Haematology in 1 hourHaematology in 1 hour

Dr Simon WattDr Simon Watt

Research SpR, MRIResearch SpR, MRI

Topics to be coveredTopics to be coveredAnaemiaAnaemia– Iron deficiencyIron deficiency– Causes of macrocytosis and treatmentCauses of macrocytosis and treatment– HaemoglobinopathiesHaemoglobinopathies– Haemolytic anaemiaHaemolytic anaemia

PolycythaemiaPolycythaemiaLeukaemiaLeukaemia– Chronic v acuteChronic v acute– Consequences of leukaemiaConsequences of leukaemia

Bone marrow failureBone marrow failureTissue infiltrationTissue infiltration

MyelomaMyeloma

Approach to the investigation of Approach to the investigation of AnaemiaAnaemia

MCV

LOW NORMAL HIGH

Film appearance

History-diet

-drugs-alcohol

Normal

Assess iron statusFerritin

Iron deficiencyNormal

(or raised)? Ethnic origin

Define and treat cause

Treat with Fe

Establish response

Hb screen

Β thal trait(Putative α thal trait)

Counsel

Associated FBC abnormalities

Liver function inc γGT

B12/folateThyroid function

Treat appropriately

Spherocytes Abnormal cellshapes

Raised ESR

Investigate for ACD

DATReticulocyte count

Refer to Haematologist for further investigation

Microcytic anaemia -questionsMicrocytic anaemia -questions

Is it iron deficiency or thalassaemia?Is it iron deficiency or thalassaemia?– or both?or both?

If iron deficiency: If iron deficiency: – what is the cause?what is the cause?– what further investigations are required?what further investigations are required?– What is the treatment?What is the treatment?– What if the patient fails to respond to oral What if the patient fails to respond to oral

iron?iron?

Iron deficiencyIron deficiency

Produces a drop in MCV proportional to the degree of Produces a drop in MCV proportional to the degree of anaemiaanaemiaRDW increases, reflecting anisocytosisRDW increases, reflecting anisocytosisBeware effect of acute disease in interpretation of Beware effect of acute disease in interpretation of Ferritin and TIBC resultsFerritin and TIBC resultsBeware of counteracting effect of drugs/alcohol causing Beware of counteracting effect of drugs/alcohol causing macrocytosis on MCV in iron deficiency – look at macrocytosis on MCV in iron deficiency – look at previous resultsprevious resultsTreatment dose is 200 mg Fe/day (=200mg tds of Treatment dose is 200 mg Fe/day (=200mg tds of Feso4, look up other Fe preparations in BNFFeso4, look up other Fe preparations in BNF

Failure to respond to oral ironFailure to respond to oral iron

Insufficient dose Insufficient dose

Thalassaemia traitsThalassaemia traits

Non complianceNon compliance

Continuing lossesContinuing losses

Malabsorption (coeliac disease, post Malabsorption (coeliac disease, post gastrectomy)gastrectomy)

Thalassaemia traitsThalassaemia traits

Produce microcytic, hypochromic indices Produce microcytic, hypochromic indices Clinically asymptomaticClinically asymptomaticMild anaemia, MCH<27pgMild anaemia, MCH<27pgLook for steady state Hb in notes – will tell Look for steady state Hb in notes – will tell if additional problemif additional problemDo not give iron unless iron deficiency Do not give iron unless iron deficiency provenprovenββ thalassaemia trait causes raised Hb A2thalassaemia trait causes raised Hb A2αα thal traits by exclusion of other causesthal traits by exclusion of other causes

23 y male from Cyprus23 y male from Cyprus

Hb 13.0Hb 13.0

WCC 5.4WCC 5.4

PLT 196PLT 196

MCV 68.7MCV 68.7

MCH 23MCH 23

MRCP question: Which is the best test to MRCP question: Which is the best test to perform next?perform next?

Laboratory featuresLaboratory features

Mild anaemia with reduced Mild anaemia with reduced MCV and MCH (27pg)MCV and MCH (27pg)RDW normal (c.f. iron RDW normal (c.f. iron deficiency)deficiency)Raised Hb ARaised Hb A22 (>3.5%) is (>3.5%) is diagnostic: higher levels seen diagnostic: higher levels seen with with ββ0 or severe 0 or severe ββ++Raised Hb F in 1/3 – ½ cases Raised Hb F in 1/3 – ½ cases (2-7%)(2-7%)Normal ANormal A2 2 and iron = probable and iron = probable alpha thal alpha thal

Haemolytic anaemia questionsHaemolytic anaemia questions

How is diagnosis of haemolytic anemia How is diagnosis of haemolytic anemia made?made?– Clinical – jaundice, dark urine, splenomegalyClinical – jaundice, dark urine, splenomegaly– Lab-normocytic anemia, unconjugated Lab-normocytic anemia, unconjugated

hyperbilirubinaemia, reticulocytosishyperbilirubinaemia, reticulocytosis– Further tests: direct antiglobulin test Further tests: direct antiglobulin test

(Coombs), blood film, Hb screen(Coombs), blood film, Hb screen

Haemolytic anaemiaHaemolytic anaemia

Consider causeConsider cause– Inherited: haemoglobinopathy, membrane Inherited: haemoglobinopathy, membrane

disorderdisorder– Acquired: drugs, transfusion reaction, immune Acquired: drugs, transfusion reaction, immune

disordersdisorders

Treatment directed at causeTreatment directed at cause

Transfuse if symptomatic (problems with Transfuse if symptomatic (problems with cross match)cross match)

Sickle cell disease: clinical Sickle cell disease: clinical problemsproblems

AnaemiaAnaemia

InfectionsInfections

Painful crisesPainful crises

StrokeStroke

Leg ulcersLeg ulcers

Visual lossVisual loss

Chronic organ damageChronic organ damage– Kidneys, lungs, joints, heartKidneys, lungs, joints, heart

Sickle cell basic factsSickle cell basic facts

Not exclusive to black racesNot exclusive to black races

Hb SS steady state Hb 7-9g/dlHb SS steady state Hb 7-9g/dl

Transfuse only for certain indicationsTransfuse only for certain indications

Milder forms may have normal Hb so Milder forms may have normal Hb so always do Hb Screenalways do Hb Screen

% Hb S is constant and bears no relation % Hb S is constant and bears no relation to acute crisisto acute crisis

Patients have functional aspleniaPatients have functional asplenia

Blood film appearancesBlood film appearances

Sickle cell

Target cell

Howell Jolly body

Macrocytic anaemia - questionsMacrocytic anaemia - questions

Is it a new problem?Is it a new problem?

Is it due to alcohol?Is it due to alcohol?

Is it due to diet /haematinic deficiencyIs it due to diet /haematinic deficiency

Is it due to drugs?Is it due to drugs?

When to refer to the haematologist?When to refer to the haematologist?

20 yr old vegan20 yr old vegan

Hb 9.8Hb 9.8

MCV 110MCV 110

Plt 115Plt 115

WCC 3.0WCC 3.0

Management of low B12Management of low B12

HistoryHistory– Diet, previous surgery, GI diseaseDiet, previous surgery, GI disease

IF antibodiesIF antibodiesSchilling test (distinguishes intrinsic factor def from Schilling test (distinguishes intrinsic factor def from malabasorption)malabasorption)

Symptoms/signs - give i.m. B12 with folic acidSymptoms/signs - give i.m. B12 with folic acid– levels unhelpful and unnecessary after thislevels unhelpful and unnecessary after this

Asymptomatic - ?dietary can give oral B12 and reassess Asymptomatic - ?dietary can give oral B12 and reassess levels after a few weekslevels after a few weeksFailure to respond to haematinics may indicate MDSFailure to respond to haematinics may indicate MDS

n.b. if normal Hb, MCV can take several weeks to falln.b. if normal Hb, MCV can take several weeks to fall

LeukaemiaLeukaemia

Clonal proliferations of one of more types Clonal proliferations of one of more types of white cellsof white cellsMature cells = chronic leukaemiaMature cells = chronic leukaemia– CLLCLL lymphocyteslymphocytes– CMLCML Mature + immature Myeloid cellsMature + immature Myeloid cells

Immature cells = acute leukaemiaImmature cells = acute leukaemia– characterised by presence of blasts and characterised by presence of blasts and

immature cells in blood/BMimmature cells in blood/BM– e.g AML, ALLe.g AML, ALL

Classification of leukaemiasClassification of leukaemias

Acute Chronic

Myeloid origin

Lymphoid origin

Acute Myeloid Leukaemia (AML)

Acute Lymphoblastic Leukaemia (ALL)

Chronic Myeloid Leukaemia (CML)

Chronic Lymphocytic Leukaemia (CLL)

25 year old male. 25 year old male. Recurrent upper Recurrent upper respiratory infections with respiratory infections with fever & nausea.fever & nausea.Submandibular swelling Submandibular swelling for several months for several months Noted that cuts on his Noted that cuts on his hands did not heal well.hands did not heal well.On examination: On examination: Submandibular Submandibular adenopathy. No adenopathy. No organomegaly.organomegaly.

HGB 9.9 g/dLHGB 9.9 g/dLHCT 28.7 %HCT 28.7 %MCV 106.3 fLMCV 106.3 fLWBC 7.9 x 10[9]/L.WBC 7.9 x 10[9]/L.PLT 50 x 10[9]/LPLT 50 x 10[9]/L

Automated differential was:Automated differential was:– NN 4%4%– LL 16%16%– MM 11– EE 00– BB 00– Flag!!! Immature Flag!!! Immature

Granulocytes ??Granulocytes ??– Blasts ??Blasts ??

Effects of leukaemiaEffects of leukaemia

Bone marrow failureBone marrow failure– anaemiaanaemia– thrombocytopenia - bleeding riskthrombocytopenia - bleeding risk– neutropenia - infection riskneutropenia - infection risk

Tissue infiltrationTissue infiltration– Tumour deposits e.g skin, nodes, gums,CNS, Tumour deposits e.g skin, nodes, gums,CNS,

liver or spleenliver or spleen

Immune suppression - infectionImmune suppression - infectionDeath usually due to infection or bleedingDeath usually due to infection or bleeding

How does acute leukaemia How does acute leukaemia present?present?

InfectionInfectionSymptoms of anaemiaSymptoms of anaemiaBruising/bleedingBruising/bleedingTissue infiltrationTissue infiltrationBlood film shows cytopenias with blastsBlood film shows cytopenias with blastsConfirm on Bone marrow and Confirm on Bone marrow and immunophenotyping/cytochemistry. Chromosomesimmunophenotyping/cytochemistry. ChromosomesTreatment: intensive chemotherapyTreatment: intensive chemotherapyPrognosis: depends on characterisitcs and patient Prognosis: depends on characterisitcs and patient comorbidity. e.g childhood ALL very good prognosis, comorbidity. e.g childhood ALL very good prognosis, elderly AML, poorelderly AML, poor

Chronic lymphocytic leukaemiaChronic lymphocytic leukaemia

May be incidental finding e.g CLLMay be incidental finding e.g CLLAssociated with symptoms/signs of marrow Associated with symptoms/signs of marrow infiltrationinfiltrationIncreased infections (bacterial/fungal)Increased infections (bacterial/fungal)LymphadenopathyLymphadenopathyAutoimmune features eg AIHA in CLLAutoimmune features eg AIHA in CLLDiagnosis on film/marrow/special investigationsDiagnosis on film/marrow/special investigationsTreatment variable: observation only to intensive Treatment variable: observation only to intensive chemotherapychemotherapyPrognosis very variable eg. CLLPrognosis very variable eg. CLL

What is Myeloproliferation?What is Myeloproliferation?

megakaryocytes

monocytes

neutrophils

red cells

Stem cells Proliferating/maturing cells Mature cells

This is normal myeloid cell production (hopelessly simplified)

Myeloproliferation arises when normal blood cell production goes wrong!

39 year old female.39 year old female.Fibrocystic breast disease.Fibrocystic breast disease.Routine work-up prior to breast biopsy.Routine work-up prior to breast biopsy.Physical Exam:Physical Exam:Moderate splenomegaly.Moderate splenomegaly.

RBCRBC 4.28 x 10[12]/L4.28 x 10[12]/L HGBHGB 13.4 g/dL13.4 g/dLHCTHCT 41.2 %41.2 % MCVMCV 96.3 fL96.3 fLWBCWBC 133.6 x 10[9]/L133.6 x 10[9]/LN segN seg 52%52% N bandN band 15%15%N metaN meta 13% 13% N myeloN myelo 4 % 4 % N proN pro 3 %3 % LymphLymph 3 %3 %MonoMono 4 %4 % EosinoEosino 1 %1 %BasoBaso 5 %5 %

CML is a classic example in haematologyCML is a classic example in haematology

Distinctive natural historyDistinctive natural history

First “chromosomal” malignancyFirst “chromosomal” malignancy

Massive research interest – some understanding of how it Massive research interest – some understanding of how it formsforms

Real effectiveness of biological therapies: bone marrow Real effectiveness of biological therapies: bone marrow transplant; interferon; donor lymphocyte infusiontransplant; interferon; donor lymphocyte infusion

First targeted malignancy: GlivecFirst targeted malignancy: Glivec

The Philidelphia Chromosome (described Nowell and Hungerford in 1960

Material is exchanged between chromosomes 9 and 22

Reciprocal translocation

The BCR-ABL tyrosine kinase (described 1983)

The chromosomal translocation causes the formation of a fusion between two gene: BCR and ABL.

This activates ABL activating many signalling pathways:

PolycythaemiaPolycythaemia

Raised haematocrit (in well hydrated patient)Raised haematocrit (in well hydrated patient)

Consider causeConsider cause– primary (uncommon) v secondary (common)primary (uncommon) v secondary (common)

– cause of secondarycause of secondaryHypoxia (respiratory disease, cardiac disease R – L shunt)Hypoxia (respiratory disease, cardiac disease R – L shunt)

Excessive EPO (renal /hepatic disease/tumours)Excessive EPO (renal /hepatic disease/tumours)

Drugs and lifestyleDrugs and lifestyle

Increased thrombotic riskIncreased thrombotic risk

PolycythaemiaPolycythaemia

Investigations, if not apparent from historyInvestigations, if not apparent from history– CXR, Arterial gas, lung function, EPO levelCXR, Arterial gas, lung function, EPO level

Refer to haematology if no obvious Refer to haematology if no obvious secondary causesecondary cause

Management: Venesection to Hct as Management: Venesection to Hct as defined for underlying causedefined for underlying cause

Chemotherapy (primary cause)Chemotherapy (primary cause)

Raised WBC questionsRaised WBC questions

Is it confined to one type of cell or all white Is it confined to one type of cell or all white cells?cells?

Are abnormal cells present?Are abnormal cells present?

What are appearances of blood film?What are appearances of blood film?

Common cause is reactive (neutrophilia, L Common cause is reactive (neutrophilia, L shift, in context of shift, in context of infection/inflammation/malignancy)infection/inflammation/malignancy)

CRP may be a pointer to reactive causeCRP may be a pointer to reactive cause

Neutropenia questionsNeutropenia questions

Is it isolated or associated with other Is it isolated or associated with other cytopenias?cytopenias?Is it recent or longstanding?Is it recent or longstanding?Is it associated with history of infection?Is it associated with history of infection?Common causes of isolated neutropenia:Common causes of isolated neutropenia:– Viral infection (acute and chronic eg HIV)Viral infection (acute and chronic eg HIV)– Drug related (look up list)Drug related (look up list)– Ethnic (longstanding, asymptomatic, no other Ethnic (longstanding, asymptomatic, no other

cause)cause)

Severe neutropeniaSevere neutropenia

Infection risk increased if neuts<1.0 x 109/lInfection risk increased if neuts<1.0 x 109/l

High risk of infection of neuts<0.5High risk of infection of neuts<0.5

Risk is also related to duration of neutropenia Risk is also related to duration of neutropenia and neutrophil functionand neutrophil function

Consider prophylaxis of infection if neuts<0.5Consider prophylaxis of infection if neuts<0.5

Fever in Neutropenic patient is a medical Fever in Neutropenic patient is a medical emergency – investigate and treat empirically emergency – investigate and treat empirically with broad spectrum antibiotics pending micro with broad spectrum antibiotics pending micro results. Hospital should have a protocol.results. Hospital should have a protocol.

ParaproteinsParaproteins

Common incidental finding, esp in elderlyCommon incidental finding, esp in elderly

Due to clonal proliferation of plasma cellsDue to clonal proliferation of plasma cells

Is it significant? Is it significant?

Causes: Causes: – secondary: (autoimmune disorders/infections)secondary: (autoimmune disorders/infections)– Malignant: myeloma/lymphomaMalignant: myeloma/lymphoma– Uncertain: MGUS (20% evolve into Uncertain: MGUS (20% evolve into

malignancy)malignancy)

MyelomaMyeloma

Clinical features due to combinations of:Clinical features due to combinations of:– Marrow failureMarrow failure– immunsuppressionimmunsuppression– Paraprotein (renal disease)Paraprotein (renal disease)– Bone disease (pain, fractures, lytic lesions/hypercalcaemia)Bone disease (pain, fractures, lytic lesions/hypercalcaemia)

Investigation of PPInvestigation of PP– HistoryHistory– FBC, Biochem, Serum electrophoresisFBC, Biochem, Serum electrophoresis– Bone X raysBone X rays– Bone marrowBone marrow– MGUS is defined by lack of evidence for malagnancy or reactive MGUS is defined by lack of evidence for malagnancy or reactive

cause.cause.

Remember differential may be metastatic malignancy!Remember differential may be metastatic malignancy!