Joe - myCMEmedia.mycme.com/documents/29/umdnj_module_5... · Joe Schwenkler, MD ... Extracorpuscular Defects‐ Autoimmune Hemolytic Anemia Positive coombs test - [PDF Document] (2023)

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JoeSchwenkler,MD

MedicalDirector

UMDNJ‐ PAProgram

June2011

ThisimageisaworkoftheNationalInstitutesofHealth

Anemiaisasign,notadisease.

Anemia'sareadynamicprocess.

Itisnevernormaltobeanemic.

Correctuseoflabtestsisparamount.

Concomitantcausesofanemiaarecommon.

Thediagnosisofirondeficiencyanemiamandatesfurtherwork‐up.

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MicrocyticAnemia‐>MCV<80 Reducedironavailability— severeirondeficiency,theanemiaofchronicdisease,copperdeficiency

Reducedhemesynthesis— leadpoisoning,congenitaloracquiredsideroblasticanemia

Reducedglobinproduction— thalassemicstates,otherhemoglobinopathies

M ti A i MCV MacrocyticAnemia‐>MCV>100

Megaloblasticanemias‐ FolicacidandVitaminB12deficiency

alcoholabuse,liverdisease,andhypothyroidism

NormocyticAnemia

Anemiaofchronicdisease

Anemiaofchronicrenalfailure

Normallifespanabout120days

Destroyedbyphagocytes

spleen,liver,bonemarrow,lymphnodes

heme biliverdin unconjugated (indirect)bilirubinbilirubin

liverconvertstoconjugated (direct)bilirubinwhichenhanceseliminationfromthebody

globinandiron recycled

RBCdestructioninbloodvessels freeHbinurine(Hemoglobinuria vs.Hematuriawhichiswholeredbloodcellsinurineduetokidneyortissuedamage)

ErythrocytesnewlyreleasedfromBoneMarrow

ContainsmallamountofRNA

Stainwithmethyleneblue

Increaseinresponsetoerythropoietin (EPO)p y p ( )

http://en.wikipedia.org/wiki/Image:Hematopoiesis_%28human%29_diagram.png

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WhereisEPOproduced?

1) Bonemarrow

2) Kidney

3) Pancreas

Li 4) Liver

5) Spleen

DecreasedProduction(LowReticcount)

Lackofnutrients…iron,VitaminB12,Folate

BoneMarrowSuppression…Aplasticanemia

Lowlevelsoftrophicfactors…chronicrenaldisease(lowEPO),lowthyroid,testosterone

f h d Anemiaofchronicdisease

Increaseddestruction(HighReticcount)

HemolyticAnemias Inherited…sicklecell,thalassemias

Acquired…idiopathic,drug‐induced,andmyelodysplasticsyndrome.

LowRetic countsuggestspoorlyfunctioningbonemarrow

NormalPlateletsandWBC Acutebloodloss Renaldisease Infections Drugs

LowplateletsandWBC Leukemia

Aplastic anemia

Infection

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Serumironisfree

Transferrin bindsironincirculation

TIBCi id ti l TIBCisidentical

%Saturationisserumiron/TIBC

Ferritin storesironinliverandRES

76yofemalecomesinc/obeing“rundown”foroveramonth

OnlymedisdailyibuprofenforchronicLBP

PMHunremarkable,noprevioushosp.

Deniesextrastress problemssleepingexceptfor Deniesextrastress,problemssleepingexceptforrestlesslegs

Recentlyhasbeencravingicetochew(Pagophagia)

Physicalexamunremarkableexceptangularstomatitis,glossitis,paleconjunctiva,2/6SEMatLUSB,andspoonnailsasbelow

Hgb9.2(12.3– 15.3),Hct27.4(36– 44)

MCV80.8(80‐100)

RDW(12.7‐14.5)14.6‐ Anisocytosis

Reticcount(1 1‐2 1)1 6Reticcount(1.1 2.1)1.6

Serumferritin11.2(10‐200)

Serumiron28.6(30‐160)

TIBC(transferrinlevel)376(230‐400)

Transferrinsaturation10.2(9.6‐29)

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Whatisyournextstep?

1) Bonemarrowtest

2) RxwithvitaminB12

3) Transfuse2unitspackedcellspackedcells

4) GIwork‐upforoccultbleeding

5) TreatwithEPO

Microcyticanemiacausingspoonnails(koilonychia).

Glossitis esophagealwebformation(dysphagiaduetoPlummer‐Vinsonsyndrome).

Restlesslegsisoftenassociatedanemia,checkferritin!

Pica isuniquetoiron‐deficiencysyndrome.

IncreasedRequirements BleedingfromsomeGIsource Menses Blooddonation(oneunit=250mgiron) Growthperiods,pregnancy,lactationI f t f d ’ ilk ff f d d Infantsfedcow’smilksufferfromreducedbioavailabilityironandinducedGIbleeding

Inadequatesupply• Intestinalmalabsorption‐ ironabsorbedinduodenum Sprue,celiac,atrophicgastritis

• Gastricsurgerybypassingduodenum(Rxhighdoses)• CalciuminhibitsGIabsorption

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Treatment

Ferroussulfate325mgb.i.d.

Bewareconstipation

Recheckbloodtests6weekslater

Continueoralironuntilserumferritinnormalizes(upto6months)

Ironsaltsnotabsorbediftakenwithfood

Ironpills needtobegiven2hoursbefore,orfourhoursafterantacids

VitaminChelpsabsorption

NormalFedeficiencywithoutanemia

Fedeficiencywithmildanemia

SevereFedeficiencywithsevereanemia

Marrowiron 2+to3+ None None None

Serumiron 60to150 60to150 <60 <40

Ironbindingcapacity(transferrin)

300to360 300to390 350to400 >410

Saturation(SI/TIBC),percent

20to50 30 <15 <10

Hemoglobin Normal Normal 9to12 6to7

Redcellmorphology

Normal NormalNormalorslighthypochromia

Hypochromiaandmicrocytosis

Plasmaorserumferritin

40to200 <40 <20 <10

Othertissuechanges

None None NoneNailandepithelialchanges

47yomalewith10yearh/otype2comesforPE Currentlytakingmaxdosesmetformin &glyburide BP148/92,retinalexamshowscottonwoolexudates

Diminishedmonofilamentsensationonfeet DiabetespoorlycontrolledwithA1c 10 6% DiabetespoorlycontrolledwithA1c=10.6% Microalbumin 300(<20),creatinine 1.4(<1.4) CBCshowsHgb 9.1,MCV85,normalplatelets Stoolguiac negativex3 Serumferritin 170(10‐200),Retic count.5% Serumiron65(60‐150),TIBC320(300‐360)

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WhatcancauseelevatedferritinANDlowserumiron?

1) Chronicinflammation

2) Aplasticanemia

) Hemolysis3) Hemolysis

4) Hemoglobinopathies

5) Perniciousanemia

SecondmostcommonanemiaafterIronDeficiency

Inducedbyinflammatorycytokines(IL‐6)

Reductioninredbloodcell(RBC)productionbyBMReductioninredbloodcell(RBC)productionbyBM

Trappingofironinmacrophages

reducedplasmaironlevelsmakingironrelativelyunavailablefornewhemoglobinsynthesis

Erythroid precursorsareimpaired

Interferons arepotentinhibitors

Bluntederythropoietinresponse

chronic disease

iron deficiency

serum iron

TIBC (t f i )

Diagnosis of Anemia of Chronic Disease is often complicated…

(transferrin)

iron saturation

serum ferritin

nL or

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Acuteevent‐relatedanemia

aftersurgery,majortrauma,myocardialinfarction,orsepsis

SecondarytotissuedamageandacuteSeco da y to t ssue da age a d acuteinflammatorychanges

SharesmanyofthefeaturesofACD

lowserumiron

highferritin

bluntedresponsetoEPO

Acuteandchronicinfections TB

Endocarditis

ChronicUTI

Malignancies Metastaticcancer

Leukemia

Lymphoma

Chronicarthriticconditions

Chronicrenalinsufficiency

Hypothyroidism

ANYCHRONICINFLAMMATORYCONDITION!

Generallymild/moderateanemia(Hb8‐10)

Normochromic,normocytic(maybeslightlylow)

Lowtonormalreticulocytecount

R d d i dt f i t ti Reducedserumironandtransferrinsaturation

ReducedornormalTIBC/transferrinlevels

Normalferritinlevels(acutephasereactant)

Needtoexcludechronicrenalfailure,hyperthyroidism,hypothyroidism

Mayhaveconcomitantirondeficiencyanemia

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Whatisthebesttreatmentforthispatient?(Hb=9.1)

1) EPO

2) Transfuse2unitspc

3) Oraliron

4) Parenteraliron

Erythropoietin(EPO)ismosteffectivetherapy

Oralironoflittlebenefitunlessalsoirondeficient

Transfusionsonlyforshort‐termifHb<8

WhototreatwithEPO? Hemoglobin<10

Additionalriskfactors(pulmonary,CV,renal)

Whatisgoaloftherapy? Hb 11to12generallyaccepted

NEJM11/16/2006comparedhighertarget13.5 Increasedsideeffects‐>heartdisease

Noimprovementqualityoflife

Sicklecelldisease‐ homozygous Autosomal recessivedisease Substitutionoftheaminoacidvaline forglutamine 8%to10%ofAfricanAmericanscarrygene

Sicklecelltrait‐ heterozygotes Splenic infarctioncanoccurwithhypoxia(altitude) Splenic infarctioncanoccurwithhypoxia(altitude) Renalhematuria common Bewarebacteruria duringpregnancy(pyelonephritis)

Thalassemias‐ imbalancedsynthesisofnormalglobinchains Beta Alpha

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NameofHemoglobin Distribution Structure

A 95%‐98%ofadultHb α βA 95%‐98%ofadultHb α2β2

A2 1.5%‐3.5%ofAdultHb α2δ2F Fetal,0.5%‐1.0%of

adultHbα2γ2

On deoxygenation, hemoglobin S polymersform, causing cell sickling and damage to themembrane

Vasocclusive episodes result from a Vasocclusive episodes result from acombination of vascular adhesion of youngsickle cells and consequent trapping ofdense sickle cells

Functional asplenism

Chronichemolysisofsicklecelldiseaseisusuallyassociatedwith: amildtomoderateanemia(hematocrit20to30percent)

reticulocytosisof3to15percent(accountingforthehighorhigh‐normalmeancorpuscularvolume[MCV])

unconjugatedhyperbilirubinemia

elevatedserumlactatedehydrogenase

Redcellsarenormochromicunlessthereiscoexistentthalassemiaorirondeficiency

HbelectrophoresishighlevelsHbF

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WhatisthemajorreasonthatsicklecellpatientsvisitPhysicianAssistants?

1) Infections

2) Gallstones

3) Chroniclegulcers

Si kl ll i i4) Sicklecellcrisis

5) Splenomegaly

Precipitatedbyweather,infection,stress

Lasts2to7days

Oftenundertreated!

Lowriskofnarcoticaddiction

Generatefeelingsofdespair,depression

ManagementHydration

Painmanagement

Seeksourceofinfection‐>Antibiotics?

Hydroxyurea haspromise‐>raisesHbF levels

1) Renalinfarction

2) Acutechestsyndromesyndrome

3) Cerebrovascularinfarct

4) Myocardialinfarct

5) Suicide

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Hand&footsyndrome(dactylitis)‐ commonchildren

Aplasticcrisis*canresultfromParvovirus19finfect.

Splenicsequestrationwithenlargingspleen

Acutechestsyndrome*

CVA*

*Exchangetransfusionindicated

Infections:StreppneumoniaandH.Influenza

Gallstones

Renalfailureduetopapillaryinfarcts painlesshematuria iscommonpainlesshematuria iscommon

Chroniclegulcers

Priapism needstobetreatedwithin4to6hours

Asepticnecrosisinfemoralandhumeralheads

Chronicosteomyelitis (salmonelli typhi)

Routinevisitswithprimaryprovider

Folicacid1mgdaily

Transcranial doppler exam DetectpatientsthatwouldbenefitfromregulartransfusionstopreventCVA

Retinaexamtolookforproliferativechanges

Streppneumoniavaccinebelowage5both7and23‐valent,then23‐valentevery7years H.flu,meningococcal,influenzastartingage6months

Dailyprophylacticoralpenicillinuntilage5* *newrecommendation

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34yo femalecomesinforcheck‐up

Nocomplaints

Normalpastmedicalhistory

Neverremembershavingbloodtestsbeforeg

Unremarkablefamilyhistory

Nomeds,non‐smoker,rarealcohol

MotherborninTaiwan

Normalphysicalexam

CBCshowsHb 11.6,MCV76,markedmicrocyticRBCwith basophilicstippling

WhatisthemostlikelyDx?

1) IronDeficiencyanemia

2) Beta‐Thalessemiatrait

3) Perniciousanemia

4) Anemiaofchronicdisease

5) Beta‐Thalessemiamajor

Diminished production of ß‐globin chains

causing unmatched α‐globin chains to accumulate andaggregate

If MCV less than 75 fl and the RBC count greaterthan 5million cells/µl‐> Thalassemiaµ

ß‐Thalassemia major (Cooley anemia)

no ß chains are synthesized; only HbF and HbA2

severe anemia that appears in the first year

ß‐Thalassemia minor (ß‐thalassemia trait) Heterozygous condition

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severeanemia

bloodfilm pronouncedvariationinredcellsizeandshape(HighRDW)

paleredcells,targetcells,basophilicstippling(ribosomalprecipitates) nucleatedredcells moderatelyraisedreticcountprecipitates),nucleatedredcells,moderatelyraisedreticcount

infantswellatbirthbutdevelopanemiainfirstfewmonthswhenswitchoccursfromgamma(HbF)tobetaglobinchains

progressivesplenomegaly;ironloading;pronetoinfection

Allogenic BoneMarrowtransplantationRxofchoice

mildhypochromicmicrocyticanemia

HGB9‐11g/dL

MCV50 70fL MCV50‐70fL

MCH20‐22pg

noclinicalfeatures,patientsasymptomatic

oftendiagnosedonroutinebloodcount

raisedHbA2level

α‐thalassemia‐2 trait (minima)

Loss of one of the four alpha globin genes

No abnormalities of blood testing

α‐thalassemia‐1 trait (minor)

loss of two of the four alpha globin genes

MCV is often less than 80 but Hb electrophoresis is normal MCV is often less than 80, but Hb electrophoresis is normal

Hemoglobin H disease

Hemoglobin H, composed of four beta chains (beta4)

three of the four alpha globin loci are nonfunctional

chronic hemolytic anemia, due to the formation of inclusionbodies in circulating red cells as Hb H precipitates

Hydrops fetalis with Hb Barts

none of the four alpha globin loci is functional

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Disorder GenotypicAbnormality ClinicalPhenotype

β‐Thalassemia

Thalassemiamajor(Cooley'sanemia)

Homozygousβ0‐thalassemia

Severehemolysis,ineffectiveerythropoiesis,transfusiondependency,ironoverload

Thalassemiaintermedia Compoundheterozygousβ0‐ andβ+‐thalassemia

Moderatehemolysis,severeanemia,butnottransfusiondependent;mainlife‐threateningcomplicationisironoverload

Thalassemiaminor Heterozygousβ0‐ orβ+‐thalassemia

Microcytosis,mildanemia

α‐Thalassemia

Silentcarrier α‐/αα Normalcompletebloodcount

α‐Thalassemia trait αα/‐ ‐ (α‐thalassemia1)OR Mildmicrocyticanemia

α‐/α‐ (α‐thalassemia2)

HemoglobinH α‐/‐ ‐ Microcyticanemiaandmildhemolysis;nottransfusiondependent

Hydrops fetalis ‐ ‐/‐ ‐ Severeanemia,intrauterineanasarca fromcongestiveheartfailure;deathinutero oratbirth

• AnemiaofChronicrenalInsufficiency• EPOiseffectivetreatment

• Acutebloodloss• OrthostaticSymptomspredominate

• Restingtachycardiaandhypotension• Cantake24hr forHct tofall• Cantake24hr.forHct tofall• 3‐5daysreticulocytosis elevatesMCV

• Anemiaofliverdiseasemultifactorial:• RemodelingofRBCmembranes• Hypersplenism• Folate deficiency• Co‐existingirondeficiency

CausedbyprematurebreakdownofRBCs IntracorpuscularDefects‐ RBCmembranedefects HeriditarySpherocystosis&Elliptocytosis

ExtracorpuscularDefects‐ AutoimmuneHemolyticAnemia

PositivecoombstestPositivecoombstest

Rxprednisonehighdoseandtaperslowly

G6PDDeficiency

SeverityofanemiarelatedtorateRBCdestructionandabilityofbonemarrowtoproducereticulocytes

Freehemoglobinbindstohaptoglobin RemovedbyRESunlessexceedscapacity(lowhaptoglobin)

Excessfilteredthroughkidney‐>darkurine

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Acuteonsetpallorfromanemia

Jaundicewithhighindirectbilirubin

IncreasedserumLDH

Reduced(orabsent)serumhaptoglobin

Increasedreticulocytes

Positivecoombstestifautoimmuneetiology

Formsspherocytic cellsthataredestroyedinspleen

Presentwithjaundiceandsplenomegaly

Elevatedretic count

Spherocytes onsmear Spherocytes onsmear

Splenectomy oftenrequired majorriskisbacterialsepsis:pneumococcus,H.Flu,meningococcus

especiallyinchildrenyoungerthanage3

needtoimmunizepriortosurgery

34yo african american malecomestotheER

c/oseverefatiguegettingworseover2days

HIVpositivex10years HIVpositivex10years

Takingmedtopreventpneumocystis Changed2weeksagoduetopersistentrash

Deniesfever,chills,cough,abd.pain,dysuria

CXRnormal,Hct 22%,bitecellsonsmear

Urinalysis4+blood,rareWBConmiscroscopy

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Whatisthemostlikelycause?

1) Aplasticanemia

2) Acuteleukemia

3) Sicklecellanemia

G 6 PDd fi i4) G‐6‐PDdeficiency

5) Irondeficiency

• RBCsdependonanaerobicmetabolism

• Firstenzymeinpentosephosphateshunt• CatalyzesconversionNADP+‐>NADPH

• RBCsdeficientifG‐6‐PDsusceptibletohemolysis

• 10%ofmaleblacksintheU.S.areaffected• GenecarriedonX‐chromosome

• Hemolysisoccursafterexposuretoadrugorsubstancethatproducesanoxidantstress

• Favism‐ Ingestionof,orexposureto,favabeansmaycauseadevastatingintravascularhemolysis

antimalarials primiquine

pamaquine

analgesicsh ti phenacetin

acetylsalicylicacid

others sulfonamides

nalidixicacid dapsone

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Presentwithrecurrentinfections(duetoprofoundneutropenia) Mucosalhemorrhageduetothrombocytopenia Fatigueanddyspnea Pancytopenia,lackofreticulocytes Marrowisprofoundlyhypocellular withadecreaseinallelements

Rxoptions: HematopoieticcelltransplantationifHLAcompatiblesibling Immunosuppressiveregimens(cyclosporine) Antithymocyte globulin(ATG)‐ selectivelydestroysT‐cells Antiserumfromanimalsimmunizedagainsthumanthymocytes

Idiopathic

CytotoxicdrugsandRadiation

Chloramphenicol

Gold

NSAID‐ phenylbutazone,indomethacin

Sulfonamides

Antiepilepticdrugs‐ felbamate

Arsenicals

Benzene

Lindane

Gluevapors

Non‐A,non‐B,non‐Chepatitis

HIVinfection

Epstein‐Barrvirus

Systemiclupuserythematosus

Graftversushostdisease

76yooldmalewithseveralmonthsofprogressiveweaknessandmemoryloss

Alsotinglinginlegs,broad‐basedgait

Nomeds,usuallyhealthy,rareetohy y

P.E.showsatrophyoflingualpapillae,+rhombergsign,lossofvibrationsense,generalizedweakness,butnormalreflexesandnegativebabinski

Hb.13.6,MCV116,MCH33,RDWnl.

Smearshowshypersegmentedneutrophils

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Whattestconfirmsthediagnosis?

1) Bonemarrow

2) Bonescan

3) CTabdomen

S hilli t t4) Schillingtest

5) Elevatedfolicacid

Alcoholism frequentlycauseselevatedMCV

VitaminB12deficiencydueto: InadequateabsorptionduetoPerniciousAnemiaInadequateabsorptionduetoPerniciousAnemia

GastricDisease/Removalofterminalileum

StrictVegan

FolicAciddeficiencyduetoinadequatedietand/oralcoholism

Chemotherapeuticdrugscancausemegaloblastic anemia

• NeurologicsymptomsarerelatedtolackofCobalmin• Neuro symptomsoftenunrelatedtodegreeofanemia• Upto50%havenormalMCVandnoanemia• Ifyoutreatwithfolate,onlyanemiaimproves

• SerumlevelsarehelpfulifLOW*,butcanbenormal

• SchillingTestrarelyneeded‐measureabsorptionradioactiveB12

• MethylmalonicAcidhighwithcobalmindeficiency• Homocysteineelevatedinbothconditions• Usetestsforfollow‐uptoconfirmsuccessfultherapy

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Autoimmunegastritis

Autoimmuneattackongastricintrinsicfactor(IF)

70%haveelevatedanti IFantibodies 70%haveelevatedanti‐IFantibodies

Increasedriskgastriccancer

Gastriccarcinoidtumors

25%haveautoimmunethyroiddisorders

Lab:RBCshowmacrocytosis(MCV>100)

Hypersegmentedneutrophils

Dementiaordepressioncanbemajorsymptom

12%presentwithneuropathybutnotanemia

Progressivecasesdevelopperipheralneuropathy

Ataxia,broad‐basedgait,rhomberg,slowreflexes

Lossofpositionsense vibration reducedskin Lossofpositionsense,vibration,reducedskinsensation

Treatment: OldRx:weekly1000microgramscobalminx6thenmonthlyforlifetime

NewRx:dailyhighdose1‐2mgdaily.Atleast2%isabsorbedandresultslooksuperiortoparenteralroute

Mostcommoncauseisnutritional

Connectedtoalcoholabuse,malnutrition,faddism

Clinicalsyndromesimilartoperniciousanemia

Diagnosewithserumfolicacidlevel

Treatwith1mgdailysupplement

Homocysteinelevelisbestwaytomonitorprogress

Pregnancyincreasesdemandforfolicacid

Helpstopreventfetalneuraltubedefects

Allwomenofchild‐bearingagedaily.4mg

PrescriptionPrenatalvitaminshave1mg***

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25yofemaleseenforroutinecheck

Feelswell,buthash/oheavymensesandeasybleedingpostdentalwork

PEallWNLexceptfewpetechiaeonhershinsandbarelypalplablespleentip

Hct32,platelets56,000(150,000to300,000)

NormalPT,PTT,withprolongedbleedingtime

Whatisthelikelycause?

1) VonWillebranddisease

2) IdiopathicThrombocytopeniaThrombocytopeniaPurpura

3) HemophiliaA

4) DIC

5) Acuteleukemia

PlateletAbnormalities

Thrombocytopeniaduetodecreasedproduction

Aplasticanemia,drugreaction

IdiopathicThrombocytopenicPurpura(ITP)

ThromboticThrombocytopenicPurpura(TTP)

Drugs(heparin3‐5%),Viruses,SLE

Sequestrationinenlargedspleen

Commoninadvancedliverdisease

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Self‐limittedinchildren(postvirus)in70% Petechialhemorrhage,mucosalbleeding,andthrombocytopenia,withcountsoftenlowerthany p ,20,000/mcL

Antiplateletantibodytest?Useful(manyfalse+)

Mostcliniciansprefertotreatchildrenwithsteroidsorintravenousimmunoglobulin(IVIG)ifplateletcounts<10,000

Chronicinadults:treatifplateletcount<10 000 20 000<10,000‐20,000 Steroidsfirstchoicex4weeks

IntravenousImmunoglobulin(IVIG)

Splenectomycausesremissionin60% Immunosuppressiveagents

Features Acute ITP Chronic ITP

Peak age Children (2-6 yrs) Adults (20-40 yrs)Female:male 1:1 3:1Antecedent infection Common RareAntecedent infection Common RareOnset of symptoms Abrupt Abrupt-indolentPlatelet count at presentation <20,000 <50,000Duration 2-6 weeks Long-termSpontaneous remission Common Uncommon

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Clinicalcharacteristic

Bleedingdisorder

PlateletdefectClottingfactordeficiency

Siteofbleeding

Skin,mucousmembranes(gingivae, Deepinsofttissues

Siteofbleedingnares,GIandgenitourinarytracts)

(joints,muscles)

Bleedingafterminorcuts

Yes Notusually

Petechiae Present Absent

Ecchymoses Small,superficial Large,palpable

Hemarthroses,musclehematomas

Rare Common

Bleedingaftersurgery Immediate,mild Delayed,severe

Falselylowplateletcounts

InvitroplateletclumpingcausedbyEDTA‐dependentagglutininsorgiantplatelets

Commoncausesofthrombocytopenia

Pregnancy

l h b Gestationalthrombocytopenia

Preeclampsia

Drug‐inducedthrombocytopenia:Heparin,Quinidine,Quinine,Sulfonamides,Gold

Viralinfections:HIV,infectiousmononucleosis,Hepatitis

Hypersplenismduetochronicliverdisease

34yomalewhohasahistoryofexcessivelybleedinggumsafterdentalcleaning.

Frequentepistaxiswhenyoung

Oth i h lth t k d f il h Otherwisehealthy,takesnomeds,nofamilyhxbleedingdisorders

Physicalexamisnormal,nobruisesorpetechiae

Bleedingtimemildlyelevated,plateletsWNL

aPTTslightlyelevated

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Whattestwouldyouordertoconfirmthediagnosis?

1) FactorIXlevel

2) ProthrombinTime

3) vWFlevel3)

4) Fibrinogenlevel

5) FibrinDegradationProducts

BleedingTime(BT):measuresplateletfunction

Plateletcount:normal150,000‐300,000

ProthrombinTime(PT):testofextrinsic system(INR)

PartialThromboplastin time(aPTT):intrinsic PartialThromboplastin time(aPTT):intrinsicsystem

ThrombinTime(TT):testsfibrinogen‐>fibrinDIC

FibrinogenLevel:DIC

D‐Dimer:specifictoplasmindegradationseeninDIC,pulmonaryembolus

Mostcommonbleedingdisorder(1‐3%population)

Majorityasymptomatic

Autosomal dominantinheritance

VonWillebrandfactor(vWF)isdefective/deficient

L lti t i t i f h Largemultimetric proteinfromchromosome12

Formsadhesivebridgebetweenplateletsandendothelium

CarriermoleculeforFactorVIII

Labmostlynormal:

aPTT andbleedingtimeslightlyelevated

vWF levelsarelow

Ristocetin‐inducedplateletaggregationtest

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DDAVP (deamino-8-arginine vasopressin) plasma VWF levels by stimulating secretion from

endotheliumendothelium

Duration of response is variable

Dosage 0.3 µg/kg q 12 hr IV an hour before surgery

Factor VIII concentrate ContainslargeamountvWF

Rarediseaseofunknowncause *Severethrombocytopenia *Hemolyticanemiawithschistocytes andhelmet

cells *Neurologicabnormalitiesg Seizures Cloudedsensorium

*Fever *Mildrenaldiseasewithcreatinine <3.0 Minimalchangesincoagulationtests Rxlarge‐volumeplasmapharesis

*Classicpentadseeninlessthan25%

CASE#9

26yofemalehadanormalspontaneousvaginaldeliveryanhourago

Followingthedeliverytheobstetricianhaddifficultyremovingtheentireplacenta

Patientnowmildlyhypotensiveandconfusedy yp

OozingaroundIVsite,increasedbloodydischargefromvagina

LabshowedHb10.3,prolongedPT,aPTT,ThrombinTime(TT)andhighlevelsofD‐dimer

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Whatisthebesttreatment?

1) HeparinIV

2) Warfarinpo

3) Transfuse2unitspackedcellspackedcells

4) DDAVP

5) VitaminKsubQ

Systemicdisorderproducingboth: Thrombosis

Hemorrhage

Complicatesabout1%hospitaladmissions

AcuteDICresultsfrom: Bloodexposedtolargeamountsoftissuefactor

Massivegenerationofthrombin

Coagulationtriggeredinoverwhelmingfashion

ChronicDICislowgradedisorder

Procoagulantsubstancestriggersystemicactivationofcoagulationsystem

Coagulationfactorsconsumedfasterthanlivercanproducenewfactors

Pl t l t df t th BM PlateletsareconsumedfasterthanBMcancope

Acuteformisoftensevere

Chronicformassociatedwithmalignanciesespeciallypancreatic

Thromboticcomplications(Trousseausyndrome‐migratorythrombophlebitis)

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Bleeding(64percent)

Renaldysfunction(25percent)

d f ( ) Hepaticdysfunction(19percent)

Respiratorydysfunction(16percent)

Shock(14percent)

Thromboembolism(7percent)

Centralnervoussysteminvolvement(2percent)

Sepsis Meningococcemia

Gram+or‐

Obstetrical complications Amniotic fluid embolism Abruptio placentae

Activation of both coagulation and fibrinolysisTriggered by:

Trauma Head injury Fat embolism

Malignancy Solid cancers (pancreas) Trousseau Syndrome-

Migratory thrombophebitis

p p

Vascular disorders

Reaction to toxin (e.g. snake venom, drugs)

Immunologic disorders Severe allergic reaction Transplant rejection

DICTreatmentOptions

Treatment of underlying disorder

Anticoagulation with heparing p

Platelet transfusion

Fresh frozen plasma

Coagulation inhibitor concentrate (ATIII)

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Sex‐linkedrecessive

GenesonlongarmofXchromosome

HemophiliaAaffectsonein10,000males

deficientordefectiveclottingfactorVIIIg

HemophiliaB‐ FactorIXDeficiency

FactorXIDeficiency‐AshkenaziJews

Replacementtherapy

Recombinantformsnowavailable($100,000/yr)

Cryoprecipitateeffectivebutrisky

Typesofbleeding: Hemarthrosis ofjoints

Retroperitoneal

Hematuria

Mucosalbleeding

Intracranialbleeding Intracranialbleeding

Complications: Jointdeformities

Arthritis

Muscleatrophy

Contractures

Factorconcentratesthatcanbevirallyinactivatedorrecombinant

Lowdoseprophylacticusep p y Boostthedosewithtraumaoranyformofsurgery

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AcuteLymphocyticLeukemia(ALL)

Peakincidenceage3‐5

20%adultleukemia,mostchildhoodcases

Philadelphiachromosome25%to30%ofallPhiladelphiachromosome25%to30%ofalladultcases

AcuteMyeloidLeukemia(AML)

Peakincidenceage60

AuerRodsformedbytheaggregationofmyeloidgranules

lymphadenopathy infectionssuchasmonoorlymphoma

hepatosplenomegaly myeloproliferativeorlymphoproliferativedisorder,myelodysplasis,metabolicstorageorautoimmunedisorders

noperipheralleukemiablastsbutpancytopenia aplasticanemiaorinfiltratedBMinvolvement

myelodysplasia‐ dysplasticbloodcellproduction

lymphoblasticlymphoma lymphomatouspresentationwith<25%blastsinmarrow

ChronicLymphocyticLeukemia mostcommonformofleukemiainadultsinWesterncountries

medianageatdiagnosisis62years therapyshouldbeinitiatedonlywhenindicatedbyoneortherapyshouldbeinitiatedonlywhenindicatedbyoneormoredisease‐relatedsymptoms,hepatosplenomegaly,orrecurrentinfections

ChronicMyelogenous Leukemia causedbythetransformingcapabilityoftheproteinproductsresultingfromthePhiladelphiatranslocation(PhChromosome)

Averagesurvival5years(untilnewtherapies)

30

Chronicphaselasts3to5years AsymptomaticwithhighWBCcounts

Acceleratedphasewithincreasingsymptoms 10to20%blastcellsonperipheralsmear

Blastcrisis Evolvestoacuteleukemia(2/3AML,1/3ALL)

Deathoccurswithinweekstomonths

Gleevec (imatinib)isnewtreatment 80%gointoremission

LifelongRxneeded

fatigue

weightloss

sweating

anemia

easybruising

splenomegalywithorwithouthepatomegaly

raisedWBCcount(30‐400X109/L)

differential

granulocytesatallstagesofdevelopment

increasednumbersofbasophilsandeosinophils

blast(primitive)cells(maximum0%)

neverpresentinbloodofnormalpeople

Hgbconcentrationmaybereduced

RBCmorphologyusuallyunremarkable

nucleatedRBCmaybepresent

plateletcountmayberaised(300‐600X109/L)

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Accumulationofplasmacellsinthebonemarrowand,lessoften,softtissuesorvisceralorgans

Lyticbonelesionsaremosttypical Lyticbonelesionsaremosttypical

Anemia,hypercalcemia,renalinsufficiency

Increasedriskforlife‐threateningbacterialinfections

EncapsulatedorganismslikeStrep.Pneum.,H.Flu

>10%plasmacellsinBoneMarroworplasmacytoma onbiopsy

clinicalfeaturesofmyeloma

bonepain,ofteninlowback

l l f plusatleastoneof:

serumparaprotein spike(IgG.30g/L;IgA>20g/L)

Seenonserumelectrophoresis(SPEP)

urineparaprotein (Bence Jonesproteinuria)

osteolytic lesionsonskeletalsurvey‐ oftencauseHypercalcemia

26yomalec/oenlarged,painlesslumpRsideneck

c/ofever,nightsweats,10#wt.losspastmonth

l ti d li d it f th alsonoticedgeneralizedpruritusformonths

examshowsgeneralizedcervicalandaxillaryadenopathywithRsidenode2x3cm,non‐tender

nootherlymphadenopathyororganomegaly

CXRshowsmediastinaladenopathy

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1) Philadelphiachromosome

2) Reed Sternbergcell2) Reed‐Sternbergcell

3) SPEPMonoclonalantibodyspike

4) Auerrods

LymphomaisthesixthmostcommontypeofcancerintheUnitedStates

15%Hodgkin’sLymphomas

85%Non‐Hodgkinslymphomas

Higherincidenceinmenthaninwomen

Occursinabimodalagedistribution greatestpeakinthethirddecade

lesserpeakintheseventhdecade

IncreasedincidenceofHodgkinl mphomain IncreasedincidenceofHodgkinlymphomainpersonswithahistoryofinfectiousmononucleosis

Neoplastic cellofHodgkinlymphomaisalmostalwaysaBcell eithertheReed‐Sternbergcelloroneofitsmononuclearvariants

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HodgkinsClinicalFeatures

Mostcommonpresentingfeatureispainlesslymphnodeenlargement

Mediastinallymphadenopathyiscommonatpresentation presentation.

Orderlyspreadfromonelymphnoderegiontocontiguousnodalsites.

Thespleenandthelymphnodesintheceliacaxisareoftenthefirstsitesofsubdiaphragmaticdisease

Drenchingsweatsatnight,fever,andunexplainedweightloss. Pel‐Ebstein feversareintermittentepisodesofeveningfeversthatlastforepisodesofeveningfeversthatlastforseveraldaysandalternatewithafebrileperiods.

Totalbodypruritus

Auniquefeatureispainatsitesoflymphadenopathyimmediatelyafteringestionofalcohol.

Hodgkins Disease Non‐Hodgkins

Lymphoma

Incidence Unchanged Increasing

Age Median29years Incidenceincreases

with agewithage

Sites Mostlynodal:

Supradiaphragmatic

Nopredictablepattern

Clinical

Features

Mediastinalmass

Pruritus

Alcoholinducespain

Nothingspecific

Prognoosis 70—80%cure Mostincurablebut

veryvariable

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# Diagnosis Feature(added)

one Irondeficiencyanemia NeedGIwork‐upforoccultbleed

two Anemiaofchronicdisease Chronicinflammation

four Beta‐thalassemia trait (microcytosis outofproportiontoanemia)

five G‐6‐PDdeficiency (fava beans!)

six Perniciousanemia Schillingtest

seven ITP (childvs. adultforms)

eight VonWillebrand’s disease VonWillebrand factorlevel

nine DIC HeparinRx

ten Hodgkins lymphoma Reed‐Sternberg cells