HAEMATOLOGYAnemia:

1. Definition: hg% < 2 standard deviations below the mean for age with2. Classification of anemia:I. Etiologic classification i. 1. Impaired RBC production ii. 2. Excessive destruction iii. 3. Blood loss ii. Ii. Morphologic classification i. 1. Macrocytic anemia ii. 2. Microcytic hypochromic anemia iii. 3. Normochromic normocytic anemiaiii. Types of RBCs1.Normocytic 2.Microcytic 3. Macrocytic

IRON D EFICIENCY ANAEMIA1.Normal daily iron requirement:1. 1 mg /day is the daily requirement2. Only 10% is absorbed from the gut3. Hence 10 mg is the daily requirement2.Causes so iron deficient anemia: 30% of world population is anemicNewborn:1. Early cord clamping < 2 mts.2. Blood samplingInfants:1. Milk has less iron2. Lack of cereal diet3. Cows milk allergry4. Peptic ulcer5. Meckels diverticulitis6. Rectal polyp7. Hemaangioma8. Chronic diarrhea Adolescents:1. Growth spurt2. Menstrual loss3. Iron chelators- eg. Tea4. Iron deficient food- faddism5. Peptic ulcer6. Hook warm7. Helicobacter pylori infection of stomach3. Symptoms: 1. Chronic anemia is compensated2. Acute or severe anemia: symptoms develop 3. Pallor4. Tiredness, easy fatigability and irritability5. Generalized muscle weakness 6. Phagophagia and pica7. School failure8. Loss of hair9. Cardiac de compensation4. Physiological anemia of infancy: 1. Fetus lives in sterile condition and less need for wbc 2. Lives in hypoxic condition and hence need for RBCs more3. Site of production of RBC from fetus to nb:a. Yolk sac (mesoblastic erythropoiesis)b. Liver (hepatic erythropoiesis)c. Bone marrow ( myeloid erythropoiesis)4. Normal values in NB: 1. Newborn:I. Pcv: 45-65%II. Reti. Count: 2-8%III. Hb: 16-18gm%2. 6-8 weeks (Physiological anemia of infancy)i. Hb: 10 gm%ii. Pcv 30% 3. Causes of physiological anemia:i. Decreased RBC life spanii. Decreased eryhtropoietin iii. Rapid increase in body weight 5. Lab tests: 1. HB%2. Pcv3. Serum ferritin 4. Serum iron5. Iron binding capacity6. Blood smear study7. Stool occult blood8. Bone marrow6. Differential diagnosis of Microcytic hypochromic anemia: 1. Iron deficiency2. Hemoglobinopathiesa. Thalassemia ( and ) b. Hemoglobin Leporec. Hemoglobin Hd. Hemoglobin E3. Disorders of heme synthesis caused by a chemicala. Leadb. Pyrazinamidec. Isoniazid4. Sideroblastic anemias 5. Chronic infections or other inflammatory states6. Malignancy7. Hereditary orotic aciduria8. Hypotransferrinemia:a. Congenitalb. Acquired:1. hepatic disorders; 2. malignant disease, 3. protein malnutrition (decreased transferrin synthesis), 4. nephrotic syndrome (urinary transferrin loss)9. Copper deficiency10. Inborn error of iron metabolismCongenital defect of iron transport to red cells7. Lab diagnosis:1. Iron deficiency anemia: 1. Blood smear: Hypochromic microcytic red cells, confirmed by RBC indices:2. MCV less than acceptable normal for age 3. MCH less than 27.0 pg4. MCHC less than 30%5. Wide red cell distribution width (RDW) greater than 14.5%6. Free erythrocyte protoporphyrin: elevated7. Serum ferritin: decreased8. Serum iron and iron binding capacity9. Decreased serum iron10. Increased iron-binding capacity11. Decreased iron saturation (16% or less)2. Lab: Differential Diaosis:NoDiseaseLab findings

2- and -thalassemia traitRDW (Red cell distribution width) is elevated in iron deficiency and normal in - and -thalassemia trait

4-thalassemia (or thalassemia major)Pronounced erythroblastosis and severe hemolytic component

5-thalassemia traitnormal results of iron studies (including ferritin), normal levels of Hb A2and Hb F, and a normal hemoglobin electrophoresis

6Hb H disease -another form of -thalassemia Hb H is readily identified by hemoglobin electrophoresis.

7The anemia of chronic disease (ACD) and infectionNormocytic,

8Lead poisoningCoarse basophilic stippling of the RBCs often is prominent. Elevated blood lead, and urinary coproporphyrin levels are seen

8. Treatment of iron deficiency anemia1. Oral administration of simple ferrous salts (e.g., sulfate, gluconate, fumarate) provides inexpensive and satisfactory therapy. 2. A daily total dose of 46 mg/kg of elemental iron in 3 divided doses; abdominal discomfort can be minimized by administering iron with food3. A parenteral iron preparation (iron dextran): response to parenteral iron is no more rapid or complete than that obtained with proper oral administration4. Milk consumption should be limited to 500 mL (1 pint)/24 hr 5. Iron fortification:a. Iron deficiency can be prevented in high-risk populations by providing iron-fortified formula or cereals during infancy. 6. Adolescent girls:a. Iron deficiency in adolescent females secondary to abnormal uterine blood flow loss is treated with iron and hormone therapy7. Response to treatment:a. Within 7296 hr after administration of iron to an anemic child, peripheral reticulocytosis is noted followed by a rise in the hemoglobin level, which may increase as much as 0.5 g/dL/24 hr. Iron medication should be continued for 8 wk after blood values are normal. 8. Blood transfusion: In general, severely anemic children with hemoglobin values 1520% of the cells when hemolytic anemia is present. 5. Erythroid hyperplasia is evident in the marrow aspirate or biopsy. 6. Osmotic Fragility Test:a. The presence of spherocytes in the blood can be confirmed with an osmotic fragility test. b. The RBCs are incubated in progressive dilutions of an iso-osmotic buffered salt solution. c. Exposure to hypotonic saline causes the RBCs to swell, and the spherocytes lyse more readily than biconcave cells in hypotonic solutions. d. This feature is accentuated by depriving the cells of glucose overnight at 37C, known as the incubated osmotic fragility test.e. This test is abnormal in immune and other hemolytic anemias. f. A normal test result also may be found in 1020% of patients.7. Molecular diagnosis also is possible. Most patients have family-specific private mutations that can be detected by DNA analysis.Management:1. Anemia is treatd by blood transfusion2. Splectomy is the cure THALASEMIAS1. Thalassemia Syndromes: 1. Thalassemias are genetic disorders in globin chain production with varying degrees of ineffective hematopoiesis and increased hemolysis.2. There are four genes for -globin synthesis ( HBA1 gene and HBA2 gene two on each chromosome 16). Most -thalassemia syndromes are due to deletion of one or more of the -globin genes rather than to point mutations 2. There are two HBB genes for -globin synthesis(chromosome 11); -thalassemias are due to point mutations in one or both of the two -globin genes.2. EPIDEMIOLOGY:1. 3% of the world's population carries genes for -thalassemia, and in Southeast Asia, 510% of the population carries genes for -thalassemia3. PATHOPHYSIOLOGY:1. Gene mutations leading to decreased production of globin chains either alpha or beta with variable severity is the basic defect2. In thalassemia inadequate -globin production leads to decreased levels of normal hemoglobin (Hb A), and an imbalance in - and -globin chain production3. In bone marrow:1. Thalassemic mutations disrupt the maturation of red blood cells, resulting in ineffective erythropoiesis in the following way:2. In -thalassemias, there is an excess of -globin chains and less of - and -globin chains; 3. Excess -globin chains have tendancy to join with eacfh other to form -globin tetramers (4) 1. -globin tetramers (4) again have affinity to enter red cells with intracellular precipitation of insoluble -chains. They interact with the young red cell membrane and shorten red cell survival, leading to hemolysis.2. This in turn leads to anemia and a compensatory increase in erythroid production and expansion of bone marrow. 3. When the -globin chains are produced in less amounts there is relative increase in the production of and -globin chains for which the genes are normal.4. Now there is plenty of , and -globin chains, leading to an elevated Hb F (22) and Hb A2(22) in -thalassemia. 5. In RBCs:1. thalassemia: 1. Low levels of Hb A2. More Hb F3. More Hb A22. thalassemia:1. More Barts Hb (4) and Hb H (4)2. HbF can is less and hence death in fetal period is common.4.Demographics: i. Found most frequently in the Mediterranean, Africa, Western and Southeast Asia, India and Burmaii. Distribution parallels that of Plasmodium falciparum iii. Abnormal Hb in RBC leads to resistance to malaria and while people with normal gene die of malaria epidemics those with abnormal genes survive.5.Thalassemia types:1. - thalassemia: 1. There are four genes for -globin synthesis (two on each chromosome 16). 2. Most -thalassemia syndromes are due to deletion of one or more of the -globin genes rather than to point mutations.3. Types:1. Silent trait: deletion of 1 -globin gene 2. -thalassemia trait: deletion of 2 -globin genes 3. Hb h disease: deletion of 3 -globin genes 4. - thalassemia major: deletion of all 4 -globin genes causes profound anemia during fetal life, resulting in hydrops fetalis2. Beta thalasemia: 1. Most -thalassemias are due to point mutations in one or both of the two -globin genes in chromosome 11.2. -Thalassemia1. 0 Thalassemia: No detectable -chain synthesis due to absent -chain gene 2. + Thalassemia: Reduced -chain synthesis due to reduced or non-functional -chain gene 3. -Thalassemia: - and -chain genes deleted4. E-Thalassemia: Hemoglobin E (lysine-glutamic acid at 26) combined with -thalassemia mutation. May be 0 or 1.5. Hb Lepore: a fusion globin due to unequal crossover of the - and -globin genes (the globin is produced at a low level because it is under -globin regulation).1. Clinical types:1. Major - homozygous2. Minor (trait) - heterozygous3. Intermedia: combination of -thalassemia mutations (0/+, 0/variant, E/0)3. Hereditary persistentce of fetal hemoglobin (HPFH).

Thalassemia Major- Cooleys anemia:1. Pathogenesis1. Variable reduction of -chain synthesis 2. Relative -globin chain excess 3. ineffective erythropoiesis and rbcs are prematurely destroyed; 4. Shortened red cell life span 2. Clinical:1. A spectrum of clinical severity (major, minor and intermedia)2. Failure to thrive in early childhood3. Anemia4. Jaundice, usually slight; 5. Gallstones6. Hepatosplenomegaly, which may be massive; 7. Hypersplenism8. Bone abnormalities:i. Abnormal facies, ii. prominence of malar eminences, iii. frontal bossing, iv. depression of bridge of the nose and v. exposure of upper central teethvi. Skull radiographs showing hair-on-end appearance due to widening of diploic spaces vii. Fractures due to marrow expansion and abnormal bone structureviii. Generalized skeletal osteoporosis.9. Growth retardation, delayed puberty, primary amenorrhea in females and other10. Endocrine disturbances secondary to chronic anemia and iron overload11. Leg ulcers12. Skin bronzing.13. If untreated, 80% of patients with beta thalassemia major die in the first decade of life.14. With current management, the life expectancy has dramatically increased.Patients now reach the fifth decade of life and are expected to live even longer.1. Complications: 1. Chronic anemia may lead to CCF 2. Iron overload Due to repeated red cell transfusions and increased absorption of dietary iron.Even in carefully managed patients, the following complications may develop:I. Endocrine disturbances (e.g., growth retardation, pituitary failure with impaired gonadotropins, hypogonadism, insulin-dependent diabetes mellitus, adrenal insufficiency, hypothyroidism, hypoparathyroidism)II. Cirrhosis of the liver and liver failure (exacerbated if concomitant hepatitis B or C infection is present)III. Cardiac failure due to myocardial iron overload (often associated with arrhythmias and pericarditis may occur)IV. Osteopenia and osteoporosis are common and the risk is directly proportional to V. Pulmonary hypertension (tricuspid regurgitant jet velocity greater than 2.5 m/s) occurs in both -thalassemia major and -thalassemia intermedia. Splenectomy may exacerbate this risk, particularly in patients who are not regularly transfused.Causes of Death1. Congestive heart failure.2. Arrhythmia.3. Sepsis secondary to increased susceptibility to infection post-splenectomy.3. Lab findings 1. Elevated HbF and A2 in Hb electrophoresis2. Severe anemia 500 U/L) correlate with tumor mass 6. The St. Jude staging system defines tumor extent, which is important for designing treatme. a. Stage I applies to localized disease, b. Stage II to regional disease c. Stage III to extensive disease, and d. Stage IV to disseminated (CNS and/or bone marrow) disease. 7. DD:a. Head and neck lymphadenopathy should be differentiated from infectious nodal etiologies; b. Mediastinal masses from Hodgkin and germ cell tumors; c. Abdominal involvement from Wilms tumor, neuroblastoma, and rhabdomyosarcoma; d. Bone marrow involvement from lymphoblastic leukemia 8. Treatment and Prognosis:a. The primary modality of treatment for childhood and adolescent NHL is multiagent systemic chemotherapy and intrathecal chemotherapy. b. Surgery is used mainly for diagnostic and/or biologic specimens and staging but rarely is used for debulking large masses. c. Radiation therapy is rarely, if ever, used, except in special circumstances such as CNS involvement in LL or occasionally BL, acute SVC, and acute paraplegias. d. Common regimens include COPAD (cyclophosphamide, vincristine, prednisone and doxorubicin or COMP (cyclophosphamide, vincristine, methotrexate, 6-mercaptopurine and prednisone). e. Advanced disease usually is treated by 46 mo of multiagent chemotherapy f. Intrathecal chemotherapy is administered to moderate to advanced disease in all subtypes of childhood and adolescent NHL and may include intrathecal methotrexate, hydrocortisone, or Ara-C9. Prognosis:a. The prognosis is excellent for most forms of childhood and adolescent NHL. b. Patients with localized disease have a 90100% chance of survival, and patients with advanced disease have a 6095% chance of survival.

LEUKEMIAS Definition 1. A group, of malignant diseases in which a genetic abnormality in hematopoietic cells gives rise to clonal proliferation of maliganat cells:2. Classification:I. Acute leukemias constitute 97% of all childhood leukemias and consist of the following types:i. Acute lymphoblastic leukemia (ALL) 75%ii. Acute myeloblastic leukemia (AML), also known as acute nonlymphocytic leukemia (ANLL) 20%iii. Acute undifferentiated leukemia (AUL) ,0.5%iv. Acute mixed-lineage leukemia (AMLL).II. Chronic myeloid leukemias constitute 3% of all childhood leukemias and consist of:i. Philadelphia chromosome positive (Ph1 positive) myeloid leukemiaii. Juvenile myelomonocytic leukemia (JMML).4. Leukemias are common malignancy in pediatrics; 41% of all malignancies < 15 years; 4.1 % per 100 000 children annually

ACUTE LYMPHOBLASTIC LEUKEMIA ALL1.Epidemiology:1. ALL 77%; AML 11%; CML 2-3%; rest unclassified2. Age: 2-6 years; More in males3. Higher incidence in:a. Downb. Bloomc. Fanconi d. Turnere. Klinefilter n. Ataxia telangiectasia (Immune deficiency)o. 100% monozygotic; 50% in dizygotic twins2.Etiology1. Unknown2. Radiation : in utero, diagnostic, therapeutic 3. Epstein Barr virus?4. Advanced maternal age5. Alkylating agents6. Benzene3.Pathogenesis: a. Malignant transformation of a single clone of cells belonging to lymphoid series due to a genetic damage to DNA; b. This is followed by proliferation of affected clonec. Chromosomal translocation: e.g: Philadelphia Chromosome t (9;22) d. Surface markers:i. 85% are derived from B cellsii. 15% from T cells4. ALL Morphologic Classification - The French-American-British (FAB) Cooperative Working GroupL 1: Lymphoblats: 85% 1. Small cells2. High nucleus-to-cytoplasm ratio 3. Indistinct nucleoli 4. Cytoplasm is scanty L 2: Lymphoblast - 14 %1. Larger, often in a more 2. Heterogeneous population, with a3. Lower nucleus-to-cytoplasm ratio4. Prominent nucleoliL3 Lymphoblasts 1 % 1. Heterogeneous group of cells2. Deeply basophilic cytoplasm 3. Prominent cytoplasmatic vacuolization. 5.Philadiphia chromosome1. The ABL gene on chromosome 9 is mistakenly transferred to chromosome 22 and attaches to the BCR gene.2. This creates a new fusion gene called BCR-ABL which leads to leukemic process.7.Clinical features 1. General Systemic Effects1. Fever (60%).2. Lassitude (50%).3. Pallor (40%).2. Hematologic Effects Arising from Bone Marrow Invasion1. Anemia causing pallor, fatigability, tachycardia, dyspnea and sometimes congestive heart failure.3. Neutropenia causing fever, ulceration of buccal mucosa and infection.3. Thrombocytopenia causing petechiae, purpura, easy bruisability, bleeding from mucous membrane and sometimes internal bleeding (e.g., intracranial hemorrhage).4. Clinical Manifestations Arising from Lymphoid System Infiltration1. Lymphadenopathy sometimes presents with bulky mediastinal lymphadenopathy causing superior vena cava syndrome. More common in T-cell leukemia in adolescents.2. Splenomegaly.3. Hepatomegaly.5. Clinical Manifestations of CNS Invasion1. Signs and symptoms of raised intracranial pressure 2. focal neurologic signs such as hemi paresis, cranial nerve palsies, convulsions, 3. cerebellar involvement ataxia,dysmetria, hypotonia, hyperflexia)4. Hypothalamic syndrome (polyphagia with excessive weight gain, hirsutism and behavioral disturbances)5. Diabetes insipidus (posterior pituitary involvement)6. Chloromas of the spinal cord (very infrequent in ALL) may present with back pain, leg pain, numbness, weakness, BrownSequard syndrome and bladder and bowel sphincter problems7. CNS hemorrhage 6. Genitourinary Tract Involvement: 1. Testicular Involvement: painless enlargement of the testis.2. Ovarian Involvement: Occurs very rarely.3. Priapism: Occurs rarely. It is due to leukemic infiltrates or by the coagulation of the platelet-rich leukemic blood in the corpora cavernosa.7. Renal Involvement1. Occasionally may present with hematuria, hypertension and renal failure.8. Gastrointestinal Involvement1. The most common manifestation is bleeding.2. Infilotrayion of cecum, giving rise to typhlitis.9. Bone and Joint Involvement1. Bone pain is one of the initial symptoms 2. X ray: Transverse metaphyseal radiolucent bands10. Skin Involvement: Besides signs of bleeding maculopapular skin infiltration often of a deep red color (leukemia cutis) can be observed;11. Cardiac Involvement: leukemic infiltrates and hemorrhage of the myocardium or the pericardium.12. Lung Involvement: Large mediastinal mass in adolescent boys with T cell leukemia8 Diagnosis 1. Blood counta. Hemoglobin: Moderate to marked reduction. b. Normocytic; normochromic red cell morphology. c. White blood cell count: Low, normal, or increasedd. Blood smear: Blasts are present on blood smear. When the white blood cell (WBC) count is greater than 10,000/mm3, blasts are usually abundant. e. Eosinophilia is seen uncommonly in children with ALL; 20% of patients with AML have an increased number of basophilsf. Thrombocytopenia: 92% of patients have platelet counts below normal.2. Bone marrow: a. Bone marrow is usually replaced by 80100% blasts. b. Megakaryocytes are usually absent. c. Leukemia must be suspected when the bone marrow contains more than 5% blasts. d. Lymphoblast: The hallmark of the diagnosis of acute leukemia is the blast cell, a relatively undifferentiated cell with diffusely distributed nuclear chromatin, one or more nucleoli and basophilic cytoplasm. Special bone marrow studies, which help in detailed cell classification, include the following:e. Special bone marrow studies, which help in detailed cell classification, include the following:a. Histochemistryb. Immunophenotypingc. Cytogenetics.3. X-Ray:1. Chest radiograph: Mediastinal mass in T-cell leukemia.2. X ray long bones:a. Periosteal elevationb. Growth arrest lines4. Blood chemistry: Increase in LDH, uric acid, liver function tests, immunoglobulin levels.5. Cerebrospinal fluid: Chemistry and cells. Cerebrospinal fluid findings for the diagnosis of CNS leukemia require:1. Presence of more than 5 WBCs/mm32. Identification of blast cells on cytocentrifuge examination.6. Coagulation profile: Decreased coagulation factors that frequently occur with AML are: hypofibrinogenemia, factors V, IX and X.7. Cardiac function: Electrocardiogram (ECG) and echocardiogram.8. Immunologic screening: Serum for immunoglobulin levels, C3 and C4.9. Abd.Us:1. Kidney infiltartion 2. Intra abdominal lymphadenopathy 9. Classification of ALL: Acute leukemia is classified based on:1. Morphologic characteristics, 2. Cytochemical features, 3. Immunologic characteristics and 4. Cytogenetic and molecular characteristics.5. The World Health Organization has developed a new classification of ALL based on cytogenetic and molecular characteristics a. Morphologic classification:1. Morphologic subtyping of the various forms of ALL used to be done according to the French-American-British (FAB) classification. The FAB classification: ALL-L1: small uniform cells ALL-L2: large varied cells ALL-L3: large varied cells with vacuoles (bubble-like features) 2. The recent WHO International panel on ALL recommends that this classification be abandoned, since the morphological classification has no clinical or prognostic relevance. It instead advocates the use of the immunophenotypic classification mentioned below.b. Immunophenotyping:1. Blast cells are classified by determining the surface markers of the abnormal lymphocytes, called immunophenotyping. 2. There are 2 main immunologic types: pre-B cell and pre-T cell. 3. The mature B-cell ALL (L3) is now classified as Burkitt leukemia/lymphoma (BL). 4. Phenotypically, surface markers show that about 85% of cases of ALL are derived from progenitors of B cells, about 15% are derived from T cells, and about 1% are derived from B cells. 5. Subtyping helps determine the prognosis and most appropriate treatment in treating ALL.c. Cytogenetic classification:1. With current methods, more than 90% of cases of childhood ALL demonstrate cytogenetic (chromosomal) abnormalities either in number (ploidy) or structure. 2. Ploidy: abnormal number of chromosomes in blast cells:1. Approximately 40% of cases are pseudodiploid;2. Another 40% are hyperdiploid 3. Fewer than 2% of cases are hypodiploid (fewer than 45 chromosomes). 3. Structural abnormalities in blastcells:1. Among the structural abnormalities, translocations are the most common and occur in 40% of cases. 13. D.D:1. Chronic infections by Epstein-Barr virus (EBV) and cytomegalovirus (CMV), cause lymphadenopathy, hepatosplenomegaly, fevers, and anemia. 2. Prominent petechiae and purpura suggest a diagnosis of immune thrombocytopenic purpura. 3. Significant pallor could be caused by autoimmune hemolytic anemias, or aplastic anemia.4. Fevers and joint pains, with or without hepatosplenomegaly and lymphadenopathy, suggest juvenile rheumatoid arthritis (JRA). Serum LDH levels may help distinguish JRA from leukemia, as the LDH is usually normal in JRA.5. An elevated WBC count with lymphocytosis is typical of pertussis; however, in pertussis the lymphocytes are mature, and neutropenia is rarely associated.14. Prognostic Factors:1) The disease is invariably fatal without treatment.2) Favourable prognostic factors are: 1. Age 1 to 10 yrs; 2. Female child3. WBC count < 25,000/L4. French-American-British (FAB) L1 morphology5. hyperdiploid ALL 5. t (12;21) translocation6. No CNS disease at diagnosis7. Good speed of response to treatment3) Unfavourable factors 1. Age < 1 year.2. Mature T cell ALL3. A leukemic cell karyotype with chromosomes that are normal in number but abnormal in morphology (pseudodiploid)4. Translocations involving 11q23 5. Hypodyploid ALL 6. Presence of the Philadelphia: t(9;22)7. Increased age in adults8. B-cell immunophenotype 9. The presence of CNS disease at diagnosis: 10. Minimal residual disease (MRD) present at the end of consolidation therapy4) Risk groups 1. Standard (low) risk: a. Children aged 1 to 10 years b. White blood cell count of less than 50,000/mL at diagnosis.c. Generally includes two-thirds of pre-B ALL patients, have a 4-year event-free survival of 80%.2. High risk: a. Children younger than 1 year or older than 10 years b. White blood cell count of 50,000/ml or more at diagnosisc. Chromosomal abnormalities such as t(9;22) or t(4;11),d. Have a 4-year event-free survival of 65%.15. Treatment:1. Supportive care:a. Correction of dehydration and anemia b. Treatment of sepsisc. uric acid nephropathy are prevented by allopurinol 10 mg/kg/day in divided doses together with a fluid intake of 23 L/m2/day.d. Live vaccines are contraindicated; inactivated vaccine should be employede. Psychosocial support of child and family2. Treatment of Newly Diagnosed Acute Lymphoblastic Leukemia:a. International standard protocols for treatment of Leukemias:1. Childrens Cancer and Leukaemia Group (CCLG), 2. Children's Cancer Group (CCG)3. Paediatric Oncology Group (POG). 4. Recently, these two groups have joined together to form the largest group - Children's Oncology Group (COG). 5. There are many ongoing trials6. Most favorable and successful trial will later become a standard protocolb. Goals of treatment:1. To induce a clinical and hematologic remission 2. To maintain remission by systemic chemotherapy and prophylactic CNS therapy 3. To treat the complications of therapy and of the diseasec. Dfinitions:1. A complete remission is defined as:1. Complte regression of symptoms including CNS 2. A normal blood count, with minimal levels of 500/mm3 granulocytes, 75,000/ mm3 platelets and 12 g/dl hemoglobin with no blast cells seen on the blood smear3. A moderately cellular bone marrow with a moderate number of normal granulocytic and erythroid precursors, together with adequate megakaryocytes and less than 5% blast cells. 2. Relapse is defined by the appearance of any of the following: 1. Progressive repopulation of blasts in excess of 5%, 2. More than 25% blasts in the bone marrow and 2% or more circulating lymphoblasts 3. Leukemic cell infiltration in CNS or gonads (biopsy proven) d. Therapy for Standard-Risk ALL: Treatment duration is 2.5 years. The 6-year event-free survival for this protocol was 86.6% with an overall survival of 97.2%.1. The 4 general phases of chemotherapy for ALL include: 1. Induction of remission: 2. Post remission consolidation or intensification:3. CNS prophylaxis:4. Maintenance:e. Remission induction:1. Treatment is for 4 weeks2. Weekly vincristine : 1.5 mg/m2/iv3. Prednisolone 40 mg/m2/oral/divided dose or oral dexamethasone for 28 days (6 mg/m2/day in three divided doses),4. L-Asparaginase 10 000 U/m2/IM biweekly or a single dose of a long-acting, pegylated asparaginase5. Daunomycin weekly for high risk cases6. For T-cell ALL, intravenous cyclophosphamide may be added during induction.f. CNS prophylaxis: i. Triple intrathecal therapy e.g.for 2 yr old child; Weekly for 6 weeks followed by every 2 months for 2 yearsa. Methtrexate 10 mgb. Hydrocortisone 10 mgc. Cytosine arabinoside 10 mgii. CNS irradiation: craniospinal irradiation for high risk groupsg. Consolidation (1 month):a. Oral 6-mercaptopurine (75 mg/m2/d on days 128 of consolidation), b. IV vincristine (1.5 mg/m2 on day 1) and c. Age-adjusted intrathecal methotrexate on days 1, 8 and 15 for patients without CNS disease at diagnosis. h. Maintenance (girls, 20 months; boys, 32 months):1. Dexamethasone (6 mg/m2/day on days 0 to 4, 28 to 32 and 56 to 60),2. oral mercaptopurine (75 mg/m2/day on days 0 to 83), 3. IV vincristine (1.5 mg/m2 on days 0, 28 and 56), 4. weekly oral methotrexate (20 mg/m2 beginning on day 7 of each course) and age-adjusted intrathecal methotrexate on day 0 of each course16. Prognosis 1. 5 year survival is 80% with aggressive therapy2. Minimal residual Disease:a. Refers to the burden of leukemic cells at end of inductionb. It has a prognostic valuec. High MRD at the end induction suggests a poor prognosis3. Other treatment options:a. Bone marrow transplantb. Stem cell transplant

ACUTE MYELOGENOUS LEUKEMIA (AML)Incidence: 11 % of childhood leukemiaEtiology:1. Ionizing radiation2. Alkylating agents3. Syndromes:1. Trisomy 212. Fanconi Anemia3. Bloom syndrome4. Diamond-Blackfan syndrome 5. Neurofibromatosis Type I4. Children who live near nuclear power plants or high-voltage power lines5. The risk of AML was slightly increased in people who smoked compared with those who did not smoke. 6. Antecedent hematologic disorders that predispose patients to AML include:1. Aplastic anemia, 2. Myelofibrosis, 3. Paroxysmal nocturnal hemoglobinuria4. Polycythemia vera5. myelodysplastic syndromeEpidemiology 1. Acute myeloid leukemia affects all races nearly equally. 2. Male and female distributions are nearly equal 3. More in the first year of life and the incidence increases in adulthoodPathogenesis 1. Acute myeloid leukemia is most commonly associated with the development of fusion genes resulting from chromosome translocations. 2. Multiple genetic mutations are required for the complete leukemic transformation.Clinical features 1. Hemorrhage due to thrombocytopenia2. Fever due to infections3. Infiltration may manifest as adenopathy, hepatomegaly and splenomegaly. 4. Mediastinal mass may cause symptoms of respiratory insufficiency or superior vena cava syndrome5. Abdominal masses obstruct the GI or urogenital tracts. 6. Nodules of myeloblasts, called chloromas, in the skin, orbit, CNS or any other organ. 7. Monoblastic leukemia is often associated with gingival hyperplasia 8. Weight loss and cachexia are unusual 9. Bone pain is less common in patients with acute myelocytic leukemia 10. Compression fractures cause back pain and dysfunction of the lower extremity 11. Elevated intracranial pressure, 12. Visual complaints. 13. Involvement of cranial nerves, most often the facial nerve and the abducens nerve 14. Intracranial hemorrhage 15. Splenomegaly is sometimes massive16. Typhlitis can mimic signs of appendicitis17. Severe anemia may lead to congestive heart failure. 18. Skin nodules are firm, raised, and often bluish-purple in color- blueberry muffinWork up1. Anemia is usually normocytic 2. Platelet counts are less than < 20,000/l 3. WBC counts may be decreased or elevated. 4. Hyperleukocytosis with WBC counts of more than >100,000/l 5. Primitive granulocyte or monocyte precursors are observed on peripheral smears. 6. Numbers of mature neutrophils are usually diminished. 7. Serum uric acid and lactic dehydrogenase levels are elevated 8. Serum muramidase (lysozyme) levels are increased 9. Evidence of disseminated intravascular coagulation 10. Auer rods:1. Auer rods (thin, needle-shaped eosinophilic cytoplasmic inclusions) in blast cells 2. Auer rods can be seen in the blasts of acute myeloid leukemia3. They are composed of fused lysosomes and contain peroxidase, lysosomal enzymes Imaging: 1. Chest radiography to rule out mediastinal masses2. Metaphyseal bands at the distal femurs Bone marrow: hyperplastic marrow with monotonous sheets of leukemic blasts. FAB classification:M0Minimally differentiated acute myeloblastic leukemia

M1Acute myeloblastic leukemia, without maturation

M2Acute myeloblastic leukemia, with granulocytic maturation

M3Acute promyelocytic leukemia (APL)

M4Acute myelomonocytic leukemia

M4eoMyelomonocytic together with bone marrow eosinophilia

M5Acute monoblastic leukemia

M6Acute erythroid leukemias

M7Acute megakaryoblastic leukemia

M8Acute basophilic leukemia

Treatment:The Children's Oncology Group (COG): Induction Remission: 2 cycles of induction therapy with infusions of daunomycin, cytosine arabinoside, etoposide (ADE therapy). Maintenance: sequential cycles of chemotherapy are administered by using combinations of :1. Cytosine arabinoside and etoposide, 2. Mitoxantrone and cytosine arabinoside, and, finally, 3. High-dose cytosine arabinoside with L-asparaginase. Supportive:1. Marrow transplant2. Stem cell transplant3. Transfusion support 4. Management of Hyperkalemia and hyper phosphatemia with associated hypocalcemia 5. Broad-spectrum antibacterial, antiviral, and antifungal antibiotics;

Classification of Platelet DisordersCongenital:1. May-Hegglin anomaly2. Wiskott-Aldrich syndromeAcquired1. Thrombocytopenicquantitative platelet deficiency1. Autoimmune or idiopathic thrombocytopenia purpura2. Thrombotic thrombocytopenia purpura3. Cytotoxic chemotherapy4. Drug-induced (eg, quinine, quinidine, gold salts, trimethoprim/ sulfamethoxazole, rifampin5. Disseminated intravascular coagulation2. Nonthrombocytopenic - qualitative or functional platelet defect:1. Drug-induced (eg, aspirin, NSAIDs, penicillin, cephalosporins)2. Uremia3. Alcohol dependency4. Liver diseaseThrombocytopeniaThe normal platelet count is 150 to 450 109/L. Thrombocytopenia refers to a reduction in platelet count below 150 109/L. Causes of thrombocytopenia include: (1) Decreased production on either a congenital or an acquired basis, (2) Sequestration of the platelets within an enlarged spleen or other organ, (3) Increased destruction of normally synthesized platelets either on an immune or a nonimmune basis.

IDIOPATHIC THROMBOCYTOPENIC PURPURA The most common cause for acute onset of thrombocytopenia in an otherwise well child is (autoimmune) idiopathic thrombocytopenic purpura (ITP)Etiology 1 to 4 wk after exposure to a common viral infection, a small number of children develop an autoantibody directed against the platelet surface. A preceding history of a viral illness is described in 50-65% of cases of childhood ITP Virtually every common infectious virus has been described in association with ITP, including Epstein-Barr (EBV) and HIV.Clinical Manifestations1. previously healthy 1-4 yr old child who has the sudden onset of generalized petechiae and purpura2. bleeding from the gums and mucous membrane may be present3. The physical examination is normal other than the finding of petechiae and purpura4. Splenomegaly is rare5. Spontaneous resolution of their ITP will occur within 6 mo. 6. Less than 1% of cases develop intracranial hemorrhage7. 10 to 20 percent of children who present with acute ITP go on to develop chronic ITP. ( >6 mo duration)Laboratory Findings1. platelet count < 20 109/L2. The hemoglobin may be decreased if there have been profuse nosebleeds or menorrhagia3. white blood cell (WBC) count, and differential count should be normal4. The bone marrow: normal granulocytic and erythrocytic series with normal or increased numbers of megakaryocytes5. An antinuclear antibody (ANA) test is positive in adolescents with ITP who may go in for chronic ITP6. HIV studies should be done in at-risk populations, especially sexually active teens. 7. Platelet antibody testing is seldom useful in acute ITP. 8. A Coombs test should be done if there is unexplained anemia to rule out Evans syndrome (autoimmune hemolytic anemia and thrombocytopenia9. Bleeding timea. The bleeding time assesses the function of platelets and their interaction with the vascular wall. b. A blood pressure cuff is applied to the upper arm and inflated to 40 mm Hg for children and adults. c. After the incision with the bleeding time device, blood is blotted from the margin of the incision at 30 sec intervals until bleeding ceases.d. Although each laboratory must establish its own normal range, bleeding usually stops within 4-8 min.Differential Diagnosisa. Drug-dependent antibodies, b. Splenic sequestrationc. Aplastic processes such as fanconi anemiad. Hemolytic-uremic syndrome, e. Disseminated intravascular coagulationf. Autoimmune thrombocytopenia may be an initial manifestation of SLE, HIV, or lymphomag. Wiskott-aldrich syndrome: young males; low platelet counts, eczema and recurrent infectionsTreatmenta. Platelet transfusion in ITP is contraindicted unless life-threatening bleeding is presentb. Intravenous immunoglobulin (IVIG). IVIG in a dose of 0.8-1 g/kg/day 1-2 daysc. 1-4 mg/kg/24 hr for 2-3 wk of prednisolone appear to induce a more rapid rise in platelet countsd. IV Anti- D Therapy 50 g/kg have demonstrated a rise in platelet count e. Splenectomy a. Indications:a. The older child (4 yr) with severe ITP that has lasted longer than 1 yr (chronic ITP) b. whose symptoms are not easily controlled with therapy c. life-threatening hemorrhage (intracranial hemorrhage) b. Splenectomy is associated with a lifelong risk of overwhelming post-splenectomy infection caused by encapsulated organismsc. Before splenectomy the child should receive pneumococcal vaccine, and after splenectomy he or she should receive penicillin prophylaxis for a number of years

Disseminated Intravascular Coagulation (Consumptive Coagulopathy)

Consumption of clotting factors, platelets, and anticoagulant proteins.widespread intravascular deposition of fibrin leading to tissue ischemia and necrosis, a generalized hemorrhagic state, and hemolytic anemiaEtiologya. Hypoxia, acidosis, tissue necrosis, shock, and endothelial damage, may trigger DIC.b. septic shock (especially meningococcemia), incompatible blood transfusions, rickettsial infections, snakebite, purpura fulminans, giant hemangioma, and malignancies, especially acute promyelocytic leukemiac. clotting consumes both the physiologic:I. Anticoagulants (protein C, protein S, antithrombin III) II. Procoagulants, resulting in a deficiency of factor VIII, factor V, prothrombin, fibrinogen, and platelets. d. The clinical result of this sequence of events is hemorrhageClinical Manifestationsa. Bleeding from sites of venipuncture or surgical incision.b. The skin may show petechiae and ecchymoses. c. Tissue necrosis may involve infarction of large areas of skin, subcutaneous tissue, or kidneys.d. Anemia caused by hemolysis may develop rapidly owing to microangiopathic hemolytic anemiaLaboratory Findingsa. Factors (II, V, VIII, and fibrinogen) and platelets may be consumed by the ongoing intravascular clotting process, b. Prolongation of the prothrombin, partial thromboplastin, and thrombin times. c. Platelet counts may be profoundly depressed.d. The blood smear may contain fragmented, burr, and helmet-shaped red blood cells (schistocytes). e. Fibrinogen degradation products (FDPs, d-dimers) appear in the bloodTreatmenta. Treat the trigger that caused the DIC b. Restore normal homeostasis by correcting the shock, acidosis, and hypoxia that usually complicate the DICc. Platelet infusions (for thrombocytopenia),d. Cryoprecipitate (for hypofibrinogenemia), e. Fresh frozen plasma (for replacement of other coagulation factors) f. Heparin at a dose of 5-10 U/kg/hr without a loading dose may be used for those with acute promyelocytic leukemia. g. Heparin is not indicated and has been reported to be ineffective in septic shock, snake envenomation, heat stroke, massive head injury, and incompatible blood transfusion reaction, unless there is clear evidence of vascular thrombosis.h. The heparin is usually started together with clotting factor and platelet replacement

Hemolytic-uremic syndrome

Most common cause of acute renal failure in young children; characterized by triad:a. microangiopathic hemolytic anemia,b. thrombocytopenia, and c. Uremia.Etiologya. Toxin-producing escherichia coli precedes 80% or more of HUSb. Shigella, salmonella, campylobacter, streptococcus pneumoniae, bartonella) and c. Viral (coxsackievirus, echovirus, influenza, varicella, hiv, epstein-barr) infections. d. Oral contraceptives, mitomycin, cyclosporine e. SLE, malignant hypertension, preeclampsia, postpartum renal failure, and radiation nephritis. f. Occurrence in more than one member of a family suggests some genetic predisposition Pathologya. Glomerular changes include thickening of the capillary walls, narrowing of the capillary lumens, and widening of the mesangium. b. Electron microscopy shows these changes to be the result of subendothelial and mesangial deposition of a granular, amorphous material of unknown origin.c. Fibrin thrombi can be found in glomerular capillaries and arterioles and may lead to cortical necrosis.Pathogenesis.a. The primary event in pathogenesis of the syndrome appears to be endothelial cell injury. b. The microangiopathic anemia results from mechanical damage to the red blood cells (rbcs) as they pass through the altered vasculaturec. Thrombocytopenia is caused by intrarenal platelet adhesion or damageClinical manifestationsa. Hus is most common in children < 4 yr.b. Preceded by a gastroenteritis characterized by fever, vomiting, abdominal pain, and diarrhea that is often bloodyc. Sudden onset of pallor, irritability, weakness, lethargy, and oliguria usually occurs 5-10 days after the initial gastrointestinal or respiratory illnessd. Physical examination may reveal edema, petechiae, hepatosplenomegaly, and marked irritability.Diagnosis and differential diagnosisa. The hemoglobin value is commonly in the range of 5-9 g/dlb. Plasma hemoglobin levels are elevatedc. Coombs test result is negative.d. The leukocyte count may increase to 30,000/mm3. e. Thrombocytopenia (20,000-100,000/mm3)f. Low-grade microscopic hematuria and proteinuriag. Partial thromboplastin time and prothrombin time are usually normalComplications include a. Anemia, b. Acidosis, c. Hyperkalemia, d. Fluid overload, e. Heart failure, f. Hypertension, and g. UremiaPrognosis and treatmenta. Peritoneal dialysis: a. Controls fluid and electrolyte abnormalities,b. Maintains a normal intravascular volume, c. Contribute to the dissolution of vascular thrombi by removing fibrinolysis inhibitors and circulating plasminogen activating inhibitor-1, thereby promoting endogenous fibrinolytic pathways.b. A silicon dioxide-derived univalent absorbent that binds shiga toxin within the intestinal lumen, suggested a reduction in the risk of developing HUS in children when given within 3 days of the onset of a diarrheal prodrome. c. More than 90% of patients survive the acute phase of HUS with a diarrheal prodrome with aggressive management.d. End-stage renal disease occurs in approximately 9% of these patients

Haemophilia A (factor VIII deficiency) & B (factor XI deficiency)Introduction:1. Haemophilia is a group of hereditary genetic disorders that impair the body's ability to control blood clotting or coagulation 2. Haemophilia A: clotting factor VIII deficiency; is the most common;1 in 5,00010,000 male 3. Haemophilia B: factor IX deficiency; 1 in about 20,00034,000 male births..4. Hemophilia C: reduced levels of factor XI; an autosomal deficiency;mild to moderate bleeding CausesGenetics:1. Haemophilia A:a. It is a recessive X-linked genetic disorder involving a lack of functional clotting Factor VIII and represents 80% of haemophilia cases. b. Female carriers can inherit the defective gene from either their mother or father, or it may be a new mutation. c. Only under rare circumstances do females actually have haemophilia. Eg. XO Turner.d. spontaneous mutations are common.2. Haemophilia B:a. It is a recessive X-linked genetic disorder involving a lack of functional clotting Factor IX. It comprises approximately 20% of haemophilia cases.3. Haemophilia C:a. It is an autosomal genetic disorder (i.e. not X-linked) involving a lack of functional clotting Factor XI. Haemophilia C is not completely recessive: heterozygous individuals also show increased bleeding.Clinical: 1. The hemostatic level for factor VIII is >3040%, and for factor IX, it is >2530%. The lower limit of levels for factors VIII and IX in normal individuals is approximately 50%.2. In hemophilia A or hemophilia B, clot formation is delayed and is not robust. Thus, patients with hemophilia do not bleed more rapidly. There is, instead, a slowing of the rate of clot formation. 3. When untreated bleeding occurs in a closed space such as a joint, cessation of bleeding may be the result of tamponade. With open wounds, in which tamponade cannot occur, profuse bleeding may result in significant blood loss. 4. Occasionally, neonates with hemophilia may sustain intracranial hemorrhage. 5. But, surprisingly, only about 30% of affected male infants with hemophilia bleed with circumcision. 6. Bleeding from minor traumatic lacerations of the mouth may persist for hours or days 7. Haemorthrosis:a. The hallmark of hemophilia is the hemarthrosis. b. Bleeding into joints may be induced by minor trauma; but may be spontaneous. c. The earliest joint to suffer is the ankle, because of the lack of stability of this joint as the toddler assumes an upright posture.d. In the older child and adolescent, hemarthroses of the knees and elbows are the most debilitating. e. Patients with severe hemophilia often develop a "target" joint where repetitive episodes of bleeding occur. 8. Patients may lose large volumes of blood into the iliopsoas muscle with inability to extend the hip and symptoms of shock. 9. Life-threatening bleeding in the hemophilic patient is caused by bleeding into vital structures (central nervous system, upper airway) or by exsanguination (external, gastrointestinal, or iliopsoas hemorrhage). 10. Patients with mild hemophilia may experience prolonged bleeding only after dental work, surgery, or injuries from moderate trauma.Complications1. Joint damage from haemarthrosis, 2. Transfusion transmitted infection from blood transfusions 3. Adverse reactions to clotting factor treatment, 4. Intracranial haemorrhage is a serious medical emergency DIFFERENTIAL DIAGNOSIS. In young infants with severe bleeding manifestations, the differential diagnosis includes:a. Severe thrombocytopenia; b. Severe platelet function disorders, such as bernard-soulier syndrome and glanzmann thrombasthenia; c. Type 3 (severe) von willebrand disease; d. Vitamin K deficiency. Laboratory Findings:a. Activated partial thrompoblastin time: In severe hemophilia, this APTT is usually two to three times the upper limits of normal. b. The other screening tests of the hemostatic mechanism, platelet count, bleeding time, prothrombin time, and thrombin time are normal. c. vWF activity will be normald. Unless the patient has an inhibitor to factor VIII, the mixing of normal plasma with patient plasma results in correction of the PTT. If correction does not occur on mixing, an inhibitor may be present.e. The specific assay for factor VIII and factor IX will confirm the diagnosis of hemophilia. Management:Hemophilia Aa. The prevention of trauma is important b. Aspirin and other nonsteroidal anti-inflammatory drugs that affect platelet function should be avoided c. Immunizatin against hepatitis B virus d. Periodic screening for hepatitis and abnormalities in liver function.e. REPLACEMENT THERAPY:i. When bleeding occurs, levels of factor VIII or IX must be raised to hemostatic levels (35-40 U/dL) and for life-threatening or major hemorrhages to 100 U/dL (100%). ii. Prophylaxis has been recommended for severe haemophilia to prevent spontaneous bleeding and early joint deformitiesiii. Augmentation of Factor VIII release in mild haemophilia: The patient's endogenously produced factor VIII can be released by the administration of desmopressin acetate; Hemophilia Bi. The mainstay of treatment in hemophilia B is exogenous factor IX. Therefore, 1 U/kg of plasma-derived factor IX concentrate or recombinant factor IX is expected to increase plasma factor IX activity by approximately 1%. Hemophilia C:a. Treatment includes infusion of fresh frozen plasma (FFP); b. Platelet transfusion may also be useful for acute hemorrhage in patients with deficiency of platelet-associated factor XI. c. Desmopressin has been used in some cases. d. The prognosis for an average life span in patients with factor XI deficiency is excellent.Prophylaxis:a. Prophylactic treatment is usually provided every 2-3 days to maintain a measurable plasma level of clotting factor (1-2 U/dL) b. Because gene therapy may be available within the lifetime of paediatric patients, keeping joints normal through prophylaxis is important. Chronic Complications: a. Chronic joint destruction due to bleeding into joints.b. The risk of HIV and Hepatitis C or B, due to multiple transfusions c. The development of an inhibitor to either factor viii or factor ix. d. Factor IX therapy has also resulted in nephrotic syndrome in some patients.Prognosis:1. Prior to the 1960s average life expectancy was only 11 years.2. Today with appropriate treatment, males with haemophilia typically have a near normal quality of life with an average lifespan approximately 10 years shorter than an unaffected male

VON WILLEBRANDS DISEASEI. Epidemiology:a. Von Willebrand disease (VWD) is the most common hereditary bleeding disorder, and is present in 1-2% of the general population. b. VWD is inherited autosomally, but most centers report more women than men being affectedc. Because menorrhagia is a major symptom, it may cause more women to seek diagnosis. II. Classification:a. The protein is quantitatively reduced but not absent (type 1), b. Qualitatively abnormal (type 2), c. Absent (type 3)III. VWF:a. vWF is a large glycoprotein that is synthesized in megakaryocytes and endothelial cells as pre-pro-vWF. Sequential cleavage releases mature vWF which undergoes multimerization and is stored in specific cellular storage granules in endothelial cells and the granule in platelets. VWF is released from these storage sites into the plasma, where it circulates. It has two major physiologic roles.i. As a carrier protein for the procoagulant cofactor FVIII. This has the consequence that low levels of VWF result in correspondingly low levels of FVIII ii. It has an essential role in platelet adhesion, platelet aggregation and eventual platelet plug formation.IV. Clinical features:a. Patients with VWD usually have symptoms of mucocutaneous hemorrhage, including excessive bruising, epistaxis, menorrhagia, and postoperative hemorrhage, particularly after mucosal surgery such as tonsillectomy or wisdom tooth extraction. b. teenager's menstrual history is abnormal c. Because VWF is an acute-phase protein, stress will increase its level. Thus, patients may not bleed with procedures that incur major stress, such as appendectomy and childbirth, but may bleed excessively at the time of cosmetic or mucosal surgery. d. Bruising symptoms may diminish during pregnancy, because the VWF levels may double or triple during pregnancy. V. Treatment of VWD:a. Desmopressin therapy:i. The most common form of VWD is type 1. In these patients the synthetic drug desmopressin (DDAVP) induces the release of VWF from the endothelial cells. ii. A small subset of children and adults, especially infants, fail to release VWF in response to DDAVP. In these circumstances replacement therapy must be used. b. Replacement therapy:i. Replacement therapy uses plasma-derived VWF containing concentrates that also contain factor VIII. ii. These will be useful in presurgical management or in prophylaxis. iii. When used for acute bleeding, however, these VWF concentrates may need to be supplemented by an infusion of recombinant factor VIII for the first infusion.

LYMPHADENOPATHYLymphadenoapathy:a. Lymphadenopathy: abnormal in either size, consistency or numberb. They are not considered enlarged until their diameter exceeds 1 cm for cervical and axillary nodes and 1.5 cm for inguinal nodes. Adenopathy in the supraclavicular and epitrochlear regions >.5 cm are usually pathologicc. "generalized: enlarged in two or more noncontiguous areas d. regional" if only one area is involved.Etiology:1. Lymphadenopathy might be caused by proliferation of cells:a. Intrinsic to the node, such as lymphocytes, plasma cells, monocytes or histiocytes or b. By infiltration of cells extrinsic to the node, such as neutrophils and malignant cells. 2. Reactive hyperplasia, defined as a polyclonal proliferation of one or more cell types 3. Lymphadenopathy is also a presenting sign of malignancies such as leukemia, lymphoma, Epidemiology 1. Adenopathy in childhood vary from 38-45%, and lymphadenopathy is one of the most common clinical problems encountered in pediatrics2. (3.2 percent) required a biopsy, (1.1 percent) had a malignancy. Etiology of Generalized Lymphadenopathy I. Nonspecific reactive hyperplasia (polyclonal)II. InfectionA. Bacterial:Staphylococcus, streptococcus, anaerobes, tuberculosis, atypical mycobacteria, Bartonella henselae (cat scratch disease, brucellosis, Salmonella typhi, diphtheria, C. trachomatis lymphogranuloma venereum), calymmatobacterium granulomatis, francisella tularensisB. Viral:EpsteinBarr virus, cytomegalovirus, adenovirus, rhinovirus, coronavirus, respiratory syncytial virus, influenza, coxsackie virus, rubella, rubeola, varicella, HIV, herpes simplex virus, human herpes virus 6 (HHV-6)Protozoal:Toxoplasmosis, malaria, trypanosomiasisD. Spirochetal:Syphilis, rickettsia typhi (murine typhus)E. Fungal:Coccidioidomycosis (valley fever), histoplasmosis, cryptococcus, aspergillosisF. Postvaccination:Smallpox, live attenuated measles, DPT, Salk vaccine, typhoid feverIII. Malignant etiologies The acute leukemias: Acute lymphoblastic leukemia (ALL) Acute myeloblastic leukemia (AML). Lymphomas More often present with regional lymphadenopathy, but generalized lymphadenopathy occurs. IV. Storage diseases: Niemann-pick disease: Sphingomyelin and other lipids accumulate in the spleen, liver, lymph nodes, and CNS. Gaucher disease:The accumulation of the glucosylceramide leads to the engorgement of the spleen, lymph nodes, and the bone marrow. Additional findings: hepatosplenomegaly and developmental delay; diagnoses are established by leukocyte assay. IV. Drug reactions: Phenytoin, Pyrimethamine, Phenylbutazone, Allopurinol, Isoniazid. V. Other non neoplastic disorders:Langerhans cell histiocytosis Epstein-Barr virus (EBV)- VI. Autoimmune etiologies:Juvenile rheumatoid arthritis, Sarcoidosis ; SLEGraft verses host disease Clinical evaluation 1. Size: > 2.5-3 cm granulomas and cancer2. Site: i. epitrochlear: cancer; syphilisii. cervical or axillary adenopathy: cat-scratch disease , iii. infectious mononucleosis : cervical adenopathy iv. sexually transmitted diseases - inguinal adenopathyv. right supraclavicular node : cancer in the mediastinum, lungs or esophagus. vi. The left supraclavicular (Virchow's) node: testes, ovaries, kidneys, pancreas, prostate, stomach or gallbladder. 3. Pain and tenderness: pyogenic4. Consistency:i. Stony-hard nodes: cancerii. Firm, rubbery nodes: lymphoma.iii. Softer nodes: infections or inflammationiv. Fluctuant: abscessv. Shotty: viral illnesses. 5. Matting. Tuberculosis, sarcoidosis or lymphogranuloma venereum or malignant (e.g., metastatic carcinoma or lymphomas). Generalized lymphadenopathy:1. Mononucleosis-type syndromes1. Epstein-Barr virus: lymphadenopathy, fatigue, malaise, fever and an increased atypical lymphocyte count; positive results on a heterophilic antibody test (Monospot test) confirms the diagnosis2. Other causes of the mononucleosis syndrome: identified with IgM and Ig M serology1. Toxoplasmosis, 2. Cytomegalovirus infection, 3. Streptococcal pharyngitis, 4. Hepatitis b infection and 5. Acute human immunodeficiency virus (hiv) infection.2. Ulceroglandular syndrome1. This syndrome is defined by the presence of a skin lesion with associated regional lymphadenopathy. 2. The classic cause is tularemia, acquired by contact with an infected rabbit or tick; 3. More common causes include streptococcal infection (e.g., impetigo), cat-scratch disease and Lyme disease3. Oculoglandular syndrome1. This syndrome involves the combination of conjunctivitis and associated preauricularnodes. 2. Common causes include viral kerato-conjunctivitis and cat-scratch disease resulting from an ocular lesion.4. Hiv infection1. Enlargement of the lymph nodes that persists for at least three months in at least two extrainguinal sites is defined as persistent generalized lymphadenopathy and is common in patients in the early stages of HIV infection. Evaluation 1. Blood count and erythrocyte sedimentation rate2. EBV: heterophilic antibody test (Monospot test)3. Skin testing for tuberculosis4. Bacteriologic culture of regional lesions (e.g., throat)5. serologic tests for:Bartonella henselae (IFA), syphilis (VDRL) toxoplasmosis, cytomegalovirus (CMV), human immunodeficiency virus (HIV),6. Chest radiograph and CT scan (if necessary); abdominal sonogram and CT, if indicated7. EKG and echocardiogram if Kawasaki disease is suspected8. Lymph node aspiration and culture; 9. Fine needle aspiration cytology; 10. Bone marrow examination if leukemia or lymphoma is suspectedIndications for Biopsy 1. Persistent or unexplained fever, weight loss, night sweats 2. Hard nodes, or fixation of the nodes to surrounding tissues3. Increase in size over baseline in 2 wk4. No regression to normal in 812 wk, 5. If new signs and symptoms develop. 6. Initial physical examination and history suggest malignancy7. size is > 2.5 cm in absence of signs of infection8. Supraclavicular adenopathy.Choice of node:1. Upper cervical and inguinal areas should be avoided; lower cervical and axillary nodes are more likely to give reliable information2. The largest node should be biopsied, not the most accessible one. 3. The node should be removed intact with the capsule, not piecemeal4. The lymph node should be immediately submitted to the pathologist fresh or in sufficient tissue culture medium to prevent the tissue from drying out.TREATMENT: 1. Guided by the probable etiologic factor2. If bacterial infection is suspected, antibiotic treatment covering at least streptococci and staphylococci is indicated3. If pus is present, it may be aspiratedSurgical drainage is required for an abscess