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DEFINITION OF ANEMIADEFINITION OF ANEMIA ::

Anemia may be defined as a reduction in Anemia may be defined as a reduction in red blood cell mass or blood hemoglobin red blood cell mass or blood hemoglobin concentration.concentration.

It is particularly important to use It is particularly important to use ageage and and

sexsex adjusted norms when evaluating a adjusted norms when evaluating a pediatric patient for anemiapediatric patient for anemia

Normal limit of Hb in children: Normal limit of Hb in children:

CLASSIFICATIONS OF ANEMIACLASSIFICATIONS OF ANEMIA : :

Physiologic classificationPhysiologic classification

Morphologic classificationMorphologic classification

Mean corpuscular volumeMean corpuscular volume

AnemiaAnemia

BBlood loss (acute)lood loss (acute) Normal spleen, Normal spleen, high retic count, normal bilirubin, normal high retic count, normal bilirubin, normal urinalysisurinalysis

Hemolytic anemia Hemolytic anemia Splenomegaly, Splenomegaly, increased reticulocyte count, high bilirubin increased reticulocyte count, high bilirubin (indirect), urobilinogen or hemoglobinuria(indirect), urobilinogen or hemoglobinuria

Impaired red cell formationImpaired red cell formation Normal spleen, low retic count, normal Normal spleen, low retic count, normal bilirubin, normal urinalysisbilirubin, normal urinalysis

Retic, bilirubin, spleen, Retic, bilirubin, spleen, U/AU/A,,

Approch to anemia : blood loss(Acute): : blood loss(Acute): ((Normal spleen, high retic count, normal bilirubin, Normal spleen, high retic count, normal bilirubin, normal urinalysis)normal urinalysis)

Neonatal problem (fetofetal transfusion, (fetofetal transfusion, fetomaternal transfusion,…)fetomaternal transfusion,…)

Hemorrhagic disease of newborn

Meckel’s diverticulum, …..

AnemiaAnemia

BBlood loss (acute)lood loss (acute)

Hemolytic anemia Hemolytic anemia Splenomegaly, Splenomegaly, increased reticulocyte count, high bilirubin increased reticulocyte count, high bilirubin (indirect), urobilinogen or hemoglobinuria(indirect), urobilinogen or hemoglobinuria

Impaired red cell formationImpaired red cell formation

Approch to anemia: : Hemolytic anemia Hemolytic anemia ((Splenomegaly, increased reticulocyte count, high bilirubin (indirect), Splenomegaly, increased reticulocyte count, high bilirubin (indirect), urobilinogen or hemoglobinuria):urobilinogen or hemoglobinuria):

1) 1) CorupuscularCorupuscular ::

2) 2) Extra corpuscularExtra corpuscular

Enzyme defect, Membrane defect, Hemoglobin disorder

immune, non immune

Hemolytic anemia: Hemolytic anemia: CorpuscularCorpuscular

1) Enzyme defect:1) Enzyme defect: G6PD deficiency PK deficiency

Glucose 6 phosphate dehydrogenase(G6PD)Glucose 6 phosphate dehydrogenase(G6PD)

G6PD DEFICIENCY:G6PD DEFICIENCY:

X-linked disorderX-linked disorder Affecting 200 to 400 million people Affecting 200 to 400 million people Contains 515 amino acids Contains 515 amino acids Over 400 variant enzymes have been Over 400 variant enzymes have been

reported reported (90 according to specific mutations)(90 according to specific mutations)

Classification of G6PD variantsClassification of G6PD variants::

Class I variantsClass I variants: : are rare, have severe enzyme deficiency (less than 10 are rare, have severe enzyme deficiency (less than 10 percent of normal) and have chronic hemolytic anemia(44 variants) percent of normal) and have chronic hemolytic anemia(44 variants)

Class II variants Class II variants : have severe enzyme deficiency, but there is usually only : have severe enzyme deficiency, but there is usually only intermittent hemolysis (28 variantsintermittent hemolysis (28 variants))

Class III variantsClass III variants: have moderate enzyme deficiency (10 to 60 percent of : have moderate enzyme deficiency (10 to 60 percent of normal) with intermittent hemolysis usually associated with infection or normal) with intermittent hemolysis usually associated with infection or drugs (16 variants)drugs (16 variants)

Class IV variantsClass IV variants: have no enzyme deficiency or hemolysis: have no enzyme deficiency or hemolysis(2 variants)(2 variants)

Class V variantsClass V variants: : have increased enzyme activity have increased enzyme activity

PATHOPHYSIOLOGY OF G6PD DEFICIENCY:PATHOPHYSIOLOGY OF G6PD DEFICIENCY:

The in vivo half-life of enzymeThe in vivo half-life of enzyme: : normal normal enzyme (G6PD B): 62 days, G6PD A- :13 days, G6PD enzyme (G6PD B): 62 days, G6PD A- :13 days, G6PD Mediterranean: in hoursMediterranean: in hours

G6PD A- G6PD A- : : Patients usually have hemolysis that is mild Patients usually have hemolysis that is mild and limited to older deficient erythrocytes (class III). and limited to older deficient erythrocytes (class III).

G6PD B+(Mediterranean): G6PD B+(Mediterranean): red cells of all ages red cells of all ages are grossly deficient (class II). are grossly deficient (class II).

DIAGNOSISDIAGNOSIS ::

Clinical presentation Clinical presentation (should be considered in the (should be considered in the differential diagnosis of any nonimmune hemolytic anemia)differential diagnosis of any nonimmune hemolytic anemia)

Laboratory findings: Laboratory findings: Hemolysis (Hb, Retic count, Hemolysis (Hb, Retic count, bilirubin, hemoglobinemia, hemoglobinuria), PBS bilirubin, hemoglobinemia, hemoglobinuria), PBS (polychromatophlia,Heinz bodies, bite cells ),Rate of (polychromatophlia,Heinz bodies, bite cells ),Rate of

NADPH generationNADPH generation


1) Enzyme defect:1) Enzyme defect: G6PD deficiency PK deficiency

Pyruvate kinase deficiencyPyruvate kinase deficiency : :

Clinical presentationClinical presentation : : a a broad spectrumbroad spectrum of clinical and hematologic of clinical and hematologic

findings occurs, findings occurs, ranging from a mild, completely ranging from a mild, completely compensated hemolytic state to severe anemiacompensated hemolytic state to severe anemia..

Anemia and hyperbilirubinemia may occur in Anemia and hyperbilirubinemia may occur in the the neonatalneonatal period. period.

In the In the older patientolder patient, pallor, scleral icterus, and , pallor, scleral icterus, and splenomegaly are usual findings. splenomegaly are usual findings.

Pyruvate kinase deficiencyPyruvate kinase deficiency : :

Laboratory findingsLaboratory findings : : Elevated reticulocyte count. Elevated reticulocyte count. A few small spiculated erythrocytes A few small spiculated erythrocytes No increased number of spherocytes No increased number of spherocytes Osmotic fragility is normal. Osmotic fragility is normal.


1)1)Enzyme defectEnzyme defect

2)2) Membrane defect:Membrane defect: Spherocytosis, Elliptocytosis

Membrane defectMembrane defect ::SpherocytosisSpherocytosis

PathophysiologyPathophysiology : : A deficiency or A deficiency or abnormality of the erythrocyte membrane abnormality of the erythrocyte membrane structural protein: spectrin , ankyrin, band 3, structural protein: spectrin , ankyrin, band 3, and protein 4.2. and protein 4.2.

The spherocyte is relatively rigid and non-The spherocyte is relatively rigid and non-deformable deformable

Membrane defectMembrane defect ::SpherocytosisSpherocytosis

Clinical presentationClinical presentation: : anemia, anemia, hyperbilirubinemia, splenomegaly Expansion of hyperbilirubinemia, splenomegaly Expansion of the marrow cavities .the marrow cavities .

Laboratory findingsLaboratory findings reticulocytosis, anemia, reticulocytosis, anemia, hyperbilirubinemia, spherocyte in PBS, Erythroid hyperbilirubinemia, spherocyte in PBS, Erythroid hyperplasiain BMA, osmotic fragility test, hyperplasiain BMA, osmotic fragility test, Autohemolysis,Autohemolysis,

Hemolytic anemia: Hemolytic anemia: Corpuscular Corpuscular

1)Enzyme defect1)Enzyme defect

2) Membrane defect2) Membrane defect

3) 3) Hemoglobin disorderHemoglobin disorderNormal variant, Functional disorder, Structural problem, Thalassemia

Hemolytic anemia: Hemoglobin disorderHemoglobin disorder:

Normal variant,Normal variant,

Functional disorder,Functional disorder,

Structural problem,Structural problem,

Thalassemia Thalassemia

عوارضکم عوارضکم خونیخونی

استخوانی استخوانی تغییرات تغییرات طحال طحال بزرگی بزرگی مغز خارج سازی مغز خون خارج سازی خون

استخواناستخوان یک پاتولوژ یک شکستگی پاتولوژ شکستگی هوشی سطح هوشی افت سطح افت تحتانی اندام تحتانی زخم اندام زخم رشد رشد توقف توقف انعقادی سیستم انعقادی عوارض سیستم عوارض

Hemolytic anemia: : ExtracorpuscularExtracorpuscular

Immune:Immune:

Nonimmune:Nonimmune:

Alloimmune, isoimmune, Autoimmune

HUS syndrome, TTP, DIC, Infection, Burn, Hypersplenism, ……..

Typical Hemolytic Uremic Syndrome:Typical Hemolytic Uremic Syndrome:

In the majority of cases, Stx HUS is associated with strains of Escherichia coli that produce a Shiga toxin

D+ HUS associated with Shigella dysenteriae serotype 1 will be included in the discussion of Stx HUS

Cases of HUS in children due to Shiga toxin-producing E. coli infections other than colitis (e.g. UTI) can occur .

AnemiaAnemia

Blood loss (acute)

Hemolytic anemia

Impaired red cell formationImpaired red cell formation Normal spleen, low retic count, normal Normal spleen, low retic count, normal bilirubin, normal urinalysisbilirubin, normal urinalysis

Approch to anemia : Impaired red cell formation: Impaired red cell formation (Normal spleen, low retic count, normal bilirubin, normal (Normal spleen, low retic count, normal bilirubin, normal urinalysis)urinalysis)

1)Deficiency

2)Bone marrow failure

3)Bone marrow infiltration

Iron deficiency Megaloblastic anemia vitamins, Thyroxine deficiency

Failure of a single cell line Failure of all cell line:

Malignant: Non malignant:


1)Deficiency



Iron deficiency Megaloblastic anemia vitaminsThyroxine deficiency

Clinical manifestation of IDA;Hematological symptomsHematological symptoms The The most common most common

presentation of IDApresentation of IDA is is an otherwise an otherwise asymptomatic, well asymptomatic, well nourished infant or nourished infant or child who has a child who has a mild mild to moderate to moderate microcytic, microcytic, hypochromichypochromic anemia anemia

Clinical manifestation of IDA; Non hematological symptomsNon hematological symptoms

Neurodevelopmental and Cognitive function Neurodevelopmental and Cognitive function Immunity Immunity Exercise capacity Exercise capacity Pica and pagophagia Pica and pagophagia Thrombosis Thrombosis Epithelial changeEpithelial change: : dysphagia, esophageal web, dysphagia, esophageal web,

atrophic glossitis, spoon nails, blue sclerae atrophic glossitis, spoon nails, blue sclerae


1)Deficiency



Failure of a single cell line : CPRA, TEC, A.crisis

Failure of all cell line: Aplastic anemia

Fanconi Anemia:Fanconi Anemia:Clinical featuresClinical features Incidence is 3/1,000,000Incidence is 3/1,000,000

– Heterozygote frequency ~1/300 in U.S. and EuropeHeterozygote frequency ~1/300 in U.S. and Europe

Median age at diagnosis is 5-7Median age at diagnosis is 5-7

Median survival is 20-30 yrs. Median survival is 20-30 yrs.

Phenotypic variability occurs even within famPhenotypic variability occurs even within familiesilies

Frequency of abnormalities in FA

AbnormalityAbnormality Frequency (%)

Skeletal (radial ray, hip, vertebral scoliosis, rib)Skeletal (radial ray, hip, vertebral scoliosis, rib) 71

Skin pigmentation (café au lait, hyper- and hypopigmentation)Skin pigmentation (café au lait, hyper- and hypopigmentation) 64

Short stature (median height 5Short stature (median height 5thth %ile) %ile) 63

Eyes (microphthalmia)Eyes (microphthalmia) 38

Renal and urinary tractRenal and urinary tract 34

Male genitaliaMale genitalia 20

Mental retardationMental retardation 16

Gastrointestinal (eg, anorectal, duodenal atresia)Gastrointestinal (eg, anorectal, duodenal atresia) 14

Cardiac abnormalitiesCardiac abnormalities 13

HearingHearing 11

Central nervous system (eg, hydrocephalus, septum Central nervous system (eg, hydrocephalus, septum pellucidum)pellucidum)

8

No abnormalitiesNo abnormalities 30


1)Deficiency


3)Bone marrow infiltrationMalignant: Leukemia…

Non malignant: Metabolic disease Osteopetrosis

Fast CasesFast Cases

A 15 yo girl with a history of systemic lupus erythematosus comes to the clinic for evaluation of fatigue and pallor.

Hgb is 7.2, MCV 85, Retic 10%, WBC 3.5 (50% polys, 40% lymphs, 10% atypicals), and plts of 125.

The smear shows microspherocytes and rouleaux formation. She does not have a history of blood loss.

What does she have?

Autoimmune hemolytic anemia

17 mounts age infant with an unexplained 17 mounts age infant with an unexplained persistent anemiapersistent anemia

History of neonatal jaundiceHistory of neonatal jaundice Requirement of pRBC transfusion * 2 early infancyRequirement of pRBC transfusion * 2 early infancy Hb stable 7-9 gr/dl from age 3-17 monthsHb stable 7-9 gr/dl from age 3-17 months spleen 5 cm below costal marginspleen 5 cm below costal margin Retic 20%, with indirect hyperbilirubinemiaRetic 20%, with indirect hyperbilirubinemia What does she have? Pyruvate kinase deficiencyPyruvate kinase deficiency

A 3 yo girl has had diarrhea, sometimes bloody, for several days. Now, she has fever, edema, petechiae & hypertension.

The CBC shows: Hgb 7.5, MCV 79, Retic 15%, Plts 35, and WBC 13.5 with a normal differential. The smear shows several helmet cells and polychromasia and confirms the thrombocytopenia

What does she have?Hemolytic uremic syndromeHemolytic uremic syndrome

A 3 month old boy is brought to the ED lethargic and with a fever of 40° C. While attending to the airway, correcting hypotension and initiating antibiotics, the nurse informs you of the CBC results: Hgb 5.8, MCV 81, Retic 16%, WBC 23.5 (56% polys, 24% bands, 10% lymphs, & 10% atypical lymphs) and plts of 350.

He has blood on dipstick analysis of his urine with no RBC’s on microscopic analysis.

The blood shows polychromasia, and several bite cells.

What does he have?G6PD deficiencyG6PD deficiency

A 9 month old boy comes the Dr.’s office A 9 month old boy comes the Dr.’s office for evaluation of a cold. Further hx for evaluation of a cold. Further hx reveals introduction of whole cow’s milk reveals introduction of whole cow’s milk at 5 months and no well baby visits.at 5 months and no well baby visits.

He appears quite pale and has the He appears quite pale and has the following findings: Hgb 5.3, MCV 48, following findings: Hgb 5.3, MCV 48, plts 780, WBC 12.5 and retic 1.7%plts 780, WBC 12.5 and retic 1.7%

What does he have?What does he have?

Iron Deficiency anemiaIron Deficiency anemia

An 18 month old girl was in good health until An 18 month old girl was in good health until she developed a cold 10 days ago.she developed a cold 10 days ago.

Now she is pale but without visible jaundice.Now she is pale but without visible jaundice.

The CBC shows a Hgb of 6.8, MCV of 78 The CBC shows a Hgb of 6.8, MCV of 78 and retic of 0.1%, WBC & Plts are normal and retic of 0.1%, WBC & Plts are normal as is the peripheral blood smear.as is the peripheral blood smear.

What does she have?What does she have?

Transient Erythroblastopenia Transient Erythroblastopenia of Childhoodof Childhood

The CBC of an 8 yo girl reveals the The CBC of an 8 yo girl reveals the following: Hgb 10, MCV 102, Retic following: Hgb 10, MCV 102, Retic 0.4%, WBC normal, Plts 125. 0.4%, WBC normal, Plts 125.

She is slightly short, has several large She is slightly short, has several large café-au-lait spots, is performing below café-au-lait spots, is performing below average in school and has short average in school and has short thumbs. thumbs.


Fanconi’s AnemiaFanconi’s Anemia

You are asked to assist in the care of political You are asked to assist in the care of political refugees from Afghan. On the screening refugees from Afghan. On the screening entrance exam you note that one of them, a 2 yo entrance exam you note that one of them, a 2 yo girl, is very pale and lethargic. Her spleen is girl, is very pale and lethargic. Her spleen is down to the level of the umbilicus. down to the level of the umbilicus.

The labs reveal: Hgb 6.3, Retic 6%, MCV 55, with The labs reveal: Hgb 6.3, Retic 6%, MCV 55, with normal WBC & plts.normal WBC & plts.

The smear shows many target cells, polychromasia, The smear shows many target cells, polychromasia, basophilic stippling, red cell fragment, basophilic stippling, red cell fragment, anisocytosis and hypochromia.anisocytosis and hypochromia.


thalassemia majorthalassemia major

People may doubt what you saybut they will believe what you

do

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