Polycythaemia is myeloproliferative disorder of the erythroid cell line. By this we mean that there is uncontrolled proliferation of the stem cell. It is a form of bone marrow cancer.
It refers to an increase in haematocrit, red cell count and haemoglobin concentration. It is sometimes known as erythrocytosis.
The normal haematocrit range is:
- Male - 0.4-0.54%
- Female - 0.37-0.47%
🔢 Classification
Polycythaemia can be divided into 2 types:
- Absolute polycythaemia - normal plasma volume but simply an increase in the number of RBCs. It can further be broken down into:
- Primary polycythaemia
- Secondary polycythaemia
- Relative polycythaemia - normal number of RBCs but there is a decrease in the volume of plasma.
Primary polycythaemia
A myeloproliferative polycthaemia.
- Polycthaemia vera (polycthaemia rubra vera)
Secondary polycythaemia
This is a physiological polycythaemia due to an increase in production of erythropoietin. It may be due to:
- COPD
- Altitude
- Obstructive sleep apnoea
- Neoplasms - cerebellar haemangioma, hypernephroma, hepatoma.
Relative polycythaemia
Caused by a loss of fluid volume due to:
- Dehydration
- Burns
- Stress
- Gaisbock’s syndrome
Pathophysiology
Polycythaemia vera (PCV) is the primary form of polycythaemia. It occurs due to genetic mutations of bone marrow HSCs.
The mutation involved in ~95% of cases is the JAK2 V617F mutation. The JAK2 V617F mutation activates erythropoietin receptor signalling → increased RBC production (morphological normal, simply overexpressed).
This increase in RBC concentration causes hyperviscosity which increases risk of thrombosis (however, some evidence may point to it being due to increased WBC count and the increase in prothrombotic markers).
⚠️ Risk factors
- >40 years of age - 90% of patients are over 40 at diagnosis. The incidence peaks in the sixth decade.
- Budd-Chiari syndrome - there is an association with Budd-Chiari syndrome (disease characterised by occlusion of hepatic veins) and PCV. This especially true in young women.
😷 Presentation
It is often asymptomatic and an elevated haemoglobin may be seen on an FBC incidentally (needs to be confirmed after a minimum of 1 week).
- Pruritus - especially when in contact with warm water (aquagenic pruritus)
- Splenomegaly - causing abdominal discomfort.
- Fatigue
- Headache
- Arterial or venous thrombosis - this is sometimes the presenting complication. Manifestations include stroke, MI, PE, DVT.
- Visual disturbances - secondary to hyperviscosity.
- Haemorrhage - common sites being intracranial and gastrointestinal. It occurs due to impaired platelet function that occurs with the disease.
- Erythromelalgia - a tender or painful burning sensation ± redness in fingers, palms, heels, toes.
- Facial redness (ruddy complexion) and conjunctival plethora
🔍 Investigations
A clinical history (asking about history haemorrhage, thrombosis, Budd-Chiari syndrome) and physical examination (looking for conjunctival plethora, ruddy complexion, splenomegaly) should be done first.
- 🥇 FBC
- Haemoglobin - >185g/L in men or >165g/L in women.
- MCV - often is low in PCV.
- Haematocrit - >0.52 in men or >0.48 in women.
- WBCs - raised.
- Platelet count - raised.
- LFTs - deranged LFTs could indicate a secondary cause of erythrocytosis (hepatic tumour). However, they are mostly normal.
- U&Es - abnormal renal function could indicate secondary cause due to increased erythropoietin release.
Other features we may see include a low ESR and raised leukocyte alkaline phosphatase.
- Serum EPO - an increased EPO suggests secondary erythrocytosis and decreased levels suggest PCV. Normal levels do not rule out PCV.
- 🏆 JAK2 V617F mutation screen - definitive diagnosis. But a negative finding does not rule it out as around 5% of cases have other mutations.
- If JAK2 mutation is negative and no obvious secondary cause is found, the British Committee for Standards in Haematology (BCSH) suggest the following:
- Arterial oxygen saturation
- Abdominal ultrasound
- Bone marrow aspirate
- Cytogenetic analysis
- Erythroid burst-forming unit culture
💯 Criteria
The BCSH has some guidelines on the diagnostic criteria for polycythemia vera.
- For JAK2-positive PCV, 2 criteria need to be met:
- Mutation in JAK2
- Elevated haematocrit - >0.52 in men or >0.48 in women OR raised red cell mass (>25% of predicted).
- For JAK2-negative PCV requires 3 mandatory criteria + 1 other A-criteria OR 2 other B-criteria:
- Mandatory criteria
- Raised red cell mass (>25% of predicted) OR elevated haematocrit >0.6 in men or >0.56 in women.
- Absence of mutation in JAK2
- No cause of secondary erythrocytosis
- A-criteria
- Palpalble splenomegaly
- Acquired genetic abnormality in HSCs
- B-criteria
- Thrombocytosis (>450)
- Neutrophil count >10 in non-smokers and >12.5 in smokers
- Radiological evidence of splenomegaly
- Low serum EPO or endogenous erythroid colonies
🧰 Management
- Referral to haematology and secondary care management is necessary to ensure optimal management of the disease.
- PCV patients require annual follow-up.
- Manage CVD risks - such as hyperlipidaemia, diabetes, hypertension and smoking.
Low-intermediate thrombotic risk:
- 🥇Venesection - to reduce haematocrit to <0.45
- 🥇 Aspirin - 75mg OD
- CVD risk management
High thrombotic risk:
- Cytoreductive therapy - this is the mainstay of management in high-risk patients. It is used to reduce the number of RBCs.
- 🥇 Hydroxycarbamide - is the first-line option.
- 🥈 Ruxolitnib - a JAK1/JAK2 inhibitor. It is second-line after hydroxycarbamide.
- 🥈 Peginterferon alfa 2a - is an alternative second-line option to patients that are intolerant or resistant to hydroxycarbamide.
- 🥇 Aspirin - needs to be included.
- CVD risk management
Secondary polycythemia is the excess of RBC production due to excessive EPO.
The driver of excessive erythropoietin can be:
- Chronic hypoxia - seen in COPD, OSA, or high altitudes. Can be confirmed on an ABG or overnight oximetry (for OSA) or pulmonary function tests in underlying lung disease.
- Inappropriate secretion of EPO - seen in EPO-secreting tumours such as renal cell cancer, hepatocellular carcinoma, cerebellar haemangioblastoma, hypernephroma. To investigate this we should do abdominal CT, MRI or USS as well as brain MRI or CT without contrast.
It may also be caused by exogenous EPO which can be seen in testosterone therapy or due to iatrogenic causes.
This is a falsely elevated haemoglobin due to a low plasma volume which may be seen with stress, burns, diuretic use or in Gaisbock’s syndrome.
A pseudo-polycythaemia that is found in young male adults (especially those that smoke). It is associated with hypertension → controlled with diuretics → plasma volume depletion → pseudo polycythaemia due to raised haemoglobin concentration.
So how do we differentiate between absolute and relative polycythaemia?
Red cell mass studies are sometimes used to distinguish between the two. This tells us how many RBCs there are in the blood. Normal ranges for men are 30±5ml/kg and 25±5ml/kg in women.
- Absolute polycythaemia - total red cell mass >35ml/kg and >32ml/kg in women.