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1. AMEMIA

2. anemia in children Anemia is a common problem in children. About 20% of children in the U.S. will be diagnosed with anemia at some point. A child who has anemia does not have enough red blood cells or hemoglobin . Hemoglobin is a type of protein that allows red blood cells to carry oxygen to other cells in the body.

3. types of anemia Iron deficiency anaemia - This is not enough iron in the blood. Iron is needed to form haemoglobin. This is the most common cause of anaemia. Megaloblastic anaemia- This is when red blood cells are too large from a lack of folic acid or vitamin B-12. One type of megaloblastic anaemia is pernicious anaemia. In this type, there is a problem absorbing vitamin B-12, important to making red blood cells. Haemolytic anaemia- This is when red blood cells are destroyed. There are many different causes, such as serious infections or certain medicines. Sickle cell anaemia - This is a type of hemoglobinopathy, an inherited type of anaemia with abnormally-shaped red blood cells. Cooley's anaemia (thalassemia) - This is another inherited type of anaemia with abnormal red blood cells. Aplastic anaemia- This is failure of the bone marrow to make blood cells.

4. What causes anemia in a child? Anemia has 3 main causes: Loss of red blood cells Inability to make enough red blood cells Destruction of red blood cells

5. Cont … Decreased red blood cells or hemoglobin levels may be due to: Inherited red blood cell defects Infections Some diseases Certain medicines Lack of some vitamins or minerals in the diet

6. Classification of anemia Anemia can be classified in many ways, such as congenital or acquired , acute or chronic , hemolytic or nonhemolytic , based on peripheral blood (PB) smear findings , or based on erythrocyte size . Hemolytic anemia may be further classified as inherited or acquired , immune or nonimmune , acute or chronic , whether hemolysis occurs in the vasculature (intravascular) or the reticuloendothelial system (extravascular), and whether there is a cellular defect of the erythrocyte (intrinsic) or extracellular (extrinsic) abnormality.

7. cont … Whereas most intrinsic defects are inherited, such as membrane disorders, metabolic defects, and Hb disorders, most extrinsic defects are acquired, such as immune-mediated anaemia, systemic disease, and drug- or toxin-mediated effects. A few disorders, such as paroxysmal nocturnal hemoglobinuria , exhibit intrinsic and extrinsic hemolysis . One clinically useful classification based on MCV and reticulocyte count initially classifies anemias as microcytic, normocytic, and macrocytic based on MCV, then further refines the differential diagnoses based on the reticulocyte count. This classification scheme will be used to review etiologies of anemia in infants and children.

8. Risk factors for anemia include: Premature or low birth weight Living in poverty or immigrating from developing country Early use of cow’s milk Diet low in iron, or some vitamins or minerals Surgery or accident with blood loss Long-term illnesses, such as infections, or kidney or liver disease Family history of an inherited type of anemia , such as sickle cell anemia

9. Clinical manifestations The delivery of oxygen throughout the body is the primary role of the erythrocyte. When anemia develops and tissue oxygen is compromised, the body compensates in several ways, including increasing erythropoietin production to increase red blood cell production, increasing erythrocyte 2,3-diphosphoglycerate, reducing oxygen affinity, and shifting the oxygen dissociation curve to the right to enhance erythrocyte release of oxygen to the tissues, increasing cardiac output, and selectively shunting blood to vital organs.

10. …Symptoms and signs Symptoms and signs vary based on the duration and severity of anemia . Patients with acute, severe anemia are overtly symptomatic with hypoxia, hypovolemic shock, congestive heart failure, and seizures which may lead to death. Common findings in chronic anemia include pallor, dyspnea , fatigue, exercise intolerance, dizziness, anorexia, and syncope. If there is hemolysis , jaundice and dark urine may be present. In young children, chronic anemia may lead to poor growth and failure to thrive, and if there is iron deficiency or iron deficiency anemia , affects on neurocognitive and behavioral development. Patients with mild to moderate chronic anemia are sometimes asymptomatic relative to the degree of anemia as compensatory mechanisms have had time to be activated.

11. Blood tests for diagnosing anemia Hemoglobin and haematocrit- This is often the first screening test for anemia in children. It measures the amount of hemoglobin in the blood and the amount of red blood cells in the blood sample. Complete blood count (CBC)- If hemoglobin or hematocrit is abnormal, a complete blood count may be done. This test adds important information about the blood, including the size of red blood cells (called the mean corpuscular volume or MCV).

12. Cont … Peripheral smear . This test is done with a smear of blood on a slide that is checked under a microscope. By looking at a child's blood cells under a microscope, a lab specialist may be able to diagnose a type of anemia that causes red cells to grow or develop abnormally. Reticulocyte count . Reticulocytes are immature blood cells. A reticulocyte count measures the amount of newly formed red blood cells in the child's blood sample. Anemia caused by not enough red blood cells being made results in a low reticulocyte count. Anemia caused by too many red blood cells being lost causes a high reticulocyte count. An elevated reticulocyte count indicates increased erythropoietic response to blood loss or hemolysis , whereas a low reticulocyte count , especially relative to the degree of anemia , indicates inadequate erythropoietic response.

13. Cont … Examination of erythrocyte indices may give clues to the diagnosis; for instance, microcytosis in an anemic infant may suggest the presence of a hemoglobinopathy or iron deficiency, whereas an elevated mean corpuscular Hb concentration may suggest a disorder of the erythrocyte membrane such as hereditary spherocytosis. Red cell distribution width is a measure of the size and volume of populations of circulating erythrocytes. When used with other indices, it may provide clues to the diagnosis, such as thalassemia. Reticulocyte Hb concentration is included on many cell counters, providing information on iron status.

14. Cont … A positive Direct antiglobulin test (DAT) suggests immune-mediated hemolysis . The presence of anemia with findings of hemolysis on PB smear and hyperbilirubinemia in a child with a negative DAT suggests an intrinsic erythrocyte defect. The child with acute onset normocytic, normochromic nonhemolytic anemia and a negative DAT test should be suspected of having had acute blood loss. Additional diagnostic evaluation is indicated. The use of a diagnostic algorithm may facilitate evaluation

15. Normocytic anemia Many paediatric anaemias are associated with normocytic erythrocyte indices, MCV 80-100 fL.

16. Normocytic anemia with elevated reticulocyte count This large group of pediatric anemias includes inherited disorders of the erythrocyte membrane , cellular metabolism , and unstable Hbs , as well as acquired disorders including immune hemolysis and microangiopathic disorders such as hemolytic uremic syndrome , thrombotic thrombocytopenic purpura , and disseminated intravascular coagulation . A hallmark of many of these disorders is hemolysis , premature breakdown of erythrocytes. Mechanisms of hemolysis include poor deformability of the erythrocyte leading to splenic trapping and subsequent phagocytosis, antibody-mediated destruction through phagocytosis or direct complement activation, fragmentation due to microthrombi or direct mechanical trauma, oxidation, or direct cellular destruction.

17. Nonimmune hemolysis Nonimmune hemolysis is associated with intrinsic disorders of the erythrocyte including ( Hemoglobin disorders, α- Thalassemias , Sickle cell disease , membrane abnormalities , defects of metabolism , and unstable Hbs . Microangiopathic hemolysis is associated with hemolytic uremic syndrome, TTP, and disseminated intravascular coagulation (DIC).

18. Immune hemolysis Immune-mediated hemolysis in the pediatric age group includes neonatal alloimmune hemolytic disease, primary autoimmune hemolytic anemia , and secondary autoimmune hemolytic anemia . In some cases of immune-mediated anemia , antibodies are against antigens expressed on early erythroid progenitor cells, leading to an inappropriately low reticulocyte count clouding the diagnosis . Similarly, diagnosis of immune-mediated anemia in infants at their physiologic nadir with relative reticulocytopenia may be challenging.

19. Neonatal alloimmune hemolytic anemia Occurs when maternal antibodies produced against incompatible antigens present on fetal red blood cells cross the placenta and attack fetal erythrocytes. After birth, maternal antibodies continue to circulate and attack neonatal erythrocytes. This may lead to hemolysis with neonatal anemia and hyperbilirubinemia requiring treatment with phototherapy, erythrocyte transfusion, or exchange transfusion. While Rh-linked hemolysis has markedly decreased after the introduction of anti-D immunoglobulin prophylaxis . ABO incompatibility, usually adequately treated by phototherapy alone. Alloimmunization to other erythrocyte antigens such as Kell, Fy , Jk , C, and E may also lead to neonatal alloimmune hemolytic anemia .

20. Erythrocyte membrane disorders Disorders of the erythrocyte membrane present at any age, in utero , in the neonatal period, in childhood , and some escape detection until late in life. Hereditary spherocytosis- associated with qualitative or quantitative defects in major erythrocyte membrane proteins , including ankyrin-1, β- spectrin , band 3, α- spectrin , and protein Hereditary elliptocytosis , hereditary pyropoikilocytosis , and related disorders Hereditary stomatocytosis syndromes- is a heterogeneous group of disorders characterized by abnormal permeability of erythrocytes to sodium and potassium , leading to alterations in water content.

21. Microangiopathic hemolysis Thrombotic microangiopathy, clot formation in small blood vessels throughout the body , can lead to microangiopathic hemolytic anemia and thrombocytopenia. Disseminated intravascular coagulation, hemolytic uremic syndrome (HUS), and TTP are the most common causes of microangiopathic hemolysis in childhood.

22. Normocytic anemia with normal or decreased reticulocyte count This category of anaemias is associated with acute blood loss due to haemorrhage, early stages of acute haemolysis , chronic disease , acute inflammatory states, and malignancies.

23. Acute hemorrhage Acute trauma due to motor vehicle accidents , falls , and assaults are 3 of the most common causes of trauma in pediatric patients associated with acute hemorrhage . In some cases, a high index of suspicion is needed when blood loss may be occult ( eg , from a ruptured spleen or lacerated liver) due to an event not initially reported, such as a sports collision or a bicycle fall. Outside of trauma , in older children, the GI tract is a common site of blood loss associated with a variety of disorders, including Meckel’s diverticulum, ulcerative colitis, Crohn’s disease, single or multiple polyps, esophageal and gastric varices, and in menstruating girls , blood loss due to dysmenorrhea. Dysmenorrhea may be associated with von Willebrand disease and other bleeding disorders, so it is important to inquire about frequent nose bleeds, easy bruising, and family history of the same. In neonates , acute blood loss may have occurred due to fetomaternal or fetoplacental hemorrhage , abruptio placentae , or placenta previa.

24. Acute hemolysis Patients with acute onset hemolysis may present with marked normocytic anemia before there has been a reticulocyte response . Acute hemolysis may occur after an acute oxidant challenge in patients with Glucose-6-phosphate dehydrogenase (G6PD) deficiency , an unstable Hb , or metabolic defects . It may occur with acute splenic sequestration in SCD and other disorders. S. pneumoniae infection may produce an enzyme that exposes the Thomsen- Friedenreich cryptoantigen (or T antigen ) found on erythrocytes, platelets, and glomeruli. Antibodies to the T antigen , which are normally found in human serum, bind the exposed T antigen, and the antigen-antibody reaction leads to atypical HUS and hemolytic anemia . A similar situation may occur in neonates with necrotizing enterocolitis and Clostridium welchii or C. perfringens infection. One of the toxins produced by clostridial organisms cleaves sialic acids from erythrocyte membrane glycoproteins exposing the T antigen.

25. Chronic disease/inflammation Anemia of chronic disease/inflammation is found in patients with a wide variety of disorders, infection, malignancies, renal disease, rheumatologic disorders, heart failure, chronic lung disease, and GI diseases such as ulcerative colitis, Crohn’s disease, and celiac disease. Several factors contribute to anemia . These include mild hemolysis , decreased sensitivity of erythroid precursors to erythropoietin due to inflammatory cell-produced cytokines, and inflammation-mediated increased synthesis of hepcidin, which binds ferroportin , blocks iron export from the liver and GI tract, and decreases iron levels available to developing erythroid cells. Many of these patients also have iron deficiency and chronic inflammation, exacerbating the anemia . Anemia of chronic disease/inflammation is typically normocytic but may be microcytic if iron deficiency is prominent . Erythropoietin levels are low commensurate to the degree of anemia . Hepcidin levels, erythrocyte sedimentation rate, and C-reactive protein levels are often elevated. Treatment of the underlying condition improves the anemia . In some patients, erythropoietin-stimulating agents are prescribed . Severe cases require transfusion.

26. Cont … Treatment Hemolytic disease of the newborn is managed by treating hyperbilirubinemia with phototherapy and exchange transfusions if needed. Routine universal screening with transcutaneous bilirubin ( TcB ) often occurs at 24 hours of life, but screening should be conducted as soon as hyperbilirubinemia is suspected

27. Transient erythroblastopenia of childhood (TEC) TEC is a rare red cell aplasia of young children or infants , usually occurring after a viral infection . Normocytic normochromic anemia and reticulocytopenia are sometimes accompanied by neutropenia and thrombocytosis. Marrow examination is normal. After 1 to 2 months, patients undergo spontaneous recovery.

28. Microcytic anemia Microcytic anemia with normal or decreased reticulocyte count Iron deficiency anemia Iron deficiency is the most common nutritional deficiency. Universal screening for anemia in all children around 1 year of age, including assessing for risk factors such as history of prematurity, low birth weight, lead exposure, exclusive breastfeeding without iron supplementation beyond 4 months , as well as feeding problems, poor growth, low socioeconomic status. Iron deficiency occurring in older children and adolescents may be associated with poor diet, malabsorption syndromes, and chronic blood loss, particularly in menstruating girls and women . In developing countries, infection with hookworm and schistosomiasis are important causes of iron deficiency.

29. Cont … Iron deficiency is often symptomatic and may or may not be accompanied by anemia . Signs of iron deficiency in infants include poor feeding and irritability . In older children and adolescents, iron deficiency may be associated with lethargy, fatigue, pallor, difficulty concentrating, headache, and tinnitus . Other signs may include atrophic glossitis(red, glazed, smooth tongue) , alopecia(loss of hair) , dry hair , dry skin , and koilonychia (spooning of the fingernails). Some iron-deficient patients exhibit pica , the compulsive ingestion of non-nutritive substances, sometimes attributed to lack of iron in some areas of the brain. Iron deficiency has been associated with poorer functional outcomes such as impaired neurocognitive development, exercise performance, and pregnancy outcome.

30. Cont … Laboratory testing reveals decreased Hb levels , decreased mean corpuscular volume , and decreased mean corpuscular Hb level . PB smear shows significant anisocytosis , hypochromia , and microcytosis . A variety of tests have been employed in the assessment of iron deficiency anemia . Decreased serum ferritin <10-12 mg/L in conjunction with a normal C-reactive protein, decreased reticulocyte Hb concentration ( CHr ), decreased serum iron levels , and decreased transferrin saturation are indicative of iron deficiency . CHr , a good indicator of iron availability and iron-deficient erythropoiesis , is a popular test as it is easily obtained from most automated blood cell analyzers . The RDW is elevated in iron deficiency. In otherwise well children, a trial of iron supplementation without additional laboratory testing is a strategy frequently used to diagnose iron deficiency.

31. Cont … Treatment is with an iron-rich diet and oral iron supplementation . Infants <1 year of age should be provided breast milk or iron-fortified formula , and cow’s milk avoided . In addition, after 6 months of age, foods rich in iron, such as iron-fortified cereal and pureed meats, can be given. After a year of age, cow’s milk intake should be limited. Supplementation is initiated with 3 mg/kg ferrous sulfate given once a day in the morning or between meals without milk or other dairy products , which may inhibit absorption.

32. Cont … In cases of iron deficiency unresponsive to oral therapy , poor compliance to therapy, persistent low-iron diet, ongoing malabsorption or blood loss, and an incorrect diagnosis should be considered. Conditions in the differential diagnosis include cow’s milk protein-induced colitis, celiac disease, inflammatory bowel disease, malaria, hookworm, schistosomiasis, as well as thalassemia trait or presence of the anemia of chronic inflammation . In the anemia of chronic inflammation, systemic immune activation leads to alterations in iron metabolism leading to iron retention in macrophages and reduced iron absorption, with iron deficiency one of the contributors to anemia . In refractory cases, the diagnosis of iron-refractory iron deficiency anemia (IRIDA), a recessively inherited disorder due to mutations in TMPRS6, should be considered. In both anemia of chronic inflammation and IRIDA, dysregulation of hepcidin, the primary regulator of systemic iron homeostasis, lead to iron-restricted or iron-deficient erythropoiesis with poor response to oral iron therapy.

33. Hb disorders Microcytosis with mild to no anemia and minimal reticulocytosis may be due to α- or β- thalassemia trait or heterozygous γδβ- thalassemia . Determining the etiology of microcytic anemia includes assessment of iron stores and Hb electrophoresis . The Red cell distribution width is elevated in over half the cases of iron deficiency anemia but normal in the thalassemia trait . A Mentzer index (MCV/RBC) of <13 suggests thalassemia trait, whereas >13 suggests iron deficiency.

34. Microcytic anemia with increased reticulocyte count Disorders of Hb The thalassemias are disorders characterized by a decreased or absent globin chain production due to numerous point mutations or deletions in either the α- or β-globin genes . Globin chain deficiency leads to ineffective erythropoiesis as excessive unpaired globin chains produce insoluble tetramers leading to oxidant damage of erythrocyte membrane lipids and proteins. Thalassemic -deficient erythrocytes demonstrate a selective advantage against P. falciparum infection, leading to a high frequency of Hb disorders worldwide via natural selection.

35. Hb H disease Patients with Hb H disease present in the neonatal period with hypochromic, microcytic hemolytic anemia and hyperbilirubinemia . A few patients suffer from nonimmune hydrops fetalis in utero, with microcytosis and red cell fragmentation. Hb electrophoresis is diagnostic, demonstrating Hb Barts and Hb H, β4.

36. Macrocytic anemia with normal or decreased reticulocyte count Erythrocyte underproduction is an uncommon cause of anemia in pediatric patients . Associated abnormalities include nutritional deficiencies , genetic syndromes, congenital dyserythropoietic anemias , BM replacement syndromes, drug-induced anemia , infectious suppression, and other rare causes. Depending on the time in the disease course and any associated diagnoses, anemia may be normocytic, microcytic, or macrocytic, particularly for nutritional and infectious etiologies of anemia .

37. Nutritional anemias Vitamin B12 deficiency Vitamin B12 deficiency in pediatric patients is found when there is a decreased intake , reduced absorption , or inherited abnormalities of vitamin B12 absorption, transport, or metabolism. Decreased intake is associated with a strict vegetarian diet or breastfeeding by a vitamin B12-deficient mother. Decreased absorption is associated with decreased stomach acid, gastrectomy, bowel resection, poor pancreatic function, parasitic infection, bacterial overgrowth, Crohn’s disease, or celiac disease. Inherited disorders include abnormalities of intrinsic factor, transcobalamin-II deficiency, cobalamin R-binder protein deficiency, defects in vitamin B12 intestinal absorption known as Imerslund-Gräsbeck syndrome, and several very rare metabolic disorders. Antibody-mediated vitamin B12-deficient pernicious anemia , common in adults, is rare in childhood.

38. Cont … Vitamin B12 deficiency typically presents with poor growth , developmental delay , and neurologic abnormalities such as weakness or irritability . Macrocytic anemia , and sometimes pancytopenia, is observed with anisocytosis, basophilic stippling, and hyper segmented neutrophils on PB smear. In a few cases, infants have presented with transfusion-dependent anemia . Treatment of symptomatic B12 deficiency is with vitamin B12, along with dietary or medication adjustments as indicated. For moderate or severe <30 nmol 1000 -2000 units daily for 6 month or 3000 -4000 units daily for 3 months or 150,000 units stat and repeated at 6 weeks

39. Folate deficiency Folate deficiency in pediatric patients is found when there is a decreased intake, reduced absorption, impaired utilization, or increased requirements, Decreased intake is seen in infancy when there is feeding of a folate-poor diet such as goat’s milk or milk that has been boiled. Impaired folate absorption is seen in patients with celiac disease , congenital malabsorption syndromes , after intestinal resection, and those receiving certain medications such as sulfasalazine. Impaired utilization of folate is seen in patients receiving folic acid antagonists such as methotrexate , sulfa antibiotics, and several antiepileptics. Increased folate requirements are seen during pregnancy, in preterm infants, and in patients with hyperthyroidism, malignancies , and chronic hemolytic disease.

40. Cont … The megaloblastic anemia of folate deficiency in infants and children is like that observed in adults. Treatment depends on treatment of the underlying cause and supplementation . Folate deficiency due to dietary deficiency or increased demands is best treated with folate supplements along with a folate-rich diet . Deficiency due to folic acid antagonists such as sulfa drugs is treated with folate supplementation or by reducing or eliminating the offending drug.

41. Infectious suppression In addition to hemolysis , infection may lead to BM suppression with resultant cytopenias . Infectious suppression has been associated with several viral infections , including parvovirus B19, human immunodeficiency virus, Epstein-Barr virus, CMV, hepatitis A, B, C, and E, and T-cell leukemia -lymphoma virus. It has been described in patients with tuberculosis, streptococcal infections, and those with overwhelming sepsis. In some cases of infection there may be hemolysis along with marrow suppression, particularly in malaria and CMV infection.

42. Cont … Parvovirus B19 infection is a significant cause of anemia in susceptible patients. Parvovirus B19 is the cause of the common childhood illness, erythema infectiosum , also known as Fifth disease, characterized by fever, chills, vomiting, and diarrhea , and a maculopapular exanthem on the face mimicking “slapped cheeks” which appear with the resolution of the fever . During infection, parvovirus B19 selectively infects erythroid precursors and inhibits their growth, leading to an acute decrease in Hb and reticulocytopenia, which gradually resolves. This drop in Hb is tolerated by normal children and adults. However, in patients with chronic hemolysis and shortened erythrocyte life span, such as those with inherited hemolytic anemias , interruption of erythropoiesis leads to acute anemia with reticulocytopenia that can lead to significant symptomatology, including cardiovascular compromise and death . Treatment for this group of patients is supportive.

43. Copper deficiency Copper deficiency may be caused by inadequate intake as occurs in anorexia nervosa , malnutrition , vegan diets , parenteral nutrition , and postpyloric feeds, increased demand as occurs in pregnant or lactating women and growing premature infants , abnormal copper metabolism as occurs in Menkes disease and familial hypoceruloplasminemia , and inadequate absorption or increased loss in inflammatory bowel disease, Crohn’s disease, celiac disease, and recently after bariatric surgery. Copper deficiency has neurologic and hematologic manifestations . Neurologic findings mimic subacute combined degeneration , myeloneuropathy , and optic neuropathy . Hematological manifestations include anemia , sometimes with neutropenia and thrombocytopenia . Similar to myelodysplasia, marrow examination shows dysplastic erythroid precursors with ring sideroblasts , nuclear budding, and multilobulation . Unlike MDS, copper-deficient marrow demonstrates cytoplasmic vacuolization in erythroid and myeloid cells. Hematologic findings are reversible with copper supplementation, whereas neurological manifestations are only partially reversible. Treatment is parentral copper is usually given as copper histidine 250mcg subcutaneous injection twice a day to age 1 year, then 250 mcg subcutaneously once a day after the first year.

44. Macrocytic anemia with increased reticulocyte count Active hemolysis with brisk reticulocytosis is the most common etiology of macrocytic anemia with elevated reticulocyte count.

45. How is anemia in a child treated? Treatment will depend on child’s symptoms, age, and general health. It will also depend on how severe the condition is. The treatment for anemia depends on the cause. Some types do not require treatment. Some types may require medicine, blood transfusions, surgery, or stem cell transplants. Your child's healthcare provider may refer you to a hematologist . This is a specialist in treating blood disorders. Treatment may include: Vitamin and mineral drops or pills Changing your child's diet Stopping a medicine that causes anaemia Medicine Surgery to remove the spleen Blood transfusions Stem cell transplants

46. complications of anemia The complications of anemia depend on what is causing it. Some types have few complications, but others have frequent and serious complications. Some anemias may cause: Problems with growth and development Joint pain and swelling Bone marrow failure Leukemia or other cancers

47. prevention Some types of anaemia are inherited and can’t be prevented. Iron deficiency anaemia, a common form of anaemia, may be prevented by making sure your child gets enough iron in his or her diet. To do this: Breastfeeding, the baby will get enough iron from the breastmilk. Give formula with iron. If the child is on formula, use formula with added iron. Don't give cow’s milk until after age 1. Cow’s milk does not have enough iron. It should not be given to babies until after 1 year of age, when he or she is eating enough other food. Feed your child iron-rich foods. When your child eats solid foods, choose foods that are good sources of iron. These include iron-enriched grains and cereals, egg yolks, red meats, potatoes, tomatoes, and raisins.

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