An Abnormal FBC -

Knowing when to refer

Dr Patrick Hayden

Consultant Haematologist

Beacon Hospital

March 2019

While the information in this presentation is believed to be true and

accurate, the author does not accept any legal responsibility for the

content of this guidance and advises that specialist haematology

services are contacted in all cases of concern

Disclaimer

An absolute neutrophil count less than 2.0 x 109/l

Mild 1.0-2.0 x 109/l

Moderate 0.5-1.0 x 109/l

Severe <0.5 x 109/l

Agranulocytosis <0.2 x 109/l

The risk of infection increases when the neutrophil count is

below 1.0 x 109/l and correlates with the depth of the neutropenia

Neutropenia

Infection – viral, bacterial sepsis (children, elderly)

Drugs –Anti-thyroid medications (carbimazole), anticonvulsants (carbamazepine),

psychiatric (clozapine), Cotrimoxazole, NSAIDs (trial off agent, if possible)

Immune - primary (infants) or secondary (RA, Felty’s, SLE) neutropenia

Splenomegaly (patients with chronic liver disease)

BM failure - Leukaemia, MDS, Large Granular Lymphocytic Leukaemia

Rituximab can be associated with a delayed neutropenia

Nutritional deficiencies - B12 or folate, hypothyroidism, hyperthyroidism

Rare – congenital – Cyclical and Severe Congenital Neutropenia (SCN)

Finally, Chronic Idiopathic Neutropenia or

Idiopathic Cytopenia of Undetermined Significance (ICUS)

Causes of Neutropenia

Management in Primary Care

Repeat Full Blood Count (? Aged sample)

Blood film +/- reticulocyte count

Biochemistry profile including LDH

B12 and folate

Autoimmune screen/Connective Tissue Disease screen

Consider stopping medications which may be implicated

Repeat FBC in 4-6 weeks

Transient neutropenia in association with viral infection is common

Consider referral to haematologist if persistent unexplained neutropenia

(<1.5) when repeated 4-6 weeks apart

Take Home Messages on Neutropenia

Be aware of ethnic neutropenia in those of African ancestry - normal

A history of mild neutropenia over years and evidence of fluctuating

counts are usually reassuring findings allowing for continued observation

Referral to a haematology clinic for bone marrow aspirate and biopsy

still sometimes necessary to rule out haematological disease

An isolated chronic asymptomatic mild neutropenia (>1.0) often results

in a diagnosis of Chronic Idiopathic Neutropenia or Idiopathic Cytopenia

of Undetermined Significance (ICUS)

New onset and/or progressive neutropenia in association with infection

suggesting impaired immunity requires urgent investigation/referral

Age an important factor in determining the pre-test probability of an

significant underlying haematological abnormality in that such diseases

are much less likely in younger patients

Neutrophilia

Infection – mainly bacterial

Inflammation – trauma, autoimmune disease, burns

Medications – corticosteroids (demargination of neutrophil pool)

Growth factor (G-CSF) use in patients with cancer, adrenalin

Cigarette smoking

Post-splenectomy

Cancer - Leukemoid reaction

Primary haematological causes

Myeloproliferative diseases (MPN)

Chronic Myeloid Leukemia (CML) rare - neutrophilia and splenomegaly

Blood film in CML reveals left shift with plentiful myelocytes

In children and young adults, usually viral infection

EBV, CMV, Toxoplasma gondii, Bordetella pertussis

Mumps, Varicella, Hepatitis

EBV – lymphocytosis, adenopathy, splenomegaly, thrombocytopenia

Older adults – need to rule out lymphoproliferative disorders (LPD)

Ask about weight loss, night sweats

Examine for adenopathy and organomegaly

Lymphocyte reference range 1.5-3.5, >5.0 required to diagnosis CLL

If less than 5.0 and clonal by immunophenotyping (‘flow’), MBL

Monoclonal B-cell Lymphocytosis (MBL)

CLL most common LPD, immunophenotyping of peripheral blood sample

will allow for diagnosis, BM biopsy not required

Other causes of lymphocytosis - Trauma, Post-splenectomy, Exercise++

Lymphocytosis

Seldom of significance in isolation

Usual Reference range ~1.5-3.5x 109/l

Questionable benefit in referring asymptomatic isolated lymphopenia

Common causes of lymphopenia

Corticosteroids

Autoimmune diseases (RA, SLE)

Sarcoidosis, liver failure, renal failure

HIV

Lymphoproliferative diseases

Work-up

HIV, Autoimmune screen/Connective Tissue Disease (CTD) screen

Lymphopenia

Microcytic Anaemia

Iron deficiency is the most common cause of anaemia worldwide

First line test is a serum ferritin to assess body iron stores

Other serum iron studies (serum iron, TIBC, transferrin saturation) less

useful in the evaluation of iron deficiency anaemia

Menstrual loss is commonest cause in pre-menopausal women

GI blood loss is commonest cause in all other groups - consider direct

referral to endoscopy, esp. if GI symptoms

If Hb relatively preserved and MCV inappropriately low (discrepant

microcytosis), consider thalassaemia trait +/- iron deficiency ; consider

referral to haematology service for formal diagnosis, if required

Anaemia of chronic disease (AOCD), though usually normocytic, can

present with microcytic indices

Hypoxia

Lung disease - Heavy smoking with or without COPD

Cyanotic congenital heart disease (e.g. Down’s syndrome & VSD shunt)

High BMI and sleep apnoea (Pickwickian syndrome)

High altitude habitat - Denver, Colorado

Relative polycythaemia due to plasma depletion (diuretics)

Polycythaemia Vera (PV)

Pruritis after bath or shower – aquagenic pruritis

Burning sensation in digits - erythromelalgia

Very rarely, erythropoietin-secreting tumours

Causes of Polycythaemia

Symptoms of PV

Common to all erythrocytoses

Headache, decreased mental acuity, weakness

More specific to PV

Pruritis after bath or shower – aquagenic pruritis

Burning sensation in digits - Erythromelalgia

Constitutional symptoms

Arterial or venous thrombosis

(Look at Hct/Hb/RCC when you diagnose a new DVT)

Rarely, bleeding tendency - markedly elevated platelet count

http://www.mpnvoice.org.uk/

Myeloproliferative Neoplasm

Support group website

Management of Polycythaemia in Primary Care

Repeat Full Blood Count (uncuffed, if possible)

Modify lifestyle factors – stop smoking

Reduce alcohol consumption

Stop thiazide diuretics

Consider OPD referral if repeatedly raised Hct

(>0.48 in men, >0.45 in women) in absence of chronic

hypoxia

Urgent referral if raised Hct (>0.48 in men, >0.45 in women)

and acute thrombosis or bleeding, visual loss or any

neurological symptoms

Take Home Messages on Polycythaemia

Most polycythaemia is an appropriate response to hypoxia

There is no proven benefit to venesection for patient with chronic

compensatory polycythaemia (e.g. cyanotic heart disease)

The JAK2 mutation is a sensitive and specific test for PV

Refer to haematology OPD clinic for this assay

The major risk of untreated Myeloproliferative Disease (MPD) is thrombosis

The following findings are often seen in myeloproliferative disease –

History of arterial or venous thromboembolism, pruritus, splenomegaly,

elevated white cell or platelet counts, basophilia

Vitamin B12 deficiency - challenges

Neurological symptoms - sub-acute combined degeneration,

cognitive decline - may occur with a normal FBC

Marginally low B12 levels

Usually not associated with true deficiency

B12 test methods quite variable –

inter-assay biases from +10 to -20%

OCP use associated with artefactually low B12 levels

https://b-s-h.org.uk/guidelines/

British Society for Haematology Guidelines

All patients with anaemia, neuropathy or glossitis and

suspected of having Pernicious Anaemia should be tested for

anti-Intrinsic Factor (IF) antibodies regardless of vitamin B12

levels

Patients found to have a low B12 level in the absence of

anaemia and who do not have food malabsorption or other

causes of deficiency should be tested for anti-IF antibodies in

case it is an early/latent presentation of PA

Testing for anti-Parietal Cell (PC) Antibodies to diagnose PA

is not recommended

BSH Guideline

Treatment of Pernicious Anaemia

Hydroxycobalamin (Vitamin B12) 1mg IM or SC

Always give folic acid 5mg once daily aswell

Never treat a macrocytic anaemia with folic acid alone

Hypokalaemia is occasionally observed within days

Reticulocytosis within 5 days

Often a subjective improvement within 24 hours

Five B12 injections during the first two weeks

Then three monthly for life

Follow-up - check FBC and TFTs

Causes of Macrocytic anaemia

Megaloblastic anaemia – B12 or folate deficiency

B12 Deficiency

• Malabsorption e.g. Pernicious Anaemia, Crohn’s disease

• Dietary e.g. vegan

Folate Deficiency

• Poor diet e.g. homeless, alcoholism

• Increased demand e.g. pregnancy, haemolysis

• Malabsorption e.g. coeliac disease

• Drugs e.g. anti-epileptics, methotrexate

Take Home Messages on Macrocytic Anaemia

Pernicious Anaemia is a relatively common autoimmune disease

Folate deficiency is associated with social deprivation

A raised LDH is found in significant megaloblastic anaemia

Treat with Vitamin B12 and folic acid

Myelodysplasia not uncommon in an elderly population

Advances in treatment options justify referral for diagnosis

Isolated macrocytosis may be due to alcohol, liver disease or smoking

Macrocytosis found in 8.4% of adults >45 years in a recent Irish study

Associations with an elevated GGT and smoking

Important aspects of bleeding history

Mucosal bleeding seen with thrombocytopenia

e.g. epistaxis, gingival bleeding, menorrhagia

Haemostatic challenges

Surgery, dental procedures, childbirth

Alcohol can cause thrombocytopenia both due to direct toxicity on the

bone marrow and via hypersplenism due to cirrhosis

History of liver disease - hypersplenism

Medications

OTC medications Quinine

Causes of Thrombocytopenia

Decreased production

Rare in isolation, more commonly seen in context of pancytopenia

Viral infections (e.g. IM), alcohol

Increased consumption

Idiopathic Thrombocytopenic Purpura (ITP) – autoimmune

Drugs

Pregnancy

Hypersplenism

Rare serious conditions e.g. HUS, TTP – if low Plts, check for high LDH

ITP

Children

Acute

Usually seen after viral infection

Spontaneous resolution the norm

Adults

Slow onset

Commonly a chronic disorder

Frequently does not require treatment

First line options – corticosteroids, IV immunoglobulins

Rituximab has a role though Splenectomy also remains appropriate

Novel agents available for refractory difficult-to-manage ITP

Management in Primary Care

Repeat Full Blood Count

Blood film

Coagulation screen (PT, APTT)

Autoimmune screen (ANA)

HIV assay in selected cases

Common causes of thrombocytopenia in referrals in Haematology OPD

Hypersplenism

ITP

Alcohol

drugs

Bone marrow failure (MDS, B12 or folate deficiency)

Take Home Messages on Thrombocytopenia

Stable thrombocytopenia between 100 and 150

Ultrasound of abdomen to assess for splenomegaly may be warranted

Persistent thrombocytopenia less than 100 should be referred

Urgent referral if other cytopenias, adenopathy or organomegaly

Refer to Emergency Department if low platelets and elevated LDH

(possibility of TTP or leukaemia)

Monoclonal Gammopathy

of Undetermined Significance (MGUS)

Low risk MGUS – 40% of cohort

(1) IgG isotype

(2) Less than 15g/l

(3) Normal serum free light chain Kappa: Lambda ratio

The Serum free light chain (SFLC) assay is an expensive test requiring

specialist interpretation and should only be performed in Haem. Clinic

Low risk MGUS - 5% risk of progression to myeloma after 20 years

Lifetime risk of 2% when competing causes of death are taken into

account

75-90% of patients with MGUS will not develop myeloma or a related

disorder in their lifetime

Take Home Messages on Paraproteins

The detection of elevated immunoglobulins in the absence of a

monoclonal paraprotein does not require referral to haematology

Polyclonal hypergammaglobulinaemia reflects a generalised immune

response and is not a haematological disorder

The diagnosis of myeloma is based on evidence of end-organ damage –

C hypercalcaemia

R renal impairment

A anaemia

B bone disease

If suspected spinal cord compression, refer to Emergency Department

MGUS Discharge policy – IgG, less than 15g/L, normal SFLC ratio

Repeat SPEP in general practice annually

Long term follow up - FBC, RLB, Calcium, dipstick urine for protein

How to Interpret and Pursue an Abnormal Complete Blood Cell Count in Adults

http://www.mayoclinicproceedings.org/article/S0025-6196(11)61568-1/abstract

GP haematology referral guidelines Southend NHS Trust

http://www.southend.nhs.uk/media/22256/referralguidelineshaematology.pdf

GP Haematology referral Guys and Thomas’s NHS Trust

https://www.guysandstthomas.nhs.uk/resources/our-services/oncology-

haematology-cellular-pathology/haematology/khp-gstt-joint-adult-

haematology.pdf

British Society for Haematology

https://b-s-h.org.uk/guidelines/

Elevated serum ferritin - What should GPs know?

http://www.racgp.org.au/afp/2012/december/elevated-serum-ferritin/

Useful Websites