Clinical haematology

  • Haemophilia
  • Sickle cell anaemia
  • Thalassaemia
  • Immune thrombocytopenia (ITP) and related disorders such as haemolytic anaemia
  • Inherited bone marrow failure syndromes

We help diagnose and treat blood cancers such as leukaemia, lymphoma and myeloma, in conjunction with the Barts Cancer Centre based at St Bartholomew’s.

Our blood transfusion department is the largest in the UK. Our haematology consultants work closely with the pathology laboratories at the Trust to help diagnose many different diseases. Our laboratories provide routine and specialised blood tests and our experts provide advice to GPs and doctors in many different hospitals in north London and Essex.

We are located at four of our hospital sites but function as one department with individual consultants being predominantly site-specific. We are closely linked to the haematology and blood transfusion laboratories at our hospitals, with our consultants providing expertise in diagnosis as well as treatment.

Clinical Haematology at Newham

Newham has one of the largest population of patients with sickle cell disease in east London, and they have fast-track access in our Emergency Department for the management of acute painful crises.

Most diagnostic work and patient care is accommodated within our outpatient clinics, inpatient wards and the Forest Haematology Day Unit for patient assessment. The haematology laboratory provides a comprehensive service in conjunction with the central laboratories at The Royal London.

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Clinical Haematology at St Bartholomew’s

Our service at St Bartholomew’s provides general haematology support and advice to patients, but specialist care of patients with blood cancers (haematological malignancies) is provided by the haemato-oncology service of the Barts Cancer Centre based at St Bartholomew’s Hospital.

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Clinical Haematology at The Royal London

The Haematology Department at The Royal London provides many specialist treatments and diagnostic tests for patients with blood disorders. It is a comprehensive care centre for haemophilia, sickle cell anaemia, thalassaemia, paediatric haematology and is a national referral centre for ITP and inherited bone marrow failure syndromes. Most diagnostic work and patient care is accommodated within outpatient clinics, inpatient wards and the haematology day unit (Knutsford ward) including the administration of specialist treatments, blood transfusion therapy, venesections and patient assessment.

The purpose-built state of the art pathology building at The Royal London is the central pathology laboratory for the Trust. We provide specialist diagnostic tests for a large region that includes north London and Essex.

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Clinical Haematology at Whipps Cross

Our service at Whipps Cross cares for patients with all varieties of haematological disorder. Most the diagnostic work and patient care is accommodated within outpatient clinics, inpatient wards and the Woodlands Day Unit (WDU), including the administration of chemotherapy, blood transfusion therapy, venesections and patient assessment. The haematology laboratory provides a comprehensive service in conjunction with the central laboratories at The Royal London.

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Lab tests online UK

Need information about blood tests? Lab tests online UK has been designed to help patients better understand the many clinical lab tests, but is also used widely by healthcare professionals as a source of information.

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For clinicians

Clinical haematology across our sites

We are located at four of our hospital sites but function as one department with individual consultants being predominantly site-specific. We are closely linked to the haematology and blood transfusion laboratories at our hospitals, with our consultants providing expertise in diagnosis as well as treatment.

Haematological condition guidelines

GPs are commonly faced with abnormalities of the full blood count or may suspect their patient has a haematological condition. These guidelines provide a practical way of managing these problems, with reference to the British Society of Haematology guidelines and others where appropriate. The approach to other common disorders such as haemochromatosis, as well as antibodies in pregnancy, thrombophilia, lymphadenopathy and paraproteins is also discussed.

Select from the following guidelines:

  • Haemochromatosis
  • White cell disorders - including Lymphocytosis, Neutropenia, Eosinophilia and Monocytosis
  • Disorders of platelets - including Thrombocytopenia and Thrombocytosis
  • Red cell disorders - including Raised MCV, Polycythaemia and ESR
  • Thrombophilia
  • Paraproteins
  • Lymphadenopathy

The guidelines are adapted from a journal article by kind permission of Dr James Aries, Dr Shubha Allard and Rila Publications Ltd. Please note that whilst these guidelines are evidence based, they cannot be comprehensive and cover all scenarios. They should be interpreted in a clinical context and not used on their own. Please liaise with a haematologist if there are any uncertainties. Download our haematology user guide [pdf] 1MB

Lab tests online UK

Need information about blood tests? Lab tests online UK has been designed to help patients better understand the many clinical lab tests, but is also used widely by healthcare professionals as a source of information.

You can access information on referring patients to the Clinical Haematology Service on our referring patients..

Referring patients

General guidance on referrals is provided on the referrals page on our website here.

Two week wait cancer pathway

Guidance on suspected cancer referrals via the two week wait pathway is available on the London Cancer website here.

General guidance on referrals

If you are unsure if a patient needs to be seen in outpatients or you have a quick question that can be answered without us seeing the patient, contact us at: bhnt.advice-haematology-Barts@nhs.net We endeavour to answer all queries within 48 hours.

Please refer your patients to the following clinics:

  • General Haematology
  • Haemophilia (for people with possible bleeding tendencies)
  • Anticoagulation
  • Thrombosis
  • Myeloproliferative/MGUS clinic
  • Haemoglobinopathy (sickle cell disease, thalassaemia)
  • Paediatric Haematology

Urgent referrals

If you have a more urgent referral or want to speak to a haematologist, contact our switchboard on 020 3416 5000 and ask to speak to the haematology registrar (bleep 1243).

Contacting clinics at our sites

Patients often have blood tests analysed or see us in our clinics at specific hospital sites, so it may more useful to contact the registrar at those hospital sites. They can also be contacted using:

For The Royal London

Tel: 020 7377 7000 bleep 1243 (generally Tower Hamlets patients)

For Newham

Tel: 020 7476 4000 bleep 130, Bleep 247 (generally Newham patients)

For Whipps Cross

Tel: 020 8539 5522 bleep 075/076/352 (generally Waltham Forest patients)

Patients with haematological malignancies

These are generally seen by the Haemato-oncology Service based at St Bartholomew's. The appropriate haemato-oncology registrar can be contacted via the main switchboard: 020 3416 5000 or by email: bhnt.advice-Bloodcancer-Barts@nhs.net

Haemochromatosis

The classical symptoms of skin bronzing, hepatomegaly and diabetes is a now rare presentation of the disease, although 50% of homozygotes for the C282Y mutation will have some features by the time patients are 60 years old. These may be nonspecific findings such as chronic fatigue, weakness, abdominal pain, arthralgia and elevation of liver enzymes. Unrecognised haemochromatosis will lead to increased hepatic iron deposition, consequent fibrosis and cirrhosis. Diabetes, hypothyroidism, gonadal failure as well as cardiac arrhythmias can ensue.

Treating patients with haemochromatosis

First-degree relatives of affected patients should be screened for iron overload and the need for genetic testing should be discussed in haematology outpatients.

Once a diagnosis of haemochromatosis has been made the patient will start either weekly or fortnightly venesections on our day unit until the ferritin level is less than 50 µg/L. Further, less frequent venesections are then likely to be needed to maintain this ferritin level. Patients with haemochromatosis can become blood donors provided they fulfil donor selection criteria.

When to refer

  • If a raised ferritin level is found in the patient, and there are no obvious secondary causes and / or a family history of haemochromatosis, transferrin saturation should be performed immediately.

  • A raised transferrin saturation of more than 50%, should be repeated by a fasting transferrin saturation (this is significant if it is more than 55% in men and more than 50% in women)

  • A significant transferrin saturation should be followed by referring the patient to haematology outpatients for further assessment and genetic testing.

Lymphadenopathy

When to refer

Urgent outpatient haemato-oncology referral should be made for:

  • Lymphadenopathy more than 1cm persisting for more than six weeks in the absence of an infective cause
  • Lymphadenopathy for less than 6/52 in association with: B-symptoms, hepatosplenomegaly, rapid nodal enlargement, disseminated / generalised nodal enlargement, anaemia / leucopenia / thrombocytopenia / hypercalcaemia

Appropriate initial investigation in primary care should include a blood film made for the attention of the haematology doctor, biochemistry, LDH and glandular fever screen.

Useful websites

Paraproteins and light chains

Serum free light chains and paraproteins

What are serum free light chains?

Serum free light chains are immunoglobulin light chains that are not bound to an immunoglobulin heavy chain. Usually, immunoglubulins (antibodies) are produced with the light and heavy chains in balance but some disease states can result in excess light chains. Light chains are produced by plasma cells in the bone marrow and lymph nodes and are excreted by the kidneys. They come in two forms: K (kappa) and L (lambda).  The usual ratio of these is K: L 2:1. 

Why do we test for these? What is a paraprotein?

In myeloma, the bone marrow produces an abnormal clone of plasma cells. As each plasma cell can only produce either kappa or lambda, an abnormal clone arising from a single abnormal cell will produce only kappa or lambda light chains, thus skewing the ratio. Although most cases of myeloma produce an immunoglobulin (paraprotein) there is often an imbalance between heavy and light chains and myeloma cells some produce light chains only. Analysing free light chains and the K:L ratio can be one way of screening for myeloma, as well as monitoring response to treatment in someone with known myeloma.

What is monoclonal gammopathy of undetermined significance (MGUS)?

MGUS may be the precursor to myeloma and is much more common. A paraprotein is often found when performing blood tests for other symptoms. It is present in approximately 5% of those over 70 and MGUS has a risk of progression to myeloma of 1% per year. The distinction between MGUS and myeloma is the presence of end-organ damage in myeloma (as suggested by renal impairment, anaemia, hypercalcaemia and lytic bony disease). Patients with MGUS are generally followed up in clinic to monitor for evidence of myeloma developing

What other things can cause an abnormal result?

  • Renal impairment
  • Inflammation e.g. infections and autoimmune disease

It is common that these conditions raise the levels of both kappa and lambda light chains and the ratio often is altered slightly   A kappa/lambda ratio marginally outside the reference range and raised absolute total serum free light chain concentrations should not prompt referral unless there is other evidence of myeloma. Inflammation also causes a polyclonal rise in immunoglobulins.

When should I refer?

Serum free light chain result should be interpreted in the context of the patient's clinical history, other laboratory test results and indication for having requested the myeloma screen. In the absence of clinical symptoms of myeloma, do not refer to hospital for raised free light chains, unless:

  • A kappa/lambda ratio <0.125 or  >8 may require discussion with or referral to a haematologist.
  • A ratio >100 or <=0.01 requires urgent referral to haematology (refer  to haemato-oncology via 2ww)
  • If there is an associated paraprotein (‘monoclonal band’) on the protein electrophoresis. Haematology will make a clinic plan which will probably include regular outpatient review to monitor for development of myeloma
  • Urgent outpatient haemato-oncology referral should be made for a new paraprotein in association with:
    • Anaemia, thrombocytopenia or neutropenia
    • Lytic lesions on imaging or pathological fractures
    • Bone and back pain
    • Hypercalcaemia
    • Unexplained renal impairment
    • Symptoms of hyperviscosity
    • Symptoms of amyloidosis

References

  1. International Myeloma Working Group (IMWG) Criteria for the Diagnosis of Multiple Myeloma (2015)
  2. London Cancer myeloma guidelines 2015

Thrombophilia

Thrombophilia means an inherited or acquired predisposition to VTE. A pathophysiological model proposes that each person has a baseline thrombosis risk which increases as the person ages. Transient risk factors such as surgery temporarily increase a person’s risk of VTE, although this threshold is rarely reached. Most people therefore never have a thrombosis, however, an individual with an acquired or inherited thrombophilia may cross this thrombosis threshold whilst exposed to a risk factor.

It is natural that after a thrombosis both the patient and clinician will want to look for the cause of a thrombosis, however it is important to recognise the limitations of thrombophilia testing. There are many thrombophilic defects we know about and there are many that we don’t. It is well-known that testing for a thrombophilia after a VTE does not predict a recurrence. The personal and family history of the patient is always more important than the thrombophilia test result itself and in fact a negative test result can provide false reassurance to patients.

Despite the increasing knowledge regarding the aetiology of VTE, testing for thrombophilia serves a limited purpose. In asymptomatic relatives with a high risk thrombophilic defect, who intend to become pregnant or who are likely to use the oral contraceptive pill, testing can occasionally provide information regarding risk.

Useful websites

The British Society Of Haematology has a useful guideline for further reference.

Disorders of platelets

Thrombocytopenia

Thrombocytopenia is defined as a platelet count of less than 150 X 10/L. The risk of
spontaneous haemorrhage increases significantly below 20 X 109/L although most patients with a count of more than 50 X 10/L have few bleeding problems.

Primary care investigation

Any new thrombocytopenia discovered in primary care should be followed by a request for a blood film. This will be done by most laboratories automatically if the count is less than 120 X 109/L and it is important to exclude platelet clumping artefact (if the platelets are clumped, the count can be artificially low). Similarly, if there is marked platelet anisocytosis (variation in size between platelets) then the automated counter can sometimes report the count as being lower than it actually is. If there is significant clumping reported, then requesting a repeat full blood count in a citrate blood tube (as opposed to an EDTA) can be helpful. As well as a blood film, liver biochemistry and autoimmune profile should also be sought. An alcohol history and consideration of discontinuing precipitating medications are also essential. Common medications that are known to cause thrombocytopenia are sulphur-containing antibiotics and psychotropic agents.

The differential diagnosis of thrombocytopenia includes:

  • immune peripheral destruction (ITP)
  • any cause of bone marrow failure (aplasia, malignant infiltration, myelodysplasia, B12/folate deficiency)
  • alcohol
  • medications
  • sepsis
  • hypersplenism
  • disseminated intravascular coagulation (DIC)
  • thrombotic thrombocytopenic purpura (TTP) / haemolytic uraemic syndrome (HUS)

When to refer

  • Non-urgent referral should be made if the platelet count is 50-100 X 109/L in the absence of any other features.
  • Urgent outpatient referral should be made if the platelet count is less than 50 X 109/L or if the platelet count is 50-100 X 109/L in association with other cytopenias, splenomegaly, lymphadenopathy, pregnancy or upcoming surgery
  • Patients with a new thrombocytopenia of less than 20 X 109/L or less than 150 in association with new thrombosis or renal impairment should be urgently discussed with the haematologist on-call

Useful websites

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High platelets/thrombocytosis/thrombocythaemia

Thrombocytosis/Thrombocythaemia is defined as a platelet count of more than 450 X 109/L. It can be due to a primary myeloproliferative neoplasm (formerly known as myeloproliferative disorder) such as polycythaemia vera or essential thrombocythaemia, but is more likely to be ‘reactive,’ that is, secondary to infection, inflammation, chronic bleeding, iron deficiency or another kind of cancer. High platelet counts in the setting of myeloproliferative neoplasms carry risk of thrombosis and abnormal bleeding (due to platelet dysfunction).

What tests should I perform in primary care?

Initial investigation in primary care should consist of a blood film, ferritin, iron studies, c-reactive protein and a thorough search for a reactive cause. 

When to refer

Urgent referral for outpatient assessment should be made for:

  • Platelet count more than 1000 X 109/L
  • Platelet count 600-1000 X 109/L in association with recent arterial / venous thrombosis, neurological symptoms, abnormal bleeding

Non-urgent: Persistent (> 3 months) unexplained thrombocytosis of more than 450 X 109/L should be considered non-urgently for referral

Should I prescribe aspirin? Following review by a haematologist, in the context of a primary myeloproliferative neoplasm, aspirin is generally indicated to reduce the risk of thrombosis, though caution is needed with platelets >1000 as the risk of bleeding is high. However, aspirin is not recommended in the context of a reactive thrombocytosis alone.

Useful websites

MPN Voice provides information and emotional support to everyone who has been diagnosed with a myeloproliferative neoplasm.

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Red cell disorders

Raised Mean Cell Volume (MCV)

The causes of red cell macrocytosis (MCV more than 100fl) include B12 and folate deficiency, excess alcohol consumption, hypothyroidism, reticulocytosis and myelodysplastic syndrome. It is a normal finding in pregnancy and can be seen in individuals taking Hydroxycarbamide or anti-retrovirals. Myelodysplastic syndromes are a heterogeneous group of clonal disorders of ineffective haematopoiesis, characterised by peripheral blood cytopenias. They are important to identify given they can progress to acute leukaemia and as well as supportive care, there are some therapeutic alternatives in selected patients.

Primary care investigation

Investigations in primary care prior to referral to haematology include B12 / folate levels, blood film examination, routine liver, thyroid and biochemistry tests, immunoglobulins and protein electrophoresis as well as alcohol history. The level of Haemoglobin doesn’t always correlate well with the B12 level.

When to refer

Referral to haematology should be considered for suspected MDS on blood film report, MCV more than 100fl in the absence of haematinic deficiency and persistent unexplained MCV of less than 105fl.

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High Haemoglobin/Haematocrit/polycythaemia

An elevated haemoglobin / haematocrit (HCT) has apparent, primary and secondary causes. The main differential as far as haematologists are concerned is between a primary myeloproliferative neoplasm (polycythaemia vera), apparent polycythaemia resulting from reduced plasma volume and secondary causes (such as hypoxic lung disease and erythropoietin-secreting tumours).

Polycythaemia Vera (PV) results in elevated red cell mass and is almost always associated with mutation in the JAK2 kinase. Symptoms include headache, fatigue and pruritus, with some suffering from visual changes, weight loss, dyspnoea, excessive sweating or painful paraesthesias. The most important morbidity is arterial or venous thrombosis and it is for this reason that it is important to make a firm diagnosis in order to determine treatment. If a raised haematocrit is associated with new thrombosis, neurological symptoms, visual loss or abnormal bleeding, then the patient needs to be referred urgently.

The intervention for someone with PV depends on age and thrombohaemorrhagic risk, but will often be a combination of lose-dose aspirin, phlebotomy and possibly cytoreductive agents such as hydroxycarbamide.

Useful website for patients: MPN Voice

When to refer

Urgent outpatient referral to haematology should be made if:

  • HCT is more than 0.60 (males) or is more than 0.56 (females)
  • HCT is more than 0.51 (males) or is more than 0.48 (females) in association with thrombosis, neurological symptoms, visual loss or abnormal bleeding

Non-urgent outpatient referral to haematology should be made if the HCT is more than 0.51 (males) or 0.48 (females) if it is:

  • Persistent
  • Associated with splenomegaly, pruritus, raised white cells, raised platelets

Helpful tests to perform prior to referral:

Repeat FBC, ferritin, iron studies, erythropoietin, creatinine, LFTs. 

If someone has established or suspected polycythaemia and coexistent iron deficiency, do not replace iron as this can cause a rapid rise in Haemoglobin. 

Erythrocyte Sedimentation Rate (ESR)

ESR is a relatively nonspecific test that is frequently ordered during the diagnosis and monitoring of disease. A variety of factors influence the sedimentation rate. Disease-related factors that may affect the ESR include the plasma immunoglobulin and fibrinogen concentrations, and the presence and degree of anaemia. Factors unrelated to disease process that may affect ESR values include age, sex, and drug therapy.

There is no evidence to support the use of the ESR in asymptomatic individuals.

The ESR may be used to evaluate patients with unexplained symptoms or a deterioration of health status when:

  • an inflammatory, neoplastic, or infectious disease is suspected
  • a specific diagnosis is not made effectively by other means

Therefore, it may be used to identify that something is wrong when a patient has non-specific symptoms, but it does not usually suggest what the disease process is.

The ESR may be used to monitor the activity of temporal arteritis, polymyalgia rheumatica, inflammatory arthritis, childhood inflammatory disorders and some infections.

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White cell disorders

Lymphocytosis 

What is lymphocytosis?

Lymphocytosis is a lymphocyte count above the upper limit of normal. In our lab, this is >3.0 x 109/L

What are the commonest causes of lymphocytosis?

  • Infections, particularly viral such as influenza, CMV, EBV, HIV, hepatitis and HTLV-1. Non-viral infections that are known to cause lymphocytosis include pertussis, toxoplasmosis and TB
  • Smoking
  • Any acute inflammatory event e.g. any acute cardiac event, seizures, trauma
  • Autoimmune disease
  • Post-splenectomy
  • Clonal lymphocytosis (leukaemia or lymphoma)

What is clonal lymphocytosis?

Clonal lymphocytosis is seen in a number of lymphoproliferative disorders e.g. Chronic lymphocytic leukaemia (CLL), monoclonal B lymphocytosis (MBL) and non-Hodgkin lymphoma (NHL). MBL is a pre-malignant condition that occurs in around 5% of healthy adults over the age of 60. Whilst there is a clonal population of lymphocytes, the population is <5 x 109/L.  It progresses to CLL at a rate of around 1%/year. We use leucocyte immunophenotyping to see if the population of lymphocytes is clonal. 

What investigations should I do?

If symptoms of acute viral infection, repeat around 4-6 weeks after viral symptoms resolve.

If there are no symptoms and the lymphocyte count is persistently raised, then check:

  • HIV, Hepatitis B and C, HTLV-1 serology. TB screening if indicated
  • Autoimmune screen
  • Blood film 

What does ‘atypical lymphocytes’ mean?

‘Atypical lymphocytes’ is a comment often seen on blood films, which is rather vague and unhelpful. This comment generates anxiety about an underlying haematological disease, including potential haematological malignancy, whilst in fact it describes an appearance that is reactive to other causes, e.g. viral infection or rheumatological disease. We are trying to discourage the phrase in the haematology lab

When should I refer to Haematology?

Refer to us if:

  • There are features on the blood film suggestive of a malignancy (e.g. leukaemia)
  • There is lymphadenopathy, splenomegaly or hepatomegaly
  • B symptoms (weight loss >10%, soaking sweats, unexplained fever)
  • There is associated anaemia, neutropenia or thrombocytopenia
  • The above investigations are unremarkable and there is a persistent lymphocytosis >5.0 x 109/L despite stopping smoking. This is an arbitrary threshold.
  • Haematology will make a clinic plan which will usually include immunophenotyping and consideration of imaging to screen for lymphoma. If serious conditions are excluded, we will usually discharge with reassurance and explicit criteria for re-referral 

References

  1. Smellie W et al. Best practice in primary care pathology: Review 7 J Clin Pathol. 2007 May; 60(5): 458–465.
  2. ICSH recommendations for the standardization of nomenclature and grading of peripheral blood cell morphological features, Palmer L et al, International Journal of Laboratory Haematology, 2015, 37, 287-303

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Neutropenia

What is neutropenia?

Neutropenia is defined as a circulating neutrophil count less than the lower limit of normal. This varies depending on the institution but the WHO define it as <1.8 x 109/L. The main concern is the risk of infection and of an underlying blood disorder but most episodes of neutropenia are transient or due to a non-cancer cause. The risk of infection is related to the degree of neutropenia with a major increased risk being seen with counts of less than 1 X 109/L.

Benign Ethnic Neutropenia (BEN) has found in up to 25-50% of patients of African descent, as well as some patients of Caribbean or Middle Eastern descent. There is no increased risk of infection. In these groups, a normal neutrophil count can be 0.9 X 109/L and BEN is most likely. In this situation it is helpful to know previous results to compare and it is still important to consider other causes and referral if the neutropenia is worse than their normal baseline

Other important causes of neutropenia include viral infection (including HIV), sepsis, drugs, autoimmune disorders and bone marrow failure due to blood cancers (myelodysplasia, leukaemia), aplasia or severe B12 / folate deficiency. 

Which drugs commonly cause neutropenia?

Drugs typically cause neutropenia within the first three months of starting. The most common drugs that cause neutropenia are:

  • Antibiotics: Macrolides, cephalosporins, co-trimoxazole, chloramphenicol, amoxicillin, co-amoxiclav
  • Anticonvulsants: Carbamazepine, phenytoin, sodium valproate
  • Anti-inflammatory drugs: NSAIDs, Sulfasalazine, methotrexate, colchicine
  • Antipsychotics: Clozapine, tricyclic antidepressants
  • Antihypertensives: ACE inhibitors, furosemide, bendroflumethiazide, spironolocatone
  • Others: antithyroid drugs, allopurinol, tamoxifen, chlorpropamide

Which infections cause neutropenia?

  • Bacterial, viral or fungal infections can all cause neutropenia. If you see a patient with an infection and low neutrophils, repeat the bloods 4-6 weeks after the infection has resolved.
  • It is important not to miss HIV or chronic hepatitis

What other investigations should I do?

  • Check: HIV, hepatitis B and C serology, an autoimmune screen and B12/folate
  • Request a blood film

When should patients be referred to Haematology?

  • Patients with fever and  with neutrophils <1.0 x 109/L should attend hospital as an emergency
  • If the neutrophils are <0.5 x 109/L (refer urgently to haemato-oncology via 2ww)
  • If there is an associated anaemia or thrombocytopenia, or abnormalities seen on the blood film
  • Presence of splenomegaly 
  • Recurrent infections or mouth ulcers that are thought be due to neutropenia
  • If the neutropenia is persistent (2 episodes at least 4-6 weeks apart) and the above causes have been excluded
  • Haematology will make a clinic plan which may include regular outpatient review to monitor for development of a serious blood condition or discharge with reassurance and explicit criteria for re-referral 

References

  1. Haddy T, Rana S, Castro O. Benign ethnic neutropenia: what is a normal absolute neutrophil count? J Lab Clin Med. 1999 Jan;133(1):15-22.
  2. Littlewood T. Neutropenia in primary care BMJ 2014; 349

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Eosinophilia

Most eosinophilias are reactive in nature and should be investigated for a secondary cause such as infections (especially parasites), allergy/hypersensitivity disease, medications, connective tissue disease, pulmonary disease, cardiac disease, dermatological disorders, malignancy, gastrointestinal disease and adrenal insufficiency. Primary eosinophilia accounts for about 2% cases and includes myeloproliferative neoplasms, chronic myeloid leukaemia, acute or chronic eosinophilic leukaemia and systemic mastocytosis.

An eosinophil count of more than 0.4 X 109/L is abnormal, however, a persistent count of more than 1.5 X 109/L (moderate eosinophilia) is widely regarded as appropriate for further investigation. Severe eosinophilia is a count of more than 5 X 109/L.

When to refer

  • Secondary eosinophilia is more common than primary eosinophilia
  • A repeat full blood count should always be performed after discovering an incidental eosinophilia, as well as biochemistry, liver function tests, inflammatory markers and autoimmune profile. Stool microscopy should be performed and consideration given to parasite serology.
  • Haematology referral should be considered for persistent eosinophilia of more than 1.5 for more than six months, end-organ damage not attributable to another cause or a count more than 5 X 109/L.

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Monocytosis

An absolute monocytosis is defined as a count more than 1 X 109/L. A reactive monocytosis can be seen with chronic infections, inflammatory conditions, splenectomy and malignancy (e.g. carcinoma, myeloma and lymphoma). A persistent monocytosis in the absence of any obvious cause should prompt referral to haematology as this may represent a myeloproliferative process such as Chronic Myelomonocytic Leukaemia or Chronic Myeloid Leukaemia.

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Haematology iron deficiency guidelines

Haematology referral is not required for the majority of people with iron deficiency but we can offer advice and treatment with intravenous iron.                                               

Definitions

Anaemia:  WHO Haemoglobin (Hb) thresholds are Hb equal to or less than 130g/L for men and Hb less than or equal to 120g/L for women.

Iron deficiency anaemia (IDA): NICE states that Iron deficiency can be confirmed if the ferritin <15. However, coexistent inflammation will increase the ferritin even in iron deficiency and so a cut-off ferritin of <50 has been proposed by the British Society of Gastroenterology if there is coexistent disease. It can be difficult to interpret iron deficiency in people who have infective or inflammatory conditions but, as a guide, a patient is unlikely to be iron deficient if their ferritin is above 100. Ferritin, transferrin saturation, Hb and MCV need to be considered together. Results needs to be considered in a clinical context and sometimes iron deficiency is only confirmed with an improvement in Hb level following iron treatment.

Causes

The most common cause in a pre-menopausal women is menstruation (20-30% of women). In men and post-menopausal women the most common cause is gastrointestinal (GI) blood loss. Additionally, pregnancy is a common cause as physiological requirements for iron in pregnancy are three times higher than they are in menstruating women.

Other causes include poor dietary intake, poor absorption (coeliac disease, gastrectomy and H. pylori) and urinary tract losses.

Investigation

History and examination should be focused on ruling out the causes highlighted above. If anaemia is significant then questions to rule out cardiac dysfunction should also be asked to assess the need for urgent correction.

The following areas should covered in the history and examination:

  • Gastrointestinal alarm and non-alarm symptoms
  • Menstrual history
  • Malabsorption
  • Nutritional deficiency
  • Diet content; Vegetarians are at increased risk of IDA
  • NSAIDs / aspirin / clopridogrel / warfarin /DOACs other anticoagulants
  • Haematuria (dipstick urine)
  • Frequent blood donation

All iron deficient patients should be tested for coeliac disease with anti-TTG antibodies. If positive, they should be referred to gastroenterology and tested for B12 and folate deficiencies as well.

For menstruating women with no GI symptoms and without a significant family history of GI malignancies, further investigation is not necessary. If there is a history of menorrhagia or dysfunctional menstrual bleeding then a referral to gynaecology may be warranted. In men and post-menopausal women, upper and lower GI investigations should be considered unless another non-GI reason has been confirmed. In patients who have had gastroscopy, lower GI investigations should still be carried out, unless coeliac disease or advanced gastric cancer has been confirmed.

Although rare, it is also useful to do a urinalysis looking for blood to pick the 1% of people who are iron deficient secondary to urinary tract malignancy. If there is no cause is found after both lower and upper GI investigations it is also useful to test for Helicobacter pylori and eradicate if found as this may be impairing absorption.

In patients who do not have an adequate response to iron or who rapidly become iron deficient after iron supplementation, consider further discussion with the gastroenterologists about small bowel investigations to rule out small bowel disease such as malignancy or angiodysplasia.

In patients who have suspected functional iron deficiency a trial of iron may be useful and sometimes the best diagnostic test is an increase in Hb in response to iron supplements.

Treatment

Oral supplementation

This is the recommended first line treatment and the preparation of choice is ferrous sulfate with a 200mg tablet providing 65mg of elemental iron. One to two tablets should be taken on an empty stomach. If this treatment is taken, absorbed and tolerated then an expected 20g/L rise in Hb is expected over 3 to 4 weeks.

However, oral iron supplementation is not well tolerated in up to 20-30% of people with gastric complaints being the most common reason. Therefore, tolerance should be assessed within a week of starting the tablets as often patients will just stop taking the tablets due to the side effects. Patients can then be advised to try taking the iron tablets with meals; drop the dose to one a day; or change formulation to ferrous gluconate, which has a lower amount of elemental iron. Ascorbic acid 50mg/day can also be added in to help increase absorption.

If oral iron has been effective at 8 weeks the treatment with oral iron should be continued for at least 3 months to ensure iron stores are replete, but if the reason for the iron deficiency is still present, for example in menorrhagia, then it is advisable to continue with oral iron but at a lower dose of one a day or every other day. The patient’s FBC and iron status should be rechecked every at a suitable interval (four example every 3 months) whilst they are receiving treatment, to ensure iron overload does not occur and the patient is responding.

Intravenous (IV) iron

If a patient has failed two oral formulations of iron then they should be referred for consideration of IV iron. If the failure is not due to intolerance, further tests should be done to rule out bleeding from the GI tract or poor absorption. Additionally, if rapid correction of iron deficiency is needed; for example pre operatively or very symptomatic patients, then IV iron first line can also be considered. We should ensure that the relevant investigations have been sent for these patients and adequate follow-up is arranged for them.

The FBC and ferritin should be rechecked 3-4 weeks after IV iron and if there is not a response then an alternative diagnosis should be investigated.

If responsive then they should have blood tests every 3 months to ensure they have not become iron deficient again for the first year. If they remain iron replete after this then their FBC and iron status should only be rechecked when clinically indicated.

How to refer for IV iron

If your patient has failed oral iron therapy and needs IV iron, please complete the referral template and refer via the e-referrals system. Internal referrals require the same template but will be emailed to the haematology team. The Haematology clinical team will vet the referral and pass it on to the Haematology Day Unit, who will contact the patient to arrange for the infusion.

The default pathway is that the patient will have one iron infusion and then will be discharged back to their GP with a standardized letter recommending additional investigations. We will advise re-checking their FBC in 3-4 weeks to ensure response to IV iron and if no response an alternative diagnosis should be sought. We would expect an increase in Hb by 20-30g/L

If oral iron has not previously been tried and the patient becomes iron deficient again, then please start ferrous sulfate 200-400mg per day and they should expect a rise of at least 20g in 4 weeks, if the tablets are taken. If there has been a previous history of intolerance to oral iron supplementation and there is a risk of further iron deficiency we would suggest a trial of ferrous sulfate 200mg every other day. This has been shown in studies to be as effective as daily administration and has fewer side effects. Many patients do benefit from a single iron infusion and starting low dose oral iron. Identifying and treating the underlying cause (such as treatment for menorrhagia) is also important.

Some patients appear to require regular (i.e. more than once a year) iron infusions. If the cause of the iron deficiency cannot be treated and/or oral iron cannot be tolerated then please refer back to haematology. If a patient requires more than one IV iron infusion a year then we will organize for the patient to receive regular blood tests and further IV iron on the day unit at suitable intervals but also be seen in our haematology clinic for review once a year. This is to ensure that all necessary investigations for the iron deficiency have been sent and decide how often the patient will need an iron infusion. If the patient does not require more than one iron infusion a year, we will discharge them back to care under their GP.

Abnormal B12 and folate levels

Uncomplicated B12 or folate deficiency does not require referral to haematology.

What are the causes of B12/folate deficiency?

  • Dietary (vegetarian/vegan/poor diet)
  • Malabsorption: coeliac disease, Crohn’s, gastrectomy, small bowel resection,  hemicolectomy, chronic pancreatitis
  • Drugs: Metformin, PPIs, OCP, anticonvulsants (folate deficiency). 
  • Pernicious anaemia ( B12 deficiency)

What investigations are needed in a patient with B12 deficiency?

  • Anti-intrinsic factor antibodies (positive in 40-60%). Note that negative test does not exclude pernicious anaemia
  • Autoimmune screen (may support diagnosis of pernicious anaemia)
  • Coeliac screen

What treatment should I give for B12 deficiency?

  • Neurological involvement: 1mg intramuscular injection on alternate days for 3 weeks then review to see if neurological symptoms have resolved, then every 2 months’ thereafter.
  • No neurological involvement: 1mg hydroxocobalamin intramuscular injection three times a week for 2 weeks.
  • Maintenance dose (where the vitamin B12 deficiency is not thought to be diet related): administer hydroxocobalamin 1 mg intramuscularly every 3 months for life .
  • Maintenance dose (where vitamin B12 deficiency is thought to be diet related): advise people either to take oral cyanocobalamin tablets 50–150 mcg daily between meals, or have a twice-yearly hydroxocobalamin 1 mg injection. The injection regimen may be preferred in the elderly (who are more likely to have malabsorption), and vegans (as currently available brands of oral cyanocobalamin may not be suitable for vegans). 
  • In vegans, this treatment may need to be life-long, whereas in other people with dietary deficiency replacement treatment can be stopped once the vitamin B12 levels have been corrected and the diet has improved. 
  • Advise people to eat foods rich in vitamin B12. Foods which have been fortified with vitamin B12 (for example some soy products, and some breakfast cereals and breads) are good alternative sources to meat, eggs, and dairy products.
  • You do not usually need to test further levels
  • Serum folate may appear low in Vitamin B12 deficiency so treat with B12 first 

What about patients on metformin?

  • In the case of deficiency in patients on metformin, with a negative anti-intrinsic factor antibody,  a short course of oral B12 (50mcg once a day) can be trialled for a month, then levels rechecked at 6 months, and annually thereafter. 

What treatment should I give for folate deficiency?

Note that delayed samples can result in a false low folate level and that folate levels are very dependent on recent diet. The results should be interpreted in the clinical context and with consideration of the presence of anaemia.

  • 5mg once a day for 4 months in the case of megaloblastic anaemia due to folate deficiency due to diet, pregnancy or anticonvulsants. In cases of malabsoprtion up to 15mg once a day for 4 months can be given. 
  • Folic acid can be maintained in people with poor diets (lacking in leafy green vegetables) by continuing 400mcg folic acid once a day as maintenance

When should I refer a person with vitamin B12 or folate deficiency anaemia?

  • Seek urgent advice from a haematologist if the person has neurological symptoms, or is pregnant.
  • Refer to a haematologist if the cause of vitamin B12 or folate deficiency is uncertain following investigations, or the suspected cause is haematological malignancy (urgently refer) or other blood disorder.

Refer to a gastroenterologist if:

  • Malabsorption of vitamin B12 (other than due to pernicious anaemia) or folate is suspected.
  • The person has pernicious anaemia and gastrointestinal symptoms, especially if there is a suspicion of gastric cancer (for example co-existing iron deficiency). The urgency of referral will depend on the nature of the symptoms.
  • The person is folate deficient, and antibody testing suggests coeliac disease (positive for anti-endomysial or anti-transglutaminase antibodies).

Consider referral to a dietician if vitamin B12 or folate deficiency is thought to be due to a poor diet.

My patient, who is not on B12 injections or tablets, has a high B12. What should I do?

High B12 is a non-specific finding, but can be found in some myeloproliferative disorders such as polycythaemia vera, chronic myeloid leukaemia and acute leukaemia. It can also be found in acute or chronic liver disease. Although there are no formal guidelines on these, we would advise that you refer the patient if there are any abnormalities in the full blood count (raised Hb, WBC or platelets) or blood film. If this is entirely normal and there is no evidence of liver disease and no other suggestions of haematological disease, we suggest that no further investigation is needed.  

Why does my patient on B12 injections every 3 months get symptoms before their injection is due?

Some experts acknowledge that there is a small group of patients who report a recurrence of their symptoms earlier than 3 monthly. There is no consensus on what to do in the situation.

References

  1. Devalia, V., Hamilton, M. S., Molloy, A. M. and the British Committee for Standards in Haematology (2014), Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol, 166: 496–513. 
  2. NICE Anaemia - B12 and folate deficiency guidance 2015

Contact us

Newham University Hospital
Tel:
 020 7363 9413 / 020 7363 8730
Fax: 0207 363 8098

The Royal London Haematology Offices
Tel:
 020 3246 0338
Fax: 020 3246 0351

The Royal London Haematology Day Unit   
Tel:
 020 3594 1855 / 020 3594 1901

Whipps Cross Haematology Offices
Tel:
 020 8535 6687
Fax: 0208 535 6890

Whipps Cross Haematology Day Unit (Woodlands) 
Tel:
 020 8535 6917
Fax: 020 8535 6918

Contact the main Haemophilia Office
Tel:
 020 3594 1869