MitzMitzMitzMitz

1

ANEMIA Pedia II

Anemia – diminution in the ff: 2SD below the mean

• Circulating RBC

• Hct

• Red cell count - occurs when erythropoeisis fails to compensate Non-specific symptoms Anemia

• Fatigue

• Dyspnea

• Exertional dyspnea

• Dec. Exercise tolerance � If anemia develops rapidly, symptoms will be more pronounced � If anemia develops very slowly, symptoms may be minimal even

though the anemia may be profound. Physical examination

• Pallor of face, nailbeds, palms

• Tachycardia

• Flow murmurs The initial diagnostic approach to the anemic patient includes a detailed history and physical examination and a minimum of essential laboratory tests Historical Factors of Importance in Evaluating Patients with Anemia

Age Double birthweight

Sex x-linked disorders

Race G6PD Asians & Filipinos α thalassemia genes – may present with jaundice β – Mediterranean

Ethnic

Neonatal

Diet For hemoglobin production Fe

++, Folic Acid, Vit B12

Drugs Chloramphenicol – ↓ production Cotrimoxazole – ↑destruction Or any w/ sulfa

Infection Malaria – can cause hemolysis Hepa B, C – notorious for acquired aplastic anemia IM Monocytosis & sometimes thrombocytopenia

Inheritance G6PD Thalassemia

Diarrhea Malabsorption Occult blood loss

Physical Findings as Clues to the Etiology of Anemia

Skin • Hyperpigmentation, petechiae

• purpura

• jaundice

• Fanconi’s aplastic anemia

• AIHA w/ thrombocytopenia

• Hemolytic anemia

• Hepatitis Facies • Frontal bowing?,

prominence of molar & maxillary bone

• Congenital hemolytic anemia

• Thalassemia major

• Severe IDA Mouth • Glossitis

• angular stomatitis

• Vit B12 def.

• Iron deficiency

Hands • Triphalangeal thumbs

• hypoplasia of thenar eminence

• spoon nails

• Red cell aplasia

• Fanconi’s aplastic anemia

• IDA

Spleen • Enlargement • Congenital hemolytic anemia

• Leukemia

• Lymphoma

• Acute infection

• Portal hypertension Initial Laboratory Tests

• Hgb, Hct

• Red cell indices

• Platelet count

• White cell count & differential

• Reticulocyte count

• Examination of Peripheral smear The examination of the blood smear is the single most useful procedure in the initial evaluation of patients with anemia.

Two Main Classifications of Anemia

I. Morphologic classification – based on red cell size, MCV Normochromic, normocytic Hypochromic, microcytic Macrocytic

II. Physiologic Classification Anemias due to red cell underproduction Anemias due to increase red cell destruction Anemia of blood loss Sequestration in spleen

Red Cell Values for Different Age

Age Hgb g/dL Hct% MCV Retic

Birth 13.5 – 20 42 – 60 98 – 118 1.8 – 4.6

3-6 months

9.5 – 13.5 28 – 42 74 – 108 0.4 – 1.0

0.5 – 2 yrs 10.5 – 13.5 33 – 39 70 – 86 0.2 – 1.8

6 – 12 yrs 11.5 – 15.5 35 – 45 77 – 95 0.2 – 1.8

12 – 18 yrs M F

13 – 16 12 – 16

37 – 49 36 – 46

78 – 98 78 – 102

0.2 – 1.8

18 – 49 yrs M F

13.5 – 17.5 12 – 16

41 – 53 36 – 46

80 – 100 80 – 100

0.2 – 1.8

RED CELL INDICES

Hematocrit x 10 MCV (fl) =

RBC/ul - directly derived from automated blood counter - most reliable - Average size of individual RBC

Hemoglobin x 10

MCH (pg) = RBC/ul

- Expression of absolute units of hemoglobin contained in rbcs

Hemoglobin x 100

MCHC (g/dl) = Hematocrit

- Express mean concentration of Hb

Anemia

MCV

Low Normal High

Iron deficiency Thalassemia Lead Poisoning Chronic Disease

Folate Deficiency Vit B12 deficiency Aplastic anemia Preleukemia Immune Hemolysis Liver Disease

Reticulocyte count

High Low

High bilirubin BM defect

Hemolytic Anemia

Maturation Time in Days

Hematocrit %

Marrow normoblasts & reticulocytes

Blood reticulocytes

45 3.5 1.0

35 3.0 1.5

25 2.5 2.0

15 1.5 2.5

Number of days for maturation of reticulocytes of the marrow & blood. The duration of maturation in blood reticulocytes is taken as is. Corrected Reticulocyte count

Observed Hct Retic count (%) X

Normal Hct for Age Reticulocyte production index N: ≥2

1 Corrected Retic count (%) X

Maturation time *maturation time depends on Hct level (see Nelson)

MitzMitzMitzMitz

2

Hemolytic Anemia

Coomb’s Test Negative Positive

Corpuscular Extracorpuscular Extracorpuscular

Hemoglobinopathies Enzymopathies Membrane defects

Morphology Autohemolysis Osmotic Fragility

AUTOIMMUNE HEMOLYTIC ANEMIA

• Primary

• Secondary (CT disease, drugs, infection)

• Isoimmune Hemolytic disease

Rh, ABO, mismatched transfusion

HEMATOPOEISIS

• Competent microenvironment – BM failure/infiltration

• Growth Factors – EPO

• Nutrients Vitamin B12 Folic acid – essential in the formation of thymidine

triphosphate for DNA synthesis

• Porphyrin, globin, iron ANEMIA OF INADEQUATE PRODUCTION

PURE RED CELL APLASIA

- Congenital (DBA) � Intrinsic hematopoetic stem cell defect where erythroid

progenitors & precursors are highly sensitive to death by apoptosis

� Dominant inheritance in majority of cases - Acquired (TEC)

� Usually occurs after a non specific viral illness producing serum (IgG) and cellular (mononuclears) inhibitors of erythropoesis.

Difference between DBA & TEC

Features DBA TEC

Frequency Rare (5-10/106 live

births) Common

Age at dx 90%, by 1yr 25%, at birth or w/n 2 mos

6 mo-4 yrs Occas. older

Etiology Genetic Acquired (viral, idiopathic)

Familial Yes (in 10-20% of cases)

No

Antecedent Hx None Viral illness

Congenital abnormality

Present 50% cases (heart, kidneys, musculoskeletal)

Absent

Course Prolonged, 20% actuarial probability of remission

Spontaneous recovery in weeks to months

Transfer dependence

Transfer or steroid dependent

Not dependent

MCV (for age) Macrocytic Normocytic

Hb F (for age) Elevated chronic Normal

I Ag Elevated Usually normal Erythrocyte adenosine deaminase

Elevated (dec 85% of cases)

Not elevated

Treatment PRBC transfusion Prednisone 2mkd & taper to lowest effective dose Stem cell transplantation

PRBC transfusion, if required

APLASTIC ANEMIA

- Congenital (Fanconi anemia) � Hypersensitivity to chromosomal breakage � Autosomal recessive, generally associated with multiply

congenital abnormalities - Acquired

� Results from immunologically mediated, tissue-specific, organ-destructive mechanism

� IFN δ messenger RNA and ↑ number of activated cytotoxic lymphocytes

Difference between Fanconi Anemia & TAR

Features Fanconi Anemia Aquired AA

Age of onset of hema sxs

Median 7 yrs Infancy to adulthood

Low birth weight -10% N/A

Stature Short Normal

Skel deform Absent rad? LE deform

66% 0

-40% N/A

Anomalous pigmentation of skin

77% cafe au lait spots

N/A

Hemangiomas 0 10%

Mental retardation 17% 7%

Peripheral blood Pancytopenia Macrocytosis

Dec. Platelet, eosinophilia, leukemoid reaction, anemia

BMA

Aplastic

Absent megakaryocyte Normal myeloid & erythroid precursors

Marrow CFU-GM, CPU-E

Decreased Normal

HbF Increased Normal

Chromosomal breaks in leukocytes

Present None

Malignancy Common Rare N/A

Sex ratio (M/F) 1:1 1:1

Inheritance pattern Autosomal recessive

Autosomal recessive

Associated leukemia

Yes Rare Preleukemic stage

Prognosis Poor 80% survival rate

Aquired Aplastic Anemia

- BM failure results from immunologically mediated, tissue-specific, organ-destructive mechanism

- IFN δ messenger RNA, undetectable in most patients with AA - ↑ number of activated cytotoxic lymphocytes are present in the

blood and BM - Tx w/ ATG & Cyclosporine ↓ cytotoxic cells - Immunosuppressive tx improves pancytopenia

Causes

- Idiopathic (70%) or more of cases, 30% identifiable - Secondary ◦ Drugs.

Predictable, dose dependent, rapidly reversible

unpredictable, normal doses

6MP MTX cyclophosphamide busulfan chloramphenicol

antibiotics – chloramphenicol, sulfonamides anticonvulsants – mephentoin, hydantoin antirheumatics – phenybutazone, gold antidiabetics – tolbutamide, chlorpropamide antimalarial - quinacrine

◦ Chemicals: insecticides ◦ Toxins (benzene, carbon tetrachloride, glue) ◦ Irradiation – high dose (AA/radiation induced malignancy) ◦ Infections: viral heap (a, b, c, etc), HIV, infectious mono,

measles, mumps, rubella, chronic parvovirus ◦ Immunoopathologic dse ◦ Malnutrition ◦ Pregnancy

Clinical Findings

- Anemia – pallor, easy fatigability, weakness - Thrombocytopenia – bleeding (fever) - Leukopenia – infections, oral ulcers - Hepatosplenomegaly & lymphadenopathy do not occur � NO

ORGAN ENLARGEMENT IN AA - Hyperplastic gingivitis is also a symptom of AA

(bec of some infection � AML M4, M5) Lab findings

- pancytopenia (normochromic or macrocytic) - reticulocytopenia - fetal hgb – maybe elevated - BM – replaced by fatty tx - Chromosomal blockage assay: normal (to r/o FA)

Severe AA

- BM cellularity <25% - And at least 2 of the ff

o Anc <500/mm3 o Pc < 20,000/mm3 o Retic count < 40,000/mm3

MitzMitzMitzMitz

3

Treatment - supportive care - for severe AA

o BM transplantation o Immunosuppressive treatment

ANEMIA OF CHRONIC DISEASE AND RENAL DSE

- associated with infections, inflammation or tissue breakdown (pyogenic inflammation)

� release of IL1 and TNF leading to production of IFN B and IFN gamma

- s/sx those of underlying dse - normocytic, normochromic (unless there’s iron deficiency) - lab: NNRBC, retic count normal or low

� leukocytosis common � serum ferritin maybe elevated

• does not mean you are replete with iron � diagnostic feature: serum iron low, TIBC low to normal

- Anemia of Renal Dse � Dec production of EPO � Normocytic normochromic � Microcytic hypochromic if there is concomitant IDA in Px

undergoing dialysis IRON DEFICIENCY ANEMIA

- 60% of iron is in the circulating hemoglobin - 15 to 20% is stored in reticuloendothelial system

� if needed can be delivered into plasma -> bone marrow - use only 1-2mg of iron per day - same amt of iron is absorbed from the GIT - increased blood loss / inc demand for iron -> IDA - most common cause of anemia - peak prev occurs in late infancy and early childhood

� period of rapid growth � low levels of dietary iron � complicating effect of cow’s milk (exudative enteropathy)

- second peak: adolescence - causes:

� deficient intake � increased demand � blood loss � impaired absorption

Tissue effects of IDA

- GIT – anorexia, pica, atrophic glossitis, leaky gut syndrome (exudative enteropathy)

- CNS – irritability, conduct disorder, dec cognitive function - CVS – inc HR and CO, cardiac hypertrophy, inc plasma

volume - Immunologic – inc propensity to infection

DX

- low Hb - low RBC indices, high RDW - retic count usually normal; if associated with bleeding, retic

count of 3-4% may occur - platelet – low in severe IDA, high if with GI bleeding - free erythrocyte protoporphyrin – high - low serum ferritin (<12ng/ml) - serum iron low, serum transferrin high - therapeutic trial – most reliable criterion

Stages

• Iron depletion - Storage iron is absent or decreased - Normal serum Fe concentration & Hgb levels

• Iron deficiency without anemia - Decreased or absent storage iron - Low serum iron concentration - Low transferrin - No frank anemia

• Iron deficiency anemia - Low Hgb/Hct values

Clinical consequences of Iron deposition

1. cardiac abnormalities 2. hepatic abnormalities 3. endocrine abnormalities

a. growth retardation b. failure of sexual maturation c. subclinical hypothryoidism d. diabetes mellitus e. hypoparathyroidism

MEGALOBLASTIC ANEMIAS - folate – green veggies, fruits, animal organs - clinical manifestation: sign and symptoms of anemia - Lab

� Macrocytic RBC � Low retic count � Nucleated RBC in PBS � Hypersegmented neutrophils � Low serum and RBC folate � BMA – erythroid hyperplasia

Vit B12 – from animal sources

- older children – sufficient stores 3-5 years - infants born to mothers with low B12 – 4-5 months - clinical manifestations

� signs and symptoms of anemia � neurologic symptoms

- - laboratory � similar to folic acid deficiency � inc methylmalonic acid in the urine

- - Treatment � Vit B12, IM

ANEMIA OF INCREASED DESTRUCTION

Areas of RBC important in normal function and survival - membrane - hemoglobin structure

Approach to Dx : Clinical features suggesting hemolysis Laboratory demonstration of hemolytic process Determination of precise cause

Clinical Features

1. Ethnic factors – Thalassemia – Mediterreanean ancestry, Asians

2. Age factors – infants with ABO/Rh incompatibility setting 3. Hx of anemia, jaundice, gallstones in the family 4. persistent and recurrent anemia w/ reticulocytosis 5. anemia unresponsive to hematinics 6. splenomegaly 7. hemoglobinuria

� Membrane defects - HS � Enzyme defects - G6PD deficiency � Hemoglobinopathies – HbS, Thalassemia � AIHA � Fragmentation hemolysis – px w/ heart valves, DIC Membrane Composition and Structure RBC Membrane Lipids

- bilayer of phospholipids interspersed with molecules of unesterified cholesterol and glycolipids

- cholesterol composes 25% of RBC membrane lipid in 1:1 molar ratio with glycolipids

- accumulation of cholesterol – target cells, acanthocytes, chronic HA

Normal adult RBC contain the ff types of hemoglobin

- Hemoglobin A (alpha2, beta2) – 95-97% - Hemoglobin A2 (alpha2, delta2) – 2-3.4% - Hemoglobin F (alpha2, gamma2) – 1-2%

Disorders of Hemoglobin Production

- Thalassemias – decreased production of alpha or beta globin - Hemoglobinopathies – abnormal polypeptide chains are

produced

• Hb S – alpha chains are normal but in Beta chain, 1 glutamic residue was replaced by valine reside

• Polymerizes at low O2 tension RBC Metabolic Pathways

- necessary for the production of adequate ATP levels to maintain

� Hb function � Membrane integrity and deformability � RBC volume � Adequate amounts of reduced pyridine nucleotides

- Embden Mayerhoff Pathway - Methemoglobin reductase pathway – maintain iron in ferrous

state - Phosphogluconate pathway

MitzMitzMitzMitz

4

THALASSEMIA

• ↑nRBC & polychromasia

• ineffective erythropoeisis

• hemolysis α – thalassemias syndromes

Syndrome Clinical/Lab features α-thalassemia

chains affected

Silent carrier No anemia N RBC 1-2% Hgb Bart’s @ birth

1

Thal. Trait Mild anemia Hypo micro RBC 10% Hgb Bart’s @ birth

2

HbH disease Mod anemia Hypo micro RBC Inclusion bodies may be demonstrated 5-30% HbH (?) β>α Golf ball cells – ppt!

3

Hydrops fetalis Incompatible to life Death in utero caused by severe anemia Mainly Hgb Bart’s

4

Clinical Classification of β-thalassemias

Silent carrier Hematologically normal

Thal. Trait Mild anemia w/ microcytosis & hypochromia

Severe beta thal. (Cooley’s anemia)

Severe anemia Growth retardation Hepatosplenomegaly BM expansion Bone deformities

G6PD DEFICIENCY

• Sex-linked recessive inheritance (x chromosome)

• Fully expressed in hemizygous male and homozygous female

• 3% of world’s population affected Clinical Manifestations

1. Acute Hemolityc Anemia - Within 6-24 hours after exposure to exudative challenge - There may be passage of dark, brown or black urine - With 24-28 hrs – elevationof temperature, nausea,

abnominal pain, diarrhea 2. Neonatal jaundice

Diagnosis

• Screening tests - dye decolorization test

• G6PD Enzyme Assay Treatment

• Prevention from exposure to agents that cause hemolysis

• Blood transfusions HEREDITARY SPHEROCYTOSIS

• Autosomal dominant

• Characterized osmotically fragile

• Spherical red cells that are trapped by the spleen

• Defect in spectrin Clinical Features:

• Anemia – most frequent presenting complaint

• Jaundice

• Splenomegaly

• (+) family history Laboratory Features: Peripheral smear – microspherocytes Reticulocyte count – elevated Osmotic Fragility test Treatment Splenectomy Diseases associated with AIHA in childhood Infections

Viral infections, especially respiratory infections Infectious mononucleosis and cytomegalovirus Mycoplasma, especially pneumonia HIV infection

Disorders associated with antibody production SLE Thyroid disorders Neonatal Lupus syndrome Ulcerative colitis Rheumatoid arthritis Chronic active hepatitis

AIHA Immunodeficiency syndromes

X-linked agammaglobulinemia Dysgammaglobulinemia Common variable hypogammaglobulinemia IgA deficiency Wiskott-Aldrich syndrome HIV infection

Malignancies Non-hodgkin’s lymphoma Carcinoma Hodgkin’s disease Thymoma Acute lymphocytic leukemia Ovarian cysts & tumor

Clinical Features:

• Pallor, jaundice, dark urine, abdominal pain, fever

• Splenomegaly, hepatomegaly Laboratory Features:

• Anemia

• Reticulocytosis

• (+) Coomb’s test

• PBS- spherocytes, polychromasia, nucleated RBC

• May be associated with thrombocytopenia, leukopenia Treatment:

1. Corticosteroid 2. Transfusion 3. Plasmapheresis 4. IVIG 5. Splenectomy 6. Immunosuppressives

HEMOLYTIC ANEMIA Evidence of destruction

1. Anemia 2. Jaundice 3. Bilirubin (B1) 4. Hemoglobinuria 5. Urinary urobilinogen 6. Hepatosplenomegaly

Regeneration 1. Reticulocytosis 2. Normoblastemia 3. Erythroid hyperplasia

Laboratory anomalies in Hemolytic Anemia Test Abnormality

PBS Spherocytes Fragments Blister cells Agglutination Macrocytes Polychromatophilia Sickle cells

Reticulocyte count Usually elevated

Serum haptoglobin Low Serum LDH Elevated

Red cell survival Shortened

Bilirubin Elevated indirect fraction

Laboratory Procedures:

1. Stool guiac test 2. Serum ferritin, iron, TIBC, transferrin saturation, FEP 3. Coomb’s test (direct & indirect) 4. Hemoglobin electrophoresis 5. Osmotic Fragility test 6. Ham’s test / Sucrose lysis test 7. RBC enzyme assay / G6PD screening test

Treatment:

• Depends on the cause Nutrient replacement

Ferrous sulfate Folic acid/Vit B12

rhuEPO � 50-300 u/kg 3x a week � indication: end stage renal dse � other uses: cancer related anemia, post chemotherapy

or BMT, anemia in aplastic anemia, MDS and AIDS Steroids Blood transfusion

Transcribed by: Ann Mitzel Gawaran Mata-(?)