Haematology in Primary Care: The Full Blood Count

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Haematology in Primary CareThe Full Blood Count

• Charles Crawley
• George Follows

Cambridge Haematology Partners
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The FBC
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Haemoglobin

• Low haemoglobin defines anaemia
• Males 13-18g/l
• Females 11.5-16g/l
• Variations
• Children
• Neonates 14-24g/l
• 2 months 8.9-13.2g/l
• 9-12ys - 11.5-15.4g/l
• Pregnancy
• 3rd Trimester 9.8-13.7g/l
• Age
• 5-7th decade falls in men rises in women
• Exercise
• Increases Hb
• Altitude
• Smoking

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MCV

• Mean Cell Volume average size of RBC
• Normal adult 76 (80) - 100 fL
• MCV lt 76 fL (microcytic)
• MCV gt 100 fL (macrocytic)
• MCV 80 - 100fL (normocytic)

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Practical Classification of Anaemia

Microcytic (lt76fL) Normocytic Macrocytic (gt100)
Iron deficiency Thalassaemia Haemoglobinopathies Anaemia of chronic disease Lead Hyperthyroidism Blood loss Haemolytic - RBC membrane - Enzyme defects - Extrinsic Stem cell defects Megaloblastic Excess alcohol Hypothyroid Liver disease Reticulocytosis Drug therapy Marrow failure

• Reticulocyte count In the investigation of
  anaemia
• Reduced Failure of erythropoiesis
• Increased Appropriate BM erythroid response

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35 year Male

• Hx Lethargy, SOB
• Sx Pale
• FBC Hb 6.4 g/dL
• MCV 71 fL
• RDW 0.19
• WCC 5.2
• Platelets 375
• Film Severe hypochromasia and microcytosis

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Commonest Causes Iron Deficiency
Female Male
1 5 yr Nutrition Nutrition
5 15 yr Increased utilisation/ growth Increased utilisation/ growth
15 40 yr Menstruation Pregnancy Coeliac disease (Malabsorption)
gt 40 yr Gastrointestinal Blood loss Gastrointestinal Blood loss
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Blood Film
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Differential Diagnosis

• Causes of microcytic hypochromic anaemia
• Iron deficiency
• Blood loss
• Malabsorption - Coeliac disease gastrectomy
• Increased utilisation - parasites
• Dietary deficiency - rare
• Haemoglobinopathy
• Anaemia of chronic disease

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Fe Deficiency vs Anaemia of Chronic Disease
Variable Fe deficiency Chronic disease
Serum Iron ? ?
Transferrin ? ? or Normal
Transferrin Saturation ?? ?
Ferritin ? or Normal ? or normal
CRP Normal ?
GIT studies endoscopy etc
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26 year Female

• Hx Antenatal visit First trimester
• FBC Hb 11.0 g/dL
• MCV 73 fL
• MCH 27 pg
• RDW 0.14
• WCC 8.5 x 109/L
• Platelets 164 x 109/L
• Film Microcytic RBC

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Fe Deficiency vs Hbinopathy

• Check iron status Ferritin
• Family history / ethnicity
• Thalassaemia / haemoglobinopathy
• Need to determine risk to fetus of severe
  thalassaemic syndrome (in 1st rimester)
• Homozygous thalassaemia (a or ß)
• Homozygous Hb S (sickle cell disease)
• Severe compound heterozygous states
• E.g. HbS/ß HbE/ß HbSC
• Determine need to check partner

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Red Cell Distribution Width (RDW)

• The degree of variation in size of RBC N lt14
• Increased RDW corresponds with anisocytosis
• Iron deficiency (increased RDW is the earliest
  lab feature anisocytosis precedes the anaemia)
• Megaloblastic anaemia (can be very high gt20)
• Anaemia with bone marrow erythroid response (i.e.
  reticulocytosis)
• RDW useful in DDx of microcytic anaemias.
• Most cases of iron deficiency raised RDW
• Most cases thalassaemia trait normal RDW

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MCH

• Mean Cell Haemoglobin (27-32 pg)
• The mean haemoglobin per red blood cell
• MCH usually rises or falls as the MCV is
  increased or decreased.
• MCH lt 25 pg used as a guide to the presence of
  thalassaemia or haemoglobinopathy.
• MCH usually markedly reduced in thalassaemia
  (e.g. beta thalassaemia trait MCH 19 pg)

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Haemoglobin Studies
1. Normal adult 2. HPFH (heterozygote)3. Hb
S--HPFH 4. Hb C--HPFH 5. Normal newborn
A/F/S/C control
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73 year male

• Hx Tiredness
• FBC Hb 4.0 g/dL
• MCV 102 fL
• RDW 0.24
• WCC / Plt Normal
• Film Macrocytes, fragmented red cells,
  occasional NRBC

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Blood Film73 yr old male
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Severe Macrocytic Anaemia

• Megaloblastic anaemia
• Liver disease end-stage failure
• Red cell aplasia
• Parvovirus thymoma, other malignancy
• Bone marrow failure or infiltration
• Myelodysplasi
• Multiple myeloma

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Investigations

• 1. Serum vitamin B12
• Red cell folate (serum folate)
• 2. Reticulocyte count (BM erythroid function)
• 3. Liver function
• 4. Parvovirus serology
• 5. Bone marrow examination

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Dont Forget the Alcohol
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Other Causes of Macrocytic Anaemia

• Severe liver disease
• Excess alcohol
• Haemorrhage / haemolysis reticulocytosis
• Drug therapy esp. cytotoxics
• Hypothyroidism
• Myelodysplasia
• Marrow infiltration
• Bone marrow examination may be indicated

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Myelodysplasia (MDS)

• Clonal disorder
• Ineffective haematopoiesis
• Incidence increases with age
• Age 50yrs - 1 per 100,000
• Age 70yrs 25 per 100,000
• RBC, WCC, and platelets affected

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Myelodysplasia
Bone Marrow
Peripheral Blood
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Myelodysplasia

• Prognosis
• Number of cytopenias
• BM Blast percentage
• Cytogenetics
• Age
• Survival
• Varies 11.7 yrs 0.4yrs
• Management
• Supportive
• Stem cell transplantation
• New drugs

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Normocytic Anaemia

• Multiple aetiologies
• Primary marrow production defect
• Myelodysplasia
• Marrow infiltration
• Haematinic deficiencies
• Reduced red cell survival
• Blood loss
• Intrinsic defects (eg. Enzyme membrane)
• Extrinsic defects (eg. Plasma problems)

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Approach to Normocytic Anaemia

• History
• Acute blood loss jaundice dark urine
• Exclude treatable causes
• Check ferritin, folate, vitamin B12
• Renal and hepatic function
• Acute phase reactants
• Consider haemolysis
• The blood film may have the answer !

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78 year male

• Hx Chest pain
• PMHx Myocardial infarct
• FBC Hb 7.2 g/dL
• MCV 97 fL
• WCC 4.5 x 109/L
• Platelets 320 x 109/L
• Reticulocytes 320 (10-100)

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Blood Film
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Blood Film

• RBC Spherocytes
• Polychromasia
• Nucleated red cells
• Spherocytic haemolytic anaemia
• Auto-immune haemolytic anaemia
• Hereditary spherocytosis

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Other Investigations

• Biochemistry
• Bilirubin 100 µmol/L (lt20)
• Other LFT Normal
• LDH 1,500 U/L (120-240)
• Haptoglobin lt0.1
• Haematology
• Reticulocyte count
• Direct anti-globulin (Coombs) test Positive
• Enzymes,
• Hereditary spherocytosis screen

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Haemolytic Anaemia

• Primary Red Cell Problem
• Red cell membrane Hereditary spherocytosis
• Enzyme defect G6PD deficiency
• Haemoglobin defect thalassaemia
• Abnormal red cells dyserythropoiesis (MDS)
• Secondary Red Cell Destruction
• Autoimmune
• Severe hepatic dysfunction
• Red cell fragmentation DIC HUS TTP
• Infections malaria clostridium

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Blood Film
blister or helmet cells
Glucose-6-phosphate dehydrogenase deficiency
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Normocytic Anaemia

• Blood film may have the answer
• Normal red cell morphology
• Dimorphic (high RDW) 2x RBC populations
• Marked anisocytosis marrow dysfunction/MDS
• Is there polychromasia?
• Yes Anaemia with marrow response
• No Impaired marrow response
• Anaemia of Chronic Disease
• BM failure
• Red cell aplasia Parvovirus aplastic anaemia

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Polycythaemia

• Pseudopolycythaemia
• Primary
• Polycythemia vera
• Secondary
• Hypoxia
• Altitude
• Cardiac/Pulmonary disease
• Cirrhosis
• Abnormal Haemoglobins
• Chronic CO exposure
• Inappropriate erythropoietin
• Renal lesions
• Tumours
• Drug

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Clinical Features

• Hyperviscosity
• Headaches
• Blurred vision
• Breathlessness
• Confusion
• (Plethora)
• Thrombosis
• Venous arterial
• Bleeding
• Other
• Pruritis
• Gout

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Polycythaemia investigations

• FBC Film
• CXR
• Cardiac assessment
• Red Cell mass
• Blood gasses
• Major advance JAK 2 mutation screens

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JAK2

• Presence of the V617F mutation indicates that the
  patient has an acquired, clonal hematological
  disorder and not a reactive or secondary process.
  
• Absence of the JAK2 V617F mutation does not
  exclude a MPD as up to 50 of patients with ET
  and IMF will have wildtype JAK2.
• The V617F mutation does not help in
  sub-classifying the type of MPD of a given
  patient

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Pathogenesis Deregulated Tyrosine Kinases in MPD
CML BCR-ABL CMML TEL-PDGFRB CEL
FIP1L1-PDGFRA
SM KIT D816V PV JAK2 V617F ET JAK2
V617F IMF JAK2 V617F
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Questions so far?
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Platelets

• Too many (thrombocytosis)
• Too few (thrombocytopenia)
• Dysfunctional
• When should we worry?

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Thrombocytosis

• gt 450 x 109/l
• Causes
• Reactive (almost anything!)
• Common bleeding, infection, malignancy
• Tend to be less than 1000 x 109/l
• Primary bone marrow disorder
• Myeloproliferative disorders (up to 3000)
• (essential thrombocythaemia, myelofibrosis,
  polycythaemia, chronic myeloid leukaemia)

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Thrombocytosis

• History, examination should guide investigations
  and referrals
• Should the patient be on aspirin?
• Only firm evidence is MPDs
• Reactive often given if gt 1000, but little
  evidence for this

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Thrombocytosis

• Essential Thrombocythaemia (ET)
• Long term management balancing thrombotic vs
  bleeding risk
• Aspirin for intermediate risk
• Cytoreduction aspirin for higher risk
• (beware the pseudohyperkalaemia!!)

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Thrombocytopenia

• Is it real???
• Poor sample
• Clumped in EDTA blood film
• If at all possible confirm with a repeat sample

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Thrombocytopenia

• Pancytopenia
• vs
• Isolated low platelets
• Pancytopenia
• always serious (marrow failure)
• Isolated
• may be relatively unimportant

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Thrombocytopenia

• Decreased production
• Rare in isolation
• Viral infections
• Increased consumption
• Autoimmune ITP
• Drugs
• Pregnancy
• Large spleen / portal hypertension
• Infections (HIV)
• RARE but serious TTP HUS - DIC

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Thrombocytopenia

• Investigations depend on clinical suspicion
• Platelet volume may be helpful
• (small - think marrow)
• lt8.0 and gt10.5
• BM often not required

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Thrombocytopenia
(not joint bleeds!)
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Thrombocytopenia

• How real is the bleeding risk?
• Cause of low platelets
• Wet vs dry purpura
• Platelet transfusions often not useful

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ITP a few useful reminders

• Children
• Acute, post viral,
• spontaneous resolution (often no therapy)
• Adult
• More insidious onset
• Chronic common
• Many (not all!) cases do require treatment
• Steroids splenectomy
• Novel therapies

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Platelet Dysfunction

• Range of rare inherited causes
• Family history
• Refer the child that bleeds abnormally!
• Dont forget the acquired dysfunction
• Renal failure
• Liver disease
• ASPIRIN

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Questions and break!
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White Cells
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White Cells
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White Cells

• Important (and commonly problematic!)
• Neutrophils
• Lymphocytes
• Important (less commonly problematic)
• Monocytes
• eosinophils
• Less important
• basophils

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Neutrophils
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Neutrophilia

• Often result expected
• History
• Examination
• primary haematological cause NOT common

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Neutrophilia

• Infection
• Inflammation / necrosis
• Cancer any sort reported
• Bone marrow disease (MPDs, CML)
• Drugs (steroids!!, growth factors)
• Not always pathological
• Pregnancy, smoking, normal variant!

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Neutropenia (lt1.5 x 109/l)

• Isolated neutropenia
• vs
• Pancytopenia

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How worried should I be?

• Pancytopenia is ALWAYS worrying
• Many cases of isolated neutropenia are less
  serious
• What should I do with a neutropenic patient?
• How common is neutropenic sepsis?

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Pancytopenia

• Marrow Failure
• Drugs (chemotherapy)
• Infiltration (cancer, MF,lymphoma etc.)
• Myelodysplasia / leukaemia / myeloma
• Aplastic anaemia / PNH
• Dont forget B12 / folate (anorexia)
• Peripheral consumption
• hypersplenism

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Pancytopenia

• Referral usually required
• Bone marrow biopsy usually required

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Isolated Neutropenia

• Not always easy to identify a cause!
• Always think drugs (idiopathic vs dose)
• Viral infection
• Auto-immune disease
• Marrow causes
• (sepsis / very ill elderly)
• Dont forget
• Racial variation
• cyclical neutropenia (clinical and lab details)
• If child, think congenital

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Isolated Neutropenia

• Investigations will depend on clinical
  presentation
• Chance finding vs ill patient
• Viral serology may be indicated (hepatitis, EBV
  etc Think HIV!)
• Autoimmune (SLE, sjorgrens, RA Feltys)
• Serial blood counts
• Referral may be required

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Isolated Neutropenia

• When to refer urgently
• Cause of neutropenia
• Is the patient acutely ill?
• Neutropenic fever vs sepsis
• Incidence etc
• Antibiotic policies etc.
• Prophylactic antibiotics - controversial

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Lymphocytes

• Lineage B vs T vs NK
• Origin
• Role

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Lymphocytosis

• Causes
• Reactive
• (CMV, EBV, hepatitis, toxo, adenov)
• Pertussiss
• Inflammatory reaction (not common)
• Lymphoproliferative disorder
• Acute and chronic leukaemias
• lymphomas

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Lymphocytosis

• Priorities for investigation
• Clinical picture
• If other FBC abnormalities, speak to a
  haematologist
• If in doubt, ask for an opinion on a blood film
• Monospot test vs viral serology
• Flow cytometry
• Molecular tests

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Lymphocytosis (gt4 x 109/l)
vs
vs

• Blasts vs more mature cells
• Clinical picture very important
• Young sick child vs older well patient

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Lymphocytosis

• Young patient with clinical picture of infectious
  mononucleosis
• Monospot useful
• Film useful (rule out ALL)
• Flow cytometry less helpful
• Serology as second line investigation
• ID referral occasionally required
• (worth thinking about acute HIV)

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Lymphocytosis

• Acute lymphoblastic leukaemia
• Children gtgt adults
• Often presents very acutely
• Range of clinical features
• Laboratory features typical
• Referral mandatory

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Lymphocytosis

• Older patient with lymphocytosis
• Blood film required (CLL vs LGL)
• Flow cytometry usually required
• ? Refer
• Clinical picture
• Underlying diagnosis

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Lymphocytosis

• CLL
• Relatively common (300 / year)
• New entity of Monoclonal B Lymphocytosis (MBL)
• Age
• Clinical presentation
• Asymptomatic stage A
• VS
• Symptomatic stage C

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Lymphocytosis

• CLL
• History
• Night sweats, weight loss, INFECTIONS
• Examination
• Lymphadenopathy, hepato-splenomegaly
• Investigation
• Flow cytometry

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Lymphocytosis

• Flow cytometry

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Lymphocytosis

• Should I refer CLL?
• Long stage A phase in many patients
• Patients and the leukaemia word!
• Rough guide
• Symptomatic
• Unusual / lymphoma phenotype
• Lymphadenopathy / splenomegaly
• Lymphocyte doubling time lt 12 months
• with lymphocytes gt 30 x 109/l
• Hb lt 10 g/dl (or haemolysing)
• Platelets lt 100x 109/l

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Lymphocytosis

• CLL beware
• Not always benign
• Infections (hypogamma)
• Haemolysis
• ITP

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Lymphocytosis

• Rarer lymphoproliferative disorders
• LGL
• PLL
• Leukaemic phase of most lymphomas
• Hairy cell leukaemia

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Lymphopenia (lt1.0 x 109/l)

• Many cases reflect normal variants
• How hard should you chase a cause?
• More common causes
• HIV / hepatitis / Hodgkins (steroids)
• Rarer causes
• Autoimmune disease / sarcoidosis

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Lymphopenia

• Investigations
• Clinical picture
• Lymphocyte subset analysis
• RARE bone marrow

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Enlarged LN ? cause

• Clinical context is critical
• ? Symptom profile
• (?spleen)
• Please do first line investigations
• FBC may save a LN biopsy
• Neck nodes ENT fast track referral
• Axillary and groin nodes
• Much depends on the clinical context
• Haematology review first?
• Biopsy first?
• CT first?

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Eosinophils

• High
• Allergic disorders
• Drug Hypersensitivity
• Skin Diseases
• Parasitic infections
• Myeloproliferative disorders
• Connective tissue disorders
• Churg Strauss

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Monocytes

• High
• Range of infectious and inflammatory stimuli
• Primary BM conditions
• CMML (overlap between myelodysplasia and
  myeloproliferative disorder)
• CML
• Clinical picture and blood film important
• If no clear cause consider haematology referral

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Questions?
Cambridge Haematology Partners www.cambridgehaema
tology.com charles.crawley_at_cambridgehaematology.c
om george.follows_at_cambridgehaematology.com