Polycythaemia vera

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

PV is an acquired JAK2-driven myeloproliferative neoplasm. Sustained haemoglobin or haematocrit elevation is the entry point, but diagnosis integrates mutation, erythropoietin, marrow panmyelosis and exclusion of secondary causes. JAK2 V617F is present in most cases; exon 12 mutations account for many remaining cases. A normal oxygen saturation does not exclude smoking-related carbon monoxide or sleep apnoea, and a normal-range haemoglobin can conceal PV when iron deficiency produces small cells or splanchnic thrombosis causes haemodilution.

Risk management separates disease control from symptom control. Every suitable adult receives haematocrit control below 0.45, cardiovascular risk treatment and low-dose aspirin. Venesection is usually first-line haematocrit control. Cytoreduction is added for high thrombotic risk and considered for poor venesection tolerance, progressive counts or spleen, severe symptoms and other specialist indications. Hydroxycarbamide is effective and familiar; pegylated interferon can produce molecular responses and is preferred when pregnancy is possible or long-term reproductive toxicity matters.

Acute thrombosis receives standard site-specific anticoagulation or antiplatelet care plus rapid haematocrit control and cytoreduction. Splanchnic thrombosis needs specialist duration and bleeding assessment because portal hypertension and varices coexist with recurrence risk. Aspirin may be unsafe with active bleeding or acquired VWD. Extreme platelets can paradoxically reduce high-molecular-weight von Willebrand multimers; test before aspirin when bleeding history or an extreme count raises concern.

Follow-up looks for both control and evolution. Haematocrit is the principal therapeutic target, but leukocytes, platelets, symptoms, spleen and treatment toxicity matter. New anaemia is not automatically iron deficiency: post-PV myelofibrosis causes leucoerythroblastosis, constitutional symptoms and splenic growth. Hydroxycarbamide requires skin and blood monitoring; interferon requires psychiatric, autoimmune, hepatic and reproductive review. Pregnancy is jointly managed with obstetric haematology using aspirin, venesection, interferon and LMWH according to maternal risk.

Key points

Suspect PV with sustained erythrocytosis plus leucocytosis, thrombocytosis, splenomegaly, aquagenic pruritus, erythromelalgia or unusual-site thrombosis.
First-line assessment is repeat FBC and film, oxygen saturation, smoking and medicine review, ferritin, renal and liver tests, serum erythropoietin and JAK2 V617F testing.
If JAK2 V617F is negative but PV remains likely, test JAK2 exon 12 and perform marrow and secondary or hereditary erythrocytosis assessment through haematology.
Confirm with integrated haemoglobin or haematocrit, JAK2 mutation, low erythropoietin and panmyelotic marrow findings; iron deficiency can mask the true erythrocytosis.
First-line thrombosis prevention is venesection to keep haematocrit below 0.45 plus low-dose aspirin when there is no contraindication.
Age over 60 years or previous thrombosis usually defines high thrombotic risk and adds cytoreduction, commonly hydroxycarbamide or interferon according to reproductive and toxicity considerations.
An acute splanchnic thrombosis should trigger myeloproliferative testing even when counts are normal because haemodilution, iron deficiency or hypersplenism can mask PV.
Avoid routine iron replacement: treat proven symptomatic deficiency only with specialist supervision and frequent haematocrit monitoring.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

JAK2-mutant stem-cell clone

Almost all PV contains JAK2 V617F or an exon 12 mutation, producing cytokine-independent myeloid signalling and erythroid expansion.

Age and acquired evolution

Incidence rises with age as somatic clones accumulate; additional mutations influence thrombosis, myelofibrotic transformation and leukaemic progression.

Non-hereditary erythrocytosis

PV is acquired and must be separated from high-affinity haemoglobin and oxygen-sensing pathway mutations that cause lifelong familial erythrocytosis.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Panmyelosis
Erythrocytes expand most visibly, but neutrophils, platelets and marrow megakaryocytes often increase because the abnormal clone affects multiple myeloid lineages.
2
Viscosity and endothelial activation
Raised red-cell mass, activated platelets and leukocytes and inflammatory signalling impair microcirculation and promote arterial, venous and unusual-site thrombosis.
3
Iron-restricted treatment state
Repeated venesection deliberately restricts iron and can produce microcytosis; iron replacement without specialist approval may rapidly increase haematocrit.
4
Fibrotic or leukaemic evolution
Clonal progression can replace proliferative marrow with fibrosis and extramedullary haematopoiesis or acquire an acute leukaemia phenotype.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Hyperviscosity and microvascular symptoms

Headache, dizziness, visual disturbance, tinnitus and erythromelalgia often improve when haematocrit and platelet activation are controlled.

Aquagenic pruritus

Intense itching after warm water without a primary rash is characteristic but neither required nor sufficient for diagnosis.

Thrombotic presentationRed flag

Arterial events and DVT or PE occur, while portal, hepatic or cerebral venous thrombosis is especially suggestive.

Panmyelotic clues

Leucocytosis, thrombocytosis, splenomegaly, gout and raised urate support a proliferative clone rather than isolated hypoxic erythrocytosis.

Progression patternRed flag

New anaemia, teardrops, nucleated red cells, blasts, splenic pain or systemic symptoms suggests fibrotic or leukaemic evolution.

Red flags requiring action

Focal neurology, chest pain, painful swollen limb, abdominal pain with portal or hepatic-vein thrombosis, or visual loss requires immediate vascular assessment and treatment.
Major bleeding with extreme thrombocytosis may reflect acquired von Willebrand syndrome and requires urgent haemostasis testing and cytoreductive planning.
Rapid anaemia, leucoerythroblastic film, enlarging spleen, weight loss, fever or blasts suggests post-PV myelofibrosis or AML transformation.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line erythrocytosis assessmentFirst stepFirst line
Why
Confirm persistence and identify relative, hypoxic, renal, hormonal and clonal clues.
Interpretation and limitations
Repeat FBC and film, review old counts, volume, smoking, testosterone and SGLT2 exposure, measure oxygen saturation, ferritin, renal, liver and serum erythropoietin.
02
First-line molecular test: JAK2 V617FFirst line
Why
Identify the principal clonal driver in suspected PV and unusual-site thrombosis.
Interpretation and limitations
A positive result supports an MPN but does not alone distinguish PV, ET and myelofibrosis; integrate counts and marrow.
03
Confirmatory marrow and JAK2 exon 12Confirmatory
Why
Demonstrate panmyelosis and capture V617F-negative PV when clinical probability remains high.
Interpretation and limitations
Marrow shows trilineage proliferation with pleomorphic mature megakaryocytes; expert review separates masked PV and prefibrotic myelofibrosis.
04
Secondary and hereditary testing
Why
Find a treatable oxygen, renal, tumour, drug or congenital cause when clonal tests do not fit.
Interpretation and limitations
Use carboxyhaemoglobin, sleep or lung assessment, abdominal imaging and P50 or germline testing selectively from erythropoietin, age and family history.
05
Acquired VWD assessment
Why
Estimate bleeding risk before aspirin or an invasive procedure when platelets are extreme or bleeding occurs.
Interpretation and limitations
Use VWF activity and antigen with specialist multimer or function testing; cytoreduction treats the underlying high-count mechanism.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Relative erythrocytosis

Dehydration, diuretics, burns and reduced plasma volume raise haemoglobin and haematocrit without an increased red-cell mass.

Hypoxia-driven secondary erythrocytosis

Smoking, carbon monoxide, sleep apnoea, chronic lung disease, cyanotic heart disease and altitude increase erythropoietin appropriately.

Erythropoietin-producing states

Renal lesions, hepatocellular tumours, testosterone, anabolic steroids and exogenous erythropoietin can cause secondary erythrocytosis with a distinct management target.

Other myeloproliferative neoplasm

Essential thrombocythaemia, prefibrotic myelofibrosis and BCR-ABL1-positive CML can overlap counts; marrow architecture and molecular testing resolve classification.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Sustained erythrocytosisSeparate clone from hypoxia and volumeFirst stepHaemoglobin or haematocrit remains elevated on repeat testing.

1Assess volume, smoking, oxygen, sleep, medicines, renal and liver disease, thrombosis, pruritus and spleen.
2Measure erythropoietin and JAK2 V617F with ferritin and organ baseline.
3Use exon 12, marrow and directed secondary or hereditary testing when the initial pattern does not resolve the diagnosis.

02Confirmed low-risk PVControl haematocrit and vascular riskThere is no previous thrombosis and age is 60 years or younger without another cytoreduction indication.

1Perform venesection to maintain haematocrit below 0.45 and give low-dose aspirin if bleeding risk permits.
2Treat smoking, blood pressure, lipids, diabetes, weight and immobility and address pruritus and gout.
3Add cytoreduction if venesection burden, symptoms, progressive counts or risk changes make it necessary.

03High-risk or acute thrombosisAdd cytoreduction to standard vascular carePrevious thrombosis, age over 60 or an acute arterial, venous or unusual-site event raises recurrence risk.

1Treat the acute event through its standard pathway and control haematocrit urgently when elevated.
2Start hydroxycarbamide or interferon through the MPN service using pregnancy, age, skin and organ modifiers.
3Plan antithrombotic duration and bleeding surveillance, especially for splanchnic thrombosis with portal hypertension.

04Pregnancy or conceptionUse pregnancy-compatible controlA person with PV is pregnant, planning pregnancy or could conceive during cytoreduction.

1Stop teratogenic cytoreduction before conception and involve obstetric haematology early.
2Use venesection and low-dose aspirin with interferon when cytoreduction is required; add LMWH by maternal and pregnancy risk.
3Plan delivery, neuraxial timing and postpartum LMWH and count monitoring prospectively.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

First-line red-cell-mass control for essentially all adults with PV and an urgent adjunct when raised haematocrit contributes to acute thrombosis or hyperviscosity.

Venesection

Remove approximately 450 mL of blood per session in a typical adult, using smaller volumes for low body mass or cardiovascular disease, and repeat at a clinically safe interval until haematocrit is below 0.45, then maintain that target.

Assess hydration, blood pressure and cardiovascular tolerance. Monitor ferritin and symptoms but do not replace iron routinely; adjust volume and frequency in pregnancy, frailty or cardiac disease.

Reduces arterial and microvascular thrombosis alongside haematocrit control.

Low-dose aspirin

Give 75 mg orally once daily long term when there is no active bleeding, major aspirin intolerance or acquired von Willebrand syndrome that makes antiplatelet therapy unsafe.

Review gastrointestinal bleeding, anticoagulation and extreme thrombocytosis. Use gastric protection when indicated and do not substitute aspirin for anticoagulation after venous thrombosis.

First-line cytoreduction for many high-risk adults or those with inadequate venesection and symptom control.

Hydroxycarbamide

Start commonly at 500 mg orally once or twice daily and titrate to haematocrit below 0.45 and safe platelet and leukocyte control using frequent FBC; exact starting intensity follows age, renal function and local MPN protocol.

Adjust for renal impairment and cytopenia, monitor mucocutaneous ulceration and skin cancer, avoid pregnancy and breastfeeding and use effective contraception; discuss fertility and alternatives before long exposure.

Cytoreduction for younger adults, pregnancy-compatible treatment and people in whom hydroxycarbamide is unsuitable.

Pegylated interferon alfa

A common peginterferon alfa-2a start is 45 micrograms subcutaneously once weekly, increasing gradually to 90 to 180 micrograms weekly according to counts, symptoms and tolerance under the MPN protocol.

Monitor mood, autoimmune and thyroid disease, liver function, cytopenia and flu-like effects. Specialist obstetric use is established, but product-specific reproductive counselling remains necessary.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Arterial and venous thrombosis

Stroke, myocardial infarction, DVT, PE and splanchnic or cerebral thrombosis are the principal preventable causes of morbidity and death.

Bleeding and acquired VWD

Extreme platelet counts, platelet dysfunction, acquired von Willebrand syndrome and antithrombotic treatment can produce mucosal or major bleeding.

Microvascular and metabolic symptoms

Erythromelalgia, headache, visual disturbance, aquagenic pruritus, gout and peptic ulceration reflect platelet activation, viscosity, mast-cell mediators and cell turnover.

Post-PV myelofibrosis or AML

New anaemia, leucoerythroblastosis, spleen growth, systemic symptoms and blasts mark biological progression and require repeat marrow and genetics.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During venesection induction, check haematocrit frequently enough to avoid prolonged exposure above 0.45 and assess orthostasis, iron symptoms and vascular events.
During cytoreduction, monitor FBC, renal and liver function at short intervals during titration then extend when stable; document adherence and treatment intolerance.
At each review assess thrombosis, bleeding, microvascular symptoms, pruritus, spleen, cardiovascular risks and antithrombotic interactions.
Reassess marrow and molecular disease when new anaemia, leucoerythroblastosis, progressive spleen, constitutional symptoms or blasts suggest transformation.
In pregnancy, monitor counts, blood pressure, fetal growth and LMWH timing through a written obstetric-haematology plan and continue postpartum thrombosis prevention.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Iron deficiency can mask PV

Microcytosis reduces haemoglobin while red-cell number and clonal features remain high, particularly with splanchnic thrombosis.

JAK2 is not subtype-specific

The same driver occurs in PV, ET and myelofibrosis, so marrow and blood phenotype establish the disease.

Haematocrit below 0.45 matters

This is the evidence-based vascular target and should not be replaced by symptom response or haemoglobin alone.

Extreme platelets can bleed

Acquired loss of high-molecular-weight VWF multimers makes aspirin harmful until haemostasis is assessed and the count reduced.

Splanchnic thrombosis can hide counts

Portal hypertension, iron deficiency and haemodilution may normalise counts, so JAK2 testing remains important.

11Common pitfallsFrequent interpretation and management errors.

01
Calling dehydration PV from one raised haemoglobin.
02
Stopping after a normal oxygen saturation without smoking or sleep assessment.
03
Interpreting JAK2 positivity without marrow and phenotype.
04
Allowing haematocrit to remain at or above 0.45 between reviews.
05
Giving aspirin during acquired von Willebrand bleeding.
06
Replacing iron routinely during venesection without specialist control.