heriditary anemias and anemia at birth

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Slide 1: 


Definitions : 

Definitions Anemia: Central venous hemoglobin < 13 g/dL or capillary hemoglobin < 14.5 g/dL in infant > 34 weeks and 0-28 days old Average value for central venous hemoglobin at birth for > 34 weeks GA is 17 g/dL Reticulocyte count in cord blood 3-7% Average mean corpuscular volume 107 fL

Physiologic anemia of infancy : 

Physiologic anemia of infancy In healthy term infants, hemoglobin levels begin to decline around the third week of life Reach a nadir of 11 g/dL at 8-12 weeks

Differences in premature infants : 

Differences in premature infants At birth they have slightly lower hemoglobin levels, and higher MCV and retic counts The nadir is lower and is reached sooner Average nadir is 7-9 g/dL and is reached at 4-8 weeks of age Related to a combination of decreased RBC mass at birth, increased iatrogenic losses from lab draws, shorter RBC life span, inadequate erythropoietin production, and rapid body growth

Pathophysiology : 

Pathophysiology Anemia in the newborn results from three processes Loss of RBCs: hemorrhagic anemia Most common cause Increased destruction: hemolytic anemia Underproduction of RBCs: hypoplastic anemia

Hemorrhagic anemia : 

Hemorrhagic anemia Antepartum period (1/1000 live births) Loss of placental integrity Abruption, previa, traumatic amniocentesis Anomalies of the umbilical cord or placental vessels Velamentous insertion of the cord in twins, communicating vessels, cord hematoma, entanglement of the cord Twin-twin transfusion syndrome Only in monozygotic multiple births 13-33% of twin pregnancies have TTTS Difference in hemoglobin usually > 5 g/dL Congestive heart disease common in anemic twin and hyperviscosity common in plethoric twin

Hemorrhagic anemia : 

Hemorrhagic anemia Intrapartum period Fetomaternal hemorrhage (30-50% of pregnancies) Increased risk with preeclampsia-eclampsia, need for instrumentation, and c-section C-section: anemia increased in emergency c-section Traumatic rupture of the cord Failure of placental transfusion due to cord occlusion (nuchal or prolapsed cord) Obstetric trauma causing occult visceral or intracranial hemorrhage

Hemorrhagic anemia : 

Hemorrhagic anemia Neonatal period Enclosed hemorrhage: suggests obstetric trauma or severe perinatal distress Caput succedaneum, cephalhematoma, intracranial hemorrhage, visceral hemorrhage Defects in hemostasis Congenital coagulation factor deficiency Consumption coagulopathy: DIC, sepsis Vitamin K dependent factor deficiency Failure to give vit K causes bleeding at 3-4 days of age Thrombocytopenia: immune, or congenital with absent radii Iatrogenic blood loss due to blood draws

Presentation of hemorrhagic anemia : 

Presentation of hemorrhagic anemia Acute hemorrhagic anemia Pallor without jaundice or cyanosis and unrelieved by oxygen Tachypnea or gasping respirations Decreased perfusion progressing to hypovolemic shock Decreased central venous pressure Normocytic or normochromic RBC indices Reticulocytosis within 2-3 days of event

Presentation of hemorrhagic anemia : 

Presentation of hemorrhagic anemia Chronic Pallor without jaundice or cyanosis and unrelieved by oxygen Minimal signs of respiratory distress Central venous pressure normal Microcytic or hypochromic RBC indices Compensatory reticulocytosis Enlarge liver d/t extramedullary erythropoiesis Hydrops fetalis or stillbirth may occur

Presentation of other forms : 

Presentation of other forms Twin-twin transfusion Growth failure in the anemic twin, often > 20% Occult internal hemorrhage Intracranial: bulging anterior fontanelle and neurologic signs (altered mental status, apnea, seizures) Visceral hemorrhage: most often liver is damaged and leads to abdominal mass Pulmonary hemorrhage: radiographic opacification of a hemithorax with bloody tracheal secretions

Hemolytic anemia : 

Hemolytic anemia Immune hemolysis: Rh incompatibility or autoimmune hemolysis Nonimmune: sepsis, TORCH infection Congenital erythrocyte defect G6PD, thalassemia, unstable hemoglobins, membrane defects (hereditary spherocytosis, elliptocytosis) Systemic diseases: galactosemia, osteopetrosis Nutritional deficiency: vitamin E presents later

Presentation of hemolytic anemia : 

Presentation of hemolytic anemia Jaundice is usually the first symptom Compensatory reticulocytosis Pallor presents after 48 hours of age Unconjugated hyperbilirubinemia of > 10-12 mg/dL Tachypnea and hepatosplenomegaly may be present


ALLOIMMUNE HA Hemolytic disease of newborn Hemolytic transfusion reactions


ALLOIMMUNE HA - NEWBORN Maternal alloantibodies form after Rhd-negative maternal RBCs exposed to Rhd-positive fetal blood Antibodies cross placenta and destroy fetal RBCs Anemia Fetal hydrops Death Jaundice

ALLOIMMUNE HEMOLYSISHemolytic Disease of the Newborn : 

ALLOIMMUNE HEMOLYSISHemolytic Disease of the Newborn Due to incompatibility between mother negative for an antigen & fetus/father positive for that antigen. Rh incompatibility, ABO incompatibility most common causes Usually occurs with 2nd or later pregnancies Requires maternal IgG antibodies vs. RBC antigens in fetus

ALLOIMMUNE HEMOLYSISHemolytic Disease of the Newborn - #2 : 

ALLOIMMUNE HEMOLYSISHemolytic Disease of the Newborn - #2 Can cause severe anemia in fetus, with erythroblastosis and heart failure Hyperbilirubinemia can lead to severe brain damage (kernicterus) if not promptly treated HDN due to Rh incompatibility can be almost totally prevented by administration of anti-Rh D to Rh negative mothers after each pregnancy

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Kliehauer Test For Hb F


HEREDITARY HEMOLYTIC ANEMIA Characterized by: Defects of hemoglobin Defects of the RBC membrane Results in premature destruction of red cells


TYPES OF HEREDITARY HA Membrane abnormlities    Membrane skeleton proteins: spherocytosis,elliptocytosis,stomatocytosis        Membrane lipids: abetalipoproteinemia     Enzyme deficiencies Glycolytic enzymes: pyruvate kinase, hexokinase Enzymes of Hexose monophosphate shunt: glucose-6-phosphate dehydrogenase, glutathione synthetase Enzyme def. of red cell nucleotide metabolism: Pyrimidine-5’-nucleotidase deficiency Disorders of hemoglobin  synthesis    Deficient globin synthesis: thalassemia syndromes        Structurally abnormal globin synthesis (hemoglobinopathies): sickle cell anemia, unstable hemoglobins


SICKLE CELL DISEASE Inherited Autosomal recessive trait Disease seen in patients who are homozygous for the sickle cell gene (Hbss)


SICKLE CELL ANEMIA Sickle cell trait in 8% of the U.S. Black population People with trait have a normal life span and usually asymptomatic Sickle cell trait thought to be protective against malaria


SCD - PATHOPHYSIOLOGY Hemoglobin S caused by mutation of ß chain; substitution of valine for glutamine at position 6 of β-globin chain Deoxygenated hemoglobin S polymerizes, which deforms RBC and causes sickled appearance Sickled cell increases viscosity of blood, obstructs microvasculature resulting in vaso-occlusive crisis

Where Do Sickle Cells Come From? : 

Where Do Sickle Cells Come From? Sheared in microcirculation


SCD – CLINICAL SX Pts are functionally asplenic after early childhood, at risk for serious infection from encapsulated organisms(H. influenza & pneumococci) Pts may have CHF, CM, cor pulmonale, leg ulcerations, icterus & hepatomegaly Pts with ACS will have pulmonary symptoms: fever, cough, chest pain and pulmonary infiltrate.


SCD – CLINICAL SX Neurologic symptoms: cerebral infarct in kids, hemorrage in adults; TIA, seizures, coma Priapism Swelling of hands & feet due to vaso-occlusion Infarction of renal medulla, associated with flank pain and hematuria


SCD – DIAGNOSIS SCD usually diagnosed early in pt life Prescence of sickling RBCs on peripheral blood smear is diagnostic Sickling test Drop in Hb by 2 g/dl from baseline suggests acute aplastic crisis Retic count – count less than baseline of 5-15% may reflect aplastic crisis Leukocytosis with left shift – infection maybe cause of crisis

Sickle Cells : 

Sickle Cells


THALASSEMIAS Microcytic, hypochromic, hemolytic anemia Most common in African, Mediterranean, Middle eastern & Southeast Asian descent Multiple variants


THALASSEMIAS Defective synthesis of globin chains Unable to produce normal adult hemoglobin Trait thought to be protective against malaria

βThal Major anisocytosis, poikilocytosis, targets, fragments, hypochromaia, basophilic stippling. : 

βThal Major anisocytosis, poikilocytosis, targets, fragments, hypochromaia, basophilic stippling.

Quantitative hemoglobin analysis : 

Quantitative hemoglobin analysis Alkali denaturation test for quantification of fetal hemoglobin Acid elution test for fetal hemoglobin distribution Dithionite tube test- Solubility testing Flow cytometry

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HPLC Hb electrophoresis

An aproach to diagnosis of thal. syndromes : 

An aproach to diagnosis of thal. syndromes History (Race, family ,age of onset, development) Examination (pallor, jaundice, spleen+, bone, skin) CBC & PS (Hb, MCV, MCH, retic, RBC inclusion) Hb electrophoresis (Abnormal Hb, HbH, Hb Barts) HbA2 & HbF estimation (to confirm Beta thal) intracellular distribution Globin chain synt. Hb variants of HbF Eg. Hb Lepore


G6PD DEFICIENCY Most common human enzyme defect X-linked disorder Affects 15% of U.S. Black males Decrease in glutathione levels


G6PD DEFICIENCY Heinz bodies seen on peripheral blood smear Neonatal jaundice 1-4 days after birth in severe variants Increase incidence of pigmented gallstones and splenomegaly


G6PD DEFICIENCY Acute hemolytic crisis due to: Bacterial/viral infection Oxidant drugs (sulfamethoxazole) Metabolic acidosis (DKA) Renal failure Ingestion of fava beans


G6PD DEFICIENCY Diagnosis – Screening: Fluorescent screening test Methemoglobin reduction test Quantitative assay detecting low enzyme Treatment – supportive and preventative


HEREDITARY SPHEROCYTOSIS RBC membrane defect Autosomal dominant Mutations in spectrin and ankyrin (membrane proteins)


HEREDITARY SPHEROCYTOSIS Spherocytes – in peripheral blood smear Spherocytes unable to pass through the spleen Severe cases require a splenectomy


HEREDITARY SPHEROCYTOSIS Neonatal jaundice in 1st week occurs in 30-50% of HS pts Anemia, splenomegaly, jaundice, and transfusions needed vary depending on severity of disease

Diagnosis : 

Diagnosis Osmotic fragility test Incubated Osmotic fragility test Autohemolysis test Glycerol lysis test Membrane protein analysis SDS-PAGE Densitometry of protein bands on gel

Hypoplastic anemia : 

Hypoplastic anemia Congenital Fanconi anemia, Diamond-Blackfan syndrome, congenital leukemia, sideroblastic anemia Acquired Infection: Rubella and syphilis are the most common Aplastic crisis, aplastic anemia

Clinical presentation : 

Clinical presentation Determine the following factors Age at presentation Associated clinical features Hemodynamic status of the infant Presence or absence of compensatory reticulocytosis

Presentation of hypoplastic anemia : 

Presentation of hypoplastic anemia Uncommon Presents after 48 hours of age Absence of jaundice Reticulocytopenia

Fanconi Anemia : 

Fanconi Anemia

History: Guido Fanconi : 

History: Guido Fanconi Fanconi Anemia (Fanconi pancytopenia syndrome): 1927 - 3 brothers with pancytopenia and physical abnormalities, “perniziosiforme” Fanconi Syndrome (renal Fanconi syndrome): 1936 – Rickets, growth retardation, proteinuria, glucosuria, and proximal renal tubular acidosis

Fanconi Anemia (FA) : 

Fanconi Anemia (FA) Rare (< 1/ 100,000 births) Autosomal recessive Many physical features But up to 20-25% will have no physical findings Mean age at diagnosis: 7.8 yrs

Autosomal Recessive Inheritance : 

Autosomal Recessive Inheritance

FA- Clinical : 

FA- Clinical

Clinical Features : 

Progressive bone marrow failure Most common etiology of inherited bone marrow failure Others include Dyskeratosis congenita Amegakaryocytic thrombocytopenia Schwachman-Diamond syndrome Increased risk of MDS and AML (15,000x) Many have monosomy 7 or duplication of 1q Clinical Features

Clinical Features : 

Clinical Features Increased risk of solid tumor Hepatic, Esophageal, Oropharyngeal, Vulvar Average age at diagnosis is 23 Cumulative incidence ~30% by age 45

FA - genetics : 

FA - genetics Identification of subtypes (compliment groups) A, B, C, D1, D2, E, F, G Identical clinically Sub-units of a common protein/ common pathway Protein :FANCD2 FANCD2 interacts with BRCA1 and BRCA2 BRCA1 and BRCA2: needed for DNA repair


PATHOPHYSIOLOGY DNA damage activates a complex consisting of Fanconi proteins A, C, G, and F. This in turn leads to the modification of the FANCD2 protein. This protein interacts, for example, with the breast cancer susceptibility gene BRCA1.

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Fanconi anemia cells are characterized by Hypersensitivity to chromosomal breakage Hypersensitivity to G2/M cell cycle arrest induced by DNA cross-linking agents. In addition there is sensitivity to oxygen-free radicals and to ionizing radiation.

Diagnosis : 

Diagnosis Pts. with congenital abnormalities are often diagnosed as neonates/infants Others may be diagnosed when hematological problems occur Median age of onset of pancytopenia is 7 Usually normal CBC at birth First develop macrocytosis, then thrombocytopenia, and eventually neutropenia

Diagnosis : 

Diagnosis Based on chromosomal hypersensitivity to cross- linking agents Chromosome fragility test: Mitomycin C (MMC) or diepoxybutane (DEB) added to lymphoctyes – increases the number of chromosome breaks and radial structures Very specific for FA, regardless of severity of disease Can do chromosome breakage analysis on amniotic cells, chorionic villus cells or fetal blood

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Chromosome breakage in Fanconi Anemia cells FA cells were treated with mitomycin C and harvested in metaphase. Typical abnormalities include radial formation (green circle) and chromosome breaks (red arrows).

Management : 

Management Bone marrow failure Transfusions Androgens (e.g. oral oxymethalone) Can improve blood counts in 50% of pts. Growth factors (G-CSF, CM-CSF) Should not be used in patients with clonal cytogenetic abnormalities Bone marrow transplantation Gene therapy


DIAMOND BLACKFAN ANEMIA (DBA) Type of single cell cytopenia /pure red cell aplasia Presents early in infancy 75% sporadic AD:majorityof inherited cases, 25% have mutation in gene for small ribosomal protein (RPS19) located at band 19q13.2, equal sex frequency,fewer physical abnormalities Other inherited :M>F( Implying X-linked form of disease


DIAGNOSTIC CRITERIA OF DBA 90%Cases:Normochromic usually macrocytic but occasionally normocytic anemia(in 1st yr of life) Profound reticulocytopenia Normocellular bone marrow with selective ,marked deficiency of red cell precursors ↑ levels of erythropoietin normal/slightly↓WBC count Normal or often ↑platelet count


GENETICS & PATHOGENESIS X-linked inheritance (X:19 chromosome translocation) Defect of erythroid progenitor cells


CLINICAL PRESENTATION Pallor :2-4 months Congenital anomalies : 25-30% of cases -Thumb malformations (subluxation, supernumerary, bifid, triphalangeal, flat thenar eminence with/without absent radial pulse) -Craniofacial anomalies(cleft/high arched palate, hypertelorism with flat nasal bridge, strabismus, ptosis, cataracts) -Urogenital anomalies/multiple abnormalities


THERAPY Corticosteroids Regular transfusion Hematopoeitic growth factors Allogenic BMT


DYSKERATOSIS CONGENITA Triad: Abnormal skin pigmentation Nail dystrophy Mucosal leukoplakia Non-cutaneous abnormalities dental, genitourinary, gastrointestinal, neurological ophthalmic, pulmonary & skeletal >80%:Males(X-linked form of disease) DKC1 gene mutations in 40% pts.

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Unbalanced chromosomal rearrangements -Cells with a high turnover (BM,skin,git) accumulate progressive DNA damage→BM failure + epithelial abnormalities Somatic abn.: later age Mucocutaneous features :appear at age of 5-10 yrs. Haematologic abn.: BM failure resulting in peripheral cytopenia Rx:Androgens, G-CSF,GM-CSF,BMT

Swachman Diamond Syndrome : 

Swachman Diamond Syndrome BM failure(classically neutropenia) + exocrine pancreatic insufficiency AR: Mutation in Shwachman Bodian Diamond syndrome gene(SBDS) located at band 7q11 M:F=1.8/1 Cartilage & hair hypoplasia→ short stature & metaphyseal dysostosis ( manifests in early childhood) Leukemia(12-25%),MDS


CONGENITAL DYSERYTHROPOIETIC ANEMIA A group of disorders characterized by a congenital defect in erythropoiesis and reticulocytosis resulting in erythroblast multinuclearity and anemia. Considered to be one of at least 3 disorders where there is a congenital deficiency in erythroid precursors other congenital cytopenias: Diamond-Blackfan Syndrome AASE Syndrome

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Age of onset: infancy to adulthood mean age: 15 years (Types I and II), 22 years (Type III) Risk factors: Familial Autosomal recessive (Types I and II) Autosomal dominant (Type III) Sex Type I - M > F (1.25:1), Type II - M = F, Type III - M > F (1.9:1)

Genetic Defect(s) : 

Genetic Defect(s) Genetic defect(s) -> ineffective and morphologically abnormal erythropoiesis (dyserythropoiesis) -> block at the mature erythroblast level (normal proerythroblasts with erythroid hyperplasia) but abnormal mature erythroblasts (polychromatophilic and orthochromatic erythroblasts)


CLINICAL FEATURES Type I (15% of cases) mild to moderate anemia jaundice (+/- icterus), moderate splenomegaly Type II (60-65% of cases) mild to severe anemia jaundice, hepatosplenomegaly (hepatomegaly) Type III (20-25% of cases) mild to moderate anemia hepatosplenomegaly


INVESTIGATIONS Type I: Hb: macrocytic (mean = 90 g/L), low reticulocytes normal WBC and platelets smear - anisocytosis, poikilocytes, punctate basophilia, helmet and tadpole cells, Cabot's rings Elevated bilirubin (indirect), LDH

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Type II: Hb: normocytic (mean = 65 g/L), low reticulocytes smear - anisocytosis, poikilocytosis, tear drops, basophilic stippling pathognomonic - Type II CDA RBC's are lysed by 30% of acidified sera from normal individuals (these RBC's have a specific HEMPAS antigen while normal sera contain an anti-HEMPAS IgM antibody) presence of fetal membrane antigen i

Slide 90: 

Type III: Hb: macrocytic (mean = 80 g/L), low reticulocytes smear - anisocytosis, poikilocytosis, basophilic stippling

Bone Marrow : 

Bone Marrow Type I Dissociation of nuclear and cytoplasmic maturation (i.e., immature nuclear maturation) Immature megaloblastoid nuclei Binucleated Internuclear chromatin bridges

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Type II Bi- and multinucleated mature erythroblasts Double cytoplasmic membrane (excess rER) Karyorrhexis, pluripolar mitoses Type III Multinucleated mature erythroblasts Gigantoblasts (up to 12 nuclei per erythroblast)


MANAGEMENT Supportive PRBC transfusions, splenectomy (Type II) Hemosiderosis prophylactic phlebotomy iron chelators


SIDEROBLASTIC ANEMIAS Heterogeneous group of disorders with two common features: Ring sideroblasts in the bone marrow (abnormal normoblasts with excessive accumulation of iron in the mitochondria) Impaired heme biosynthesis The mitochondrion is the nexus of sideroblastic anemia Disturbed mitochondrial metabolism is at the center of all sideroblastic anemias

Slide 98: 

The common feature of these causes is a failure to completely form heme molecules, whose biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the mitochondria that form a ring around the nucleus of the developing red blood cell.

X-linked sideroblastic anemia : 

X-linked sideroblastic anemia In 1945, Thomas Cooley described the first cases of X-linked sideroblastic anemia. Although rare, the disorder nonetheless is the most common of the hereditary sideroblastic anemias. The more frequent of the two known genetic defects involves the ALAS-2 gene. The second consists of abnormalities in the Xq13 region of the X chromosome .

Slide 100: 

Decreased biosynthesis and/or activity of ALAS and consequently lower heme production. The net result is low hemoglobin production by the developing normoblasts and anemia. Ineffective erythropoiesis results from the imbalance between heme biosynthesis and globin chain production.

Slide 101: 

Hereditary X-linked sideroblastic anemia usually occurs in males, of course. Cases involving females in a pedigree derive most often from skewed lyonization patterns in the affected girls

Other hereditary forms : 

Other hereditary forms Reports exist of both autosomal dominant and autosomal recessive modes of transmission of hereditary sideroblastic anemia . The genes involved in these cases remain elusive. Some investigators postulate that the products of the affected genes somehow dampen the biosynthesis or the activity of ALAS with a consequent diminution of heme production.

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The anemia is moderate to severe and dimorphic with marked anisocytosis and poikilocytosis. The MCV is decreased (i.e., a microcytic anemia). The RDW is increased with the red blood cell histogram shifted to the left. Basophilic stippling is marked Target cells are common. Pappenheimer bodies are present. Leukocytes and platelets are normal.

Slide 104: 

Bone marrow shows erythroid hyperplasia with a maturation arrest. In excess of 40% of the developing erythrocytes are ringed sideroblasts. Stainable marrow hemosiderin is increased. Specific test: Prussian Blue stain of RBC in marrow. Shows ringed sideroblasts. Serum iron, percentage saturation and ferritin are increased. The TIBC is normal to decreased.

Diagnosis of neonatal anemia : 

Diagnosis of neonatal anemia Initial studies Hemoglobin RBC indices Microcytic or hypochromic suggest fetomaternal or twin-twin hemorrhage, or a-thalassemia Normocytic or normochromic suggest acute hemorrhage, systemic disease, intrinsic RBC defect, or hypoplastic anemia Reticulocyte count suggests antecedent hemorrhage or hemolytic anemia while is seen with hypoplastic anemia

Diagnosis : 

Diagnosis Initial studies continued Blood smear looking for spherocytes (ABO incompatibility or hereditary spherocytosis) elliptocytes (hereditary elliptocytosis) pyknocytes (G6PD) schistocytes (consumption coagulopathy) Direct Coombs test: positive in isoimmune or autoimmune hemolysis

Other diagnostic studies : 

Other diagnostic studies Blood type and Rh in isoimmune hemolysis Kleihauer-Betke test on maternal blood looking for fetomaternal hemorrhage CXR for pulmonary hemorrhage Bone marrow aspiration for congenital hypoplastic or aplastic anemia TORCH: bone films, IgM levels, serologies, urine for CMV DIC panel, platelets looking for consumption Occult hemorrhage: placental exam, cranial or abdominal ultrasound Intrinsic RBC defects: enzyme studies, globin chain ratios, membrane studies

Management : 

Management Simple replacement transfusion Indications: acute hemorrhage Use 10-15 ml/kg O, RH- packed RBCs or blood cross-matched to mom and adjust hct to 50% Give via low UVC or central UVC if time permits Draw diagnostic studies before transfusion ongoing deficit replacement maintenance of effective oxygen-carrying capacity Hct < 35% in severe cardiopulmonary disease Hct < 30% in mild-moderate cardiopulmonary disease, apnea, symptomatic anemia, need for surgery Hct < 21%

Management : 

Management Exchange transfusion Indications Chronic hemolytic anemia or hemorrhagic anemia with increased central venous pressure Severe isoimmune hemolytic anemia Consumption coagulopathy Nutritional replacement: iron, folate, vitamin E

Prophylactic management : 

Prophylactic management Erythropoietin Increased erythropoiesis without significant side effects Decreases need for late transfusions Will not compensate for anemia due to labs Need to have restrictive policy for blood sampling and micromethods in the lab Nutritional supplementation: iron, folate, vitamin E

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