Haematology

Referral Guidelines

Conditions

Adults with non-malignant and/or malignant blood diseases and disorders

Standard Investigations

Required prior to referral

• Lymphoma: FBA, U&E, Calcium, ESR, Beta 2 microglobulin, Magnesium, Electrophoresis, SFLC, PB flow cytometry if lymphocytosis >4.0
• Myeloma: FBE, U&E, Calcium, ESR, Beta 2 microglobulin, Magnesium, Electrophoresis, SFLC
• Leukaemia: FBE, U&E, LDH, Coagulation, Urate, PB flow cytometry (Myeloid panel) if circulating blasts
• Skin Lymphoma: FBE, U&E, Skin biopsies, LDH, LFT’s
• Bleeding Disorders: FBE, Coagulation studies, VWF

Referral

How to refer to Bendigo Health

• Secure eReferral by SeNT system is our preferred method of referral Practice registration – BPAC Clinical Solutions (bpacsolutions.com.au) or
• Fax to 03 5454 8816. Please address referral to Dr Nora Lee, Bendigo Health Haematology or
• Mail to Dr Nora Lee, Bendigo Health Haematology, PO Box 126, Bendigo, 3552

The referral may be declined if it does not contain essential information required for triage, if the condition is not appropriate for referral to a public hospital or is a condition not routinely seen at Bendigo Health.

Contact us

• To discuss a complex or urgent referral contact the Haematologist On-call on 0448 755 712 between 9am – 4.30pm Monday to Friday
• To discuss a declined referral contact the Haematologist On-call on 0448 755 712 between 9am – 4.30pm Monday to Friday
• If we are unable to answer immediately, please leave a voicemail or send a text with your contact details for a return call

Criteria for appropriate referral - please read before making referral

Monclonal B-cell Lymphocytosis (MBL)

• Lymphocytosis may be reactive and patients with an unexplained persistently elevated lymphocyte count should have flow cytometry on peripheral blood to determine clonality
• MBL is defined by the presence of a clonal B-cell population of fewer that 5 * 10^9 /L by flow cytometry without other sign of lymphoma (B-symptoms, organomegaly, or lymphadenopathy)
• Patients with MBL or low lymphocyte count CLL (ie <15*10^9) can be appropriately monitored with FBC every 6-12 months until a time when closer surveillance is required
• Patients with unexplained weight loss/fevers/nights sweats, lymphadenopathy (>2cm), cytopenia’s, a rapidly rising lymphocyte count (especially if <6 months doubling time), or recurrent infections or autoimmune problems should be referred to Bendigo Haematology
• See link for further details

Deep Vein Thrombosis/ Pulmonary Embolism (VTE)

• DVTs and PEs can be divided into provoked and unprovoked events 
• Provoked events usually need only a finite period of anticoagulation unless the prothrombotic factor is persistent 
• Unprovoked/minimally provoked events may require indefinite anticoagulation 
• Haematology consultation is indicated for:
  all unprovoked VTE together with basic thrombophilia screening
  provoked VTE which is associated with
  - cancer
  - pregnancy or exogenous hormone exposure
  - known thrombophilia
  - cardiac failure and/or pulmonary hypertension
  - extensive thrombus burden and/or requirement for thrombolysis at presentation
  - recurrent VTE (either provoked or unprovoked)
• A first provoked VTE with a clear preceding event (eg major surgery, immobilisation, prolonged air travel) generally does not require haematology consultation and should be treated in accordance with local guidelines https://www.thanz.org.au/documents/item/414

Monoclonal gammopathy of undetermined significance (MGUS)

• MGUS is a benign condition defined by the presence of paraprotein without features of end organ damage
• Patients with MGUS are at low risk of progression to Multiple Myeloma if they have:
  - Paraprotein <15g/L
  - Normal serum free light chain (SFLC)
  - IgG subtype
• Patients at low risk can be monitored without referral with FBE, SPEP, UEC and CMP every 6 months and when stable annually
• Patients with high risk MGUS (not meeting above criteria), or suspected active myeloma should be referred to Bendigo Haematology
• See link for further details

Serum Free Light Chain (SFLC) interpretation

• SFLC may be modestly elevated in infection or in renal impairment
• In reactive process the Kappa / Lambda ratio should remain in the normal range, with a slight skewing towards Kappa seen in stage >3 renal disease (see link)
• Consider referral in patients with an involved FLC (>100mg/L) and an abnormal ratio
• Patients with suspected Amyloidosis and an elevated FLC should be referred to Bendigo Haematology for review

Polycythemia

• Haematology consultation is required for primary polycythaemia, but generally not for secondary causes of polycythaemia as the underlying driver needs to be addressed
• Confirm a first abnormal result in a non-fasting state before further investigation
• Assess for secondary causes of polycythaemia including:
  - smoking - cannabis, nicotine, vaping
  - obstructive sleep apnoea
  - medications (anabolic steroids, testosterone, erythropoietin stimulating agents, diuretics)
  - other primary malignancy (renal cell carcinoma, hepatocellular carcinoma, uterine leiomyoma, parathyroid malignancies, cerebellar haemangioblastoma)
  - chronic lung disease (eg COPD)
  - renal artery stenosis
  - polycystic kidney disease
  - congenital heart disease; left to right shunting
•  Symptoms that are more suggestive of primary polycythaemia include itch/erythromelalgia, abdominal pain/fullness, vasomotor symptoms
• Key investigations
  - Blood film
  - UEC, urate, LDH
  - Iron studies (primary polycythemia is often associated with iron deficiency)
  - Carboxyhaemoglobin level (elevated in secondary polycythaemia)
  - EPO level (low in primary polycythaemia)
  - JAKV617F mutation testing (positive in ~ 95% of primary polycythaemia)
  - lung function tests, echocardiogram, sleep studies, abdominal ultrasound, CXR
• The commonest cause of primary polycythaemia is polycythaemia vera, an acquired clonal disorder of the bone marrow leading to deregulation of erythrocytosis
• Less common causes of primary polycythaemia involve high oxygen affinity haemoglobins, congenital methaemoglobinaemia, rare EPO receptor mutations and idiopathic familial polycythaemia
• Further reading available here 

Isolated Neutrophilia <15x10^9/L

• The vast majority of neutrophilia is reactive or secondary in origin
• Primary bone marrow disorders are much less common
• Repeat FBE in 2-3 weeks to confirm abnormality and assess rate of change
• Consider the following secondary causes including:
  - infection, chronic inflammation (eg autoimmune disorders)
  - pregnancy
  - hyposplenism/splenectomy
  - smoking
  - hyperthyroidism, cushing's disease
  - medications (eg steroids, lithium, growth factor eg GCSF)
  - non-haematological malignancy
• Neutrophilia in chronic infection or inflammation may be associated with a monocytosis and/or thrombocytosis
• Pathological/primary causes of neutrophilia include:
  - myeloproliferative disorders (polycythaemia vera, chronic myeloid leukaemia, essential thrombocytosis, myelofibrosis)
  - chronic neutrophilic leukaemia
• Initial investigations
  - blood film (essential)
  - inflammatory markers (CRP, ESR)
  - LDH
  - assessment for hepatosplenomegaly
• Haematology referral is indicated if the neutrophilia is persistently >15x10^9/L, and/or associated with
  - unexplained weight loss
  - lymphadenopathy
  - hepatosplenomegaly
  - abnormal blood film findings (eg leukoerythroblastic, presence of blasts, dyplasia, myelocyte peak, basophilia)
  - JAK2 mutation or BCR-Abl mutation
  - Marked leukocytosis of >100x10^9/L requires urgent haematological review

Lower limb Superficial Venous Thrombosis (SVT)

• Management of SVTs relates to the thromboembolic propagation risk
• Low risk: remote (>5cm away) from the saphenofemoral junction (SFJ) or saphenopopliteal junction (SPJ), distal to the knee, <=5cm in length, and absence of medical risk factors for VTE
  - Initial management: symptomatic
• Intermediate risk: close to the deep venous system (within 3-5cm); greater than 5cm length, progression despite symptomatic (non-anticoagulated) treatment, and no medical risk factors for VTE
  - Initial management: prophylactic dose anticoagulation for 45 days (eg enoxaparin, DOACs – non-PBS)

• High risk:  within 3cm of the deep venous system (esp if GSV or SSV involved), propagation despite prophylactic dose anticoagulation; recurrence after cessation of anticoagulation, or ongoing medical risk factors for VTE
  - Initial management: therapeutic anticoagulation ~ 3 months  

• Migratory SVT raises the possibility of visceral malignancy
• Medical risk factors for VTE: eg chronic venous insufficiency, immobilisation, pregnancy, obesity, chronic infection, chronic inflammatory disorders, prothrombotic medications, active malignancy)
• Consider vascular surgery referral for recurrent lower limb SVT where there is chronic venous insufficiency/ varicose veins  
• Haematology consultation is recommended for intermediate and high-risk SVT, or where active malignancy or pregnancy are present  
• Low risk SVT cases do not require a referral

Hereditary Haemochromatosis  

• Hereditary haemochromatosis (HH) relates to clinical iron overload due to genetic abnormalities affecting the regulation of iron update.
• Multiple genes are implicated including HFE, HJV, HAMP, TFR2, SLC40A1C
• Not all mutations lead to iron overload. There is varying penetrance.
• The commonest abnormality is HFE C282Y homozygosity, but not all individuals develop clinical iron overload (~ 10-15%), as other genetic and environmental factors may be contributory 
  - In order of likelihood of true iron overload – C282Y homozygous, C282Y/H63D compound heterozygous, H63D homozygous
• Iron overload is uncommon in heterozygous HFE C282Y mutation and other HFE variants.
  - Other factors should therefore be considered such as chronic liver disease, medications, metabolic syndrome, excess alcohol, chronic inflammatory disorders.
• The following parameters suggest iron overload: 
  - Tsat >45%
  - Ferritin >200ng/Ml (F), >300ng/mL (M)
  - Note: Ferritin is an acute phase reactant, and elevated results should be repeated with markers of inflammation to confirm
• Refer to gastroenterology for further evaluation where iron overload is confirmed, with abnormal LFTS, in the presence of an HFE mutation

Cytopenias

• Cytopenias are not an uncommon presentation in the general population and are more prevalent in those patients that are elderly, have multiple comorbidities and medications and may be exacerbated by renal dysfunction and nutritional deficiency. Liver cirrhosis and resultant splenomegaly is also a not uncommon cause of cytopenias
• Although cytopenias may be a function of marrow disorders, assessment of the significance of the cytopenias and exclusion of more common causes is important prior to consideration of referral to the haematology unit
• However, the presence of multiple cytopenias, dysplastic features, circulating blasts or B symptoms (weight loss, soaking night sweats) should serve as “red flags” and lead to a prompt referral to the haematology service

Isolated Anaemia  

• Iron deficiency is the most common cause for anaemia and assessment should include a bleeding history, dietary intake as well as potential absorption issues (eg coeliacs disease, medications)
• A FBC investigating for microcytosis (a low MCV) as well as iron studies looking at ferritin levels are essential
• In the setting of iron deficiency with evidence of gastrointestinal bleeding should warrant a referral to Gastroenterology as the first line
• B12 and folate deficiency are a less common presentation but levels should be tested and replaced if needed
• Anaemia due to chronic renal dysfunction should also be considered with optimisation of renal function and consideration for referral to the renal unit
• Prior to referring a patient with an isolated anaemia that is not explained by the above, consideration should also be given to the clinical significance based upon the degree of anaemia, age and comorbidities of the patient. Haemoglobins levels of greater than 100 are unlikely to be physiologically significant

Isolated neutropenia

• Neutropenia is not an uncommon presentation and does not necessarily reflect a marrow disorder nor an increased risk of infection. Increased risks of infection are not commonly seen in a neutrophil count that is greater than 1.0
• Exclusion of an infective or inflammatory component is important (eg autoimmune conditions)
• Neutropenia that is intermittent and not progressive in the absence of any other abnormal blood film findings does not necessarily require a referral to the haematology service
• Benign ethnic neutropenia (BEN) is one of the most common causes of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent and is not associated with an increased risk of infection
• In the absence of any other cytopenias, dysplasia or B-symptoms, a neutrophil count of >1.3 can be monitored in the community with routine blood tests

Isolated thrombocytopenia

• Isolated thrombocytopenia of above 100 does not warrant a haematology referral
• The risk of bleeding from thrombocytopenia is not significant until platelet counts are less than 50 and is more of concern with a platelet count less than 20
• Antiplatelet and anticoagulants can generally be used safely if a platelet count is persistently above 50
• Platelet clumping is a common cause of thrombocytopenia and is an invitro phenomenon that can be usually avoided by repeating a FBC in a citrate tube
• Excessive alcohol consumption, liver cirrhosis, portal hypertension and splenomegaly can be associated with thrombocytopenia. In these situations an appropriate history and investigations (abdominal ultrasound) should lead to a more appropriate referral to gastroenterology