Polycythaemia Flashcards
Polycythaemia - Types
Polycythaemia may be relative, primary (polycythaemia rubra vera) or secondary
Polycythaemia - Relative Causes
Relative causes
dehydration
stress: Gaisbock syndrome
Polycythaemia - Primary Cause
= POLYCYTHAEMIA RUBRA VERA
Polycythaemia - Secondary Causes
Secondary causes COPD altitude obstructive sleep apnoea excessive erythropoietin: cerebellar haemangioma, hypernephroma, hepatoma, uterine fibroids*
*uterine fibroids may cause menorrhagia which in turn leads to blood loss - polycythaemia is rarely a clinical problem
Secondary Polycythaemia - Example Question
A 57 year old man presents to his General Practitioner with persistent headaches and blurred vision. The symptoms have been present over the past six months but have worsened in recent weeks. On close questioning, the patient also reported a feeling of general fatigue and intermittent muscle aches.
One year previously, the patient had been diagnosed with obstructive sleep apnoea secondary to morbid obesity and had been provided with non-invasive ventilation to use at night. However, the patient admitted that he rarely used this equipment due to a dislike for the tight face mask. Despite dietary and lifestyle advice the patient had gained 6 kg over the past year and had a BMI of 41 kg / m².
Neurological examination including fundoscopy was unremarkable. There were no tender or inflamed joints. Blood tests requested by the GP are detailed below.
Haemoglobin 19.5 g / dL White cell count 7.5 * 109/l Neutrophils 5.7 * 109/l Lymphocytes 0.9 * 109/l Platelets 195 * 109/l Packed cell volume 0.60 Urea 5.9 mmol / L Creatinine 110 µmol / L Sodium 135 mmol / L Potassium 4.1 mmol / L eGFR 68 ml / min
Review of a full blood count performed 4 months previously was remarkable for previously unnoticed elevated PCV of 0.56. The patient was urgently referred to haematology for further management.
What is appropriate treatment for this patient’s erythrocytosis?
Aspirin > Venesection Hydroxyurea Improved compliance with nocturnal non-invasive ventilation Referral to weight management service
This patient has a secondary erythrocytosis secondary to hypoxia associated with his obstructive sleep apnoea. He is presenting with significant symptoms of hyperviscosity and should be considered to be at significant risk of thrombotic complications.
Evidence from small case series suggests that erythrocytosis secondary to OSA should be treated with venesection in the presence of hyperviscosity symptoms or a PCV > 0.56. A target PCV of 0.50-0.52 has been shown to increase exercise tolerance.
Aspirin is the mainstay of treatment in polycythaemia rubra vera and cytoreductive treatments such as hydroxyurea are used in high risk cases.
While weight-loss and improved compliance with OSA treatment may improve erythrocytosis these interventions are likely to require significant time prior to yielding any symptomatic benefit.
Polycythaemia secondary to OSA
Evidence from small case series suggests that erythrocytosis secondary to OSA should be treated with venesection in the presence of hyperviscosity symptoms or a PCV > 0.56. A target PCV of 0.50-0.52 has been shown to increase exercise tolerance.
Polycythaemia Rubra Vera - Features
Polycythaemia vera (previously called polycythaemia rubra vera) is a myeloproliferative disorder caused by clonal proliferation of a marrow stem cell leading to an increase in red cell volume, often accompanied by overproduction of neutrophils and platelets. It has recently been established that a mutation in JAK2 is present in approximately 95% of patients with polycythaemia vera and this has resulted in significant changes to the diagnostic criteria. The incidence of polycythaemia vera peaks in the sixth decade.
Features hyperviscosity pruritus, typically after a hot bath splenomegaly haemorrhage (secondary to abnormal platelet function) plethoric appearance hypertension in a third of patients
NB: the discovery of the JAK2 mutation has made red cell mass a 2nd line Ix for patients with suspected PRV
Polycythaemia Rubra Vera - Diagnosis
Following history and examination, the British Committee for Standards in Haematology (BCSH) recommend the following tests are performed
full blood count/film (raised haematocrit; neutrophils, basophils, platelets raised in half of patients)
JAK2 mutation
serum ferritin
renal and liver function tests
If the JAK2 mutation is negative and there is no obvious secondary causes the BCSH suggest the following tests: red cell mass arterial oxygen saturation abdominal ultrasound serum erythropoietin level bone marrow aspirate and trephine cytogenetic analysis erythroid burst-forming unit (BFU-E) culture
The diagnostic criteria for polycythaemia vera have recently been updated by the BCSH. This replaces the previous polycythaemia vera Study Group criteria.
JAK2-positive polycythaemia vera - diagnosis requires both criteria to be present:
Criteria
1) A1 High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
2) A2 Mutation in JAK2
JAK2-negative PRV - diagnosis requires A1 + A2 + A3 + either another A or two B criteria:
Criteria
A1 Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in men, >0.56 in women
A2 Absence of mutation in JAK2
A3 No cause of secondary erythrocytosis
A4 Palpable splenomegaly
A5 Presence of an acquired genetic abnormality (excluding BCR-ABL) in the haematopoietic cells
B1 Thrombocytosis (platelet count >450 * 109/l)
B2 Neutrophil leucocytosis (neutrophil count > 10 * 109/l in non-smokers; > 12.5*109/l in smokers)
B3 Radiological evidence of splenomegaly
B4 Endogenous erythroid colonies or low serum erythropoietin
Polycythaemia Rubra Vera Diagnosis: Example Question
A 62 year old man had a routine set of blood tests performed by his General Practitioner. These demonstrated an erythrocytosis (Packed Cell Volume 0.56) but no other abnormality. Further questioning by the GP found that the patient had no symptoms of hyperviscosity, was a non-smoker with no symptoms of daytime somnolence and took no regular medications. Past medical history included only a left knee hemiarthroplasty performed due to osteoarthritis.
Two weeks after the initial blood test, the patient’s bloods were repeated and showed a persistence of the erythrocytosis. A referral to haematology clinic was made for further investigation. Details of further investigations arranged through haematology clinic are listed below.
Haemoglobin 18.8 g / dL White cell count 6.7 * 109/l Neutrophils 3.2 * 109/l Lymphocytes 2.1 * 109/l Monocytes 0.8 * 109/l Eosinophils 0.3 * 109/l Basophils 0.3 * 109/l Platelets 202 * 109/l Packed cell volume 0.59 Urea 4.5 mmol / L Creatinine 97 micromol / L Sodium 140 mmol / L Potassium 3.9 mmol / L eGFR 85 ml / min Ferritin 80 ng / ml Albumin 38 g / L Alkaline phosphatase 89 U / L ALT 25 U / L Bilirubin 20 micromol / L JAK 2 V617F mutation Negative Serum erythropoietin 0 U / L (reference 0-19)
Blood film: no abnormality detected; no features of myeloproliferative disease
Abdominal ultrasound: liver, hepatic duct system and gallbladder unremarkable; mild-moderate splenomegaly; kidneys and renal tract unremarkable
What is the most appropriate next investigation?
> JAK2 exon 12 mutation testing Bone marrow aspiration and trephine biopsy Measurement of red cell mass CT brain Erythropoietin receptor gene analysis
Erythrocytosis is defined as a haemoglobin > 18.5 g / dL or PCV > 0.52 (male) / 0.48 (female). Patient’s with a persistent erythrocytosis without clear cause (i.e. chronic hypoxia or drug causes) should be referred to haematology for further investigation. An urgent referral should be made if symptoms of hyperviscosity or polycythaemia (raised PCV, white cells and platelets) are present.
More than 95 % of individuals with polycythaemia vera test positive for the JAK 2 V617F mutation. Other baseline investigations include a blood film to exclude myeloproliferative disease, renal and liver profiles and serum ferritin (as iron deficiency can mask degree of erythrocytosis). Abdominal ultrasound is performed in patients with high suspicion for polycythaemia vera as this condition is associated with radiographical splenomegaly in two-thirds of cases.
A low serum erythropoietin is suggestive of primary bone marrow disease even in the absence of JAK 2 mutation and should prompt testing for the rarer exon 12 mutation of JAK 2. This test should be performed the more invasive bone marrow biopsy.
Raised serum erythropoietin should prompt investigation for an exogenous source, for example CT brain to look for a cerebellar haemangioma or meningioma.
In patients without a JAK 2 mutation and a normal erythropoietin level then measurement of red cell mass will distinguish between a true erythrocytosis and an apparent erythrocytosis (normal red cell mass but reduced plasma volume).
Rare congenital mutations in the erythropoietin receptor can also cause a primary erythrocytosis.
Polycthyaemia Rubra Vera - Diagnosis: Example Question
A 52-year-old male was seen in the rapid access Transient Ischaemic Attack (TIA) clinic. He presented to his GP with new onset left leg and arm weakness three days ago. The weakness lasted for 90 minutes and fully resolved with no residual defect. He had a past medical history of hypertension, obstructive sleep apnoea and a left sided deep vein thrombosis eight years ago. His medication comprised ramipril 5mg OD. He smoked ten cigarettes per day and did not drink alcohol.
On examination, he had obvious truncal obesity and a flushed complexion. Blood pressure was 128/82 mmHg, heart rate 78/min, respiratory rate 16/min and oxygen saturations 99% on air. Cardiovascular examination revealed a regular pulse and nil else of note. Respiratory and gastrointestinal examination were normal, though examination of the abdomen was somewhat limited by the presence of truncal obesity. Neurological examination was unremarkable with normal cranial nerve, fundoscopy and peripheral neurological examinations.
Initial investigations revealed the following results:
Hb 191 g/l MCV 98 fl Hct 0.523 Platelets 502 * 109/l WBC 14.0 * 109/l Neutrophils 86% Lymphocytes 10% Monocytes 4%
HbA1c 43 mmol/mol
Fasting cholesterol 5.6 mmol/l
ECG: 76bpm normal sinus rhythm no other abnormality
Chest x-ray: unremarkable
24 hr ECG: no arrhythmia seen
Echo: normal systolic function, mild aortic stenosis with pressure gradient of 42mmHg
CT head: normal intracranial appearances, no evidence of mass shift, space occupying lesion or haemorrhage
What is the most appropriate next investigation most likely to lead to the underlying diagnosis?
Cardiac catheterization > Testing for presence of JAK2 mutation Bone marrow biopsy Radioisotope scanning of circulating blood volumes MRI scanning of the abdomen
This gentleman has polycythaemia rubra vera (PRV). Whilst all of the above investigations may facilitate the diagnostic process, this question asks What is the most appropriate next investigation most likely to lead to the underlying diagnosis?. Testing for JAK2 mutation has widely surpassed the use of radioisotope scanning and is diagnostic of PRV. It is, therefore, the best option.
Pokycythaemia Rubra Vera - Mx and Prognosis
Polycythaemia vera is a myeloproliferative disorder caused by clonal proliferation of a marrow stem cell leading to an increase in red cell volume, often accompanied by overproduction of neutrophils and platelets. It has peak incidence in the sixth decade, with typical features including hyperviscosity, pruritus and splenomegaly
Management aspirin venesection - first line treatment hydroxyurea -slight increased risk of secondary leukaemia phosphorus-32 therapy
The mainstay of treatment of polycythaemia vera is aspirin and venesection. A target PCV < 0.45 has been shown to have a significantly lower rate of death from cardiovascular disease and major thrombosis than target PCV 0.45-0.50. Treatment with aspirin reduces the risk of non-fatal myocardial infarction, non-fatal stroke, pulmonary embolus, major venous thrombosis or death from cardiovascular cause compared to placebo. Aspirin does not increase the incidence of major bleeding episodes compared to placebo.
Prognosis
thrombotic events are a significant cause of morbidity and mortality
5-15% of patients progress to myelofibrosis
5-15% of patients progress to acute leukaemia (risk increased with chemotherapy treatment)
Polycthaemia Rubra Vera - Example Question
A 50 year old woman was referred to haematology clinic for management of a persistent erythrocytosis that had been monitored by her General Practitioner over the previous 6 months. The patient was asymptomatic and in particular reported no headaches or visual changes. Past medical history was remarkable only for internal fixation of a tibial fracture sustained in a car accident 5 years previously. There is no strong family history of venous thrombosis or ischaemic heart disease. The patient took no regular medications and worked as an accountant. She is a life-long non-smoker and drinks approximately 10 units of alcohol per week.
Following assessment at haematology, further investigations were requested as listed below.
Hb # g/dl
Platelets # * 109/l
WBC # * 109/l
Haemoglobin 18.7 g / dL White cell count 6.1* 109/l Neutrophils 3.5 * 109/l Lymphocytes 1.0 * 109/l Monocytes 0.7 * 109/l Eosinophils 0.4 * 109/l Basophils 0.5 * 109/l Platelets 276 * 109/l Packed cell volume 0.57 Urea 4.5 mmol / L Creatinine 95 micromol / L Sodium 142 mmol / L Potassium 4.5 mmol / L Ferritin 56 ng / mL Albumin 35 g / L Alkaline phosphatase 80 U / L ALT 20 U / L Bilirubin 18 micromol / L JAK 2 V617F mutation Postive Serum erythropoietin 3 U / L (reference 0-19)
Blood film: no abnormality detected
Abdominal ultrasound: liver, hepatic duct system and gallbladder unremarkable; mild-moderate splenomegaly; kidneys and renal tract unremarkable
What is the appropriate management for the patient’s erythrocytosis?
> Aspirin and venesection with target PCV < 0.45 Aspirin and venesection with target PCV 0.45-0.50 Aspirin Venesection with target PCV 0.45-0.50 Hydroxyurea
This patient has polycythemia vera as evidenced by the positive JAK 2 mutation, normal blood film, splenomegaly and low serum erythropoietin.
Management of polycythemia depends on the patient’s risk of thrombosis. This patient has a low risk of thrombosis based on her age, absence of cardiac risk factors, normal white cell and platelet count and absence of hyperviscosity symptoms.
The mainstay of treatment of polycythaemia vera is aspirin and venesection. A target PCV < 0.45 has been shown to have a significantly lower rate of death from cardiovascular disease and major thrombosis than target PCV 0.45-0.50. Treatment with aspirin reduces the risk of non-fatal myocardial infarction, non-fatal stroke, pulmonary embolus, major venous thrombosis or death from cardiovascular cause compared to placebo. Aspirin does not increase the incidence of major bleeding episodes compared to placebo.
Cytoreductive treatments such as hydroxyurea are used to treat high-risk polycythaemia vera.
Transformation of Polycythaema Rubra Vera
Around 5-15% progress to Myelofibrosis or AML
Polycythaemia Rubra Vera - FBC
Raised Hb Raised Haematocrit Raised Neutrophils Raised Basophils Platelet raised in half of patients
How to differentiate between true Polycthaemia (i.e. Primary and Secondary causes) and relative (i.e. Dehydration/Stress (Gaisbock syndrome) ?
Need Total Red Cell Mass
> 35mL/kg in Men
32mL/kg in Women
