Polycythaemia and myeloproliferative neoplasms

• Polycythaemia means too many red cells in the blood, judged by haemoglobin and haematocrit. It can be relative, from a shrunken plasma volume, or absolute, from true overproduction. Absolute cases divide into primary (polycythaemia vera and the other myeloproliferative neoplasms) and secondary (driven by erythropoietin). ^[1][2]
• Polycythaemia vera is a clonal myeloproliferative neoplasm in which an acquired JAK2 gene variant makes red cell precursors hypersensitive to erythropoietin. More than 95% of cases carry JAK2 V617F. Erythropoietin is low and the bone marrow shows trilineage proliferation with pleomorphic megakaryocytes. ^{[1][3] [2]}
• Secondary erythrocytosis is commoner. Its causes range from the physiological (high altitude, smoking, chronic lung disease, sleep apnoea) to hormonal (androgens, erythropoietin) and to tumours that secrete erythropoietin, most often renal cell carcinoma. ^[1][2]
• The main harm is thrombosis: arterial and venous, including in unusual sites such as the portal or hepatic veins. Every patient with polycythaemia vera should have therapeutic phlebotomy to keep the haematocrit below 45% and low-dose aspirin unless there is a contraindication. ^[1][4]
• Risk of thrombosis, not the red cell count alone, decides on cytoreduction with hydroxyurea, interferon or ruxolitinib. ^[1]

By the end of this page you should be able to:

1. Distinguish relative from absolute polycythaemia, and primary from secondary absolute erythrocytosis, and give common causes of each. ^[2][4]
2. Explain how JAK2 V617F drives the blood changes and symptoms of polycythaemia vera, including the role of erythropoietin. ^[1]
3. Recognise the presentation of polycythaemia vera, including the pruritic and microvascular features and the thrombotic complications. ^[1][4]
4. Apply the WHO 2022 diagnostic criteria and say when a bone marrow biopsy is and is not needed. ^{[1][3] [2]}
5. Outline the management of polycythaemia vera: phlebotomy target, aspirin, risk stratification and choices of cytoreductive therapy with dose, route and monitoring. ^[1]
6. Recognise complications, including transformation, and outline care in special situations and in low-resource settings. ^[1][4]

Relative polycythaemia (also called spurious polycythaemia) is a high haemoglobin with a normal red cell mass: the plasma volume is contracted, concentrating the red cells. It is usually transient, seen with dehydration, burns, or after diuretics, and it can be caused by chronic venous stasis ("stress" or "Gaisbock" erythrocytosis). ^[1][2]

Absolute polycythaemia is a true increase in red cell mass. It is then classified by erythropoietin behaviour: ^[2]

• Primary (low or inappropriately normal erythropoietin). The marrow proliferates semi-independently of erythropoietin. Polycythaemia vera is the principal example; it is a myeloproliferative neoplasm in which JAK2-mutant progenitors are hypersensitive to erythropoietin. True JAK2-wild-type primary erythrocytosis (congenital erythropoietin receptor mutations) is rare. ^[2][3]
• Secondary (normal or raised erythropoietin). The marrow is responding to appropriate or inappropriate erythropoietin. Causes are listed in the table below. ^[2][4]

Myeloproliferative neoplasms are clonal disorders of the haematopoietic stem cell. The classic Philadelphia-chromosome-negative group comprises polycythaemia vera, essential thrombocythaemia, primary myelofibrosis and chronic neutrophilic leukaemia, chronic eosinophilic leukaemia, juvenile myelomonocytic leukaemia and myeloproliferative neoplasm not otherwise specified. ^[3] The three commonest are contrasted here to place polycythaemia vera among them. ^[1][3]

Polycythaemia vera is uncommon. In the United States it is estimated to affect about 65,000 people with an annual incidence of 0.5 to 4 cases per 100,000 people. The median age at diagnosis is 61 to 65 years, with a slightly higher incidence in men (male to female incidence ratio 1.3 to 1.6). ^[1] Among 1,545 patients studied across seven international centres, median survival after diagnosis ranged from 14.1 to 27.6 years in the centres that had reached the median. ^{[1] [4]}

Erythrocytosis of any kind is much commoner than polycythaemia vera: about 3.4% of adults in a Dutch population cohort had erythrocytosis by WHO thresholds, most without a myeloproliferative neoplasm. ^[1] Worldwide, polycythaemia vera is far outnumbered by secondary erythrocytosis, particularly where smoking and chronic lung disease are common. ^[2]

There is no single modifiable risk factor for polycythaemia vera. It arises from an acquired JAK2 mutation in a haematopoietic stem cell; how that mutation is acquired is not fully known. Risk factors reported include tobacco smoking, exposure to ionising radiation and environmental exposures such as benzene, although most patients have no known toxic exposure. ^[1] About a five-fold increased risk of polycythaemia vera among first-degree relatives suggests an inherited predisposition. ^[1]

Secondary erythrocytosis results from erythropoietin-driven or other mechanisms. Its causes are many and are best grouped by whether erythropoietin is appropriately or inappropriately raised. ^[2][4]

Other rare or newly recognised causes include POEMS syndrome, TEMPI syndrome, post-renal transplant erythrocytosis, polycystic kidneys and numerous hereditary mutations affecting oxygen sensing or haemoglobin oxygen affinity. ^[2]

Polycythaemia vera begins with an acquired activating mutation of the tyrosine kinase JAK2, most often JAK2 V617F: a single-nucleotide change in exon 14 substitutes phenylalanine for valine at codon 617. ^[1] A minority of patients have mutations elsewhere in JAK2, often exon 12, and these usually present with isolated erythrocytosis without leukocytosis or thrombocytosis. ^[1]

The mutated JAK2 activates JAK-STAT signalling and makes erythroid precursors hypersensitive to erythropoietin. Because the mutation is present in a pluripotent stem cell, it can also produce leukocytosis and thrombocytosis. ^[1] Erythropoietin falls to low levels, yet red cell production continues: hence polycythaemia vera is defined as primary (low or inappropriately normal erythropoietin) rather than secondary. ^[1][2]

The clinical consequences follow from two facts: ^[1]

• Hyperviscosity. More red cells raise blood viscosity and predispose to thrombosis, cerebral sludging and transient visual or neurological symptoms.
• Clonal inflammation. The neoplastic cells release inflammatory mediators. Interleukin-6 and other cytokines explain the aquagenic pruritus, erythromelalgia, fatigue, gout from hyperuricaemia, and the raised white cell and platelet counts.

Bleeding can occur with extreme thrombocytosis, because high platelet counts are associated with acquired von Willebrand disease. ^[4]

Many patients are asymptomatic and polycythaemia is found on a routine blood count. When symptoms occur they come from three sources: hyperviscosity, inflammation and microvascular disturbance. ^[1]

• Hyperviscosity: headache, dizziness, tinnitus, mental sluggishness, visual disturbance, breathlessness on exertion.
• Aquagenic pruritus: intense itching or prickling triggered by water of any temperature, often after a warm bath. It affects roughly one third of patients at diagnosis and can be the feature that first points to polycythaemia vera. ^[1][4]
• Erythromelalgia: painful burning and redness of the distal extremities, in about 5.3% of patients, from platelet-mediated microvascular obstruction. ^[1]
• Gouty arthritis or renal colic: from hyperuricaemia due to high cell turnover. ^[4]
• Thrombotic events: about 16% of patients have an arterial thrombosis and 7% a venous thrombosis before or at the time of diagnosis. Arterial events include acute coronary syndrome (8.3%) and cerebrovascular events (7.7%); venous events include deep vein thrombosis (4.2%) and pulmonary embolism (2.0%). Venous thrombosis may occur at unusual sites, especially the splanchnic veins (hepatic vein, causing Budd-Chiari syndrome, or portal vein) and the cerebral venous sinuses. ^[1][4]
• Constitutional symptoms: fatigue, night sweats, weight loss, though these are more typical of myelofibrosis.
• Bleeding tendency: epistaxis or gastrointestinal bleeding in some patients, especially with extreme thrombocytosis. ^[1][4]

• Plethora and rubor: a florid colour of face, conjunctivae, palms and nail beds from the high red cell count.
• Splenomegaly: present in about 36% of patients; may cause left upper quadrant discomfort, early satiety or a dragging sensation. ^[1]
• Hepatomegaly may coexist.
• Hypertension: common associated finding.
• Gouty tophi or urate deposits.
• Signs of thrombosis or its residues, and of acquired von Willebrand bleeding. ^[4]
• Retinal vein engorgement may be seen on fundoscopy and is a clue in younger patients. ^[2]

The differential has two parts: when an elevated haemoglobin is found, decide relative, secondary or primary; and when a specific myeloproliferative neoplasm is suspected, tell polycythaemia vera apart from its mimics. ^[1][4]

• Full blood count with differential and haematocrit. In polycythaemia vera the haemoglobin is above 16.5 g/dL in men or 16.0 g/dL in women (or haematocrit above 49% and 48%) and is accompanied by thrombocytosis in about half (53%) and leukocytosis in 49%. ^{[1] [2]}
• Serum erythropoietin. Low or inappropriately normal in polycythaemia vera; normal or raised in secondary erythrocytosis. It is a minor criterion. ^[1][2]
• JAK2 V617F mutation analysis on peripheral blood. Present in over 95% of polycythaemia vera. Screening for JAK2 exon 12 mutations follows a negative V617F result when suspicion remains, because these occur in JAK2-negative patients. ^[1][2]
• Iron studies. Iron deficiency is common from repeated phlebotomy or from the disease itself and lowers the measured haemoglobin, which can mask erythrocytosis ("masked polycythaemia vera"). ^[2]

• Bone marrow trephine and aspirate. WHO major criterion: hypercellularity for age with trilineage (panmyeloid) proliferation and pleomorphic mature megakaryocytes, sometimes with associated fibrosis. It is recommended for most patients, but is not always required (see criteria below). ^[1][3]
• Urine and renal imaging when renal cell carcinoma is suspected: renal masses are the commonest EPO-secreting tumour. ^[2]
• Cardiovascular and pulmonary assessment for hypoxic causes: oxygen saturation, spirometry, sleep studies, cardiac imaging. ^[2]
• Karyotype and an NGS panel for high-risk mutations (ASXL1, SRSF2, IDH2) in patients where prognosis or treatment choice depends on them. ^[1][3]
• Screening for thrombophilia is not routine but is considered in unusual-site thrombosis. ^[4]

• A JAK2 mutation with low erythropoietin makes polycythaemia vera very likely. ^[1]
• A negative JAK2 test with a low or normal erythropoietin in someone with secondary causes excluded does not exclude polycythaemia vera: up to 2% of cases are diagnosed on erythrocytosis plus a low erythropoietin level and exclusion of secondary and hereditary causes. ^[1]
• Splanchnic (and some cerebral) thrombosis provokes work-up for an underlying myeloproliferative neoplasm even when the blood count is normal, because haemodilution and iron deficiency can hide the erythrocytosis. ^[4]
• Erythrocytosis in about 3.4% of adults is usually reactive; severe erythrocytosis with leukocytosis or thrombocytosis is the group more likely to harbour a JAK2 variant (about 15.6% in a Dutch subgroup). ^[1]

The WHO (5th edition) and International Consensus Criteria last updated their diagnostic criteria in 2022. ^[1][2] For polycythaemia vera they require erythrocytosis, a major criterion in its own right, together with a JAK2 mutation and, in most cases, characteristic marrow findings. ^[1][3]

Major criteria: ^[1][3]

1. Haemoglobin above 16.5 g/dL in men or 16.0 g/dL in women, or haematocrit above 49% in men and 48% in women, or (in older practice) increased red cell mass. The WHO 5th edition no longer requires 51Cr red cell mass since it is rarely used. ^[3]
2. Bone marrow showing hypercellularity for age with trilineage (panmyeloid) proliferation and pleomorphic mature megakaryocytes. ^[1][3]
3. Presence of JAK2 V617F or a JAK2 exon 12 mutation. ^[1][3]

Minor criterion: ^[1]

• Subnormal serum erythropoietin level.

Diagnosis is made by all three major criteria, or by the first two major criteria together with the minor criterion. A bone marrow biopsy is recommended for most patients, but it may be omitted when both of the following apply: haemoglobin above 18.5 g/dL in men or 16.5 g/dL in women (the older 2008 thresholds) and a JAK2 mutation. Even so, biopsy is worthwhile when it changes management because it establishes the baseline marrow state and can identify fibrosis at presentation, which predicts progression. ^[1]

Risk stratification for thrombosis drives treatment. By National Comprehensive Cancer Network and European LeukemiaNet definitions: ^[1]

• High-risk: age 60 years or older, or prior arterial or venous thrombosis. ^[1]
• Low-risk: 60 years or younger without prior thrombosis. ^[1]

Leukocytosis (white cell count above 11 x 10^9/L) was associated with thrombosis in a prospective cohort (hazard ratio 2.35), and haematocrit above 45% carried a hazard ratio of 1.84. The JAK2 V617F allele burden carries further prognostic information: an allele burden of at least 50% was associated with more venous thrombosis (14.5% versus 2.4%) and with progression to myelofibrosis (10.5% versus 1.2%). ^[1]

The goals of treatment are to prevent thrombosis and bleeding, control symptoms and splenomegaly, and slow transformation to myelofibrosis or acute leukaemia, while keeping treatment burden acceptable. None of this is curative except allogeneic stem cell transplantation, which is reserved for transformed disease. ^[1][4]

1. Therapeutic phlebotomy to maintain haematocrit below 45% in both men and women. This is the single most important intervention: in the CYTO-PV trial, patients kept below 45% had a primary endpoint (cardiovascular death or major thrombosis) of 2.7% versus 9.8% in those kept between 45% and 50% (p=0.007). Phlebotomy is usually started at 250 to 500 mL every other day or twice weekly until the target is reached, then as required, often every 6 to 12 weeks. Each procedure removes roughly one unit. ^[1][4]
2. Low-dose aspirin 75 to 100 mg daily, unless there is a contraindication such as active bleeding, extreme thrombocytosis with acquired von Willebrand disease, or concurrent anticoagulation. A randomised trial of aspirin 100 mg daily reduced a composite of nonfatal myocardial infarction, nonfatal stroke, venous thromboembolism and cardiovascular death from 7.9% to 3.2%. Aspirin is typically withheld when therapeutic anticoagulation is started because combined therapy increases bleeding. ^[1][4]
3. Control vascular risk factors: blood pressure, lipids, smoking, diabetes. QRISK or equivalent should be assessed at baseline and annually. ^[4]
4. Avoid dehydration, which raises haematocrit. Iron supplementation should not be given routinely, though severe iron deficiency from phlebotomy can worsen pruritus. ^[4]

Cytoreduction is indicated for high-risk patients (age 60 or older, prior thrombosis) and for low-risk patients with persistent symptoms, troublesome pruritus, splenomegaly, markedly rising counts, or progressive leukocytosis or thrombocytosis despite phlebotomy and aspirin. ^[1] Choice between agents is individualised against patient goals and side effects. ^[1]

Table of cytoreductive options (typical adult doses are from current reviews; check your local formulary): ^[1]

Patients on cytoreductive therapy continue aspirin and phlebotomy with a haematocrit below 45%. ^[1]

Hydroxyurea intolerance or resistance develops in about 15% of patients and is defined as any of: need for phlebotomy to keep haematocrit below 45% after three months at at least 2000 mg per day; platelet count above 400 x 10^9/L; white cell count above 10 x 10^9/L; failure to relieve splenomegaly-related symptoms after three months at at least 2000 mg per day; or cytopenias at the lowest dose needed for a complete haematologic response (haematocrit below 45%, platelet count below 400 x 10^9/L, white cells below 10 x 10^9/L). Such patients should move to interferon or ruxolitinib. ^[1]

Interferons are uptitrated over months. Avoid in depression, anxiety and severe untreated autoimmune disease such as rheumatoid arthritis or lupus. Pegylated interferon alfa-2a has demonstrated safety in pregnant patients. ^[1][4]

Ruxolitinib is the standard second-line agent. In a randomised trial in hydroxyurea-resistant or -intolerant patients, hematocrit control was achieved in 60% and spleen volume reduction of at least 35% in 38%, with major symptom improvement in 49%. A later trial showed improved event-free survival (major thrombosis, haemorrhage, transformation, death) with ruxolitinib (hazard ratio 0.58), largely from fewer thrombotic events, and higher mutational responses. ^[1]

NCCN/European LeukemiaNet guidance allows cytoreduction for low-risk patients with persistent leukocytosis or thrombocytosis, though the thresholds to start and the thrombosis benefit are not fully established for those indications alone. ^[1] For low-risk patients troubled by symptoms, a randomised study found interferon with phlebotomy improved haematocrit control (81.3% versus 59.7%) and reduced disease progression compared with phlebotomy alone over 12 months, at the cost of more adverse events. ^[1]

Thrombosis (arterial or venous). Acute events are treated by standard guidelines (for example thrombolysis or anticoagulation as indicated) and counts are brought to target urgently, including phlebotomy to below 45%. For venous thromboembolism low-molecular-weight heparin followed by vitamin K antagonists is standard; direct oral anticoagulants are increasingly used but evidence in myeloproliferative neoplasms is limited. Indefinite anticoagulation is recommended for unprovoked venous thromboembolism because recurrence risk persists. Recurrent thrombosis calls for review of count control. ^{[4] [1]}

Splanchnic and cerebral vein thrombosis. These occur at unusually high rates in myeloproliferative neoplasms, more often in younger patients with the JAK2 mutation. The presenting blood count may be normal through haemodilution and iron deficiency, so every patient with unexplained splanchnic thrombosis must be tested for JAK2 V617F (and CALR if negative). Management is multidisciplinary: acute anticoagulation with low-molecular-weight heparin, vascular or interventional procedures where indicated, cytoreduction and long-term anticoagulation. Specialist hepatology and radiology input is needed. ^[4]

Surgery. Polycythaemia vera patients have increased bleeding and thrombosis around operations. Pre-operative planning should involve a haematologist to optimise counts; screen for acquired von Willebrand disease and platelet function abnormalities if there is a bleeding history; use standard thromboprophylaxis. Haematocrit below 45% should be documented before elective surgery. ^[4]

Pregnancy. Polycythaemia vera in women of reproductive age is very rare. Pregnancy is managed jointly by an obstetrician and haematologist, with pre-conception planning. Hydroxyurea and anagrelide are stopped at least three months before conception and in the first trimester; interferon is the cytoreductive choice if needed. Low-dose aspirin is given throughout pregnancy and the puerperium, with prophylactic low-molecular-weight heparin added for six weeks postpartum (longer and at higher dose for high-risk pregnancies). Haematocrit is kept in the gestational normal range by phlebotomy. ^[4]

Pruritus. Aquagenic pruritus can be severe and resistant. It may improve with count control by phlebotomy, with hydroxyurea or interferon, with iron replacement if severely iron depleted, and with antihistamines (often high doses, sometimes H1 and H2 blockade), selective serotonin reuptake inhibitors, anticonvulsants (gabapentin, pregabalin), or ultraviolet therapy under a dermatologist. Ruxolitinib is effective when pruritus fails hydroxyurea or interferon. ^[4] Iron replacement must be done cautiously with close monitoring of counts. ^[4]

Haemorrhage. Bleeding, usually mucocutaneous or gastrointestinal, occurs in some patients, contributed to by extreme thrombocytosis (platelet count above 1500 x 10^9/L) and acquired von Willebrand syndrome (reported in 12% of patients with high platelet counts). Counts should be optimised; screen for acquired von Willebrand syndrome if bleeding occurs; manage significant bleeds with tranexamic acid and/or platelets. ^[4]

• Thrombosis, the dominant complication: arterial (acute coronary syndrome, stroke, peripheral vascular disease) and venous (deep vein thrombosis, pulmonary embolism, splanchnic and cerebral venous). ^[1][4]
• Bleeding, principally with extreme thrombocytosis or concurrent anticoagulation. ^[4]
• Progression to myelofibrosis: about 12.7% over roughly 12 years; heralded by increasing splenomegaly, anaemia, teardrop cells, rising JAK2 allele burden and mutations such as SRSF2. Median survival after transformation is about 8 years. ^[1]
• Transformation to acute myeloid leukaemia: about 6.7% over long follow-up. ^[1]
• Post-polycythaemia vera myelofibrosis and leukaemic transformation are associated with persistent leukocytosis, JAK2 allele burden of at least 50%, and adverse mutations. ^[1]
• Symptom burden: pruritus, erythromelalgia, fatigue and reduced quality of life persist for some patients despite controlled counts. ^[1][4]

Polycythaemia vera is compatible with a long life: median survival 14.1 to 27.6 years after diagnosis in large cohorts, and not significantly different from age- and sex-matched population in at least one large analysis (p=0.14). ^[1] Patients diagnosed under 40 years of age have a median overall survival of about 37 years. ^[1]

Factors associated with reduced survival: age 67 or older (hazard ratio 8.5), white cell count of at least 15 x 10^9/L (hazard ratio 2.2) and prior venous thrombosis (hazard ratio 1.8). ^[1] Mutations in SRSF2 were associated with much higher hazard ratios (13.3). ^[1] JAK2 allele burden of at least 50% increased the risk of venous thrombosis and of progression to myelofibrosis. ^[1]

Risk of thrombosis is highest close to diagnosis; nonetheless a raised haematocrit above 45% and leukocytosis continue to identify higher event rates. ^[1]

There is no population screening for polycythaemia vera and no primary prevention. ^[1] Useful strategies include:

• Smoking cessation, which is the single most important modifiable contributor to secondary erythrocytosis and cardiovascular risk. ^[2][4]
• Annual haemoglobin and haematocrit in patients on androgen therapy or SGLT2 inhibitors (canagliflozin, empagliflozin, dapagliflozin, ertugliflozin), which cause drug-induced erythrocytosis in 3% to 37% and 5% to 66% respectively. ^[2]
• Careful evaluation of any unexplained thrombosis, particularly splanchnic or cerebral venous, for an underlying myeloproliferative neoplasm. ^[4]
• Recognition that polycythaemia vera carries familial clustering (five-fold risk in first-degree relatives) supports family awareness, although routine screening of relatives is not recommended. ^[1]

Children. Polycythaemia vera is rare in children; this is a diagnosis that in young people should prompt testing for secondary and hereditary causes, congenital erythrocytosis and the commoner childhood problems of relative erythrocytosis. ^[2]

Older adults. Older age (60 or above, and especially 67 or above) is the major risk factor for thrombosis and for reduced survival. Frailty, renal function and bleeding risk modify cytoreductive and anticoagulant choices. ^[1][4]

Pregnancy and fertility. See management above. Hydroxyurea and anagrelide are teratogenic in animal models and avoided around conception; interferon is the cytoreductive agent of choice. ^[1][4]

Immunocompromised or co-morbid patients. Ruxolitinib carries an increased risk of herpes zoster (about 4%) and non-melanoma skin cancer; recombinant zoster vaccination is recommended before starting. Hydroxyurea increases non-melanoma skin cancer risk with long-term use. ^[1]

In settings without EPO assays, JAK2 mutation testing or marrow facilities, a pragmatic pathway is still possible: ^[1][2][4]

• Confirm absolute erythrocytosis on repeated counts and after correcting dehydration. A very high haematocrit (for example above 55%) with normal or low MCV and no secondary cause is highly suggestive.
• Treat secondary causes first and most cheaply: stop smoking, treat chronic lung disease and sleep apnoea, review androgens, SGLT2 inhibitors and exogenous erythropoietin, and consider high altitude.
• Phlebotomy is universally available and is the cornerstone. Start every confirmed patient on phlebotomy to below 45% (or, if testing is unavailable, to symptom relief and a haematocrit in the low-to-mid 40s) and on low-cost aspirin 75 to 100 mg daily unless contraindicated. Ruxolitinib may not be available; hydroxyurea is cheap and generic.
• A left upper quadrant mass and unexplained thrombosis in a person with erythrocytosis point toward polycythaemia vera even without a JAK2 result; hepatosplenomegaly from myelofibrosis is a later clue.
• In unusual-site thrombosis, anticoagulation and cytoreduction with whatever is available should not wait for specialist testing, once secondary causes are reasonably excluded.
• Defer expensive mutation panels to regional or referral centres. Iron deficiency and dehydration complicate interpretation; check iron studies where possible before phlebotomy.
• Pregnancy in a woman suspected of polycythaemia vera should be managed with experienced obstetric and haematological input; interferon is often unavailable, so phlebotomy and aspirin remain central.

• Polycythaemia is relative (contracted plasma volume) or absolute (true red cell overproduction). Absolute cases are primary (polycythaemia vera and other myeloproliferative neoplasms, low or inappropriately normal erythropoietin) or secondary (erythropoietin-driven). ^[1][2]
• Polycythaemia vera is defined by erythrocytosis (men above 16.5 g/dL or 49%; women above 16.0 g/dL or 48%), a JAK2 mutation, and panmyeloid marrow with pleomorphic megakaryocytes; subnormal erythropoietin is the minor criterion. ^[1][3]
• JAK2 V617F is present in over 95% of cases. Low erythropoietin plus a JAK2 mutation distinguishes polycythaemia vera from secondary erythrocytosis. ^[1]
• Secondary causes include hypoxia (smoking, COPD, sleep apnoea, high altitude, congenital heart disease), renal artery stenosis, EPO-secreting tumours (renal cell carcinoma commonest), and drugs (androgens, testosterone, erythropoietin, SGLT2 inhibitors). ^[2]
• Presentation includes plethora, pruritus after bathing (about one third), erythromelalgia (5%), splenomegaly (36%), thrombosis (16% arterial, 7% venous before diagnosis), bleeding, hyperuricaemia and fatigue. ^[1]
• WHO 2022 criteria: all three major, or first two plus the minor; bone marrow may be omitted when haemoglobin is very high and JAK2 is positive. ^[1]
• All patients: phlebotomy to haematocrit below 45% and low-dose aspirin 75 to 100 mg daily unless contraindicated; control vascular risk factors. ^[1][4]
• High-risk patients (age 60 or above, prior thrombosis) and symptomatic low-risk patients need cytoreduction: hydroxyurea (500 mg twice daily, titrated), interferons (pegylated weekly or ropeginterferon two-weekly) or ruxolitinib (10 mg twice daily) second line after intolerance or resistance. ^[1]
• Complications: thrombosis, bleeding (extreme thrombocytosis), progression to myelofibrosis (about 12.7%) and acute myeloid leukaemia (about 6.7%); median survival 14 to 28 years. ^[1]
• Secondary erythrocytosis is treated by correcting the cause; cytoreduction is not used and phlebotomy is reserved for symptoms, with higher haematocrit targets than in polycythaemia vera. ^[2][4]
• Special situations (pregnancy, surgery, splanchnic thrombosis, pruritus) and low-resource settings need individualised practice and multidisciplinary care. ^[4]

Hematology-oncology hub; myelofibrosis; essential thrombocythaemia; secondary erythrocytosis; thrombosis and thrombophilia; anticoagulation; pregnancy in haematological disease; JAK inhibitors.