Leeds Health Pathways

Haematology - Adult Leeds

1. Background Information / Scope of Pathway

This guidance has been developed from current haematology guidelines and consultant expertise. Leeds Teaching Hospitals Trust (LTHT) Haematology department offer an electronic advice and guidance service to all GP surgeries where you will receive clinical advice from a consultant within 3 working days

2. Document is updated from last published date of 16.11.21

3. Changes that have been undertaken:

General update with minor corrections to majority of sections
Major updates: B12 section

4. Additional sections: Polycythaemia guidance

5. Referral forms:

For formal referrals please refer through the central referral pathway to LTHT; referrals will be triaged by a consultant haematologist to the appropriate clinic

6. Iron Deficiency Suspected (+/- Anaemia)

Quick info:
Iron deficiency is evidenced as either low ferritin or normal ferritin with low serum iron and high or high-normal transferrin. It can be associated with or without anaemia.

In all other cases of anaemia, please follow separate Microcytic anaemia, Normocytic anaemia or Macrocytic anaemia stem of pathway.

Once iron deficiency has been confirmed a cause should be sought bearing in mind that it is rarely due to a haematological disorder.

It is essential to confirm iron deficiency so as to avoid unnecessary invasive investigations. Always perform ferritin (if low, this confirms iron deficiency; if normal alternative testing may be needed – please seek advice through haematology advice and guidance portal).

Do not assume all microcytic anaemias are caused by iron deficiency

In case of confirmed iron deficiency anaemia, treat with oral iron supplements - generally ferrous fumarate 210mg OD (first line due to cost) or ferrous sulphate 200mg OD (second line) until the Hb normalises and then for an additional 3 months to replenish iron stored. A morning dose is preferable taken on an empty somach with water or preferably a source of vitamin C to enhance absorption such as a glass of orange juice
For pregnant patients the above also applies but please see current guideline Assessment and management of anaemia during pregnancy and the postnatal period

If the patient experiences side effects (often nausea or bowel disturbance), consider reducing the dose or try alternative oral iron preparations such as ferrous gluconate or sodium feredetate oral solution, (children or patients intolerant to large doses or with swallowing difficulty). If the patient is absolutely unable to tolerate any oral iron preparation they can be referred for intravenous iron infusion (refer Haematology at St James's Hospital)

Men and post-menopausal women with proven iron deficiency (low ferritin) should be considered for GI investigation or referral as per local guidelines.

7. Low Serum Folate Suspected

Quick info:
Definition: Folate is present in leafy vegetables and fruit. Dietary deficiency is thus extremely common.

Folate and iron are absorbed in jejunum so combined deficiency is very suggestive of coeliac disease or inflammatory bowel disease.

Serum folate reflects intake over previous few days, red cell folate reflects intake over previous 3 months but is low in either folate or B12 deficiency and may just add confusion, thus routinely checking red cell folate is not advised. The most helpful investigation is a dietary history.

Folic acid can be stopped if obvious temporary dietary cause of deficiency, with repeat folate levels 1 month post cessation of treatment.

If patients do not have an obvious dietary cause of deficiency or have recurrent deficiency, long term replacement is advised at 5mg OD

8. High Ferritin Suspected

Quick info:
Definition:
Increase in ferritin concentration >300ug/l for men and postmenopausal women or >200 ug/l for premenopausal women. Ferritin level may be increased as an acute phase reactant e.g. associated with acute liver disease, alcohol excess, infection, inflammation or neoplastic disease. These are often associated with normal iron saturation <50%. High ferritin will also be expected in patients with repeated transfusions but such patients will usually be under haematology review.

If iron saturation >50% consider genetic causes of increased iron absorption i.e. haemochromatosis.

Hereditary haemochromatosis is an autosomal recessive condition predisposing to pathological iron overload which may affect the liver, pancreas, heart, pituitary gland and joints. Over 90% of cases are caused by homozygous (C282Y) mutation of the HFE gene which can be detected by genetic screening.

Females with haemochromatosis often do not manifest high ferritin until after the menopause.

Haemochromatosis gene screening is done on an EDTA sample sent to Genetics DNA laboratory who will then forward on to
Newcastle (id essential - NHS number ideally) for testing. Patients should be counselled and their permission sought before genetic testing.

This can be requested in the community e.g. for first degree relatives of family members as per current guidelines

Reference: https://onlinelibrary.wiley.com/doi/pdf/10.1111/bjh.15164

9. Eosinophilia Suspected

Quick info:
Definition: Increase in eosinophils on WBC differential of FBC, > 0.4x10*9/l. Marked increase in eosinophils >1.5x10*9/l can be associated with organ toxicity, particularly cardiac toxicity. Majority of causes are ‘reactive’ associated with allergy/asthma/ connective tissue disease/drugs/parasites etc. Rarely primary haematological malignancies can be associated with raised eosinophils.

10. Anaemia/Low Hb suspected

Quick info:
Anaemia is a reduction in Hb, below the normal range for the laboratory; LTHT normal ranges are Hb female: 115-160g/l
Male: 135-180g/l.
Anaemia can be microcytic, normocytic or macrocytic

11. Further Investigations

Quick info:

FBC and Blood film.
Serum ferritin.
Serum folate & B12
Coeliac screen, unless definite dietary cause.
If symptoms of inflammatory bowel disease then liver function, albumin, ESR or CRP may be helpful.

12. Further Investigations

Quick info:

FBC + Blood film
Biochemistry including renal function, liver function, iron studies, LDH calcium, albumin, urate
Inflammatory markers, ESR and Plasma Viscosity and CRP. ESR and CRP rule out polymyalgia. Plasma viscosity would alert to very high levels and decisions to trigger plasmapheresis
Consider Rh F & ANA

13. Further Investigations

Quick info:

FBC + Blood film (to assess morphology including parasites if relevant travel history), repeat 4 weeks later to determine if eosinophilia persists
ESR and CRP (to see if there is acute inflammation/infection)
Biochemistry including renal function, liver function, LDH, calcium, albumin, urate

Look for underlying reactive causes, e.g. recent travel, h/o allergy; perform CCP, ANF, stools x3 for ova, cysts and parasites

14. Investigations

Quick info:
Suggested initial investigations:

Full history including menstrual history, GI history, medications, family history, dietary history
Examination – this should include rectal exam in all male patients and post-menopausal women (but do not let this delay referral). The presence of haemorrhoids should only be considered as a possible cause of IDA after other GI causes have been excluded.
Ferritin
If ferritin normal and suspicion of iron deficiency, check serum iron studies (ferritin is an acute phase reactant protein and will be normal/raised in the presence of inflammation, the patient could still be iron deficient)
If ferritin low check coeliac screen,
urinalysis for blood.

15. Macrocytic Anaemia

Quick info:
Definition: Anaemia (haemoglobin below normal range) and macrocytosis (MCV above normal range)

This guidance is also applicable to patients with macrocytosis and alternative blood abnormalities (e.g. Neutropenia, thrombocytopenia, monocytosis, or combinations or abnormalities.)

Common causes of macrocytic anaemia include B12/folate deficiency, thyroid disorders, medication and alcohol excess.

Patients who do not appear to have a simple cause for macrocytosis: Haematological disease is possible, including myelodysplasia. This is a clonal marrow disorder causing peripheral blood cytopenias (sometimes increased monocytes.) It generally requires a bone marrow test for confirmation of diagnosis. Treatments are available and may include blood transfusion, erythropoietin, or other therapies. Suggest however that this diagnosis is not discussed in primary care - there are many subtypes of myelodysplasia ranging from a very benign disorder requiring no treatment, to an extremely serious disorder very close to acute myeloid leukaemia. Much of the literature available on the internet concentrates on the more aggressive subtypes.

16. Microcytic Anaemia

Quick info:
Definition: Anaemia (haemoglobin below normal range) and microcytosis (MCV below normal range.)

The principal causes of a microcytic anaemia are iron deficiency, the anaemia of chronic disease, and haemoglobinopathies.

A microcytic anaemia with a low ferritin establishes a diagnosis or iron deficiency anaemia, please see iron deficiency advice.

The anaemia of chronic disease is suggested by low-normal or low MCV, normal or increased ferritin, raised PV. This can be caused by renal impairment, chronic infective or inflammatory disorders.

Thalassaemia is an inherited haemoglobinopathy commoner in people of SE Asian or Southern Mediterranean ancestry but may be seen in Caucasians. It is diagnosed using Hb electrophoresis and other specialised analyses. Please refer all such cases.

17. Anaemia-Normocytic

Quick info:
Definition: Haemoglobin below the normal range associated with a normal MCV

The principal cause of normocytic anaemia is the anaemia of chronic disorders (ACD.) ACD may be suggested by the following features - anaemia, raised plasma viscosity and/or CRP, normal or raised ferritin.

18. Red flags

Red flags
Quick info:

All male patients (unless obvious alternative source of blood loss), post-menopausal women, women >50 and women with a strong family history of colorectal cancer should be referred urgently to Gastroenterology. Patients should be informed that they will likely require upper and lower GI endoscopy.

19. Referral Criteria

Who to refer:

Patients not responding haematologically to replacement therapy – refer to haematology
Patients with suspected malabsorption or disease of the terminal ileum should be referred to gastroenterology

Exclusions:

Uncomplicated folate deficiency, repeat folate levels once established on treatment.

20. Urgent Referral Haematology/Hepatology

Urgent Referral Haematology/Hepatology
Quick info:
Please note LTHT offer an electronic advice and guidance service through the e-Referral system to all GP surgeries where you will receive advice from a haematology consultant if you are unsure whether the patient requires haematology outpatient review, within 3 working days

Patients with a ferritin > 1000 ug /L (on 2 occasions) and patients with raised ferritin with abnormal liver function tests initial referral should be to hepatology.
Elevated ferritin with evidence of otherwise-unexplained ‘end organ damage’: congestive cardiac failure, liver dysfunction, diabetes or hypogonadism should be referred to haematology

21. Non-Urgent Further Investigations

Quick info:

Repeat ferritin measurement in 4-6 weeks
Check liver function, fasting glucose, transferrin saturation
Careful alcohol history
Consider 'reactive' cause: infection, inflammation, neoplasia
Consider requesting genetic testing for HFE mutations

22. Referral Criteria

Quick info:
Please note LTHT offer an electronic advice and guidance service through the e-Referral system to all GP surgeries where you will receive advice from a haematology consultant if you are unsure whether the patient requires haematology outpatient review, within 3 working days
Eosinophilia is often transient; please repeat FBC 4 weeks after initial abnormal test unless there are concerns about haematological disease

Who to refer:

Patients with significant persistent eosinophilia (eosinophils >1 x10*9/l) without obvious underlying reactive cause

Exclusions:

Reactive eosinophilia may require assessment by other specialties (e.g. rheumatology, respiratory depending on cause.

23. Further Investigations

Quick info:

B12 and folate. Treat deficiency if detected
Blood film (to assess in particular red cell and white cell morphology)
Reticulocyte count. If raised, check Coomb's test (DAT/DCT), bilirubin, LDH and haptoglobins (to assess for haemolytic anaemia)
Thyroid function tests. Treat if abnormality is detected.
Liver function tests including GGT
Assess alcohol intake

24. Further Investigations

Quick info:

Ferritin - if low, please treat as below for further management
If ferritin is normal or high, check PV, haemoglobin electrophoresis and blood film.

25. Further Investigations

Quick info:

Blood film
U&Es and LFTs
Thyroid function tests
B12 and folate. Treat if deficiency is detected.
Ferritin. Investigate and treat if iron deficiency is detected
Reticulocyte count (if raised check Coomb's test (DAT/DCT), bilirubin, haptoglobin and LDH) (to assess for haemolytic anaemia)
Plasma viscosity and CRP
Immunoglobulins and serum protein electrophoresis (myeloma screen)
Urine for Bence Jones protein (myeloma screen)

26. Referral Criteria

Referral criteria:

Intolerant or resistant to oral iron (multiple preparations) should be referred to Haematology

Exclusions:

Iron deficiency anaemia in pre-menopausal women - with heavy periods or recent pregnancy.

30. Refer Haematology

Haemochromatosis should be suspected if iron saturation >50% or if there is a family history of this disease. Patients with high ferritin up to 1000 ug /L may be referred to Department of Haematology SJUH or WGH if no evidence of reactive causes e.g. Acute phase response or liver disease.

Exclusions:
Patients with normal iron saturation but high ferritin levels and with features of active liver inflammation may be best assessed by GI/liver physicians

31. Referral Criteria

Who to refer:

Macrocytic anaemia where all above investigations are normal
Macrocytic anaemia where anaemia persists despite adequate replacement/treatment as indicated
Macrocytic anaemia where blood film suggests Myelodysplasia
Macrocytic anaemia with increased reticulocyte count and/or positive Coomb's test
In severe cases - generally haemoglobin <80g/l or where patient is markedly symptomatic (breathless, angina, tachycardia) - please discuss with the haematology SpR on call through switchboard, patient will require urgent review and hospital admission (this may be under the medical team whilst investigations are arranged)

Exclusions:

Macrocytic anaemia that responds to B12/folate replacement with a complete normalisation of the FBC

32. Referral Criteria

Quick info:
Who to refer:

All patients with a haemoglobinopathy should be seen in the haematology department
Patients seen with a haemoglobinopathy trait will be seen by the counselling service
Patients with normal ferritin
Patients with IDA not tolerating or responding to various oral iron preparations

Exclusions:

Iron deficiency anaemia eferrals should be directed to the gastroenterology department

33. Referral Criteria

Quick info:
Who to refer:

Patients whose anaemia remains unexplained following above investigations or if unresponsive to haematinic replacement

Exclusions:

Anaemia due to haematinic deficiency if responsive to appropriate replacement

34. Treatment of Low B12

B12 guidelines for Leeds Health Pathways: testing, treating and reviewing B12 replacement

35. High haemoglobin or high haematocrit . Polycythaemia

Quick info:
Polycythaemia is a raised haematocrit and Hb. Polycythaemia is often secondary to COPD, Smoking, Cardiac failure, Liver disease testosterone replacement or anabolic steroids, Obesity and hypertension, dehydration, Diuretic use, known or suspected Sleep apnoea.

37. Thrombocytosis

Thrombocytosis is an increase in platelet count above 400x10*9/l. A common cause of thrombocytosis is in response to inflammation/infection and therefore this will resolve on repeat testing 4-6 weeks post-acute event.

Patients with persistently raised platelet count >450 x10*9/l and no identified cause may have essential thrombocythaemia (myeloproliferative condition) that will require treatment under the care of haematology. These patients are at an increased risk of thrombotic events including stroke.
Iron deficiency is also a cause of thrombocytosis and responds to iron replacement treatment

Patients with a platelet count 400 x10*9/l-450x10*9/l - if no other cause identified, repeat an annual FBC

38. Thrombocytopenia

Thrombocytopenia is a platelet count of <150 x10*9/l. There are many causes for thrombocytopenia including infection (in particular viral), medication, autoimmune conditions, acute illness, HIV, alcohol excess, liver failure, or haematological conditions such as immune thrombocytopenia or bone marrow disorders. Rarely this can be due to an inherited platelet disorder

39. Investigations

FBC and Blood film
Ferritin, B12 and folate (to identify causes of thrombocytosis)
Renal function, liver function, CRP (to identify reactive causes of thrombocytosis)

40. Investigations

If platelet count is 50-150x10*9/l with no other abnormalities/concerning features, repeat FBC and Blood film in 2 weeks post initial sample
If platelet count remains <150x10*9/l arrange the below tests in addition:

Virology to include Hep B+C and HIV serology
Renal function, liver function, CRP (to look for underlying causes of low platelets)
Full medication history including recent changes/new drugs - stop possible identified medication and repeat FBC in 4 weeks
Abdominal ultrasound could be considered if splenomegaly is possible

41. Referral Criteria

Please note LTHT offer an electronic advice and guidance service through the e-Referral system to all GP surgeries where you will receive advice from a haematology consultant if you are unsure whether the patient requires haematology outpatient review, within 3 working days
Patients with persistent thrombocytosis and no other cause identified refer to haematology for investigation and management.

Urgent referral: patients with platelet >1000 x10*9/l who do not have an underlying cause

42. Referral Criteria

Urgent referral to haematology - If the platelet count if <50x10*9/l, or there are other abnormalities of the full blood count as follows:

neutrophils <1x10*9/l, Hb <90 please discuss with haematology SpR on call, patient may require urgent review and possible admission
If the patient has thrombocytopaenia and bleeding please discuss with haematology SpR oncall
If the patient has thrombocytopaenia and is anticoagulated please discuss with SpR oncall

Routine referral - Please note LTHT offer an electronic advice and guidance service through the e-Referral system to all GP surgeries where you will receive advice from a haematology consultant if you are unsure whether the patient requires haematology outpatient review, within 3 working days

Repeat FBC 2 weeks post initial sample.
If there are no underlying causes for thrombocytopenia and platelet count is <100 x10*9/l, or there are other abnormalities of the FBC please refer to haematology

If there are concerns about underlying liver disease please discuss/refer to hepatology

43. Further Investigations (Bloods should be taken when well hydrated):

FBC and Blood film;
Renal function
Erythropoietin level