ANEMIA 1. Decrease in hemoglobin concentration and/or erythrocytes in comparison to normal age values 2. Reduction in the hemoglobin concentration in blood (corrected by age) 3. Decreased total circulating red cell mass

PHYSIOLOGICAL ANEMIA In 3 month of life – decrease of hemoglobin (in prematures to 80 g/L) concentration to 100 g/L Temporary decrease in erythropoietin level, due to better body oxygenation

Reticulocytes /%/ NORMAL VALUES FOR PERIPHERAL BLOOD Female Male Erythrocytes /per l/ Hemoglobin /g/dl/ Hematocrit /%/ Reticulocytes /%/ 4.8±0.6x106 14±2 42±5 1±0,5 5.4±0.8x106 16±2 47±5 1±0,5 Mean corpuscular corpuscular corpuscular volume /MCV; m3/ 82-92 27-32 hemoglobin /MCH; pg/ hemoglobin concentration /MCHC; % / 32-36

MORPHOLOGIC CLASSIFICATION OF ANEMIA Type MCV MCHC Common cause Macrocytic anemia increased Normal Vit B12 deficiency Folic acid deficiency Posthemorrhagic Microcytic anemia - hypochromic Decreased Decreased Iron deficiency Thalassemia Spherocytosis - normochromic Decreased or normal Normal Normocytic anemia - normochromic Normal Normal Aplastic anemia Chronic renal failure ~Hemolytic anemia

ETIOLOGIC CLASSIFICATION OF ANEMIAS 1. 2. Post-hemorrhagic Impaired red cell production (deficiency anemia, hypo- Increased rate of destruction and aplastic) 3. (hemolytic anemias)

POST-HAEMORRHAGIC ANEMIA I. Acute 2. Infants and older children: A. Accidents B. Coagulation disorders C. Nose bleedings (epistaxis) D. Digestive tract haemorrhage E. Urinary tract 1. Peri-natal period: A. Traumatic delivery B. Intra-uterine bleedings C. Internal bleedings D. Melaena neonatorum E. Coagulopathies II. Chronic

TREATMENT OF POST-HEMORRHAGIC ANEMIA Fluids Red Packed Blood Cells (10 ml/kg bw)

ETIOLOGIC CLASSIFICATION OF ANEMIAS AD 2. Impaired red cell production A. Disturbance of proliferation and maturation of erythrocytes: 1. Defective Hb synthesis: a) Deficient heme synthesis (iron deficiency) Defective DNA synthesis (megaloblastic anemia) Unknown or multiple mechanisms (anemia of inflammation) 2. 3. B. Disturbance of proliferation and differentiation of stem cells (aplastic anemia, pure red cell aplasia)

ANEMIA OF INFLAMMATION: EXPLANATIONS (2015): (1) During infection, iron is moved to tissue compartments – natural cytostatic mechanism against bacterias which (particularly G- bacteria) require iron (2) Infection causes release of IL-6 IL-6 upregulates HEPCIDIN HEPCIDIN decreases IRON concentration

ETIOLOGY OF DEFICIENCY ANEMIA I. Iron deficiency IA. Sideroblastic anemia Folic acid deficiency Vitamin B12 deficiency II. III. IV. V. VI. Vitamin B2, B6, PP, C deficiency Cu, Co, Mg, Zn deficiency Protein and aminoacids deficiency

ETIOLOGY OF IRON DEFICIENCY ANEMIA I. Inadequate iron uptake: A. Inadequate iron supply in newborns 1. 2. 3. Prematures, multiple pregnancy Anemia during pregnancy Uterine bleeding B. Inadequate iron dietary C. Iron malabsorption intake II. Iron loss: 1. Blood loss 2. Parasites III. Increase in physiological requirement 1. Premature infants / infancy 2. Adolescence for iron:

LABORATORY TESTS 1. Peripheral blood count (HGB, RBC, HTC, MCV, MCHC, MCH, microcytosis, hypochromia, anisocytosis, poikilocytosis). Iron and FERRITIN blood concentration. Transferrin (TIBC), serum iron curve 2. 3. Other lab tests – with respect to clinical situation

PROPHYLACTIC IRON SUPPLEMENTATION Absolute indications: 1. 2. 3. 4. 5. Prematures Infants from multiple pregnancy Low HGB concentration on delivery Children after delivery with uterine bleeding Children of mother with anemia in pregnancy Relative indications: 1. 2. 3. 4. Frequent respiratory and alimantary tract infections Growth spurt (infants, adolescents) Dietary problems (meat, fruits, vegetables) Children with recurrent bleedings

PRINCIPLES OF TREATMENT IN IRON DEFICIENCY * Determine the cause of iron deficiency and treat the underlying disease! * ORAL replacement therapy. * Dosage: 4.5-6 mg Fe / kg bw / day 50 mg in infants, 200 mg in older children t.i.d. - maximum daily dosage: * Prophylactic dosage: 1-2 mg Fe / kg bw / day * Better absorption when administered with ascorbic acid. * Adequate diet (infants!).

IRON THERAPY (EXAMPLES) Hemofer (drops) 44 mg Fe in 1 ml i.e. In 30 drops Hemofer prolongatum 105 mg Fe in 1 tablet

DAILY IRON REQUIREMENT AGE DAILY REQUIREMENT 6 – 12 m 7.8 – 12 mg 1 – 3 y 5.8 – 9 mg 4 – 8 y 6.1 – 10 mg 9 – 13 y 8 – 15 mg

PRINCIPLES OF TREATMENT IN IRON DEFICIENCY * Symptoms of improvement: - increase in reticulocyte over 2% after 10 days - increase in HGB concentration: 10-20 g/L after 10 days • Length of therapy: After HGB reaches 110-120 g/l continue therapy for 4-6 weeks, in prematures up to 3 months * Adverse effects: - gastrointestinal irritation - teeth (dental enamel)

Indications for parenteral iron therapy (i.m.): PRINCIPLES OF TREATMENT IN IRON DEFICIENCY: Indications for parenteral iron therapy (i.m.): - side effects of oral therapy - inflammatory bowel disease, peptic ulcer - malabsorption, alimentary tract diseases - severe iron defficiency

PRINCIPLES OF TREATMENT IN IRON DEFICIENCY: Intravenous iron therapy in children (2015): PAST: No iv iron therapy in children (risk of anaphylactic shock!) PRESENT: Clinical studies with iv Ferric carboxymaltose in children (Ferrinject, Injectafer) FUTURE: Probably iv iron theapy in children will be routine practice

PRINCIPLES OF TREATMENT IN IRON DEFICIENCY: Red Packed Blood Cells transfusion in iron deficiency anemia: - HGB below 30-50 g/l cerebral symptoms coexisting severe infection before surgical procedure

SIDEROBLASTIC ANEMIA Microcytic and hypochromic anemia related to inefficacy of heme synthesis (= inefficacy to synthetise iron in hemoglobin) Etiology: 1. congenital - genetic disorders (enzyme defficiences, porphyria) 2. acquired - spontaneous or secondary (lead intoxication, chronic renal disease) Therapy: congenital acquired - pyridoxine (vit. B6) - chelating agents, vit. B6

HYPO- and APLASTIC ANEMIA (SAA, BMF) 1. Hypoplastic anemia A. congenital: Blackfan-Diamond anemia B. acquired (e.g. PRCA) 2. Aplastic anemia A. congenital: Fanconi anemia B. acquired (primary, secondary)

CAUSES OF APLASTIC ANEMIA (1) I. Primary (idiopathic? probably autoaggressive reaction of T-cells against BM stroma) II. Secondary – drugs / therapy 1. Ionizing radiation 2. Antineoplastic drugs: folic acid antagonists, alkylating agents, anthracyclines, nitrosoureas, purine and pyrimidine analogous 3. Unpredictable (idiosyncratic reaction) - antiepileptic drugs (hydantoins) oral antidiabetic agents (tolbutamide, chlorpropamide) tranquillizers (chlorpromazine, chlordiazepoxide) antirheumatic drugs (indomethacin, gold salts, phenylobutazone) antibacterial agents (sulfonamides, isoniazid, steptomycin, tetracyclines, chloramphenicol) 4. Unpredictable hypersensitivity (immune reaction): many drugs

CAUSES OF APLASTIC ANEMIA (2) III. Associated diseases 1. 2. 3. 4. 5. Familiar hypoplastic anemia (Fanconi) Infective hepatitis CMV infections EBV With infections paroxysmal nocturnal hemoglobinuria IV. Industrial and household chemicals: benzene, some organic solvents, trinitrotoluene, certain insecticides

CLASSIFICATION OF APLASTIC ANEMIA 1. Severe aplastic anemia is defined if at last two of the following criteria are present: - absolute granulocyte count less than 0.5 x 109/L platelet count less than 20 x 109/L reticulocyte count less than 1% BM hypoplastic and depleted of hematopoietic cells (less than 20%) 2. Very severe aplastic anemia - criteria as above but granulocyte count less than 0.2 x 109/L 3. Non-severe aplastic anemia

APLASTIC ANEMIA: CRITERIA FOR DIAGNOSIS 1. 2. Cytopenia (Hb<6.6 mmol/l; ANC<1,5 G/L; Bone marrow histology and cytology PLT<100 G/L) - loss of hematopoietic parenchyma, increased fat cells component, no extensive fibrosis, no malignancy or storage disease 3. 4. 5. 6. No No No No preceding treatment with X-ray or antyproliferative drugs lymphadenopathy or hepatosplenomegaly deficiencies or metabolic diseases evidence of extramedullary hematopoiesis

SYMPTOMS AND SIGNS OF APLASTIC ANEMIA 1. Clinical symptoms: - due due due to to to decrease decrease decrease of of of RBC WBC PLT 2. Laboratory findings: - anemia, neutropenia, thrombocytopenia - bone marrow: hypoplastic with fatty changes

CAUSES OF PANCYTOPENIA 1. 2. 3. 4. 5. 6. 7. 8. Aplastic anemia Myelodysplastic syndromes Multiple myeloma Acute leukemias Hipersplenism Megaloblastic anemias Paroxysmal nocturnal hemoglobinuria Myelosuppression after irradiation or antiproliferative drugs

MANAGEMENT OF SEVERE APLASTIC ANEMIA 1. 2. Hematopoietic stem cell transplantation (HSCT) Immunosuppressive treatment - cyclosporine antilymphocyte/antityhymocyte methyloprednisolone globulin, 3. 4. 5. Growth factors: G-CSF, EPO Supportive therapy Androgens

HSCT in SAA 1. Advantages - correction of hematopoietic defect, long-term survival of the patients >80%, majority of the patients appear to be cured. 2. Restrictions - young age suitable donor available risk of GVHD (graft-versus-host disease).

THERAPY OF NON-SEVERE APLASTIC ANEMIA 1. 2. „Watch and wait” Supportive care: red blood cells, platelet concentrates, antibiotics. Immunosuppressive treatment in selected patients. Androgens 3. 4.

HEMOLYTIC ANEMIA Common feature: decrease in survival of red cells. Classification: A. Intracellular defects B. Extracellular defects:

ETIOLOGIC CLASSIFICATION OF ANEMIAS AD 3. Increased rate of destruction (hemolytic anemias) A. Intrinsic abnormalities Hereditary 1. Red cell membrane disorder (hereditary spherocytosis, hereditary eliptocytosis) Red cell enzyne deficiencies a) Glycolytic enzymes: pyruvate kinase, hexokinase b) Other enzymes: G6PDH Disorders of globin synthesis a) Deficient globin synthesis (thalassemia) b) Structurally abnormal globin synthesis (sickle cell anemia, unstable hemoglobins) 2. 3. Acquired 1. Membrane defect: paroxysmal nocturnal hemoglobinuria

ETIOLOGIC CLASSIFICATION OF ANEMIAS AD 3. Increased rate of destruction (hemolytic anemias) B. Extrinsic abnormalities 1. Antibody mediated a) Autoantibodies (idiopathic, drug-associated, SLE, malignancies) b) Isohemagglutinins (transfusion reactions, erythroblastosis fetalis) Mechanical trauma of RBC a) Microangiopathic hemolytic anemias (TTP, DIC) b) Cardiac traumatic hemolytic anemia Chemicals and microorganisms Sequestration in mononuclear phagocytic system - hypersplenism 2. 3. 4.

CONGENITAL SPHEROCYTOSIS Pathology: erythrocyte membrane defect (spectrin or ankyrin defficiency). Clinical and laboratory symptoms: 1. 2. 3. 4. 5. 6. 7. 8. 9. Familiar history Hyperbilirubinemia Splenomegaly High reticulocyte count Microspherocytes in blood smear Osmotic Fragility Test – abnormal EMA assay results Hemolytic crisis, aplastic crisis and megaloblastic crisis Direct antiglobulin test (Coombs) negative

TREATMENT IN CONGENITAL SPHEROCYTOSIS 1. 2. RPBC, fluids, glucose, witamins, folinic acid Splenectomy = treatment of choice - - After usually not below age of 5-7 years vaccination still limited efficacy splenectomy: prophylactic antibiotics, no TBC vaccination! 3.