Haematology in 1 hour

Haematology in 1 hourHaematology in 1 hour

Approach to low blood countApproach to low blood count

Consider causeConsider cause– Is it a lack of production = bone marrow Is it a lack of production = bone marrow

problem (intrinsic or extrinsic)problem (intrinsic or extrinsic)– Is it excess destruction = immune or other Is it excess destruction = immune or other

causescauses– Is it excess consumption = sepsis, Is it excess consumption = sepsis,

haemorrhage, large spleen etchaemorrhage, large spleen etc

Always consider DrugsAlways consider Drugs

Consider Consider inheritedinherited vsvs acquiredacquired

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

thal trait(Putative thal trait)

Counsel

Associated FBC abnormalities

Liver function inc GT

B12/folateThyroid function

Treat appropriately

SpherocytesAbnormal cell

shapes

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 if additional Look for steady state Hb in notes – will tell if additional problemproblemDo not give iron unless iron deficiency provenDo not give iron unless iron deficiency proven thalassaemia trait causes raised Hb A2thalassaemia trait causes raised Hb A2 thal traits by exclusion of other causesthal traits by exclusion of other causesIn antenatal context identification of b thal trait in women In antenatal context identification of b thal trait in women mandates partner screeningmandates partner screening

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 racesHb SS steady state Hb 7-9g/dlHb SS steady state Hb 7-9g/dlTransfuse only for certain indicationsTransfuse only for certain indicationsMilder forms may have normal Hb so Milder forms may have normal Hb so always do Hb Screen if suspicion or pre opalways do Hb Screen if suspicion or pre op% Hb S is constant and bears no relation % Hb S is constant and bears no relation to acute crisisto acute crisisPatients have functional asplenia, Patients have functional asplenia, therefore high risk of infectiontherefore high risk of infection

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?

Management of low B12Management of low B12

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

IF antibodiesIF antibodies– Schilling test no longer availableSchilling test no longer available

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

PolycythaemiaPolycythaemia

Raised haematocrit (in well hydrated Raised haematocrit (in well hydrated patient)patient)Consider causeConsider cause

– primary (uncommon) v secondary primary (uncommon) v secondary (common)(common)

– cause of secondarycause of secondaryHypoxia (respiratory disease, smoking, cardiac Hypoxia (respiratory disease, smoking, cardiac disease R – L shunt)disease R – L shunt)Excessive EPO (renal /hepatic disease/tumours)Excessive EPO (renal /hepatic disease/tumours)

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

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

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 leukaemiaChronic 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 are lymphomasWhat are lymphomas

neoplasms of lymphoid origin, neoplasms of lymphoid origin, typically causing lymphadenopathytypically causing lymphadenopathy

leukaemia vs lymphomaleukaemia vs lymphoma

lymphomas are clonal expansions of lymphomas are clonal expansions of cells at certain developmental stagescells at certain developmental stages

A practical approach to lymphomasA practical approach to lymphomas

Category Survival of untreated patients

Curability To treat or not to treat

Non-Hodgkin lymphoma

Indolent Years Generally not curable

Generally defer Rx if asymptomatic

Aggressive Months Curable in some

Treat

Very aggressive

Weeks Curable in some

Treat

Hodgkin lymphoma

All types Variable – months to years

Curable in most

Treat

Clinical manifestationsClinical manifestationsVariableVariable

severity: asymptomatic to extremely illseverity: asymptomatic to extremely ill

time course: evolution over weeks, months, or time course: evolution over weeks, months, or yearsyears

Systemic manifestationsSystemic manifestationsfever, night sweats, weight loss, anorexia, fever, night sweats, weight loss, anorexia, pruritispruritis

Local manifestationsLocal manifestationslymphadenopathy, splenomegaly most lymphadenopathy, splenomegaly most commoncommon

any tissue potentially can be infiltratedany tissue potentially can be infiltrated

Other complications of lymphomaOther complications of lymphoma

bone marrow failure (infiltration)bone marrow failure (infiltration)

CNS infiltrationCNS infiltration

immune hemolysis or immune hemolysis or thrombocytopeniathrombocytopenia

compression of structures (eg spinal compression of structures (eg spinal cord, ureters) by bulky diseasecord, ureters) by bulky disease

pleural/pericardial effusions, ascitespleural/pericardial effusions, ascites

Stage I Stage II Stage III Stage IV

Staging of lymphomaStaging of lymphoma

A: absence of B symptomsB: fever, night sweats, weight loss

Investigation of suspected Investigation of suspected lymphomalymphoma

Biopsy of affected node/massBiopsy of affected node/mass– ESSENTIAL as dictates treatment and ESSENTIAL as dictates treatment and

prognosisprognosis

Staging CT scans/Bone marrowStaging CT scans/Bone marrow

FBC, Biochemistry, LDH, etcFBC, Biochemistry, LDH, etc

Three types of lymphoma you will Three types of lymphoma you will most commonly meetmost commonly meet

Follicular lymphomaFollicular lymphoma

Diffuse large B-cell lymphomaDiffuse large B-cell lymphoma

Hodgkins lymphomaHodgkins lymphoma

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 clonal Uncertain: MGUS (20% evolve into clonal

disorder)disorder)

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.

Haemostasis and Haemostasis and thrombosisthrombosis

Physiology of haemostasisPhysiology of haemostasisBleeding disorders (congenital)Bleeding disorders (congenital)Massive blood lossMassive blood lossDICDICAnticoagulant drugsAnticoagulant drugs

Haemostasis needs…Haemostasis needs…

PlateletsPlatelets

Vessel WallVessel Wall

Clotting FactorsClotting Factors

The starter motor……..

Switched off

by Tissue Factor

Pathway

Inhibitor

Provides initial Thrombin burst

Factors measured in Prothrombin Time

PT

The engine…………..

Thrombin from initial burst back activates “intrinsic system”

Fibrin then cross linked by XIII

APTT

TT

Natural anticoagulantsNatural anticoagulants

Protein C (activated by thrombin/thrombomodulin)Protein C (activated by thrombin/thrombomodulin)Protein S - cofactor for protein CProtein S - cofactor for protein C

Protein C and S cleave factors V and VIIIProtein C and S cleave factors V and VIII

Antithrombin inhibits Thrombin and XaAntithrombin inhibits Thrombin and Xa– TAT complexes removed by liver TAT complexes removed by liver – Activity increased 000’s by heparinActivity increased 000’s by heparin

Global coagulation testsGlobal coagulation tests

•APTT : Kallikrein, HMWK, XII, XI, IX, VIII, X, V, II, I•“intrinsic system”

•PT : VII, X, V, II, I•“extrinsic system”

•TT : I

•50:50 mix with normal plasma will distunguish a lack of clotting proteins from an inhibitor of function

CAUSES OF A PROLONGED PROTHROMBIN TIME

CONGENITAL •Coagulation factor deficiencies: VII, X, V, II, I

ACQUIRED•Hepatocellular disease•Vitamin K deficiency (II, VII, IX, X): obstructive jaundice, haemorrhagic disease of the newborn•Disseminated intravascular coagulation (DIC)•Massive blood transfusion•Warfarin (monitoring test based on PT)•Gross overheparinisation, some lupus anticoagulants

CAUSES OF A PROLONGED ACTIVATED PARTIAL THROMBOPLASTIN TIME

CONGENITAL•Coagulation factor deficiencies: XII, XI, IX, VIII, X, V, II, I

ACQUIRED•Hepatocellular disease•Vitamin K deficiency•Disseminated intravascular coagulation•Massive blood transfusion•Heparin (monitoring test based on APTT)•Lupus anticoagulants

CAUSES OF A PROLONGED THROMBIN TIME

CONGENITAL•Dys/hypofibrinogenaemia

ACQUIRED•Hepatocellular disease: dys/hypofibrinogenaemia•Disseminated intravascular coagulation:

hypofibrinogenaemiaFDPs

•Heparin

HaemophiliaHaemophilia

A = reduced VIII; B = reduced IXA = reduced VIII; B = reduced IXBoth sex-linked recessiveBoth sex-linked recessiveQueen VictoriaQueen VictoriaIntronic rearrangements, point mutations, gene deletionsIntronic rearrangements, point mutations, gene deletionsHaemophilia A 1 in 10,000 male infantsHaemophilia A 1 in 10,000 male infantsProlonged APTT (normal PT and TT)Prolonged APTT (normal PT and TT)Mild Rx: Tranexamic acid, DDAVP (not HB)Mild Rx: Tranexamic acid, DDAVP (not HB)Severe Rx: factor replacement recombinant or pooled donorSevere Rx: factor replacement recombinant or pooled donor Home prophylaxisHome prophylaxisPast problem with HIV, now HCV ??? CJDPast problem with HIV, now HCV ??? CJD

Von Willebrand’s DiseaseVon Willebrand’s Disease

Functions of VWF:Functions of VWF:

11. . Sticks to platelets (GPIb)Sticks to platelets (GPIb)

2. Sticks to collagen in subendothelium2. Sticks to collagen in subendothelium

(Important in small blood vessel lesions; high shear stress)(Important in small blood vessel lesions; high shear stress)

3. Binds to and protects VIII (labile)3. Binds to and protects VIII (labile)

Therefore in VWD see long APTT (low VIII) and bleeding where Therefore in VWD see long APTT (low VIII) and bleeding where VWF platelet interaction importantVWF platelet interaction important

Treatment optionsTreatment optionsDDAVP, antifibrinolyticsDDAVP, antifibrinolyticsNB DDAVP causes fluid retention. NOT for type 2BNB DDAVP causes fluid retention. NOT for type 2BIntermediate purity VIII concentrateIntermediate purity VIII concentrateVWF concentrate (NB takes hours for VIII to follow so may VWF concentrate (NB takes hours for VIII to follow so may need to give both)need to give both)If severe bleeding consider platelet infusion and If severe bleeding consider platelet infusion and cryoprecipitatecryoprecipitate(NB type I may “auto-correct” in pregnancy)(NB type I may “auto-correct” in pregnancy)

Von Willebrand’s DiseaseVon Willebrand’s Disease

Massive blood lossMassive blood loss

Defined as loss of > one circulating volume in 24 Defined as loss of > one circulating volume in 24 hourshoursCoagulopathy is multifactorial:Coagulopathy is multifactorial:Loss of factors only once 80% of volume replacedLoss of factors only once 80% of volume replacedDilution of factors during fluid resuscitationDilution of factors during fluid resuscitationInhibitory effect of some colloids on clotting factorsInhibitory effect of some colloids on clotting factorsDIC secondary to traumaDIC secondary to traumaAcidosisAcidosisHypothermia (enzymes) (blood warmer)Hypothermia (enzymes) (blood warmer)

Regular checks of FBC and PT,APTT,TT and FibrinogenRegular checks of FBC and PT,APTT,TT and FibrinogenAim for platelets > 50x10Aim for platelets > 50x1099/l or >100x10/l or >100x1099/l if polytrauma or /l if polytrauma or CNS injuryCNS injuryAim for fibrinogen >1g/lAim for fibrinogen >1g/lAim for PT and APTT <1.5x control timesAim for PT and APTT <1.5x control timesFFP 12-15ml/kgFFP 12-15ml/kgCryoprecipitate 1-1.5 packs /10kg if fibrinogen fails to correct Cryoprecipitate 1-1.5 packs /10kg if fibrinogen fails to correct with FFPwith FFP? rVIIa? rVIIa

Massive blood lossMassive blood loss

Causes of DICCauses of DIC

sepsis/severe infection (any organism)trauma (e.g. polytrauma, neurotrauma, fat embolism)organ destruction (e.g. severe pancreatitis)malignancymassive blood loss with inadequate fluid replacementvascular abnormalities (e.g. Kassbach-Merrit syndrome)severe hepatic failuresevere toxic or immunological reactions (e.g. recreational drugs, transfusion reactions, transplant rejection)

Management of DICManagement of DIC

TREAT THE CAUSETREAT THE CAUSE

Fluid resus as needed, antibiotics if sepsisFluid resus as needed, antibiotics if sepsis

If bleeding or need surgery give FFP, Platelets, Cryoprecipitate If bleeding or need surgery give FFP, Platelets, Cryoprecipitate

(Aim Platelets>50x10(Aim Platelets>50x1099/l, PT and APTT < 1.5x normal)/l, PT and APTT < 1.5x normal)

If thrombotic manifestations eg. Dermal ischaemia consider low If thrombotic manifestations eg. Dermal ischaemia consider low dose heparin infusion. dose heparin infusion.

HeparinHeparin

NB arterial

lines !!!!!!!

HeparinHeparin

Unfractionated Unfractionated

monitor with APTT (ratio 1.5-2.5 patient’s baseline)monitor with APTT (ratio 1.5-2.5 patient’s baseline)

reversal by stopping infusion and (very rapid with protamine sulphate)reversal by stopping infusion and (very rapid with protamine sulphate)

can be hard to anticoagulate children due to low antithrombin levelscan be hard to anticoagulate children due to low antithrombin levels

bolus then continuous infusionbolus then continuous infusion

Low molecular weight heparinLow molecular weight heparin

less monitoringless monitoring

once or twice daily administrationonce or twice daily administration

more reliable pharmacokinetics (NB renal excretion)more reliable pharmacokinetics (NB renal excretion)

anti-Xa levels - 4h post doseanti-Xa levels - 4h post dose

Treatment 0.5-1; Prophylaxis 0.1-0.3 IU/mlTreatment 0.5-1; Prophylaxis 0.1-0.3 IU/ml

WarfarinWarfarin

II, VII, IX, X, protein C and S are vitamin K dependent.

NB C and S fall first so overlap with heparin (Warfarin induced skin necrosis)

Therapeutic range within 3-5 days

Monitor in anticoagulant clinic using INR

Most indications target INR 2-3

Bleeding on warfarinBleeding on warfarin

Treatment based on assessment of bleeding risk and Treatment based on assessment of bleeding risk and INRINR

Usually enough to stop and monitor INR daily until in Usually enough to stop and monitor INR daily until in therapeutic rangetherapeutic range

Reversal with Vitamin K (6-8 hours) – large doses may Reversal with Vitamin K (6-8 hours) – large doses may render subsequent antico difficult)render subsequent antico difficult)

Emergency use Plasma or clotting factor concentratesEmergency use Plasma or clotting factor concentrates

Hospital should have protocolHospital should have protocol