Treatment of Iron Deficiency Anemia

The regular response of iron-deficiency anemia to adequate amounts of iron is an important diagnostic and therapeutic feature.

Oral Iron:
Oral administration of simple ferrous salts (e.g., sulfate, gluconate, fumarate) provides inexpensive and satisfactory therapy. No evidence shows that addition of any trace metal, vitamin, or other hematinic substance significantly increases the response to simple ferrous salts. One problem encountered with administration of oral iron to young children is that liquid FeSO4nhas an unpleasant taste, but sometimes the taste can be camouflaged by mixing with flavored syrup. Other, better-tasting preparations are available over the counter, but these are much more expensive than simple liquid FeSO4. Aside from the unpleasant taste, intolerance to oral iron is uncommon in young children, although older children and adolescents sometimes have gastrointestinal complaints. Problems with constipation can be minimized by increasing water and fiber intake. For some children, abdominal discomfort can be minimized by administering iron with food, recognizing that this may decrease iron absorption to some extent.

The therapeutic dose should be calculated in terms of elemental iron; ferrous sulfate is 20% elemental iron by weight. A daily total dose of 4–6 mg/kg of elemental iron in 3 divided doses provides an optimal amount of iron for the stimulated bone marrow to use.

Splenomegaly

A soft, thin spleen may be palpable in 15% of neonates, 10% of normal children, and 5% of adolescents. In most individuals, the spleen must be 2–3 times its normal size before it is palpable.

Examination:
The spleen is best examined in a supine patient by palpating across the abdomen toward the left costal margin from below as the patient inspires deeply. An enlarged spleen might descend into the pelvis; when splenomegaly is suspected, the abdominal examination should begin at a lower starting point. Superficial abdominal venous distention may be present when splenomegaly is a result of portal hypertension.

Radiologic detection or confirmation of splenic enlargement is done with ultrasonography, CT, or technetium-99 sulfur colloid scan. The latter also assesses splenic function.

Pseudosplenomegaly.
Abnormally enlarged mesenteric connections may produce a wandering or ptotic spleen. An enlarged left lobe of the liver, a left upper quadrant mass, or a splenic hematoma may be mistaken for splenomegaly. Splenic cysts may contribute to splenomegaly or mimic it; these may be congenital (epidermoid) or acquired (pseudocyst) after trauma or infarction. Cysts are usually asymptomatic and are found on radiologic evaluation. Splenosis after splenic rupture or an accessory spleen (present in 10% of normal individuals) may also mimic splenomegaly; most are not palpable.

Laboratory Finding In Hereditary Spherocytosis

The different laboratory findings observed in patients with hereditary spherocytosis is summarized as follows.

Evidence of hemolysis includes reticulocytosis and indirect hyperbilirubinemia.

Hb Level:
The hemoglobin level usually is 6–10 g/dL, but it can be in the normal range.

Retic Count:
The reticulocyte percentage often is increased to 6–20%, with a mean of approximately 10%.

Absolute Values:
The mean corpuscular volume is normal, although the mean corpuscular hemoglobin concentration often is increased (36–38 g/dL RBCs).

Blood Film:
The RBCs on the blood film vary in size and include polychromatophilic reticulocytes and spherocytes. The spherocytes are smaller in diameter and appear hyperchromic on the blood film as a result of the high hemoglobin concentration. The central pallor is less conspicuous than in normal cells. Spherocytes may be the predominant cell or may be relatively sparse, depending on the severity of the disease, but they usually account for >15–20% of the cells when hemolytic anemia is present.

Bone marrow:
Erythroid hyperplasia is evident in the marrow aspirate or biopsy. Marrow expansion may be evident on routine roentgenographic examination.

Other Features :
Other evidence of hemolysis may include decreased haptoglobin and the presence of gallstones on ultrasonography.

Diagnosis of Sickle Cell Disease

Virtually all states in the U.S. have instituted mandatory newborn screening program for sickle cell disease. Such programs identify newborns with the disease, provide prompt diagnosis and anticipatory guidance for the parents, and make possible the initiation of treatment with penicillin before 4 mo of age.

Newborn Screening:
The most commonly used procedures for newborn diagnosis include thin-layer/isoelectric focusing and high-performance liquid chromatography. A 2-step system is recommended, in which all initially abnormal screens are retested during the 1st clinical visit and again after 6 mo of age to determine the final hemoglobin phenotype.

A complete blood cell count as well as hemoglobin analysis is recommended on both parents to confirm the diagnosis and provide an opportunity for genetic counseling.

In affected patients, the red blood cell morphology after 3–6 mo of life is helpful for sickle cell disease and other hemoglobinopathies.

Newborn screening programs 1st report the hemoglobin with the greatest quantity, followed by the other hemoglobins in decreasing quantity. In newborns with a hemoglobin analysis consistent with a diagnosis of sickle cell disease, the FS pattern is supportive of Hb SS, Hb hereditary persistent fetal hemoglobin (Hb S/?0). The FSA pattern is supportive of the diagnosis of Hb S/?+. The diagnosis of Hb S/?+is confirmed if at least 50% of hemoglobin is Hb S, Hb A is present, and an elevated amount of Hb A2is present (typically >3.5%).

Hemorrhagic Disease of Newborn

A moderate decrease in factors II, VII, IX, and X normally occurs in all newborn infants by 48–72 hr after birth, with a gradual return to birth levels by 7–10 days of age. This transient deficiency of vitamin K–dependent factors is probably due to lack of free vitamin K from the mother and absence of the bacterial intestinal flora normally responsible for the synthesis of vitamin K. Rarely, in term infants and more frequently in premature infants, accentuation and prolongation of this deficiency between the 2nd and 7th days of life result in spontaneous and prolonged bleeding. Breast milk is a poor source of vitamin K, and hemorrhagic complications are more frequent in breast-fed than in formula-fed infants. This classic form of hemorrhagic disease of the newborn, which is responsive to and prevented by vitamin K therapy, must be distinguished from disseminated intravascular coagulopathy and from the more infrequent congenital deficiencies of one or more of the other factors that are unresponsive to vitamin K.

Early-onset life-threatening vitamin K deficiency–induced bleeding(onset from birth to 24 hr) also occurs if the mother has been treated with drugs (phenobarbital, phenytoin) that interfere with vitamin K function.

Late onset (>2 wk) is often associated with vitamin K malabsorption, as noted in neonatal hepatitis or biliary atresia.

Clinical Features:
Hemorrhagic disease of the newborn resulting from severe transient deficiencies in vitamin K–dependent factors is characterized by bleeding that tends to be gastrointestinal, nasal, subgaleal, intracranial, or postcircumcision. Prodromal or warning signs (mild bleeding) may occur before serious intracranial hemorrhage.

Introduction to Hemophilia

A hereditary bleeding disorder, hemophilia results from the deficiency of specific clotting factors. Hemophilia A (classic hemophilia), which affects more than 80% of all hemophiliacs, results from a deficiency of factor VIII; hemophilia B (Christmas disease), which affects 15% of hemophiliacs, results from a deficiency of factor IX.
The severity and prognosis of bleeding disorders vary with the degree of deficiency and the site of bleeding. The overall prognosis is best in mild hemophilia, which doesn’t cause spontaneous bleeding and joint deformities.
Advances in treatment have greatly improved the prognosis, and many hemophiliacs live normal life spans. Surgical procedures can be done safely at special treatment centers for hemophiliacs under the guidance of a hematologist.

Causes
Hemophilia is caused by a deficiency of clotting factors that are genetically transmitted.

Incidence
Hemophilia is the most common X-linked genetic disease, occurring in about 1.25 in 10,000 live male births. Hemophilia A is five times more common than hemophilia B. Hemophilia causes abnormal bleeding because of a specific clotting factor malfunction. After a person with hemophilia forms a platelet plug at a bleeding site, clotting factor deficiency impairs the capacity to form a stable fibrin clot.

Signs and symptoms
Hemophilia produces abnormal bleeding, which may be mild, moderate, or severe, depending on the degree of factor deficiency.

Clinical Manifestations of Hemolytic Disease of Newborn Caused by Rh Incompatibility

The Rh antigenic determinants are genetically transmitted from each parent, determine the Rh type, and direct the production of a number of blood group factors (C, c, D, d, E, and e). Each factor can elicit a specific antibody response under suitable conditions; 90% are due to D antigen and the remainder to C or E.

A wide spectrum of hemolytic disease occurs in affected infants born to sensitized mothers, depending on the nature of the individual immune response.

The severity of the disease may range from only laboratory evidence of mild hemolysis (15% of cases) to severe anemia with compensatory hyperplasia of erythropoietic tissue leading to massive enlargement of the liver and spleen. When the compensatory capacity of the hematopoietic system is exceeded, profound anemia occurs and results in pallor, signs of cardiac decompensation (cardiomegaly, respiratory distress), massive anasarca, and circulatory collapse. This clinical picture of excessive abnormal fluid in two or more fetal compartments (skin, pleura, pericardium, placenta, peritoneum, amniotic fluid), termed hydrops fetalis, frequently results in death in utero or shortly after birth. With the use of RhoGAM to prevent Rh sensitization, nonimmune (nonhemolytic) conditions have become frequent causes of hydrops . The severity of hydrops is related to the level of anemia and the degree of reduction in serum albumin (oncotic pressure), which is due in part to hepatic dysfunction. Alternatively, heart failure may increase right heart pressure, with the subsequent development of edema and ascites. Failure to initiate spontaneous effective ventilation because of pulmonary edema or bilateral pleural effusions results in birth asphyxia; after successful resuscitation, severe respiratory distress may develop. Petechiae, purpura, and thrombocytopenia may also be present in severe cases as a result of decreased platelet production or the presence of concurrent disseminated intravascular coagulation.

Shwachman-Diamond Syndrome

Shwachman-Diamond syndrome (SDS) is inherited in an autosomal recessive manner; it occurs in all racial and ethnic groups. Essential diagnostic criteria are exocrine pancreatic insufficiency and variable hematologic cytopenias due to marrow failure.

Pathology
The mutant gene SBDS maps to chromosome 7q11 and is responsible for the multisystem, pleiotropic phenotype in 90% of cases. Pancreatic insufficiency is due to failure of pancreatic acinar development. Fatty replacement of pancreatic tissue is prominent. Bone marrow failure is characterized by a generalized marrow cell and microenvironmental dysfunction that does not support and maintain normal hematopoiesis.

Clinical Manifestations.
Although most patients have symptoms of fat malabsorption from birth caused by pancreatic insufficiency, the absence of steatorrhea does not exclude a diagnosis of SDS. Approximately 50% of patients appear to exhibit a modest improvement in pancreatic enzyme secretion with advancing age.

Short stature is a consistent feature of the syndrome; most patients show normal growth velocity, yet remain consistently below the 3rd percentile for height and weight. The occasional adult achieves the 25th percentile for height.

Folate Deficiency in Children

Folate exists in a number of different chemical forms. Folic acid (pteroylglutamic acid) is the synthetic form used in fortified foods and supplements. Naturally occurring folates in foods (pteroylpolyglutamate) are not used as well as folic acid. Folate coenzymes are involved in a variety of reactions, including synthesis of deoxyribonucleic acid and purine, amino acid interconversion, and conversion of homocysteine to methionine. Because of its role in protein synthesis, the risk of deficiency is increased during periods of rapid growth or increased cellular metabolism.

Impaired folate status may be associated with long-term drug treatment of various non-neoplastic diseases, including the use of high-dose nonsteroidal anti-inflammatory drugs; the anticonvulsants diphenylhydantoin and phenobarbital; and methotrexate used in the treatment of rheumatoid arthritis, psoriasis, asthma, and inflammatory bowel disease.

Folate deficiency may result from poor nutrient intake or poorly prepared foods ; malabsorption (hereditary folate malabsorption, celiac disease, inflammatory bowel disease, alcoholism); diseases with a high cell turnover rate (sickle cell anemia, psoriasis); inborn errors of folate metabolism (methylene tetrahydrofolate reductase, methionine synthase reductase, glutamate formiminotransferase deficiencies) ; or autoantibodies against the cerebral folate receptor in the choroid plexus.

Anemia
Anemia due to decreased folate intake usually becomes manifest under clinical conditions that have increased vitamin requirements (e.g., pregnancy, growth in infancy, chronic hemolysis). The normal infant daily requirement is 25–35microg/day. The anemia is macrocytic (mean corpuscular volume >100 fL). Variations in RBC shape and size are common . The reticulocyte count is low, and nucleated RBCs demonstrating megaloblastic morphology often are seen in the blood. Neutropenia and thrombocytopenia rarely may be present, particularly in patients with long-standing and severe deficiencies. The neutrophils are large, some with hypersegmented nuclei. The bone marrow is hypercellular because of erythroid hyperplasia, and megaloblastic changes are prominent. Large, abnormal neutrophilic forms (giant metamyelocytes) with cytoplasmic vacuolation also are seen.

Hereditary Predisposition to Thrombosis

Thromboses in children are frequently associated with a hereditary or acquired prothrombotic state. A significant number of hereditary causes of thrombosis are identified.

The newborn infant, because of the physiologic deficiency of various regulatory proteins, is particularly predisposed to both hemorrhage and thrombosis. For both anticoagulant proteins and most procoagulant factors, the more premature the infant, the greater the deficiency. The sick newborn infant is particularly at risk because interventions to provide support often include placement of large indwelling catheters into major veins or arteries. Those with hereditary deficiencies of anticoagulants may have major symptoms. After the neonatal period, young children seem to have some resistance to clinical thrombosis, even if they have a heterozygous hereditary deficiency of an anticoagulant protein. When a thrombus is identified in the young child, particularly when the family history is abnormal, a thrombotic evaluation should be initiated. In children and teenagers, thromboses are often triggered by major medical or surgical challenges.

Pathophysiology
A hereditary predisposition to thrombosis can be caused by deficiencies of the regulatory proteins protein C, protein S, antithrombin III, and plasminogen; synthesis of a procoagulant protein unable to be inhibited by its regulatory protein, factor V Leiden; elevated levels of procoagulant protein; prothrombin mutation (G20210A); and elevated levels of a toxic organic acid, homocystinemia.

Lymphopenia in Children

Lymphocytes account for about 30% of the circulating WBCs in a newborn. The proportion of lymphocytes then increases rapidly within the 1st mo, reaching an average of 60% by 2 yr of age. The normal lymphocyte count in children <2 yr of age is 3,000–9,500/?L and in adults is 1,000–4,800/?L. At 6 yr of age, the lower limit of normal is 1,500/?L.

Almost 65% of blood T lymphocytes are CD4 (helper) T lymphocytes. Most patients with lymphocytopenia have a reduction in the absolute number of T lymphocytes, particularly in the number of CD4 T lymphocytes. The average number of CD4 T lymphocytes in adult blood is 1,100/?L (range, 300–1,300/?L), and the average number of CD8 (suppressor) T lymphocytes is 600/?L (range, 100–900/?L), with the normal CD4:CD8 ratio of 1.8–2.0.

Lymphocytopenia by itself usually causes no symptoms and is often detected in the evaluation of other illnesses, particularly recurrent viral, fungal, and parasitic infections. Lymphocyte subpopulations can be measured by multiparameter flow cytometry, which uses the pattern of antigen expression to classify and characterize these cells.

Acquired Red Cell Aplasia

Acquired Pure Red Cell Aplasia (PRCA) of the adult type may be idiopathic or related to drugs, particularly phenytoin and chloramphenicol. 

Immune-mediated PRCA occurs in many idiopathic cases as well as those with thymoma, systemic lupus erythematosus, and chronic lymphocytic leukemia. 

Pathology: In vitro erythroid colony assays may reveal the presence of serum lymphocyte inhibitors of erythropoiesis, and about two-thirds will respond to immunosuppression or cytotoxic agents. RBC transfusions are the primary treatment.
B19 parvovirus infects erythroid progenitors and causes transient or chronic RBC aplasia. The chronic type occurs because of persistence of parvovirus in immunodeficient patients who cannot produce neutralizing antibody. The patients have severe transfusion-dependent anemia, and bone marrows show reduced erythroid precursors. The few RBC precursors are giant pronormoblasts. Diagnosis requires demonstration of parvovirus genome (DNA) in serum, blood, or bone marrow cells. Treatment with intravenous γ-globulin (IVIgG) is usually effective.

Transient aplastic crisis (TAC) caused by parvovirus occurs only once in patients with underlying hemolytic anemias . Occasionally, neutrophils and platelets will also be decreased. Diagnostic levels of IgM antibody appear in the first week after infection. In utero infection with parvovirus results in up to 10% fetal death during the first and second trimesters, and neonatal hydrops fetalis occurs occasionally.

Transient erythroblastopenia of childhood (TEC) is an acquired condition in previously hematologically normal children and usually involves only anemia, reticulocytopenia, and marrow erythroblastopenia. The mean age of diagnosis is 26 months, with the majority between 1 and 3 years of age. Although many patients have had an antecedent viral illness, no specific virus has been implicated, and parvovirus has usually been excluded. Pallor and tachycardia are the only relevant findings. The anemia may require one or two transfusions, but patients usually recover spontaneously within 1 to 2 months. Bone marrow shows erythroid hypoplasia, and cultures show decreased colony-forming units-erythroid (CFU-E). Serum or cellular inhibitors of erythropoiesis are often identified. TEC has an excellent prognosis, and later hematologic complications have not been reported.

Pediatric Chronic Anemia

Chronic anemia has no precise definition. Anemia that persists for 6 months or more (eg, hereditary spherocytosis [HS]) is clearly chronic; however, anemia that lasts only 2 months (eg, iron deficiency that is being treated) should also be considered chronic anemia, and other explanations must be sought.

Chronic anemia can be primary or secondary.

Primary chronic anemia
Primary chronic anemias are the true chronic anemias, in which anemia (defined as a hemoglobin level more than 2 standard deviations below the mean reference value for age) is part of the basic disease process. The basic disease process is hematologic (eg, sickle cell disease, HS), and the degree of anemia varies markedly from etiology to etiology and from patient to patient, even with the same etiology. (See Etiology and Workup.)

Secondary chronic anemia
Secondary chronic anemias are chronic anemias that may provide a diagnostic clue to an underlying pathology. They are the consequence of a nonhematologic problem (eg, chronic blood loss, chronic renal failure, osteomyelitis, inflammatory bowel disease, tuberculosis).

Etiology
Chronic anemia is classified into the following 3 primary categories:

1. Decreased red cell production
2. Increased red cell destruction (hemolysis)

Blood Components and Their Uses in Pediatrics

Many blood products are available but they have never been safe as they can transmit diseases. For this reason children should only recieve blood products when othe conservative measures have failed.

Red Blood Cells ( RBCs )
Indicated in cases of severe anemia usually when Hb is < 7 gm%. or when there is acute , severe, traumatic blood loss.

Different types include:

• Whole Blood ( rarely used )
• Packed RBCs = whole blood less 70% of plasma , most commonly used
• Leukocyte poor RBCs= for pateints with history of febrile reaction to blood products or who will recieve many transfusions
• Washed RBCs = to prevent host-versus graft disease in Ig A deficient recipients

Physiology Of Hemoglobin

Hemoglobin is a iron containing protein in the red blood cells that carries oxygen in the blood from the lungs to the rest of the body tissues. A normal hemoglobin level is necessary for the normal function of the body. If there is decreased or abnormal hemoglobin synthesis it results in number of different diseases.

Here we will discuss the brief physiology of hemoglobin in the human body which helps in understanding the diseases related to abnormal hemoglobin.

Hemoglobin Synthesis

• Erythropoietic activity is regulated by erythropoietin.
• The mitochondria of the developing erythroblast are the main sites for the sythesis of haem.
• The globin protein part is synthesized in the ribosomes .
• There are number of complex series of steps for the synthesis of hemoglobin.
• The Vitamin B6 acts as a cofactor in the process of synthesis.
• The Fe is supplied by the circulating transferrin.
• A tetramer of four globin chains, each with its own haem group attached, is formed to make a molecule of hemoglobin.

Structure and Different Types of hemoglobin
Hemoglobin has a quaternary structure characteristic of many multi-subunit globular proteins. This structure comes from its four subunits arranged roughly in a tetrahedral pattern.

HbA: In adult humans, the most common hemoglobin type is a tetramer (which contains 4 subunit proteins) called hemoglobin A, consisting of two alpha and beta subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as alpha2beta2. The subunits are structurally similar and about the same size. Hemoglobin A is the most intensively studied of the hemoglobin molecules.

Clinical Features Of Acute Leukemia In Children

Acute Lymphoblastic Leukemia is the most common childhood Leukemia. 

The Clinical Features are briefly summarized here:

1. Patients usually present with signs of bone marrow failure with anemia, Thrombocytopenia and Neutropenia.

2. Fever is also one of the most common presenting symptom in acute Leukemia.

3. Some patients complain of bone pains, arthritis and limping which is most common with B-precursor acute lymphoblastic leukemia.

4. In patients with mature B-ALL there may be signs of CNS involvement like headache, vomiting, lethargy, nuchal rigidity etc.

5. Patients with a T cell lineage ALL there may be symptoms of respiratory distress due to a mediastinal mass.

6. Easy bruising or bleeding with petechiae due to decreased platelet counts.

7. Pallor, Lethargy and tiredness due to anemia.

8. Repeated infections along with fever because of low white cell count.

Clinical Signs And Symptoms Of Thalassemia Major

Thalassemia major is a type of hemolytic anemia that is cause by a mutation in the Beta chain of hemoglobin that causes lysis of the red blood cells , decreased hemoglobin and resulting in anemia. This is a genetic condition that is passed from parents to children.

Pathophysiology: Normal adult hemoglobin has two beta chains and two alpha chains. In patients with Thalassemia major there is no normal gene for beta chain synthesis and thus there is no normal production of hemoglobin A. This leads to a significant anemia and illness.

Clinical Signs And Symptoms:

1. At birth a baby with thalassemia major seems to be completely normal, healthy and active, It is because at birth the predominant hemoglobin is the fetal hemoglobin that does not need the synthesis of beta chain.

2. Later on within the first few months after birth when the body starts to replace fetal hemoglobin with adult hemoglobin symptoms begin to appear gradually. Anemia begins to get progressively more and more severe.

3. The child fails to grow normally and shows signs of severe fatigue and lethargy. The child may have difficulties with feeding due to easy fatigue because of lack of oxygen and underlying severe anemia.

4. The child may look pale and may have repeated attacks of fever and diarrhea.

5. Liver and spleen are enlarged leading to a distended abdomen.