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Anemia Approach for the Primary Care Physician

DavidSeastone,DO,Ph.D.UPMC/AHNRegionalCancerCenter

A54yearoldmanwithmanymedicalcomorbidiGesincludingHTN,HPL,CAD,DM,RAisfoundtohaveahemoglobinof10.4onrouGnelaboratorystudies.HissymptomsincludegeneralfaGgueandhehasnosymptomsorfamilyhistoryofblooddisease.PEissignificantforconjuncGvalpallor,aprominentS4oncardiacexamandvenousstasismarkingsinhislowerextremiGes.Whatisthenextstep?

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Anemia

• ReducGonofRBCconcentraGonbelownormallimits•  DecreasedHbconcentraGon(<11.5g/dL)•  DecreasedRBCcount•  Usuallydecreasedhematocrit(cellularblood)

• CanbesymptomaGcorasymptomaGc•  Symptoms•  FaGgue•  Dyspnea•  Macroglossia•  Pallor

• Decreasedhematopoiesis

•  Bloodloss•  HemolyGcanemias

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Ini5al Work-up for anemia: considera5ons

• Bleeding(pastorpresent)?• IronDeficiency?• B12/folatedeficiency?• RBCDestrucGon?• Bonemarrowsuppressed?

Anemia of blood loss

• Acutebloodloss–noGmeforcompensaGon•  Hemorrhage-mayleadtohypovolemicshock•  Lossoftotalbloodvolumemoreimportantthanacutelossofhemoglobin•  CBCiniGallynormal(usually)•  CBCdropsoverGmeandwhenIVFaregiven

• ChronicBloodLoss–bodycancompensateifable•  UsuallyGItractoruterinebleeding•  Causesanemiaonlyifbloodloss>>capacityofbonemarrowtoreplacelostRBCs•  IntrinsicbonemarrowdiseasesornutriGonaldeficiencies•  VitaminB12,Folate,Iron,Pyridoxine,Proteinimbalance

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Anemia of decreased RBC produc5on

• DifferenGalDiagnosis:• IronDeficiency• VitaminB12Deficiency• FolicAcid/FolateDeficiency• AnemiaofChronicDisease• AnemiaofBoneMarrowStemCellFailure• Primaryfailure•  Secondaryfailurefrommalignancy

History IS important!

• HistoryofcomorbidiGesthatarecontributory•  GIBleeding,RenalFailure,Autoimmunedisease,ChronicinflammaGon

• Bsymptoms:fever,chills,nightsweats,unintenGonalweightloss•  Isanemiarecentorlong-standing?•  Symptoms:faGgue,dyspnea,somnolence,pica,icecraving

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Physical Exam – s5ll useful

• PallorofconjuncGva:50-70%reliable•  Jaundice•  Lymphadenopathy• Hepatomegaly/Splenomegaly• Bonetenderness:especiallyoversternum

Laboratory evalua5on: go straight for the gusto

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Typical peripheral blood smear

Other Cell Types

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Microcy5c/Hypochromic Anemia

Important ini5al laboratory studies

•  Hemoglobin/Hct• MCV•  RDW(variabilityinRBCsize)•  Iron•  TIBC•  TransferrinsaturaGon•  FerriGn

•  ReGculocytecount•  LDH

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Iron Deficiency • MostcommoneGologyofmicrocyGc,hypochromia• 11millioncasesperyearinUS

• Ironlossfromchronicbleeding• Menstrualbloodloss(reproducGveagewomen)• GIbleeding(age>50inmenorwoman)

Iron Deficiency • MostcommonnutriGonaldisorderthroughoutworld•  80%ofFe2+foundinHb•  20%foundinmyoglobin,cytochromes,catalase,others

• FeStoragePool:FerriGnandHemosiderin•  FerriGn:Protein-Fecomplexfoundmostlyinliver,spleen,bonemarrowandskeletalmuscle• Hemosiderin:Brownpigmentinmacrophages

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Iron deficiency •  LaboratoryTestsforFe:•  SerumFe:concentraGonoftranferrin-boundiron•  FerriGn:proporGonaltototalbodyFestores•  TotalIron-BindingCapacity:amountofironcarriedbyblood•  %TransferrinSaturaGon:iron/TIBCx100

• Usualresultsinirondeficiencyanemia:•  SerumFe:Decreased•  SerumFerriGn:Decreased•  SerumTIBC:Increased•  TransferrinSaturaGon:Low•  Platelets:Okenhigh

Treatment

•  Ferroussulfate325mg(65mgofelementaliron)•  Daily,BID,TIDdependingondegreeofdeficiency

• Niferex–polysaccharide-coated150mg•  Daily,BID,TIDdependingondegreeofdeficiency

•  LiquidIron-$$$

•  Side-effects:aversion,nausea,consGpaGon,darkstools

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Parenteral Iron Infusion

•  Irondextran–INFED•  Ferricgluconate–Ferrlecit•  Ironsucrose–Venofer

•  OnlyformulaGonwithrobustdatainpregnancy

•  Ferriccarboxymaltose–Injectafer•  Mostconvenient(30minuteinfusionx2weeklydoses)

•  Ferumoxytol–Feraheme

•  AnyformulaGoncancauseadversereacGons•  LocalinfusionreacGonsàanaphylaxis

B12/folate Deficiency

• MegaloblasGc/macrocyGcanemia:

• VitaminB12/Cobalamin:•  RequiresintrinsicfactorforabsorpGon•  IFissecretedbyparietalcellsinstomach•  IF/B12complexisabsorbedintheterminalileum(last100cm)

•  GIsurgeryorIBD•  Neuropathycanbepresent

•  FolicAcid/FolateDeficiency:•  UsuallyanutriGonalproblem(alcoholism)•  Pregnancy

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Vitamin B12/Folate deficiency: Hypersegmented neutrophils

More rare, but always a possibility…

• Thalassemia• Sickle-cellanemia

• Hemoglobinelectrophoresisisusedtodiagnose

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Sickle-cell Anemia

Hemoglobin Structure

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Thalassemias

• DecreasedproducGonofglobinchains

• α-Thalassemias:decreasedrateofproducGonofα-globinchains•  UsuallyseeninpaGentsofAsiandescent

• β-Thalassemias:decreasedrateofproducGonofbeta-globinchains•  UsuallyseeninpaGentsofAfrican/Mediterraneandescent

Target Cells

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Anemia of chronic disease

• AnemiaofChronicDisease:Chronicinflammatorydiseasesmayimpairthehandlingofironinthebody

•  3MajorCategoriesofInflammatoryDiseases:•  AutoimmuneDisorders:collagenvasculardiseases,IBD,generalinflammaGon•  MalignantNeoplasms•  InfecGousDiseases:osteomyeliGs,bacterialendocardiGs,lungabscess

Anemia of chronic disease

• DefectofironincorporaGonintoHbmoleculesduringerythropoiesis:•  ProbleminmobilizingFefromstoragepool

• UsuallynormocyGc,normochromic•  SerumFe:Decreased/Normal•  SerumferriGn:Normal/Increased(inflamma5on)•  TotalIron-bindingcapacity(TIBC):Decreased•  TransferrinsaturaGon:Normalordecreased

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Anemia of Chronic Disease Mechanism: Hepcidin

LowHepcidin InflammaGon:HighHepcidin

Anemia of Chronic Disease

•  ErythropoieGnlevelisimportant•  Okeninappropriatelylow/normal•  Mayindicaterenaldisease

• CanuseerythropoieGnsGmulaGngagentstoboostHb•  Procrit(recombinanterythropoieGn)•  Aranesp(darbepoieGn)–fragmentofrecombinanterythropoieGn

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No Solu5on? Time to get the Hematologist involved…. •  Notusuallynecessary

•  Notasbadasmostpeoplethink•  UsuallyanoutpaGentprocedurethatlasts15-20minutes

In all honesty……

• BoneMarrowbiopsyusuallyonlyemployedwhen>2celllineagesaredepletedwithnogoodclinicalexplanaGon•  RBC• WBC•  Platelets

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Hypocelluar bone marrow

Hypercellular bone marrow

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Malignancy of bone marrow

• Leukemias• Lymphomas• Myeloma• Myelofibrois• MetastaGcbonedisease

MGUS --> myeloma….can be sneaky

• ElevatedProtein/albuminraGoinCMPcanbeclue• Elevatedgammaglobulinscanbeaclue

• CheckSPEP(serumproteinelectrophoresis)•  Looksforamonoclonalproteinbeingmadebymalignantplasmacells

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Rare causes of anemia

•  AplasGcAnemia•  Mayoccuratanyageandnogenderpreference•  Hypocellularbonemarrow•  Almostnomaturingmyeloidcells

•  PNH(paroxysmalnocturnalhemoglobinuria)•  LossofCD55/CD59onRBCs(normallyinhibitcomplement)•  LeadstoacGvaGonofterminalcomplement(C5-9)•  Eculizumabistreatment

•  PureRedCellAplasia:•  Rareformofbonemarrowfailureleadingtoerythroidaplasiaonly•  granulopoiesisandthrombopoiesisarenotaffected

Hemoly5c Anemia: Increased destruc5on

• RBCsusuallylivefor120days

• Causes•  MechanicalInjury(valves)•  AutoimmunecomplementfixaGononsurfacemembrane•  ExogenoustoxicFactors(medicaGons)•  RBCmembraneabnormaliGes•  EnzymeabnormaliGes

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Hemoly5c anemia

• Clinicalpicture•  Anemiasymptoms(faGgue,dyspnea)•  Jaundice(destrucGonofHbàbilirubin)•  SomeGmeshepatomegaly/splenomegaly

•  Laboratorypicture•  DecreasedHb•  Decreasedhaptoglobin(bindsHbtopreventtoxicity)•  IncreasedLDH(lactatedehydrogenase)•  IncreasedReGculocytes(immatureRBCs)

Hemoly5c Anemia

• AutoimmuneHemolyGcAnemia(AIHA)• WarmvsCold(usuallywarm)

• PresenceofIgonthesurfaceofRBCs•  AutoanGbodies•  Coomb’sposiGve(DirectanG-globulintest)

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Autoimmune Hemoly5c Anemia (AIHA)

Cold Agglu5nin Immune Hemoly5c Anemia

•  IgMauto-anGbodiesbindtoRBCs•  IgMispentamericandbindsbestatlowtemps•  Exacerbatedinwintermonthsinnorthernclimates

• AssociaGons:•  MGUS(monoclonalgammopathyofunknownsignificance)•  Lymphoma,CLL•  InfecGons(AdenovirusandMycoplasmapneumoniae)

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Hemoly5c Anemia: Hereditary spherocytosis

•  Inheriteddisorderoferythrocytes• AbnormalmembranesandshapeofRBCs•  MutatedSpectrin,ankyrin,band3protein,orprotein4.2

•  Spherocyteslessdeformable,thereforemorelikelytobesequesteredinsplenicsinusoids•  SeenmostcommonlyinNorthernEuropeandescendants(1in5,000)•  Usuallyautosomaldominant

Spherocytes

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Hemoly5c Anemia: Glucose-6-Phosphate Dehydrogenase Deficiency:

• Keyenzymeinthehexosemonophosphateshunt(HMP)• DeficiencycausesoxidaGonofglobinchainswhichleadstodenaturedhemoglobin(Heinzbodies)• Deficiencyispresentin~10%ofAfrican-AmericansorthoseofMediterraneanancestry•  Autosomalrecessiveinheritance•  Variablephenotypicexpressionofthedisease

• UsuallycausedbyinfecGonordrugexposure•  AnG-malarial•  Sulfa-drugs

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Bite Cells in G6PD Deficiency

Other Diseases associated with hemolysis

• HELLP–pregnantwomen• HUS–bacterialinfecGons•  TTP–thromboGcthrombocytopenicpurpura

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Microangiopathic Hemoly5c Anemia

Anemia Summary

• Cause:Bleeding,poorproducGon,destrucGon• HistoryandExamareimportantclues•  LaboratoryevaluaGoncanconfirmorleadtofurthereGologies• Primarycarerole:assesscommoncauses•  Bleeding,ironandfolate/B12deficiency,considerchronicdiseaseanemia•  ErythropoieGncanbehelpful

•  Ifunexplainedormorethan1celllineisdecreased(WBC,RBC,platelets)refertohematologyforfurtherconsideraGon

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Thank You!