTE MYELOID LEUKEMIA Is a clonal proliferation of malignant myeloblasts. Etiology: -Exposure to ionizing radiation -Exposure to Benzene -Exposure to alkylating agents:-Cyclophosphamide -Chlorambucil -Nitrogen mustard Exposure to Epipodophyllotoxins: -VP 126/-VM 26 Epidemiology: 15-20% of childhood acute leukemia is AML Ratio AML to ALL= 1:4. Boys/girls affected equally Leukemia in first 6 weeks of life is AML Worse prognosis than ALL

79. S/S: Fever, Pallor, fatigue, weakness, bleeding, bruising, recurrent Inf. Bone pain (less than ALL), CNS Sx rare. Bone tenderness, purpura Hepato/Splenomegaly, Gengival hypertrophy, Petechia, ↑ lymph LAB: CBC: Normocytic normochromic anemia WBC > 10,000 Neutrophils, Platelets, Monocytes: Decreased Peripheral Smear: Myeloblasts are seen. AUER rods pathognomonic for AML Bone marrow Aspirate: Hypercellular with 30% myeloblasts, Cytochemistry: Blasts are positive for myeloperoxidase/ Sudan black PT, PTT: Increased. Fibrinogen: Decreased (DIC) CSF cytology: > 5 WBC/mm3  CNS Ds. X-RAY: Bone destruction and periosteal elevation

80. TX: Most effective drugs for remission in AML: Induction: Anthracyclines: Doxorubicin, Daunomycin Cytosine-Arabinoside (ARA-C) with or without 6-thioguanine (6TG) Dexamethasone. All drugs produces transient bone marrow aplasia. Consolidation: therapy usually with: ARA-C and L-Aspariginase Intrathecal ARA-C for CNS prophylaxis Maintenance: with VP16, ARA-C, 6TG, Daunomycin, Dexamethasone. Duration of therapy is usually 6-9 months. Allogeneic Bone Marrow transplant is best Tx for AML in remission. Supportive care: Hydration, alkalization of urine, and Allopurinol during induction. Broad spectrum ATB (Pneumocystis) Nystatin/Fluconazole -Fungal

82. HODGKIN LYMPHOMA Malignant enlargement of lymph nodes characterized by a cellular infiltrate with multinucleated giant cells (REED-STERNBERG cells) Epidemiology: Bimodal age distribution: Early, between 15 / 30 years and after 50 years Childhood cases: rare before 8 years old There is a 3:1 male predominance in childhood Hodgkin disease. Etiology: Familial clustering, suggests the role of both genetic and environmental (radiation, infection) factors Pathophysiology: Exact cause is unknown. Reed-Sternberg cells are the malignant cells of Hodgkin lymphoma. They may originate from a activated B/T lymphocytes or from antigen-presenting cell. Rye Classification: Lymphocyte predominant- Mixed cellularity, Lymphocyte depleted- Nodular sclerosis.

83. S/S: Fatigue, anorexia, weight loss, unexplained fever, night sweats Painless, firm lymphadenopathy (confined to 1or 2 nodes areas, Supraclavicular and Cervical nodes) Mediastinal lymphadenopathy causes cough or difficulty to breath. Hepatosplenomegaly and bone tenderness in advanced stages. LAB: CBC: Leukocytosis, eosinophilia ESR / Serum copper level: Elevated Cellular immunity (cutaneous antigen testing): Anergy Patient is predispose to infections: protozoal (Pcp, toxo), fungal, viral (V.Z Baseline Thyroid function (pre-radiotherapy) Echo, PFT, Liver (LDH), Renal Function tests Definitive diagnosis is BIOPSY of lymphnodes

84. Imaging: Chest X-ray (PA/Lateral)  look for mediastinal mass. !!! for staging CT scan (chest, abdomen, pelvis)  R/O metastasis. !!! for staging CT or MRI of Spine  Symptoms of cord compression suspected. Special Tests: Bone Marrow Biopsy Gallium Scan: Detects residual disease in mediastinum Bone scan: Evaluates Bone involvement (Optional) ANN ARBOR STAGING CLASSIFICATION: I- Involvement of a single lymph node region II- Two or more lymph node regions on the same diaphragm side III- Lymph node regions on diaphragm both sides with spleen involve/ IV- Diffuse or disseminated involvement of one or more extra-lymphatic organs or tissues with or without associated lymph node involvement

85. TX: Radiotherapy: Dosis administered in fractions 5 times/week Chemotherapy: Multiple agents allow different mechanism of action. Follow-Up: Monthly CBC CT scan every 3 months for 2 years, then every 6 months for 3 Ys. Prognosis: With Chemo and Radiotherapy, a five year survival ranges from: 88-100% in low stage disease 54-94% in advance stage disease

86. NON HODGKIN LYMPHOMA Is a malignant proliferation of cells of lymphocytic or histiocytic lineage Burkit Tumor- Monoclonal tumor of lymphoblasts type B Epidemiology: Incidence of 1-1,5/100,000 children Peak age: 7-11 years, Ratio of 3:1 M/F , Genetic predisposition Environmental factor: Drugs (immunosuppressive), Radiation, Virus (EBV ) Pathophysiology: NHL can be divided in 3 categories: *Small noncleaved-cell lymphoma: 40% of childhood NHL. Variety of B- cell markers are present *Lymphoblastic lymphoma: 40% of childhood NHL. Predominantly of thymocyte (T-cell origin) *Large-cell lymphoma: 20% of childhood NHL. They are of B-cell origin.

87. S/S: 1) B-cell lymphomas: Abdomen, head, neck Fever, weight loss, anorexia, fatigue, Lump in neck, abdominal mass with pain, swelling, nausea or vomiting, and change in bowel habits. Small non-cleaved cell lymphoma: Abdominal mass- ileocecal region, appendix ascending colon. Intussusception in children over 6 years, GI bleeding. Affects also testis, parotid gland. 2) T-cell lymphomas: Mediastinum Mediastinal tumor symptoms: cough, hoarseness, dyspnea, orthopnea, chest pain, headache, blurred vision, syncope Painless ↑ of the cervical, supraclavicular, and axillary nodes are associated with an anterior mediastinal tumor. Lymphoblastic lymphoma: Mediastinal mass with pleural effusions and lung infection with or without SVC (swelling, plethora, cyanosis of face and neck, diaphoresis, stridor and wheezing).

88. LAB: CBC, Liver and Renal function studies Bone marrow aspiration and biopsy (GS) Lumbar puncture with CSF cytology Cytogenetics and immunophenotyping of tumor Tissue Biopsy for definitive diagnosis and staging St. Jude Children’s Research Hospital Staging System Stage I- One Tu. (extranodal) or single nodal area, excluding mediastinum or abd Stage II- Single tumor with regional nodal involvement, two or more tumors or nodal areas on one side of the diaphragm, or a primary GI tu. with or without regional node involvement. Stage III- Tumors or lymph node areas on both sides of diaphragm, or any primary paraspinal or epidural tumors Stage IV- Bone marrow or CNS diseases regardless of other sites

89. Imaging: Chest X-ray PA/Lateral Bone Scan Abd. U/S CT abdomen, Chest and pelvis MRI TX: Depends on the staging of the tumor Radiotherapy, chemotherapy, surgery, bone marrow transplant Prognosis: Depends on Tumor infiltration/treatment initialized at diagnosis.

90. Burkitt Lymphoma