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Haematology

Polycythaemia/erythrocytosis

Last revised in September 2024

Erythrocytosis is an abnormally high haematocrit and haemoglobin concentration.

Polycythaemia/erythrocytosis: Summary

  • Erythrocytosis is an abnormally high haematocrit and haemoglobin concentration.
  • Absolute erythrocytosis occurs when there is an increase in the total number of red blood cells in the circulation (increased red-cell mass). This is classified as:
    • Primary erythrocytosis caused by polycythaemia vera, when the increased red-cell mass is caused by neoplastic proliferation of hematopoietic cells in the bone marrow. Thrombocytosis and leucocytosis may also occur with polycythaemia vera.
    • Secondary erythrocytosis, when the increased red-cell mass is caused by an increased production of erythropoietin. Most commonly erythropoietin is increased due to a physiological response to chronic tissue hypoxia caused by chronic lung disease. Inappropriate production of erythropoietin by the kidney can also occur with certain kidney disorders, renal tumours, and hepatomas.
    • Idiopathic erythrocytosis, when the increased red-cell mass has no identifiable cause.
  • Apparent erythrocytosis is defined as increased haematocrit and haemoglobin concentration with a normal red-cell mass. It is caused by a low plasma volume which most commonly occurs in people taking thiazide diuretics, and those who are heavy smokers or heavy alcohol users.
  • Erythrocytosis causes increased blood viscosity, leading to elevated risk of thrombosis and cardiovascular events. Other complications vary, depending on the type and underlying cause of polycythaemia:
    • Polycythaemia vera — the risk of haemorrhage may be increased, particularly in people with severe thrombocytosis. In a minority of people, the disease progresses to the myelofibrotic stage, where the bone marrow is replaced by dense fibrous bands of reticulin, and cytopenias are common. Rarely, progression to acute myeloid leukaemia occurs.
    • Secondary erythrocytosis — prognosis is dependent on the underlying condition.
  • To confirm a diagnosis of erythrocytosis, a blood sample (taken without a tourniquet, if possible) is required. An absolute erythrocytosis is defined as a haematocrit of more than 0.56 in women and more than 0.60 in men. Investigations may also be considered if there is an observed trend of increasing haematocrit.
  • Features which can differentiate the diagnosis include:
    • Specific clinical features of polycythaemia vera, such as generalized pruritus after bathing, splenomegaly, thrombocytosis, and neutrophil leucocytosis.
    • Presence of potential underlying causes of secondary erythrocytosis, such as chronic lung disease, cyanotic heart disease, or chronic renal disorders.
    • Presence of factors that raise suspicion for apparent erythrocytosis.
  • Additional tests that can confirm a diagnosis of polycythaemia vera include JAK2 V617F mutation testing, and measurement of erythropoietin levels (usually reduced in polycythaemia vera, often raised in secondary erythrocytosis).
  • If the person has suspected:
    • Apparent erythrocytosis — the underlying cause should be managed, where possible, and the haematocrit remeasured after two months to confirm a reduction.
    • Secondary erythrocytosis — referral to an appropriate specialist is usually required to manage the underlying cause. The haematocrit should be remeasured two months after the implementation of any measures to manage the underlying condition (such as oxygen therapy for hypoxic lung disease).
    • Polycythaemia vera — referral to a haematologist is recommended for consideration of treatment with aspirin; venesection; and in people at high risk of thrombosis, pharmacological cytoreduction.
  • Cardiovascular risk factors (including hyperlipidaemia, smoking, hypertension, and diabetes) should be managed for all people with erythrocytosis of any cause.

Have I got the right topic?

From age 18 years onwards.

This CKS topic covers the primary care management of adults with primary erythrocytosis caused by polycythaemia vera (also called polycythaemia rubra vera), secondary erythrocytosis, and apparent erythrocytosis.

This CKS topic does not cover in detail the treatments for polycythaemia vera as these will usually be arranged and performed in secondary care. 

There is a separate CKS topic on Haematological cancers - recognition and referral.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary healthcare.

How up-to-date is this topic?

Changes

September 2024 — minor update. Revised advice on management of apparent erythrocytosis to advise that these people need no further investigations. 

Previous changes

April 2023 — minor update. Typographical error corrected. 

January 2023 — reviewed. A literature search was conducted in November 2022 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. Minor updates were applied to the topic structure and up-to-date literature was incorporated to provide supporting evidence for the guidance. The clinical definition of erythrocytosis was updated to reflect the current British Society for Haematology guidance. No further major changes to the clinical recommendations have been made.

September 2020 — minor update. A link to a CCG guideline has been updated.

November 2017 to January 2018 — reviewed. A literature search was conducted in November 2017 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. The topic has undergone restructuring. No major changes to the recommendations have been made.

August 2012 — minor update. Minor typographical errors corrected.

April to July 2010 — this is a new CKS topic. The evidence-base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 November 2022.

HTAs (Health Technology Assessments)

No new HTAs since 1 November 2022.

Economic appraisals

No new economic appraisals relevant to England since 1 November 2022.

Systematic reviews and meta-analyses

No new systematic review or meta-analysis since 1 November 2022.

Primary evidence

No new primary evidence which reaches the CKS threshold for inclusion published since 1 November 2022.

New policies

No new national policies or guidelines since 1 November 2022.

New safety alerts

No new safety alerts since 1 November 2022.

Changes in product availability

  • Ruxolitinib for treating polycythaemia vera – NICE recommend ruxolitinib for polycythaemia vera in adults who cannot tolerate hydroxycarbamide (also called hydroxyurea) or when the condition is resistant to it. See more here.

Goals and outcome measures

Goals

To support primary healthcare professionals to:

  • Identify erythrocytosis (increased haematocrit and haemoglobin concentration).
  • Determine whether a person with erythrocytosis has polycythaemia vera, secondary erythrocytosis, or apparent erythrocytosis.
  • Treat the underlying cause of secondary erythrocytosis and apparent erythrocytosis, where possible.
  • Refer the person with erythrocytosis to a specialist, if appropriate.
  • Reduce the risk of thrombotic complications from polycythaemia vera, secondary erythrocytosis, or apparent erythrocytosis.

Outcome measures

No outcome measures were found during the review of this topic.

Audit criteria

No audit criteria were found during the review of this topic.

QOF indicators

No QOF indicators were found during the review of this topic.

QIPP - Options for local implementation

No QIPP indicators were found during the review of this topic.

NICE quality standards

No NICE quality standards were found during the review of this topic.

Background information

What is it?

  • Erythrocytosis is an abnormally high haematocrit and haemoglobin concentration.
    • Absolute erythrocytosis occurs when there is an increase in the total number of red blood cells in the circulation (increased red-cell mass). This is classified as:
      • Primary erythrocytosis caused by polycythaemia vera, when the increased red-cell mass is caused by neoplastic proliferation of hematopoietic cells in the bone marrow. Since these cells are capable of developing into platelets, red blood cells, and neutrophils, polycythaemia vera may also be accompanied by thrombocytosis, neutrophil leucocytosis, and splenomegaly. Approximately 95% of people with polycythaemia vera have a V617F mutation in exon 14 of the JAK2 gene, encoding Janus kinase, a regulator of myeloproliferation. A further 4% have mutations in exon 12 of JAK2, and the remaining 1% have other mutations including LNK mutations.
      • Secondary erythrocytosis, when the increased red-cell mass is caused by increased production of erythropoietin. Most commonly erythropoietin is increased due to a physiological response to chronic tissue hypoxia caused by chronic lung disease, such as chronic obstructive pulmonary disease. Inappropriate production of erythropoietin by the kidney can also occur with kidney disorders (such as renal artery stenosis), benign and malignant renal tumours, and hepatomas. Other causes include sleep apnoea, obesity-related hypoventilation, testosterone therapy or performance-enhancing drug use (anabolic steroids or erythropoietin), or hereditary genetic mutations affecting the oxygen-sensing pathway or haemoglobin oxygen affinity.
      • Idiopathic erythrocytosis, when the increased red-cell mass has no identifiable cause. Some people have a latent cause which becomes apparent in time. In other people, the condition resolves spontaneously.
    • Apparent erythrocytosis is defined as increased haematocrit and haemoglobin concentration with a normal red-cell mass. It is caused by a reduced plasma volume and most commonly occurs in people with a high body mass index, those taking diuretics, or people who are heavy smokers or heavy consumers of alcohol.

[Keohane, 2013; McMullin, 2019a; McMullin, 2019b; McMullin, 2019c; Mithoowani, 2020; Fox, 2021; Gangat, 2021; Palandri, 2021; BMJ Best Practice, 2022; White, 2022]

How common is it?

  • Apparent erythrocytosis is a common cause of increased haemoglobin and haematocrit concentrations in people who are heavy consumers of alcohol, smoke heavily, or use diuretics [Spivak, 2006]. CKS identified no studies to quantify the prevalence of apparent erythrocytosis.
  • Secondary erythrocytosis, caused by conditions such as chronic pulmonary or renal disease, is more common than polycythaemia vera [Stuart, 2004]. However, CKS identified no studies to quantify the prevalence of secondary erythrocytosis.
  • Polycythaemia vera is a rare condition.
    • Registry-based studies from the European Union suggest an incidence of between 0.4 and 2.8 per 100,000 people per year [Moulard et al, 2014].
    • A large study of US-based health plan data estimated a prevalence of 44 to 57 per 100,000 people [Mehta, 2014].
    • A large international study described a median age at presentation of 61 years for people diagnosed with polycythemia vera, with only 10% of diagnoses occurring in people aged less than 40 years [Tefferi, 2013].
    • Polycythemia vera is extremely rare in children [BMJ Best Practice, 2022].
    • Although several studies have described slightly lower risks of polycythemia vera in women [Palandri, 2021], the evidence does not consistently describe sex-related differences in the incidence of polycythemia vera [Titmarsh, 2014].

What are the risk factors?

  • Risk factors for polycythaemia vera include:
    • Advancing age — polycythaemia vera is rarely diagnosed before the age of 40 years, and the median age at diagnosis is 60 to 70 years.
    • History of Budd-Chiari syndrome — a number of people (usually young women) with idiopathic Budd-Chiari syndrome will eventually be shown to have polycythaemia vera, despite having initially normal blood counts.
    • Family history — in rare cases, a predisposition towards polycythaemia vera may be inherited.
  • Risk factors for secondary erythrocytosis include:
    • Generalized hypoxia — may be due to smoking, lung or cardiac disease, sleep apnoea, residing at high altitude, or carbon monoxide poisoning.
    • Localized renal hypoxia — may be due to renal artery stenosis, end-stage renal disease, hydronephrosis, polycystic kidney disease, or post-renal transplant erythrocytosis.
    • Pathological erythropoietin production — may be due to cerebellar haemangioblastoma, meningioma, parathyroid carcinoma or adenoma, hepatocellular carcinoma, renal cell carcinoma, pheochromocytoma, or uterine leiomyoma.
    • Exposure to certain drugs — such as diuretics, testosterone or anabolic steroids, or erythropoietin.
    • Genetic mutations which lead to upregulation of erythropoietin (rare) —  mutant forms of haemoglobin with an increased affinity for oxygen, and mutations that affect oxygen sensing leading to increased erythropoietin production.
  • Risk factors for apparent erythrocytosis include: 
    • Obesity.
    • Excess alcohol consumption.
    • Smoking.
    • Hypertension.

[Keohane, 2013; McMullin, 2019a; BMJ Best Practice, 2022; White, 2022]

What are the complications and prognosis?

  • Erythrocytosis leads to increased blood viscosity and elevated risk of thrombosis. A 34 year follow-up study of 5,209 men and women found that those with haematocrit values in the highest quintile had a statistically significant, approximately 2.7-fold increased risk of mortality due to cardiovascular disease compared to those with lower values.
  • For people with polycythaemia vera:
    • Overall, the risk of thrombosis is 1.6-fold higher than in the background population. Cardiovascular risk and mortality rate are increased accordingly.
      • Myocardial infarction, stroke, and deep vein thrombosis are the most common thrombotic events, and arterial thrombosis appears to be more common than venous thrombosis.
      • People below the age of 65 years with no history of thrombosis, and without other risk factors for cardiac disease such as hypertension, diabetes, hyperlipidaemia, or smoking, are considered to be at low thrombotic risk.
      • People below the age of 65 years, with no history of thrombosis, but who have traditional cardiac risk factors such as hypertension, diabetes, hyperlipidaemia, or smoking, are considered to be at intermediate risk.
      • People over the age of 65 years or those with any history of thrombosis are considered to be at high risk of thrombosis. 
      • Treatment with aspirin, venesection, and cytoreductive therapies significantly reduce these risks.
    • The risk of haemorrhage may also be increased, particularly in people with severe thrombocytosis.
    • Aquagenic pruritus is a common clinical feature of polycythemia vera, and may present in 31–69% of people with the condition.
      • Polycythaemia vera associated pruritus can have a significant impact on quality of life and personal hygiene, and can lead to people abandoning bathing completely.
    • People requiring cytoreductive therapy (usually those at high risk of thrombosis) are most often managed with hydroxycarbamide. Pancytopenia is the most common serious adverse drug reaction.
      • Risk may be mitigated with appropriate monitoring. 
      • Note: People with polycythaemia vera who develop cytopenias while receiving hydroxycarbamide treatment may be at increased risk of transformation to leukaemia and death.
    • Within 15 years of diagnosis, 6–15% will progress to the myelofibrotic stage where the bone marrow is replaced by dense fibrous bands of reticulin, and cytopenias are common.
    • Progression to acute myeloid leukaemia occurs in 5.5–18.7% within 15 years of diagnosis.
    • Age (60 to 67 years), leukocytosis (>15 x 109/L), and prior history of thrombosis are well-established prognostic risk factors that have been associated with increased risks of inferior survival and/or leukaemia.
    • SRSF2 gene mutation has also been associated with inferior survival.
  • For people with secondary erythrocytosis:
    • The prognosis is largely determined by the nature of any underlying condition.
  • For people with apparent erythrocytosis:
    • Evidence from small non-randomised studies indicates increased morbidity and mortality. However, it is unclear whether this is directly due to increased haematocrit values, or related to other factors.
    • There is no robust evidence that reducing the haematocrit reduces morbidity or mortality.

[Gagnon, 1994; Keohane, 2013; Alvarez-Larrán, 2016; Lelonek, 2018; McMullin, 2019a; McMullin, 2019b; Stuckey, 2021; Tefferi, 2021; BMJ Best Practice, 2022]

Diagnosis of polycythaemia/erythrocytosis

When should I suspect polycythaemia/erythrocytosis?

  • Be aware that erythrocytosis may be found incidentally as a result of a full blood count (FBC) taken from a person who has not reported symptoms. The full blood count should be repeated after a minimum of one week to see whether the rise is transient. Previous results should also be rechecked to determine whether the trend was previously present. 
  • Suspect erythrocytosis in people experiencing symptoms potentially caused by hyperviscosity, including:
    • Chest and abdominal pain.
    • Myalgia and weakness.
    • Fatigue.
    • Headache — may be described as a sense of 'fullness' in the head and neck, with dizziness, and/or perspiration.
    • Tinnitus.
    • Blurred vision, temporary loss of vision in one or both eyes.
    • Paresthesia.
    • Slow mentation, sense of depersonalisation.
  • Additional symptoms that may indicate polycythaemia vera as the cause of erythrocytosis include:
    • Bruising.
    • Pruritis, especially on contact with warm water.
    • Abdominal discomfort (relating to splenomegaly).
    • Insomnia. 
    • Vasomotor symptoms, particularly hot flushes, accompanying hyperhidrosis or night sweats.
    • Tenderness or painful burning and/or redness of fingers, palms, heels, or toes.
      • Note: 10–15% of people with polycythaemia vera are diagnosed following an acute thrombotic event, and 2–8% following major haemorrhage.
  • Take a full history:
    • Ask about/note factors which may indicate polycythaemia vera, including:
      • Age over 40 years.
      • Personal history of haemorrhage, thrombosis, or Budd-Chiari syndrome.
      • Family history of polycythaemia vera.
    • Ask about/note factors which may indicate apparent erythrocytosis, including:
      • Obesity.
      • Smoking. 
      • Alcohol excess.
      • Hypertension.
      • Use of thiazide diuretics.
    • Ask about/note factors which may underlie secondary erythrocytosis, such as:
      • Cardiac and respiratory symptoms or disease, smoking, and potential exposure to carbon monoxide.
      • Excessive daytime sleepiness, snoring, sleep disturbances, and observed night-time episodes of apnoea (particularly in people who are obese or with other respiratory conditions).
      • Previous renal transplantation.
      • Performance enhancing drug use (testosterone, anabolic steroids or erythropoietin).
  • Perform an examination:
    • Note whether there is a ruddy complexion (indicative of erythrocytosis).
    • Examine the eyes to assess whether conjunctival plethora (indicative of erythrocytosis) is present.
    • Palpate the abdomen to elicit:
      • Splenomegaly, which can be indicative of polycythaemia vera — however, bear in mind that a palpable spleen is present in only 40% of cases.
      • Abdominal masses. Benign and malignant uterine, renal, and hepatic tumours, which may be palpable, can secrete erythropoietin, leading to secondary erythrocytosis.
    • Examine the digits, measure oxygen saturation, and listen to the chest — clubbing of digits, oxygen saturation of less than 92% in room air, and/or abnormal heart or breath sounds may suggest secondary erythrocytosis caused by underlying cardiopulmonary disease.
    • Carry out urine dipstick analysis to identify possible renal causes of secondary erythrocytosis.
  • Consider differential diagnoses.
  • Take blood samples (without a tourniquet if possible) for haemoglobin, mean corpuscular volume (MCV), haematocrit, white blood cell count (WBCs), platelet count, liver function tests (LFTs), urea and electrolytes, and e-GFR.
    • The British Society for Haematology recommend that people with a persistently raised haematocrit (>0.52 in males and >0.48 in females), or with a raised red cell mass (>25% above predicted) should be investigated.
    • A significant proportion of people with these findings will have apparent erythrocytosis (where the red cell mass is normal but the plasma volume is reduced).
    • The results of these tests, alongside clinical judgement (based on noted signs and symptoms and the presence/absence of risk factors for apparent erythrocytosis), should; therefore, be used to determine which people require immediate additional testing. As a guide:
      • One-off values of elevated Hct (>0.6 in males and >0.56 in females) indicate an absolute erythrocytosis and require additional investigations.
      • Polycythaemia vera is suggested by raised white blood cell (leukocytosis) and platelet counts (thrombocytosis) in addition to a high haemoglobin and haematocrit. MCV is usually low in polycythaemia vera. LFTs are usually normal, but elevated values raise the possibility of Budd-Chiari syndrome. People exhibiting findings suggestive of polycythaemia vera should have additional investigations. 
      • Males with Hct greater than 0.52, and females with Hct greater than 0.48, with risk factors for apparent erythrocytosis or signs and symptoms suggestive of secondary erythrocytosis, and without signs or symptoms suggestive of polycythaemia vera, should be retested in two months following attempts to address apparent/secondary erythrocytosis. Repeat abnormal results should prompt additional investigations.
      • Secondary erythrocytosis may be suggested by abnormal LFTs, if there is a hepatic tumour. Abnormal renal function can indicate secondary erythrocytosis with an underlying renal cause.
      • Be aware that, in rare cases, a person (most commonly male) may present with 'masked' polycythaemia vera, where there is suggestive symptomatology or complications (such as unexplained thrombosis), but haemoglobin/haematocrit are clinically normal. In such cases, platelet counts are often elevated. Iron deficiency can also mask erythrocytosis — some cases of polycythaemia vera can therefore present with iron deficiency and a normal haemoglobin level.
  • Additional investigations that may be carried out to confirm, refute, and refine a diagnosis include:
    • Serum erythropoietin — increased serum erythropoietin suggests secondary erythrocytosis, while decreased levels suggest polycythaemia vera. Normal levels do not rule out polycythaemia vera.
    • Serum ferritin — to screen for iron deficiency if a low MCV is found. Can support a diagnosis of polycythaemia vera in people with suggestive signs or symptoms, but clinically normal haemoglobin.
    • JAK2 V617F mutation —  where this is positive in addition to a clear clinical history and haematological features it is considered definitive of polycythaemia vera. A negative finding does not rule it out, as around 5% of cases involve other mutations.
    • Serum uric acid (optional) — frequently elevated in polycythaemia vera.
    • Abdominal ultrasound — to detect splenomegaly (suggestive of polycythaemia vera) where physical examination is equivocal.

What else might it be?

The differential diagnosis of polycythaemia vera includes:

  • Essential thrombocythaemia (ET) — can be difficult to distinguish clinically from polycythaemia vera. Splenomegaly is infrequent, and JAK2 mutations are less common than in polycythemia vera. A normal erythropoietin, isolated thrombocytosis, and absence of elevated haemoglobin concentration are suggestive of essential thrombocytosis.
  • Chronic myelogenous leukaemia (CML) — may be clinically indistinguishable from polycythaemia vera; although, thrombosis is much less common with CML. Diagnosis is confirmed by screening for Philadelphia chromosome 9;22 translocation or its fusion protein product: BCR-ABL.
  • Congenital polycythaemia — an inherited condition which is present from birth, although symptoms may first develop during childhood or adulthood. Occurs due to a mutation in the genes encoding the erythropoietin receptor or proteins involved in the regulation of erythropoietin (EPOR, VHL, EGLN1, or EPAS1). Congenital polycythaemia can have different inheritance patterns depending on the affected gene.

[Mallik, 2021; Putter, 2021; BMJ Best Practice, 2022]

Basis for recommendation

The information on the diagnosis of erythrocytosis and polycythaemia vera is based on expert opinion in a British Society for Haematology Guideline for the diagnosis and management of polycythaemia vera [McMullin, 2019a], the BMJ Best Practice guideline Polycythaemia vera [BMJ Best Practice, 2022], an American Family Physician review article Polycythaemia vera: Rapid evidence review [Fox, 2021], the British Medical Journal (BMJ) review article The diagnosis and management of erythrocytosis [Keohane, 2013], an American Journal of Hematology review article Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management [Tefferi, 2020], and a Leukaemia journal review article Polycythemia vera: historical oversights, diagnostic details, and therapeutic views [Tefferi, 2021].

Interval for repeat blood tests

  • The recommendation that people with raised haematocrit with possible apparent erythrocytosis, or secondary erythrocytosis, and without signs or symptoms suggestive of polycythaemia vera should be retested within two months is based on expert opinion in the BMJ Best Practice guideline Polycythaemia vera [BMJ Best Practice, 2022] and the BMJ review article The diagnosis and management of erythrocytosis[Keohane, 2013], where the authors recommend testing several weeks later.

Management

Scenario: Management of polycythaemia/erythrocytosis

From age 18 years onwards.

How should I manage a person with erythrocytosis/polycythaemia?

  • If polycythaemia vera is suspected, and/or the person is experiencing symptoms of hyperviscosity, refer urgently to a haematologist for treatment.
  • Referral is also indicated for people testing negative for the JAK2 V617F mutation, with other features suggestive of a myeloproliferative disease, such as high platelets and/or white count, enlarged spleen, family history of myeloproliferative disease, previous history of thrombosis, and altered erythropoietin levels. Tests for uncommon JAK2 exon 12 mutations will be carried out to definitively confirm/refute polycythaemia vera. Tests for other rare congenital/familial polycythaemias may also be indicated.
  • Specialist advice should also be sought if there is any uncertainty regarding the diagnosis.
  • If apparent erythrocytosis is suspected:
    • Address factors that may lead to reduced plasma volume, including smoking, alcohol consumption, obesity, and hypertension. For further information, see the CKS topics on Smoking cessation, Alcohol - problem drinking, Obesity, and Hypertension.
    • If the person is taking a thiazide diuretic, consider switching to an alternative anti-hypertensive agent. For more information, see the CKS topic on Hypertension.
    • People with an apparent erythrocytosis required no further investigations. 
  • If secondary erythrocytosis is suspected and thought due to the use of performance-enhancing drugs:
    • Advise that the person avoids the use of performance-enhancing drugs such as erythropoietin, testosterone supplements, and anabolic steroids.
      • Blood sampling should be repeated two months after these measures are implemented, to determine whether the haematocrit has normalised. If not, further tests should be carried out to rule out other causes of secondary erythrocytosis and polycythaemia vera.
  • If secondary erythrocytosis is suspected and thought due to other causes, refer to an appropriate specialist to ensure optimal management of the underlying cause.
    • Refer people with elevated erythropoietin levels, without a chronic hypoxic disorder, to haematology to exclude an erythropoietin-secreting malignancy or other rare causes of secondary polycythaemia.
    • Refer people with suspected cyanotic heart disease to a cardiologist.
    • Refer people with suspected hypoxic lung disease to a respiratory physician if necessary, or manage in primary care if appropriate. Smoking cessation should be encouraged where applicable. For more information, see the CKS topics on Chronic obstructive pulmonary disease, and Smoking cessation.
    • Refer people with suspected sleep apnoea to a sleep clinic. For more information, see the CKS topic on Obstructive sleep apnoea syndrome.
    • Refer people with suspected renal disease to renal services.
      • Note: blood sampling should be repeated two months after any measures have been implemented to improve hypoxia (such as smoking cessation, supplemental oxygen, or continuous positive airway pressure [CPAP]) or to treat any other potentially causative conditions. If the haematocrit has not normalised, further investigation is necessary and a primary haematological disorder should be considered.
      • People with confirmed secondary erythrocytosis should receive regular blood tests to monitor haematocrit levels. The target haematocrit is usually 0.54. Where this monitoring occurs in primary care, referral for venesection should be considered for people with raised haematocrit.
  • For all people with polycythemia/erythrocytosis, manage cardiovascular disease risk factors, including hyperlipidaemia, diabetes, hypertension, and smoking. For further information, see the CKS topics on CVD risk assessment and management, Diabetes - type 2, Hypertension, and Smoking cessation.
    • Note: iron replacement should be used judiciously in people with erythrocytosis.
  • People with polycythaemia vera require annual follow-up, which can be done in primary care to detect the 2-8% who will transform to myelofibrosis or the 1-3% who will transform to acute myeloid leukaemia.
    • Features suggestive of myelofibrosis include:
      • Anaemia.
      • Sustained loss of requirement for either venesection (in the absence of cytoreductive therapy) or cytoreductive treatment for erythrocytosis.
      • A leukoerythroblastic peripheral blood picture.
      • Increasing splenomegaly, defined as either an increase in palpable splenomegaly of greater than, or equal to, 5 cm (distance of the tip of the spleen from the left costal margin), or the appearance of a newly palpable splenomegaly.
      • Development of at least one of three constitutional symptoms: greater than 10% weight loss in 6 months, night sweats, or unexplained fever (>37.5°C).
    • Cardiovascular risk should be assessed around the time of diagnosis and annually using a validated clinical risk assessment tool such as QRISK3.

Basis for recommendation

The information on management of erythrocytosis and polycythaemia vera is based on expert opinion in a British Society for Haematology guideline for the diagnosis and management of polycythaemia vera [McMullin, 2019a], the BMJ Best Practice guideline Polycythaemia vera [BMJ Best Practice, 2022], a Canadian Medical Association Journal (CMAJ) guideline Investigation and management of erythrocytosis [Mithoowani, 2020], the British Medical Journal (BMJ) review article The diagnosis and management of erythrocytosis [Keohane, 2013], and the Leukaemia journal review article Polycythemia vera: historical oversights, diagnostic details, and therapeutic views [Tefferi, 2021].

Management of erythrocytosis and iron deficiency
  • Iron deficiency may occur as a result of venesection. Whilst generally asymptomatic, symptoms such as restless legs, concentration problems, impaired cognitive function, dizziness, fatigue, and headaches may develop [McMullin, 2019a].
  • The recommendations to use iron replacement therapy judiciously is based on expert clinical experience that correcting iron deficiency in people with erythrocytosis can result in a rapid rise in the haematocrit, increasing the risk of thrombosis [McMullin, 2019a; BMJ Best Practice, 2022].
    • If systemic symptoms of iron deficiency present, a short trial of iron replacement, with careful monitoring, could be considered, but should only be undertaken by an experienced practitioner [BMJ Best Practice, 2022].
    • Alternatively, severe symptoms of iron deficiency may warrant an alternative approach to venesection, such as cytoreductive therapy [McMullin, 2019a].
Annual follow-up of people with polycythaemia vera
  • The recommendation that follow-up of people with polycythaemia vera can take place in primary care is based on expert opinion in the Oxfordshire Clinical Commissioning Group Hydroxycarbamide for myeloproliferative neoplasms (polycythaemia vera and essential thrombocythaemia) for patients within adult services Shared Care Protocol [Oxfordshire Clinical Commissioning Group, 2022]. In practice, whether follow-up occurs in primary or secondary care is likely to be directed by the haematologist, and will depend on local protocols.
  • The information on signs and symptoms of myelofibrosis is derived from the BMJ Best Practice guideline Polycythaemia vera [BMJ Best Practice, 2022].
  • Targeted assessment and management of cardiovascular risk factors, such as hypertension, hypercholesterolaemia, diabetes mellitus and smoking, is essential [McMullin, 2019a].
Management of secondary erythrocytosis as a consequence of testosterone treatment
  • Erythrocytosis is the most common dose-limiting adverse effect of testosterone treatment. An increase in haematocrit is usually observed within the first few months of testosterone treatment, and will typically return to baseline within one year of treatment cessation [White, 2022].
  • People with obstructive sleep apnea, advanced age, obesity, type II diabetes mellitus, elevated baseline hematocrit (>50%), or those living at high altitude are at increased risk of developing erythrocytosis whilst undergoing testosterone treatment [White, 2022].
  • Testosterone formulation, dose and pharmacokinetics may also influence erythrocytosis risk. It is hypothesised that an increased duration of supraphysiological testosterone levels results in an increased risk of erythrocytosis [White, 2022].
  • Short-acting intramuscular formulations are thought to present the highest risk, whilst extended-release injectable or transdermal options maintain physiological testosterone levels more effectively [White, 2022].
  • Specialist review of testosterone treatment is recommended when erythrocytosis is observed. Treatment options can include alterations of the formulation or dose of testosterone and therapeutic phlebotomy [White, 2022].

How is polycythaemia vera treated in secondary care?

  • The recommended management of all people with polycythaemia vera in secondary care includes:
    • An explanation of the risks and implications of the condition. A patient information leaflet, such as that provided by MacMillan Cancer Support, may be helpful.
    • Venesection to maintain the haematocrit at less than 0.45.
      • The volume of blood removed and frequency of venesection are adjusted depending on the person's size and tolerability to venesection.
      • Phlebotomy can result in iron deficiency which can induce symptoms of fatigue and impact cognition. However, iron supplementation is generally contraindicated as recurrent polycythaemia can emerge rapidly. A short trial of iron replacement with careful monitoring may be indicated for people who experience systemic symptoms of iron deficiency. This should only be undertaken by an experienced specialist in secondary care.
    • Prescription of aspirin 75 mg daily (unless this is contraindicated).
  • In addition, pharmacological cytoreductive therapy is recommended for people at high risk of thrombosis (people over the age of 60 years, or those with any history of thrombosis). The first-line drug is usually hydroxycarbamide, with interferon alfa or ruxolitinib as possible alternatives where hydroxycarbamide is contraindicated, not tolerated, or ineffective. Busulfan may be used in people with an advanced age or with a short life expectancy where hydroxycarbamide, interferon alfa, or ruxolitinib have not been tolerated.
    • Treatments are typically titrated over a course of several weeks to maintain the haematocrit at less than 0.45.
    • Hydroxycarbamide resistance is associated with a higher risk of disease transformation to leukaemia and death.
  • Pharmacological cytoreductive therapy may also be considered if:
    • White blood cell or platelet count is abnormally high.
    • Thrombosis or disease-related bleeding occurs.
    • There is evidence of disease progression, such as weight loss or night sweats.
    • Splenomegaly progresses or becomes symptomatic.
    • The need for venesection is frequent or persistent, or the person is poorly tolerant of venesection.
    • The person's symptom burden is too high, or where pruritis is severe despite treatment.
  • Alternative treatments may be offered to special populations such as pregnant women and children.
    • Polycythaemia vera is rare in pregnancy, and haematocrit concentrations may improve due to increases in the maternal plasma volume. Pregnant women at high risk of thrombosis may be treated with interferon alfa, while those at low risk may be managed by phlebotomy and low-dose aspirin alone.
    • Asymptomatic children at low risk of thrombosis may not receive cytoreductive or antithrombotic therapy owing to the risk of side effects. Children at high risk may be cautiously treated with low-dose aspirin (owing to the risk of Reye's syndrome in under 12s). Hydroxycarbamide and interferon alfa treatment is reserved for use in rare cases where other management options have been ineffective.
  • People with polycythemia vera will be closely monitored under the direction and supervision of a haematology specialist.
  • Aquagenic pruritus is a common clinical feature of polycythemia vera.
    • Where venesection or cytoreductive therapy has failed to control the symptoms, antihistamines may be considered, but evidence of efficacy is conflicting.
    • Other adjunctive treatments may include H2-receptor antagonists (ranitidine or cimetidine — for dual-histamine blockade), tricyclic antidepressants, selective serotonin reuptake inhibitors, and antiseizure medications such as gabapentin or pregabalin.

Basis for recommendation

The information on secondary care treatment of polycythaemia vera is based on expert opinion in the British Society for Haematology guideline for the diagnosis and management of polycythaemia vera [McMullin, 2019a], the British Society for Haematology Guideline guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis [McMullin, 2019b], the BMJ Best Practice guideline Polycythaemia vera [BMJ Best Practice, 2022], the European LeukemiaNet recommendations on the appropriate management of polycythaemia vera with cytoreductive drug therapy [Marchetti, 2022], an American Family Physician review article Polycythemia Vera: Rapid Evidence Review [Fox, 2021], and the Leukaemia journal review article Polycythemia vera: historical oversights, diagnostic details, and therapeutic views [Tefferi, 2021].

Treatment options for polycythaemia vera
  • No treatments have been shown to reduce the risk of transformation to leukemia or myelofibrosis [Fox, 2021].
  • An expert panel of 14 haematologists from seven countries has provided guidance on the use of cytoreductive medications in people with low-risk polycythaemia vera. The panel concluded that available evidence currently only supports the use of cytoreductive treatments in specific clinical sub-groups of those with low-risk disease [Marchetti, 2022]:
    • Recommended use in those reporting (i) poor tolerance to phlebotomy; (ii) symptomatic progressive splenomegaly where progression to myelofibrosis has been ruled out; and/or (iii) persistent leukocytosis.
    • Consider use in those reporting progressive and persistent leukocytosis, extreme thrombocytosis, or inadequate HC control with phlebotomy (i.e. ≥6 venesections per year).
    • A trial of cytoreductive treatment could be considered in those reporting a high symptom burden or severe itching.
    • High­ quality evidence supports the use of interferon alfa, rather than hydroxycarbamide, to attain haematocrit control and a molecular response in those with low-risk disease. Moderate ­quality evidence suggests that treatment with interferon alfa delays or reduces the risk of disease transformation into myelofibrosis and secondary malignancies compared with hydroxycarbamide.
      • As such, the expert panel recommended either pegylated or non­pegylated interferon alfa as cytoreductive drug therapy in patients younger than 60 years with polycythaemia vera. This was because their potentially longer lifespan might be associated with a higher cumulative incidence of secondary malignancies and myelofibrosis.
      • Hydroxycarbamide was confirmed to be the cytoreductive medication of choice for individuals older than 60 years.
  • There are several emerging treatment options for polycythaemia vera [Tefferi, 2021]:
    • Rusfertide is a hepcidin mimetic that restricts iron availability for red blood cell production, thereby recapitulating iron deficiency at the cellular level, without depleting iron stores.
    • Idasanutlin is a Mouse Double Minute 2 (MDM2) antagonist which stabilises TP53 activity by blocking its binding to MDM2 resulting in a restoration of P53 transcriptional activity. MDM2 expression is higher in people with PV than in healthy individuals, and preclinical studies have demonstrated that enhanced p53 activity and downstream mediators of this pathway can result in a depletion of JAK2-mutated myeloproliferative neoplasm cells [Mascarenhas, 2022].
    • Givinostat is a histone-deacetylase (HDAC) inhibitor that selectively targets JAK2-mutated myeloproliferative neoplasm cells.
  • Recommendations on the treatment of pruritus are provided in expert opinion articles [McMullin, 2019b; Tefferi, 2021].
Management of polycythaemia vera in pregnancy

As pregnancy is a prothrombotic state, pregnant women with polycythaemia vera are considered to be at increased risk of thromboembolism and haemorrhage, which carries an increased risk of obstetric complications, such as fetal loss, intrauterine growth restriction and prematurity [McMullin, 2019b]. Recommendations have been provided about the management of polycythaemia vera in pregnancy [McMullin, 2019b]:

  • Pregnant women with polycythaemia vera should be managed by a multidisciplinary team including an experienced obstetrician and haematologist.
  • The use of potentially teratogenic medications may need to be avoided.
    • Potentially teratogenic medications should ideally be discontinued prior to conception.
    • Unless there are patient-specific contraindications, all pregnant women with polycythaemia vera should receive low dose aspirin throughout pregnancy and the postpartum period.
    • Interferon may be considered for those requiring cytoreductive therapy in pregnancy.
  • The haematocrit should be closely monitored and kept within a gestational-appropriate range.

Supporting evidence

This CKS topic is largely based on recommendations and opinions provided in two British Society for Haematology guidelines for the diagnosis and management of polycythaemia vera [McMullin, 2019a] and the management of specific situations in polycythaemia vera and secondary erythrocytosis [McMullin, 2019b], the BMJ Best Practice guideline Polycythaemia vera [BMJ Best Practice, 2022], a Canadian Medical Association Journal (CMAJ) guideline Investigation and management of erythrocytosis [Mithoowani, 2020], the British Medical Journal (BMJ) review article The diagnosis and management of erythrocytosis [Keohane, 2013], an American Family Physician review article Polycythemia Vera: Rapid Evidence Review [Fox, 2021], and a Leukaemia journal review article Polycythemia vera: historical oversights, diagnostic details, and therapeutic views [Tefferi, 2021]. The recommendations relevant to primary care were developed from the expert opinion of the guideline development group or review authors following narrative reviews of the evidence, where available. The evidence for specialist management strategies is not discussed in detail as they are beyond the scope of this CKS topic.

How this topic was developed

This section briefly describes the processes used in developing and updating this topic. Further details on the full process can be found in the About Us section and on the Clarity Informatics website.

Search strategy

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of polycythaemia and polycythaemia vera, with additional searches for evidence in the following areas:

  • Diagnosis
  • Incidence/prevalence of polycythaemia vera
  • Primary and secondary causes of polycythaemia
  • Secondary care treatments
  • Risk of bleeding and thrombosis in polycythaemia and polycythaemia vera
  • Risk of myelofibrosis and leukaemia in people with polycythaemia vera
  • Prognosis of untreated polycythaemia vera and treated polycythaemia vera

Search dates

November 2017 - November 2022

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

  • exp Polycythemia/, polycythaemi*.tw, polycythemi*.tw., erythrocytosis.tw., erythrocytoses.tw.

Sources of guidelines

Sources of systematic reviews and meta-analyses

  • The Cochrane Library:
    • Systematic reviews
    • Protocols
    • Database of Abstracts of Reviews of Effects
  • Medline (with systematic review filter)
  • EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

Sources of randomized controlled trials

  • The Cochrane Library:
    • Central Register of Controlled Trials
  • Medline (with randomized controlled trial filter)
  • EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Sources of national policy

Patient experiences

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

  • Clinical accuracy.
  • Consistency with other providers of clinical knowledge for primary care.
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  • Usability.

Principles of the consultation process

  • The process is inclusive and any individual may participate.
  • To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
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  • Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
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  • Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
  • All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
  • All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

  • Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
  • Stakeholders identified from the following groups are invited to review draft topics:
    • Experts in the topic area.
    • Professional organizations and societies (for example, Royal Colleges).
    • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
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Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

  • Topic selection
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  • First draft internal review
  • Second draft internal review
  • External review
  • Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

  • Animal studies
  • Original research is not written in English

Possible exclusions for reviewed literature:

  • Sample size too small or study underpowered
  • Bias evident or promotional literature
  • Population not relevant
  • Intervention/treatment not relevant
  • Outcomes not relevant
  • Outcomes have no clear evidence of clinical effectiveness
  • Setting not relevant
  • Not relevant to UK
  • Incorrect study type
  • Review article
  • Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

  • Feasibility
    • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
  • Organizational and Financial Impact Analysis
  • Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
    • Eligible population
    • Current interventions
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    • Cost of the current or new intervention mix
    • Impact on other costs
    • Condition-related costs
    • In-direct costs and service impacts
    • Time dependencies
  • Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

  • Personal financial interests
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Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.

References

  • Alvarez-Larrán, A., Kerguelen, A., Hernández-Boluda, J.C., et al. (2016) Frequency and prognostic value of resistance/intolerance to hydroxycarbamide in 890 patients with polycythaemia vera. British Journal of Haematology 172(5), 786-793. [Abstract]
  • BMJ Best Practice (2022) Polycythaemia vera. BMJ Best Practice. https://bestpractice.bmj.com
  • Fox, S., Griffin, L. and Robinson Harris, D. (2021) Polycythemia Vera: Rapid Evidence Review. American Family Physician 103(11), 680-687. [Abstract] [Free Full-text]
  • Gagnon, D.R., Zhang, T.J., Brand, F.N. and Kannel, W.B. (1994) Hematocrit and the risk of cardiovascular disease-the Framingham study: a 34-year follow-up. American Heart Journal 127(3), 674-682. [Abstract]
  • Gangat, N., Szuber, N., Pardanani, A. and Tefferi, A. (2021) JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views. Leukemia 35(8), 2166-2181. [Abstract] [Free Full-text]
  • Keohane, C., McMullin, M.F. and Harrison, C. (2013) The diagnosis and management of erythrocytosis. BMJ 347, f6667. [Abstract]
  • Lelonek, E., Matusiak, Ł., Wróbel, T. and Szepietowski, J.C. (2018) Aquagenic Pruritus in Polycythemia Vera: Clinical Characteristics. Acta Dermato-Venereologica 98(5), 496-500. [Abstract]
  • Mallik, N., Das, R., Malhotra, P. and Sharma, P. (2021) Congenital erythrocytosis. European Journal of Haematology 107(1), 29-37. [Abstract]
  • Marchetti, M., Vannucchi, A.M., Griesshammer, M., et al. (2022) Appropriate management of polycythaemia vera with cytoreductive drug therapy: European LeukemiaNet 2021 recommendations. Lancet Haematology 9(4), e301-e311. [Abstract]
  • Mascarenhas, J., Passamonti, F., Burbury, K., et al. (2022) The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study. Blood Advances 6(4), 1162-1174. [Abstract] [Free Full-text]
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  • McMullin, M.F.F., Mead, A.J., Ali, S., et al. (2019b) A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis: A British Society for Haematology Guideline. British Journal of Haematology 184(2), 161-175. [Abstract] [Free Full-text]
  • McMullin, M.F. (2019c) Diagnostic workflow for hereditary erythrocytosis and thrombocytosis. Hematology the American Society of Hematology Education Program 2019(1), 391-396. [Abstract] [Free Full-text]
  • Mehta, J., Wang, H., Iqbal, S.U. and Mesa, R. (2014) Epidemiology of myeloproliferative neoplasms in the United State. Leukemia and Lymphoma 55(3), 595-600. [Abstract]
  • Mithoowani, S., Laureano, M., Crowther, M.A. and Hillis, C.M. (2020) Investigation and management of erythrocytosis. CMAJ 192(32), E913-E918. [Abstract] [Free Full-text]
  • Moulard O., Mehta J. and and Fryzek J,. et al (2014) Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol. 92(4), 289-297. [Abstract]
  • Oxfordshire Clinical Commissioning Group (2022) Hydroxycarbamide for myeloproliferative neoplasms (polycythaemia vera and essential thrombocythaemia) for patients within adult services Shared Care Protocol. ClinOx. http://oxccgportal.multi2.sitekit.net [Free Full-text]
  • Palandri, F., Mora, B., Gangat, N. and Catani, L. (2021) Is there a gender effect in polycythemia vera? Annals of Hematology 100(1), 11-25. [Abstract] [Free Full-text]
  • Putter, J.S. and Seghatchian, J. (2021) Polycythaemia vera: molecular genetics, diagnostics and therapeutics. Vox Sanguinis 116(6), 617-627. [Abstract]
  • Spivak, J.L. (2006) Erythrocytosis. In: Young, N.S., Gerson, S.L. and High, K.A. (Eds.) Clinical hematology. Pennsylvania: Mosby Elsevier, 1049-1059.
  • Stuart, B.J. and Viera, A.J. (2004) Polycythemia vera. American Family Physician 69(9), 2139-2144. [Abstract]
  • Stuckey, R. and Gómez-Casares, M.T. (2021) Recent Advances in the Use of Molecular Analyses to Inform the Diagnosis and Prognosis of Patients with Polycythaemia Vera. International Journal of Molecular Sciences 22(9), 5042-5067. [Abstract] [Free Full-text]
  • Tefferi, A., Rumi, E., Finazzi, G., et al. (2013) Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia 27(9), 1874-1881. [Abstract] [Free Full-text]
  • Tefferi, A. and Barbui, T. (2020) Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. American Journal of Hematology 95(12), 1599-1613. [Abstract] [Free Full-text]
  • Tefferi, A., Vannucchi, A.M. and Barbui, T. (2021) Polycythemia vera: historical oversights, diagnostic details, and therapeutic views. Leukemia 35(12), 3339-3351. [Abstract] [Free Full-text]
  • Titmarsh, G.J., Duncombe, A.S., McMullin, M.F., et al. (2014) How common are myeloproliferative neoplasms? A systematic review and meta-analysis. American Journal of Hematology 89(6), 581-587. [Abstract] [Free Full-text]
  • White, J., Petrella, F. and Ory, J. (2022) Testosterone therapy and secondary erythrocytosis. International Journal of Impotence Research 34(7), 693-697. [Abstract]
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