Polycythemia vera

01Definition and overview

Polycythaemia vera (PV) is a myeloproliferative neoplasm (MPN): a clonal disease of the haematopoietic stem cell that makes too many red cells, and often too many platelets and neutrophils, driven by a mutation in JAK2. It is one cause of polycythaemia, and far from the commonest.

Polycythaemia, or erythrocytosis, is a haemoglobin or haematocrit above the normal range for sex. The WHO 2022 thresholds for PV are a haemoglobin above 165 g/L (16.5 g/dL) or a haematocrit above 0.49 (49 per cent) in men, and above 160 g/L or 0.48 in women. The haematocrit is the better guide, because in iron deficiency the haemoglobin falls further than the haematocrit. A raised haematocrit is absolute when the red cell mass is truly increased, and relative when the plasma volume has shrunk around a normal red cell mass:

Smoking does two things at once: carbon monoxide takes up haemoglobin's oxygen sites and raises the red cell mass, and the plasma volume shrinks. Rare inherited causes (an abnormal haemoglobin, erythropoietin receptor or oxygen-sensing pathway, as in Chuvash polycythaemia) are sought in the young and in families.

Among the MPNs, chronic myeloid leukaemia is the BCR::ABL1-positive one; PV, essential thrombocythaemia and primary myelofibrosis are the classic BCR::ABL1-negative MPNs, and one can turn into another.

The sister neoplasms

Essential thrombocythaemia (ET) and primary myelofibrosis (PMF) share PV's drivers. JAK2 V617F is found in 50 to 60 per cent of each, and an activating mutation in MPL, the thrombopoietin receptor, in about 3 per cent of ET and 5 per cent of PMF. Most of the rest carry a CALR mutation (calreticulin): about two thirds of the rest in ET and nearly 9 in 10 in PMF. Those with none of the three are called triple-negative. CALR and MPL mutations are not found in PV.

An apparent ET is always tested for BCR::ABL1, because CML can present with a high platelet count alone; reactive causes (iron deficiency, infection, inflammation, cancer, a removed spleen) are far commoner than either and are excluded first. PV and ET can each end in myelofibrosis (post-PV or post-ET myelofibrosis), which is treated as PMF.

02Etiology and pathophysiology

PV is acquired. No environmental cause is known; inheritance plays a small part, through a common JAK2 variant (the 46/1 haplotype) on which the mutation tends to arise, and relatives of patients have a higher risk.

1. 1

   Receptors without a kinase

   The receptors for erythropoietin, thrombopoietin and G-CSF have no enzyme of their own. They rely on JAK2, a tyrosine kinase bound to their inner tails, which is switched on when the hormone binds and passes the signal to STAT5 and other pathways.
2. 2

   The brake removed

   JAK2 holds its own kinase in check with a neighbouring pseudokinase domain. V617F, a valine-to-phenylalanine change in that domain, releases the brake; exon 12 mutations, just before it, do much the same.
3. 3

   Red cells without a signal

   Red cell precursors now grow with little or no erythropoietin, and the kidney, sensing plenty of oxygen-carrying cells, turns its erythropoietin down: hence the low level, the opposite of secondary polycythaemia.
4. 4

   Three lines, then scarring

   The thrombopoietin and G-CSF receptors use JAK2 too, so platelets and neutrophils often rise as well (panmyelosis). In PV the clone often swaps its normal copy of 9p for a second mutant one (mitotic recombination) and becomes homozygous, and a high mutant allele burden goes with more itching, a bigger spleen and later fibrosis.

Why the same mutation gives PV in one patient and ET or PMF in another is only partly understood: the allele burden, homozygosity, the patient's background and other mutations all play a part. CALR mutants bind and switch on the thrombopoietin receptor, as MPL mutations do, which is why they raise platelets and scar the marrow but do not cause PV. Mutations in TET2, ASXL1, DNMT3A and other genes are found alongside in more than half of patients with an MPN; in PV, those in SRSF2, IDH2, RUNX1 or U2AF1 predict a worse outcome.

Thrombosis has several causes at once. More red cells make the blood viscous and push platelets towards the vessel wall; the clone's red cells, platelets and neutrophils are themselves activated and sticky; and the endothelium is inflamed. The splanchnic veins are a favoured site, for reasons not fully known. Bleeding is the paradox: very high platelets, above about 1000 to 1500 × 10⁹/L, bind and clear the largest von Willebrand factor multimers, an acquired von Willebrand syndrome that aspirin makes worse.

03Clinical features

PV is increasingly found on a blood count done for something else. When it causes symptoms:

• hyperviscosity: headache, dizziness, tinnitus, blurred vision, tiredness and poor concentration;
• plethora: a ruddy face, red conjunctivae, sometimes a dusky cyanosis;
• aquagenic pruritus: intense itching, without a rash, after a warm bath or shower, in about a third at diagnosis;
• erythromelalgia: burning pain, redness and warmth of the hands and feet, eased by cold and by aspirin; a disorder of platelets in small vessels, commoner in ET;
• splenomegaly, in about a third at diagnosis (older textbooks, from older series, say most), which helps to tell PV from secondary causes;
• gout from the high cell turnover, and peptic ulcer.

Thrombosis is the main danger. At or before diagnosis, about 16 per cent of patients have had an arterial thrombosis (stroke, transient ischaemic attack, myocardial infarction, limb ischaemia) and 7 per cent a venous one (deep vein thrombosis and pulmonary embolism). Thrombosis in unusual sites is typical of the MPNs, above all in young women: the Budd–Chiari syndrome (thrombosis of the hepatic veins, with abdominal pain, ascites and an enlarged liver), portal and mesenteric vein thrombosis, and cerebral venous sinus thrombosis.

Bleeding (skin, gums, nose, gut) is less common than thrombosis and usually milder, worst with very high platelets or after aspirin. Iron deficiency, from bleeding or past venesection, can mask PV: the haemoglobin looks normal, but the red cells are small and many, and the haematocrit rises once iron is given.

The late course brings its own signs: a spleen growing again, the need for venesection fading, falling counts, sweats and weight loss mean post-PV myelofibrosis, in which a few blasts in the blood are common; blasts rising to 10 to 19 per cent in blood or marrow mean an accelerated phase, and 20 per cent or more acute myeloid leukaemia.

04Diagnosis and management

1. 1

   Confirm it

   Repeat the count; look for dehydration, diuretics and the drugs that raise it. Raised platelets or neutrophils and a large spleen point to PV. A ferritin shows iron deficiency that may be masking it.
2. 2

   JAK2

   JAK2 V617F by a sensitive PCR on blood, positive in about 95 per cent of PV; if negative and suspicion remains, JAK2 exon 12.
3. 3

   Erythropoietin

   A serum erythropoietin: low in about 8 in 10 patients with PV, normal or high in secondary causes.
4. 4

   A cause, if JAK2 is negative

   Smoking and drug history, oxygen saturation, a sleep study, carboxyhaemoglobin, kidney and liver tests, and an abdominal ultrasound for kidney and liver lesions. Inherited causes are sought in the young or in families.
5. 5

   The marrow

   A marrow trephine shows growth of all three lines with pleomorphic mature megakaryocytes, and gives a baseline for fibrosis.

PV is diagnosed with all three major criteria, or the first two and the minor one. The marrow may be skipped when the haemoglobin stays above 185 g/L in men or 165 g/L in women with the mutation and a low erythropoietin, though only a trephine shows early fibrosis. The WHO dropped red cell mass measurement in 2022; the International Consensus Classification keeps it as an alternative (more than 25 per cent above predicted). UK guidance diagnoses JAK2-positive PV from a haematocrit above 0.52 in men or 0.48 in women with the mutation, without a marrow.

Risk and treatment

UK guidance sets the age at 65. In a low-risk patient, cytoreduction is started for poor tolerance of venesection or frequent need for it, a symptomatic or growing spleen, a white count persistently above 15 × 10⁹/L, platelets above 1500 × 10⁹/L, a heavy burden of symptoms such as itching, or a persistently high cardiovascular risk; European recommendations favour interferon for these younger patients.

the target for every patient with PV

0.45haematocritthe target for every patient with PV

carry JAK2 V617F

95per centcarry JAK2 V617F

high risk from this age, or with a past thrombosis (65 in the UK)

60yearshigh risk from this age, or with a past thrombosis (65 in the UK)

• Venesection removes about 450 mL (less in the frail), every few days or weekly at first and then as needed. The target is a haematocrit below 0.45 (45 per cent): in a randomised trial, cardiovascular death and major thrombosis came in 2.7 per cent with that target against 9.8 per cent with 0.45 to 0.50. The iron deficiency it causes is intended.
• Aspirin 75 to 100 mg daily: in a placebo-controlled trial, 100 mg cut cardiovascular death, heart attack, stroke and major venous thrombosis together by 60 per cent, with no significant rise in major bleeding. It is avoided after major bleeding, and with platelets above about 1000 to 1500 × 10⁹/L until acquired von Willebrand syndrome is excluded.
• Hydroxycarbamide by mouth: the usual first cytoreductive drug in older patients. It can cause low counts, mouth and leg ulcers and, with long use, skin cancers; it is teratogenic, and stopped 3 months before conception in men and women. It has not been shown to cause leukaemia.
• Ropeginterferon alfa-2b, injected every 2 to 4 weeks: licensed in the EU for PV without symptomatic splenomegaly, and preferred in younger patients. At 3 years the counts were controlled in 71 per cent, against 51 per cent with hydroxycarbamide, and in low-risk patients it kept the haematocrit on target more often than venesection alone (84 against 60 per cent); it can lower the mutant allele burden. Flu-like symptoms, fatigue, depression, thyroid disease and raised liver enzymes are its harms, and it is avoided after severe depression.
• Ruxolitinib, a JAK1 and JAK2 inhibitor by mouth: licensed for PV resistant to or intolerant of hydroxycarbamide. It controlled both the haematocrit and the spleen in 21 per cent against 1 per cent on standard therapy, and it relieves itching. It can cause anaemia, weight gain, shingles and skin cancers.

Busulfan, and in UK guidance radioactive phosphorus or pipobroman, are kept for the very old with a short life expectancy: the last two clearly raise the risk of leukaemia, as chlorambucil did before it was abandoned. Anagrelide lowers only the platelets and is licensed for ET alone; in PV, UK guidance adds it to hydroxycarbamide only when the platelets are hard to control.

Thrombosis, surgery and pregnancy

An acute thrombosis is treated as usual, with urgent venesection and cytoreduction added. After a venous thrombosis, anticoagulation is usually long term; for splanchnic vein thrombosis, low-molecular-weight heparin then warfarin is standard, as evidence for direct oral anticoagulants is limited. Before elective surgery the counts are controlled for some weeks, because uncontrolled PV brings thrombosis and bleeding; in an emergency the haematocrit is lowered by venesection with fluid replacement.

In pregnancy, aspirin is taken throughout, the haematocrit is kept within the normal range for gestation, and low-molecular-weight heparin is given for 6 weeks after delivery. A pregnancy at high risk also has interferon: with heparin throughout after a past thrombosis or pregnancy loss, and without heparin for very high platelets or a past major bleed. Aspirin and heparin are safe while breastfeeding.

05Epidemiology

PV is rare: about 0.8 new cases per 100,000 people a year in pooled studies, against about 1.0 for ET and 0.5 for PMF, with wide variation between registries. The median age at diagnosis is about 60, about 1 in 10 patients is under 40, and men and women are affected about equally. Secondary and relative polycythaemia, from smoking, lung disease, obesity and, increasingly, testosterone and SGLT2 inhibitors, are far commoner.

06Prognosis

Median survival is about 15 years, and more than 35 years for those diagnosed at 40 or younger; most deaths come from thrombosis, transformation and the illnesses of age. Over 20 years, about a quarter have a thrombosis, about 16 per cent develop myelofibrosis and about 4 per cent acute myeloid leukaemia. Older age, a white count of 15 × 10⁹/L or more, a past venous thrombosis, an abnormal karyotype and adverse mutations (SRSF2, IDH2, RUNX1, U2AF1) shorten survival.

Post-PV myelofibrosis is managed as primary myelofibrosis, with JAK inhibitors and, for fit patients, transplantation; leukaemia after an MPN responds poorly. Follow-up is lifelong: the haematocrit and counts, the spleen, symptoms, cardiovascular risk, and signs of transformation.