Di ti A hDiagnostic Approachiacld.ir/DL/modavan/hematology/diagnosticapproachto...Di ti A hDiagnostic Approach to Anemic Patientsto Anemic Patients 9Hg f =%Hg f =%90 90 in in 24 24

Di ti A hDi ti A hDiagnostic Approach Diagnostic Approach to Anemic Patientsto Anemic Patientsto Anemic Patientsto Anemic Patients

Hg f =%Hg f =%90 90 in in 24 24 wk wk %%70 70 in term in term %%2 2 in in 1 1 yearyear

HgA =HgA =1616--2020wk DNA assaywk DNA assay%%55 10 10 i i 2424 k f t lk f t l%%55--10 10 in in 2424wk fetalwk fetal%%30 30 in termin term

HgAHgA22= %= %1 1 in term in term HgAHgA22= %= %1 1 in term in term %%22--33..4 4 in in 1 1 yearyear

Hg A /HgAHg A /HgA2 2 ==30 30 Hg A /HgAHg A /HgA2 2 ==30 30

DefinitionDefinitionDefinitionDefinition

Reduction in RBC mass or Reduction in RBC mass or HbHbReduction in RBC mass or Reduction in RBC mass or HbHbconcentration.concentration.22SD< normal stateSD< normal state--22SD< normal stateSD< normal state

22..55% of normal population= Anemic% of normal population= AnemicBody oxygen metabolism & Body oxygen metabolism & accompanying CV compensation+ Hb accompanying CV compensation+ Hb concentration+ adjust with age & concentration+ adjust with age & sex: Functionally anemicsex: Functionally anemic

DefinitionDefinition

Age Age HB (g/dl)HB (g/dl) HCT (%)HCT (%) MCV (MCV (µµ33))

Age Age (yrs)(yrs)

MeanMean Lower Lower LimitLimit



00..55--11..99 1212..55 1111..00 3737 3333 7777 707022--44 1212..55 1111..00 3838 3434 7979 737355--77 1313..00 1111..55 3939 3535 8181 757588--1111 1313..55 1212..00 4040 3636 8383 76761212--1414FemaleFemale 1313..55 1212..00 4141 3636 8585 7878FemaleFemale 1313..55 1212..00 4141 3636 8585 7878MaleMale 1414..00 1212..55 4343 3737 8484 7777

1515--1717FemaleFemale 1414..00 1212..00 4141 3636 8787 7979MaleMale 1515..00 1313..00 4646 3838 8686 7878

1818--49491818--4949FemaleFemale 1414..00 1212..00 4242 3737 9090 8080MaleMale 1616..00 1414..00 4747 4040 9090 8080

ClassificationClassificationClassificationClassification

11-- Physiologic Classification (Best)Physiologic Classification (Best)

22-- Red Cell Size ClassificationRed Cell Size Classification

A. RBC Production Disorders (rate < expected

f d f i )for degree of anemia)

B Erythroid maturation & Ineffective B. Erythroid maturation & Ineffective

erythropoesis Disorderserythropoesis Disorders

C. Hemolytic AnemiaC o y a

RBC Production Disorders (rate < expected f d f i )for degree of anemia)

Marrow failure

Impaired EPO production

Marrow failureMarrow failure

1.1. Aplastic anemiaAplastic anemiapp

22. Pure red cell aplasia. Pure red cell aplasiapp

33. . Marrow replacementp

Marrow replacementp

MalignanciesMalignancies

Osteopetrosis

Myelofibrosis

• vitamin D deficiency

• Pancreatic insufficiency marrow • Pancreatic insufficiency- marrow

hypoplasia syndrome

Impaired EPO productionImpaired EPO productionp pp p

•• 11 Chronic renal diseaseChronic renal disease•• 11. Chronic renal disease. Chronic renal disease

22. Hypothyroidism, Hypopituitarism. Hypothyroidism, Hypopituitarism

33. Chronic inflammation. Chronic inflammation

44. Protein malnutrition. Protein malnutrition

55 HB mutants with decreased affinityHB mutants with decreased affinity55. HB mutants with decreased affinity . HB mutants with decreased affinity

for oxygenfor oxygen

Erythroid maturation & Ineffective th i Di derythropoesis Disorders

Cytoplasmic maturation abnormalitiesy p

Nuclear maturation abnormalities

Cytoplasmic maturation abnormalitiesy p

• Iron deficiency• Iron deficiency

• Thalassemia syndrome*• Thalassemia syndrome*

• Sideroblastic anemias• Sideroblastic anemias

• Lead poisoning• Lead poisoning

Nuclear maturation abnormalitiesNuclear maturation abnormalities

• Vitamin B deficiency• Vitamin B12 deficiency

• Folic acid deficiency• Folic acid deficiency

Hemolytic AnemiaHemolytic Anemia

•• 11. Defects of HB. Defects of HB

•• a. Structural mutantsa. Structural mutants

b S th ti t t ( Th l i b S th ti t t ( Th l i •• b. Synthetic mutants ( Thalassemia b. Synthetic mutants ( Thalassemia

syndrome)syndrome)

•• 22. RBC membrane defects. RBC membrane defects

•• 33. Red cell metabolism defects. Red cell metabolism defects

•• 44. Antibody. Antibody-- mediatedmediated

Hemolytic Anemia (cont)Hemolytic Anemia (cont)Hemolytic Anemia (cont)Hemolytic Anemia (cont)

•• 55.Mechanical injury to the erythrocyte.Mechanical injury to the erythrocyte55.Mechanical injury to the erythrocyte.Mechanical injury to the erythrocyte

•• 66. Thermal injury to the erythrocyte. Thermal injury to the erythrocyte

•• 77. Oxidant. Oxidant--induced red cell injuryinduced red cell injury

•• 88. Infectious agent. Infectious agent--induced red cell injuryinduced red cell injury

•• 99. PNH. PNH

•• 1010 Red cell membrane plasma Red cell membrane plasma--induced induced •• 1010. Red cell membrane plasma. Red cell membrane plasma--induced induced

abnormalitiesabnormalities

Red cell Size Classification of AnemiaRed cell Size Classification of AnemiaRed cell Size Classification of AnemiaRed cell Size Classification of Anemia

A MicrocyticA. Microcytic• 1. Iron Def.

2 Ch i L d i i• 2. Chronic Lead poisoning

• 3. Thalassemia syndrome

• 4. Sideroblastic anemia

• 5. Chronic inflammation

• 6. Some congenital hemolytic anemias with unstable HB

Important Historical FactorsImportant Historical Factors

Age:N t iti l IDA i ibl f i • Nutritional IDA is never responsible for anemia in term infants before 6 months of age; rarely seen in premature infants prior to the time seen in premature infants prior to the time they have doubled their birth weight.

• In neonatal period: recent blood loss • In neonatal period: recent blood loss, isoimmunization, initial manifestation of CHA or congenital infectionor congenital infection.

• First detected in 3-6 months: congenital disorder of HB synthesis or HB structuredisorder of HB synthesis or HB structure..

Important Historical FactorsImportant Historical FactorsGender: X-linked disorders in males (G6PD-

d, PKD)Race: HB S & C more common in blacks,

B Thalassemia mo e common in B-Thalassemia more common in whites,

α-Thalassemia trait most common among black & yellow race.

Neonatal: hyperbillirubinemia: CHA, Diet: document sources of iron, vit B12, folic acid, or vit E in diet.

Pica geophagia pagophagia=> IDAPica, geophagia, pagophagia=> IDADrugs: - Oxidant-induced hemolytic anemia

- Phenytoin- induced megaloblastic y ganemia

- Drug- induced Aplastic anemia

Important Historical FactorsImportant Historical Factors

Infection: Hepatitis-induced Aplastic anemia,

Infection- induced red cell aplasia or hemolytic anemia

Inheritance:Inheritance:FH of anemia, Jaundice, Gallstones, or Splenomegaly.

Diarrhea:Small bowel disease with

l b bti f f l t it B12malabsorbtion of folate or vit B12.IBD with blood loss.Exudative enteropathy with blood Exudative enteropathy with blood

loss.

Key Physical FindingsKey Physical FindingsSkiSki H i t tiH i t ti F i’ A iF i’ A iSkinSkin HyperpigmentationHyperpigmentation Fanconi’s AnemiaFanconi’s Anemia

Petechiae,Petechiae, Evans syndrome, HUS,Evans syndrome, HUS,etec ae,etec ae,PurpuraPurpura

a s sy d o e, US,a s sy d o e, US,BM aplasia,BM aplasia,BM infiltrationBM infiltration

CarotenemiaCarotenemia Suspect IDA in InfantsSuspect IDA in Infants

JaundiceJaundice Hemolytic Anemia, Hemolytic Anemia, Hepatitis, Aplastic anemiaHepatitis, Aplastic anemia

Cavernous Cavernous HemangiomaHemangioma

Microangiopatic Hemolytic Microangiopatic Hemolytic anemiaanemia

S & CS & CUlcer on Lower Ulcer on Lower ExtremityExtremity

S & C Hbpathies, S & C Hbpathies, ThalassemiaThalassemia

Key Physical FindingsKey Physical FindingsFaciesFacies Frontal bossing, Frontal bossing,

prominence malar prominence malar CHA, Major Thalassemia, CHA, Major Thalassemia, severe IDAsevere IDAprominence malar prominence malar

and maxillary boneand maxillary bonesevere IDAsevere IDA

EyesEyes MicroMicro-- corneacornea Fanconi's AAFanconi's AA

T t it f th T t it f th S & C H l bi thiS & C H l bi thiTortuosity of the Tortuosity of the conjunctival & conjunctival & retinal v.retinal v.

S & C HemoglobinopathiesS & C Hemoglobinopathies

MicroMicro--aneurysms of aneurysms of retinal vesselsretinal vessels

S & C HemoglobinopathiesS & C Hemoglobinopathies

CataractsCataracts GG66PDPD--d, Galactosemia+ HA d, Galactosemia+ HA in newborn periodin newborn period

Vitreous Vitreous hemorrhageshemorrhages

S HemoglobinopathiesS Hemoglobinopathies

Retinal hemorrhagesRetinal hemorrhages Chronic, severe anemiaChronic, severe anemia

Edema of the eyelidsEdema of the eyelids EBV, Exudative EBV, Exudative enteropathy+ IDA Renal enteropathy+ IDA Renal enteropathy+ IDA, Renal enteropathy+ IDA, Renal FailureFailure

BlindnessBlindness OsteopetrosisOsteopetrosis

Key Physical FindingsKey Physical FindingsGlossitisGlossitis BB12 12 deficiency, IDAdeficiency, IDA

MouthMouth Angular Angular stomatitisstomatitis

IDAIDA

Unilateral Unilateral Poland syndrome ( increased Poland syndrome ( increased

ChestChestUnilateral Unilateral absence of the absence of the pectoral musclespectoral muscles

Poland syndrome ( increased Poland syndrome ( increased incidence of leukemia)incidence of leukemia)

Shield chestShield chest DiamondDiamond--Blackfan Blackfan syndromesyndrome

Triphalangeal Triphalangeal Red cell aplasiaRed cell aplasia

HandsHands

Triphalangeal Triphalangeal thumbsthumbs

Red cell aplasiaRed cell aplasia

Hypoplasia of the Hypoplasia of the Fanconi’s AAFanconi’s AAHandsHands yp pyp pthenar eminencethenar eminence

Fanconi s AAFanconi s AA

Spoon nailsSpoon nails IDAIDA

SpleenSpleen EnlargementEnlargement CHA, leukemia, lymphoma, CHA, leukemia, lymphoma, acute infection, portal HTNacute infection, portal HTN

Paraclinical ApproachParaclinical ApproachParaclinical ApproachParaclinical Approach

Initial laboratory tests:Initial laboratory tests:Initial laboratory tests:Initial laboratory tests:•• HB & HCTHB & HCT•• Red cell indicesRed cell indices•• Red cell indicesRed cell indices•• Platelet countPlatelet count

WBC & diffWBC & diff•• WBC & diffWBC & diff•• Reticulocyte countReticulocyte count

P i h l bl d P i h l bl d •• Peripheral blood smearPeripheral blood smear

Complete Blood Count

Hemoglobin HbHemoglobin HbHematocrit HctMean corpuscular hemoglobin MCHMean corpuscular hemoglobin MCHMCH concentration MCHCMean corpuscular volume MCVMean corpuscular volume MCVRBC distribution width RDWErythrocyte count RBCErythrocyte count RBCLeukocyte countPl t l t tPlatelet countReticulocyte count

Complete Blood Count

Directly measured indices:y• – Hb (more reliable, more directly related to O2 carrying

capacity)MCV• – MCV

• – RBC countCalculated indices:Calculated indices:• – Hct = MCV x RBC• – MCH = Hb / RBC• – MCHC = Hb / Hct = Hb / (MCV x RBC)RDW:

C ffi i t f i ti f th th t l• Coefficient of variation of the erythrocyte volume distribution =cell size variability

Coulter CounterCoulter CounterCoulter CounterCoulter Counter

Most widely used methodMost widely used method.

Directly measure the MCV and compute

the HCT from the MCV and RBC.

Cold agglutinins in high titer tend to cause

spurious macrocytosis with low red cell p y

counts and very high MCHCs. Warming

h h bl d h d l leither the blood or the diluent eliminates

this problem.

Red cell volumeRed cell volume distribution width (RDW)distribution width (RDW)Red cell volumeRed cell volume distribution width (RDW)distribution width (RDW)

Index of the variation in red cell size.Index of the variation in red cell size.Index of the variation in red cell size.Index of the variation in red cell size.Detect Detect AnisocytosisAnisocytosis..Derived from RBC histogramDerived from RBC histogramDerived from RBC histogram.Derived from RBC histogram.RDW=SD/MCV X RDW=SD/MCV X 100100Because RDW reflects the ratio of SD and Because RDW reflects the ratio of SD and Because RDW reflects the ratio of SD and Because RDW reflects the ratio of SD and MCV, a wide red cell distribution curve in a MCV, a wide red cell distribution curve in a patient with a markedly increased MCV may patient with a markedly increased MCV may patient with a markedly increased MCV may patient with a markedly increased MCV may still generate normal RDW.still generate normal RDW.Normal range= Normal range= 1111..55--1414..5 5 in adultsin adultsggFor infants and children= For infants and children= 11..55--1515

MCV & RDWMCV & RDW

RDWRDWMCVMCV

LowLow NormalNormal HighHighRDWRDW LowLow NormalNormal HighHigh

NormNormalal

Heterozygous Heterozygous αα--and and ββ--

normalnormal Aplastic AnemiaAplastic Anemiaalal ββ

ThalassemiaThalassemiaLead poisoningLead poisoning

HighHigh IDAIDA Early IDAEarly IDA Newborn, Newborn, PrematurityPrematurityPrematurityPrematurity

HB HB H H diseasedisease Liver diseaseLiver disease Vitamin BVitamin B12 12 def.def.

SSββ--ThalassemiaThalassemia

Mixed Nutritional Mixed Nutritional def.def.

Folic acid def.Folic acid def.

Blood FilmBlood Film

The single most useful procedure in the g p

initial evaluation of the patient with

anemia.

Can be classified red cell hemolytic

disorders by predominant morphology:

Reticulocyte countReticulocyte count

Increased: ( RI>=Increased: ( RI>=33%)%)c eased (c eased ( 33%)%)Chronic blood lossChronic blood lossHemolysisHemolysis

Normal or decreased: (RI=<Normal or decreased: (RI=<11..55%)%)Impaired red cell formationImpaired red cell formation

Must be adjusted for the level of anemia to Must be adjusted for the level of anemia to obtain the obtain the Reticulocyte Index:Reticulocyte Index:obtain the obtain the Reticulocyte Index:Reticulocyte Index:

= Retic count X Patient’s = Retic count X Patient’s HCT/Normal HCTHCT/Normal HCT

Outline of ApproachOutline of ApproachOutline of ApproachOutline of Approach

II I iti l S i & ti I iti l S i & ti II-- Initial Screening & presumptive Initial Screening & presumptive

diagnosisdiagnosis

AA-- Careful History Careful History

and Physical Examinationand Physical Examination

BB-- Initial Lab TestsInitial Lab TestsBB-- Initial Lab TestsInitial Lab Tests

Outline of ApproachOutline of Approachpppp

IIII-- Confirmatory Studies:Confirmatory Studies:IIII Confirmatory Studies:Confirmatory Studies:•• Direct antiglobulin testDirect antiglobulin test•• GG66PD screening testPD screening test•• GG66PD screening testPD screening test•• Osmotic fragility Osmotic fragility

HB El t h iHB El t h i•• HB ElectrophoresisHB Electrophoresis•• BMA/ biopsyBMA/ biopsy

ili biili bi 22 l l b lil l b li•• Bilirubin, LDH, BBilirubin, LDH, B1212, Folate, Haptoglobulin, , Folate, Haptoglobulin, Ferritin, Iron, TIBC, ….Ferritin, Iron, TIBC, ….

Iron Deficiency AnemiaIron Deficiency AnemiaIron Deficiency AnemiaIron Deficiency Anemia

IntroductionIntroductionIntroductionIntroduction

The most common nutritional deficiency inThe most common nutritional deficiency inThe most common nutritional deficiency in The most common nutritional deficiency in children throughout the world.children throughout the world.Hi h i id i i fHi h i id i i fHigher incidence in infancy.Higher incidence in infancy.55..55% in schoolchildren, % in schoolchildren, 55--8 8 yrs.; yrs.; 22..66% in % in preadolescent; preadolescent; 2525% in pregnant teenage % in pregnant teenage girls.girls.Higher in black children.Higher in black children.Inversely proportional to economic statusInversely proportional to economic statusInversely proportional to economic status.Inversely proportional to economic status.

IntroductionIntroductionIntroductionIntroduction

Iron lack the glitter of gold and silver butIron lack the glitter of gold and silver butIron lack the glitter of gold and silver but Iron lack the glitter of gold and silver but

outshines both in biologic importance.outshines both in biologic importance.

Vital to the function of a number of critical Vital to the function of a number of critical

(T)(T)enzymes (T).enzymes (T).

Human existence is inextricably linked to Human existence is inextricably linked to yy

iron.iron.

Nonhematological ManifestationNonhematological ManifestationNonhematological ManifestationNonhematological Manifestation

II Gastrointestinal tractGastrointestinal tractI.I. Gastrointestinal tractGastrointestinal tract

II.II. Central nervous systemCentral nervous system

III.III. Cardiovascular systemCardiovascular system

l k l ll k l lIV.IV. Musculoskeletal systemMusculoskeletal system

V.V. Immunologic systemImmunologic systemV.V. Immunologic systemImmunologic system

VI.VI. Cellular changesCellular changes

VII.VII. Other tissuesOther tissues

Etiologic Factors (T)Etiologic Factors (T)Etiologic Factors (T)Etiologic Factors (T)

DietaryDietaryDietaryDietary

•• RequirementsRequirements

•• Food Iron ContentFood Iron Content

GrowthGrowthGrowthGrowth

Blood LossBlood Loss

Impaired AbsorptionImpaired Absorption

Infants at risk for IDA (T)Infants at risk for IDA (T)Infants at risk for IDA (T)Infants at risk for IDA (T)

Increased iron needsIncreased iron needs

Blood lossBlood loss

Dietary factorsDietary factors

Differential Diagnosis (T)Differential Diagnosis (T)Differential Diagnosis (T)Differential Diagnosis (T)HemoglobinopathiesHemoglobinopathiesHemoglobinopathiesHemoglobinopathies

HemeHeme synthesis disorders caused by chemicalssynthesis disorders caused by chemicals

Sideroblastic anemiasSideroblastic anemiasSideroblastic anemiasSideroblastic anemias

Chronic infections or other inflammatory statesChronic infections or other inflammatory states

M liM liMalignancyMalignancy

Hereditary Hereditary OroticOrotic aciduriaaciduria

HypoHypo-- or or AtransferrinemiaAtransferrinemia

Copper deficiencyCopper deficiency

Inborn error of metabolismInborn error of metabolism

Differential DiagnosisDifferential DiagnosisDifferential DiagnosisDifferential Diagnosis

Further evaluation in children with:• – No suspicious history of Fe deficiency• – Severe anemia• – Atypical hematological findings• – < 6mo of age• – No response to iron trialNo response to iron trial

� R/O blood loss, inflammation� RBC count (> 5 million/ ul in thal trait)� MCV/RBC ratio (<13 thal trait, >15 Fe def)� Peripheral blood smear:• – Hypochromia anisocytosis (greater in Fe deficiency)– Hypochromia, anisocytosis (greater in Fe deficiency)• – Poikilocytosis, target cells, cigar cells, basophilic stippling• (greater in thalassemia trait)

TreatmentTreatmentTreatmentTreatment

N t iti l C liN t iti l C liNutritional CounselingNutritional Counseling

Oral Iron MedicationOral Iron MedicationOral Iron MedicationOral Iron Medication

Parenteral therapyParenteral therapypypy

Blood TransfusionBlood Transfusion

Partial Exchange TransfusionPartial Exchange Transfusion

ThalassemiaThalassemiaThalassemiaThalassemiaSyndromeSyndrome

Characteristics: ThalassemiaCharacteristics: ThalassemiaCharacteristics: ThalassemiaCharacteristics: Thalassemia

•• Hereditary disorders that can result inHereditary disorders that can result in•• Hereditary disorders that can result in Hereditary disorders that can result in moderate to severe anemiamoderate to severe anemiaBasic defect isBasic defect is reduced productionreduced production ofof•• Basic defect is Basic defect is reduced productionreduced production of of selected globin chainsselected globin chains

Demographics: ThalassemiaDemographics: ThalassemiaDemographics: ThalassemiaDemographics: Thalassemia•• Found mostFound mostFound most Found most

frequently in the frequently in the Mediterranean, Africa, Mediterranean, Africa, Western and Western and Southeast Asia, India Southeast Asia, India

d Bd Band Burmaand Burma•• Distribution parallels Distribution parallels

that of Plasmodiumthat of Plasmodiumthat of Plasmodium that of Plasmodium falciparumfalciparum

HemoglobinHemoglobinHemoglobinHemoglobin

β α Two α and twoβ α

β globin chains(α2β2) make upHemoglobin A

βα

g

Globin Chain GenesGlobin Chain GenesGlobin Chain GenesGlobin Chain Genes

Chromosome 16

α α

α α

ε Gγ Aγ ψβ δ β

Chromosome 11ε Gγ Aγ ψβ δ β

Developmental Switching of Human Developmental Switching of Human HemoglobinHemoglobin

Olivieri, N. NEJM

Normal HemoglobinsNormal HemoglobinsNormal HemoglobinsNormal Hemoglobins

Hb A = Hb A = αα22ββ22Hb A = Hb A = αα22ββ22

Hb F = Hb F = αα22γγ22Hb AHb A δδHb AHb A22 = = αα22δδ22

Hb H = Hb H = ββ44

Hb Bart’s = Hb Bart’s = γγ44

Hemoglobin VariantsHemoglobin VariantsHemoglobin VariantsHemoglobin Variants

Hemoglobin S (Hemoglobin S (αα22ββ2 2 6 6 GluGlu--ValVal))Hemoglobin S (Hemoglobin S (αα22ββ2 2 ))

•• predisposes to sicklingpredisposes to sicklingHemoglobin C (Hemoglobin C ( ββ 6 6 GluGlu--LysLys))Hemoglobin C (Hemoglobin C (αα22ββ2 2

6 6 GluGlu--LysLys))•• predisposes to cellular dehydrationpredisposes to cellular dehydration

llHemogobin E (Hemogobin E (αα22ββ2226 26 GluGlu--LysLys))

•• microcytosis, slight anemiamicrocytosis, slight anemia

AA (Normal)

Elevated A2

ASAS

ACCelluloseA t t

SS

AcetatepH 8.6

S/βthal

SC

Secondary Laboratory InvestigationSecondary Laboratory InvestigationCCCellulose Acetate Hb ElectrophoresisCellulose Acetate Hb Electrophoresis

-- AA22/C S F A +/C S F A +-- AA22/C S F A +/C S F A +NormalNormal


-- AA22/C S F A +/C S F A +-- AA22/C S F A +/C S F A +NormalNormalHb SSHb SSHb SSHb SS


-- AA22/C S F A+/C S F A+-- AA22/C S F A+/C S F A+NormalNormalHb SSHb SSHb SSHb SSHb ASHb AS


-- AA22/C S F A+/C S F A+-- AA22/C S F A+/C S F A+NormalNormalHb SSHb SSHb SSHb SSHb ASHb ASHb SCHb SC


-- AA22/C S F A+/C S F A+-- AA22/C S F A+/C S F A+NormalNormalHb SSHb SSHb SSHb SSHb ASHb ASHb SCHb SCHb CCHb CCHb CCHb CC


-- AA22/C S F A+/C S F A+-- AA22/C S F A+/C S F A+NormalNormalHb SSHb SSHb SSHb SSHb ASHb ASHb SCHb SCHb CCHb CCHb CCHb CCHB ADHB AD

αα-- andand ββ--ThalassemiasThalassemiasαα and and ββ ThalassemiasThalassemias

The most common monogenic The most common monogenic The most common monogenic The most common monogenic diseasesdiseasesWidespread throughout Widespread throughout Widespread throughout Widespread throughout Mediterranean, Africa, Middle East, Mediterranean, Africa, Middle East, Indian subcontinent and Burma Indian subcontinent and Burma Indian subcontinent and Burma, Indian subcontinent and Burma, SEA, Southern China, Malaysia, and SEA, Southern China, Malaysia, and IndonesiaIndonesiaIndonesiaIndonesiaGene frequency Gene frequency 33--10 10 percentpercent•• mutations tend to be very regionally mutations tend to be very regionally

specificspecific

αα--ThalassemiaThalassemiaαα ThalassemiaThalassemiaNormal α-Thal-1 trait

Normal CBCMild

α Thal-2 trait or

CBC Normal

Mild Microcytic anemia or no anemia

Lowish MCV

Hb H Disease Hydrops fetalisHb H Disease

Moderatemicrocytic anemia

Hydrops fetalis

Rare live birthsmicrocytic anemia

Classification & TerminologyClassification & TerminologyAlphaAlpha ThalassemiaThalassemia

•• NormalNormal αααα//ααααNormalNormal αααα//αααα•• Silent carrierSilent carrier -- αα//αααα•• MinorMinor --αα//--ααMinorMinor --αα//--αα

----//αααα•• Hb H diseaseHb H disease // αα•• Hb H diseaseHb H disease ----//--αα•• Barts hydrops fetalisBarts hydrops fetalis ----//----

ββ--ThalassemiaThalassemiaββ ThalassemiaThalassemia

Due to mutations in the Due to mutations in the ββ--globin gene globin gene Due to mutations in the Due to mutations in the ββ globin gene globin gene leading to decreased production of normal leading to decreased production of normal chainschainsVarying degrees of microcytic anemiaVarying degrees of microcytic anemiaHeterozygous (thalassemia minor)Heterozygous (thalassemia minor)yg ( )yg ( )•• mild anemia, microcytosis, RBC > mild anemia, microcytosis, RBC > 5 5 X X 101066

Homozygous or compound heterozygotes Homozygous or compound heterozygotes yg p ygyg p yg(thalassemia major or intermedia)(thalassemia major or intermedia)•• moderate to severe hemolytic anemia with moderate to severe hemolytic anemia with

l ll lsplenomegalysplenomegaly

Classification & TerminologyClassification & TerminologyBeta ThalassemiaBeta Thalassemia

•• NormalNormal ββ//ββNormalNormal ββ//ββ•• MinorMinor ββ//ββ00

ββ//ββ++ββ//ββ•• IntermediaIntermedia ββ00//ββ++

•• MajorMajor ββ00//ββ00•• Major Major ββ00//ββ00

ββ++//ββ++

Olivieri, N. NEJM

Thalassemia “Trait”Thalassemia “Trait”Thalassemia TraitThalassemia Trait

Hoffbrand and Pettit

CBC in Thalassemia TraitCBC in Thalassemia TraitCBC in Thalassemia TraitCBC in Thalassemia Trait

WBC 7.2RBC 6 9 X 106RBC 6.9 X 10Hb 15.8Hct 47.6

MCV 69RDW 14

Plt 351 000Plt 351,000

β-thalassemia majorβ j

Hoffbrand and Pettit

Thalassemia Trait vs. IDAThalassemia Trait vs. IDAParameterParameter αα--ThalThal ββ--ThalThal IDAIDAHb Hb ( /dl)( /dl) 1212±±00 66 M=M=1212 66±±11 44 1010 2 2 ±± 11 66Hb Hb (mg/dl)(mg/dl) 1212±±00..66 M=M=1212..66±±11..44

F=F=1010..8 8 ±± 00..991010..2 2 ±± 11..66

RBCRBC 55..6 6 ±± 00..55 M=M=55..8 8 ±± 00..66 44..67 67 ±± 00..4343RBCRBC 55..6 6 ±± 00..55F= F= 55..1 1 ±± o.o.99

44..67 67 ±± 00..4343

MCVMCV 7272..2 2 ±± 33..33 55 55 -- 6969 67 67 ±± 66..66

MCHMCH 2323..2 2 ±± 33..33 2020..2 2 ±± 22 2121..8 8 ±± 22..99

Hb AHb A22 N or N or ↓↓ 55..2 2 ±± 00..88 N or N or ↓↓

Hb FHb F <<11%% 22..1 1 ±± 11..22 <<11%%

SummarySummarySummarySummaryThalassemias and hemoglobinopathies are Thalassemias and hemoglobinopathies are g pg pparadigms for disease that result from abnormal paradigms for disease that result from abnormal protein interactions.protein interactions.Th it d h i Th it d h i They are quite common and can have serious They are quite common and can have serious clinical consequencesclinical consequencesKnowledge of the genetics of these disorders Knowledge of the genetics of these disorders Knowledge of the genetics of these disorders Knowledge of the genetics of these disorders allows effective genetic counseling and prenatal allows effective genetic counseling and prenatal screeningscreeningI i ht i t th th i f th di d I i ht i t th th i f th di d Insight into the pathogenesis of these disorders Insight into the pathogenesis of these disorders has lead to rational drug developmenthas lead to rational drug developmentGene augmentation therapy holds the hope of Gene augmentation therapy holds the hope of Gene augmentation therapy holds the hope of Gene augmentation therapy holds the hope of eventual “cure”eventual “cure”

Di ti A hDiagnostic Approachiacld.ir/DL/modavan/hematology/diagnosticapproachto...Di ti A hDiagnostic Approach to Anemic Patientsto Anemic Patients 9Hg f =%Hg f =%90 90 in in 24 24

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