Polycythaemia Vera

Pathogenesis and Genetic Basis

• PV is primarily driven by somatic mutations in the JAK2 gene, which result in constitutive activation of cytokine receptor signalling pathways:
  • Approximately 95% of patients carry the JAK2 V617F mutation in exon 14.
  • An additional 3–4% have mutations in exon 12 of JAK2.
  • These mutations cause persistent activation of the JAK-STAT signalling cascade, independent of normal regulatory controls, leading to uncontrolled erythroid, granulocytic, and megakaryocytic proliferation.
• Though the JAK2 V617F mutation is highly characteristic of PV, it is not exclusive to it and is also found in other myeloproliferative neoplasms (e.g. essential thrombocythaemia and primary myelofibrosis).

Key Genetic Drivers

JAK2 Mutations

• The JAK2 V617F mutation is the principal driver, present in approximately 95% of PV patients.
• A smaller subset (3–4%) possess mutations in JAK2 exon 12, especially those with isolated erythrocytosis.
• JAK2 encodes a cytoplasmic tyrosine kinase essential for cytokine receptor signal transduction; the V617F substitution results in constitutive, ligand-independent activation of the JAK-STAT pathway.
• This leads to cytokine hypersensitivity and uncontrolled myeloid proliferation.

Not PV-Specific

• JAK2 V617F is not unique to PV; it is also found in other myeloproliferative neoplasms (MPNs) such as essential thrombocythaemia, primary myelofibrosis, and occasionally in chronic myelomonocytic or acute myeloid leukaemias.

Mutation Order Hypothesis

• It is hypothesised that JAK2 V617F often arises as a secondary event following earlier mutations in genes that regulate epigenetics or transcription.
• Studies suggest that if JAK2 V617F precedes mutations in TET2 or DNMT3A, a PV phenotype is favoured; the reverse order may lead to essential thrombocythaemia.

Role of Non-Driver Mutations and Clonal Complexity

Non-driver mutations

• Approximately half of PV patients exhibit additional somatic mutations beyond JAK2, particularly in genes such as TET2, DNMT3A, ASXL1, SRSF2, and IDH2.
• These are commonly implicated in clonal haematopoiesis of indeterminate potential (CHIP) and may influence disease phenotype and prognosis.

Clinical implications

• Mutations in ASXL1, SRSF2, and IDH2 are associated with worse survival and increased transformation risk.
• A higher burden of non-driver mutations correlates with elevated thrombotic risk and disease progression.

Cytogenetic Abnormalities

Abnormal karyotypes have been documented in

• ~20% of patients at diagnosis.
• 80% of patients with long-term disease (>10 years).

Common abnormalities include

• Deletions: 20q (8.4%), 13q (3%), 5q (3%), 7q (1%).
• Trisomies: 8 (7%), 9 (7%), 1q (4%).

Clonality and X-Inactivation Studies

• Studies using G6PD polymorphism and X-chromosome inactivation patterns have demonstrated monoclonality in virtually all haematopoietic lineages in PV.
• Approximately 90% of patients show skewed X-inactivation, confirming origin from a transformed multipotent stem cell.

Familial and Developmental Aspects

• Most PV cases are sporadic, but familial clustering has been observed.
  • Familial PV is typically acquired rather than congenital (normal neonatal blood counts).
  • Individuals with affected relatives have a higher risk, potentially due to inherited predisposition to somatic mutation acquisition.
• JAK2 V617F mutations may be acquired in utero or in early childhood.
  • Clonal expansion may remain subclinical for decades.
  • The variable rate of clonal evolution implies additional environmental or genetic modifying factors.

Unidentified Environmental Factors

• Although environmental contributions are suspected—as with other haematologic malignancies—no specific triggers have been definitively linked to PV.
• Research continues into potential associations with chemical exposures, radiation, and other extrinsic risk factors.

Clonal Expansion and JAK2-Mediated Signalling

JAK2 V617F mutation

• Found in over 95% of PV patients.
• Results from substitution of valine with phenylalanine at position 617.
• Leads to constitutive activation of the JAK-STAT signalling pathway, promoting cytokine-independent proliferation.
• Drives trilineage hyperplasia: erythroid, granulocytic, and megakaryocytic proliferation.

JAK2 exon 12 mutations

• Occur in approximately 3–4% of PV patients.
• Usually restricted to erythroid lineage expansion.
• Also lead to erythrocytosis, though via a slightly different molecular mechanism.

Bone Marrow Findings and Growth Characteristics

• Bone marrow biopsy in PV typically reveals:
  • Hypercellularity that is excessive for the patient’s age.
  • Panmyelosis: expansion of all three myeloid lineages — erythroid, granulocytic, and megakaryocytic.
     Erythroid progenitors
• Demonstrate growth without erythropoietin in vitro.
• Indicate a downstream defect in cytokine receptor signalling, affecting various growth factor pathways.

JAK2 Allele Burden and Clinical Implications

• Homozygosity for JAK2 V617F is more commonly observed in males.
• A higher allele burden (>50%) is associated with:
  • Greater risk of venous thrombosis.
  • Increased incidence of post-PV myelofibrosis.
  • Elevated leukocyte and platelet counts, suggesting a more proliferative phenotype.

Haemostatic Disruption and Thrombosis

• Hyperviscosity due to elevated red cell mass leads to:
  • Microvascular symptoms such as headache, dizziness, and erythromelalgia.
  • Increased risk of arterial and venous thrombotic events.
• Thrombosis is driven by multiple mechanisms:
  • Leukocyte activation and upregulation of tissue factor.
  • Release of platelet-derived microparticles, promoting coagulation.
  • Elevated platelet counts, often with abnormal function.
     Neutrophil extracellular traps (NETs)
• Formed by activated neutrophils.
• Promote thrombosis in PV.
• Inhibited by JAK inhibitors in experimental models.

Leukocytosis and Thrombotic Risk

• Leukocytosis is frequently present in PV.
• Its role in thrombosis remains unclear:
  • Some studies show a positive association.
  • Others find no independent predictive value.

Platelet Count and Thrombotic Risk

• Thrombocytosis alone is not a consistent independent risk factor for thrombosis.
• However, extremely elevated platelet counts (>1,000 × 10⁹/L) may lead to:
  • Acquired von Willebrand syndrome due to vWF binding to excessive platelets.
  • Bleeding tendency despite the high platelet count.

Bleeding Complications

• Haemorrhagic events may result from:
  • Acquired von Willebrand syndrome, seen in up to 15% of PV cases.
  • Platelet dysfunction and damage to microvascular integrity.

Inflammatory and Metabolic Factors

• Hyperhomocystinaemia
  • Present in over 50% of PV patients.
  • Adds to the risk of thrombosis.
• Inflammatory cytokines and oxidative stress
  • Contribute to endothelial dysfunction, amplifying thrombotic risk.

PV Genomic and Expression Profiles

• Gene expression profiling can identify distinct PV phenotypes:
  • Independent of age, sex, or JAK2 mutation status.
  • Associated with clinical variables such as disease duration, splenomegaly, thrombotic frequency, treatment history, and risk of progression.
• Expression patterns
  • May vary with age and sex.
  • Some are linked to adverse outcomes or differential transformation risk.

Incidence and Prevalence

• PV is a rare haematological malignancy with global variation in incidence:
  • United States: Estimated annual incidence ranges from 0.6 to 1.6 per 100,000 individuals. Another population study from Olmsted County reported an incidence of 1.9 per 100,000 person-years.
  • United Kingdom: Incidence is around 1.8 per 100,000 annually, with approximately 1,140 new cases per year (2010–2019 data).
  • Europe: Reported incidence ranges between 0.4 to 2.8 per 100,000 people per year.
  • Japan: The incidence is notably lower than in the US or Europe.
• Prevalence estimates in the US range from 22 to 57 per 100,000 persons.
• Global data outside of the US and Western Europe remain limited.

Age Distribution

• PV primarily affects middle-aged and older adults:
  • Median age at diagnosis: ~60–65 years in the US and 71 years in the UK.
  • Age range: Most cases occur between 50–70 years of age.
  • Early-onset cases: Around 25% of cases present before age 50, and ~10% before age 40.
  • Paediatric PV: Extremely rare, though occasional cases have been described in adolescents and children.

Sex Distribution

• PV occurs in both sexes, but with a slight male predominance:
  • Male-to-female incidence ratio: Approximately 1.6 in the US and 1.2 in the UK.
  • Some studies suggest no significant difference when population-based data are adjusted, while others report a marginally higher rate in men.

Ethnic and Genetic Considerations

• PV affects all ethnic groups.
  • A notably higher incidence has been observed among individuals of Ashkenazi Jewish descent.
• Although PV is usually sporadic, familial clustering has been described:
  • Familial cases may reflect an inherited predisposition (e.g. germline variants affecting haematopoietic signalling pathways) that facilitates acquisition of driver mutations such as JAK2 V617F.

Environmental and Occupational Factors

• The majority of PV cases are idiopathic, without identifiable environmental triggers.
• Proposed but unconfirmed risk factors include:
  • Exposure to ionising radiation.
  • Industrial toxins (e.g. benzene).
  • However, most patients have no known exposure history.

General Presentation

• Many patients with PV are asymptomatic at the time of diagnosis.
• Diagnosis often follows routine blood work revealing elevated haemoglobin or haematocrit.
• Others may present with symptoms due to hyperviscosity, microvascular disturbances, or thrombohaemorrhagic complications.

Common Historical Symptoms

Constitutional and Non-specific Symptoms

• Fatigue and generalised weakness (reported in up to 85%).
• Night sweats and bone pain (in 49% and 43%, respectively).
• Difficulty concentrating, insomnia, and low mood have also been frequently reported.

Hyperviscosity-related Neurological Symptoms

• Headache (seen in ~30%); may be accompanied by dizziness or a feeling of head/neck fullness.
• Vertigo, tinnitus, and visual disturbances including transient visual loss (e.g., amaurosis fugax).
• These may relate to impaired microcirculatory flow and elevated haematocrit.

Pruritus (particularly aquagenic)

• Triggered by contact with warm water (e.g., after bathing or showering).
• Described as itching, burning, stinging, or tickling—typically in chest, back, arms, and legs.
• May precede diagnosis by years and is often resistant to standard antihistamines.
• Associated with histamine release and possibly prostaglandin-mediated platelet aggregation.
• Frequently improves with aspirin, interferon, or JAK inhibitors.

Erythromelalgia and Dysaesthesia

• Burning pain and redness in the extremities (fingers, toes) with accompanying pallor or cyanosis.
• Associated with platelet-mediated microvascular thrombosis.
• Symptoms often improve with low-dose aspirin or cytoreduction.

Early Satiety and Abdominal Discomfort

• Linked to splenomegaly causing gastric compression.
• Can also be associated with portal hypertension due to splanchnic vein thrombosis.
• Epigastric pain or peptic ulcer symptoms may occur due to increased histamine release.

Thrombotic and Haemorrhagic Complications

Thrombotic History to Elicit

• Cerebrovascular accidents, myocardial infarction, deep vein thrombosis, pulmonary embolism.
• History of superficial thrombophlebitis or unusual site thromboses (e.g., mesenteric, splenic, or hepatic veins).
• Budd-Chiari syndrome or unexplained abdominal vein thrombosis in young women should raise suspicion of PV.

Bleeding History

• Epistaxis, gum bleeding, gastrointestinal bleeding, or easy bruising.
• May be exacerbated by acquired von Willebrand syndrome in patients with extreme thrombocytosis.

Other Symptoms and Quality of Life Indicators

Cognitive and Sensory Symptoms

• Numbness, tingling, or peripheral paraesthesia, possibly related to microvascular flow changes.
• Visual migraines or scintillating scotomata.

Mood and Psychosocial Impact

• Sad mood, sexual dysfunction, impaired social functioning reported in patient questionnaires.
• Severity of symptom burden may correlate with splenomegaly or need for cytoreductive therapy.

Sweating and Thermoregulatory Disturbances

• Hyperhidrosis, particularly nocturnal, is common in PV and related MPNs.

Historical Risk Factors to Inquire About

• Age >60 years – increases thrombotic risk and influences treatment decisions.
• Personal or Family History of MPNs – familial cases are rare but do exist.
• History of Budd-Chiari Syndrome – particularly in young women with normal haemoglobin.
• Known JAK2 Mutation – may be previously identified in unrelated testing.
• Environmental Exposure – past exposure to ionising radiation or benzene, although not routinely present.

General Appearance and Skin

Facial plethora (ruddy cyanosis)

• Common presenting sign reflecting increased red cell mass.
• Most evident in the face, palms, nailbeds, mucous membranes, and conjunctivae.

Excoriations and dry skin

• May indicate pruritus, particularly aquagenic, a hallmark symptom of PV.
• Excoriation is often generalised and can suggest chronicity or severity of itching.

Cardiovascular and Vascular Findings

Hypertension

• Found in nearly half of patients.
• Reflects increased blood volume and viscosity.
• Important to differentiate from pseudopolycythaemia (Gaisböck syndrome), where haemoconcentration occurs without increased red cell mass.

Stigmata of previous thrombotic events

• May include evidence of:
  • Ischaemic stroke (e.g., residual weakness or asymmetry)
  • Superficial thrombophlebitis
  • Deep vein thrombosis (leg swelling, tenderness)
  • Peripheral arterial disease (absent or diminished pulses, trophic skin changes)

Abdominal Examination

Splenomegaly

• Palpable in approximately 36% of patients.
• May present as early satiety or vague abdominal discomfort.
• Consider imaging (e.g., ultrasound) if spleen is not palpable but splenomegaly is suspected clinically.

Hepatomegaly

• Present in up to 30% of patients.
• May suggest extramedullary haematopoiesis or congestive sequelae from portal hypertension due to splanchnic thrombosis.

 Ocular and ENT Findings

Conjunctival injection and fundal engorgement

• Due to hyperviscosity from elevated red cell mass.
• Dilated and tortuous retinal veins may be seen on ophthalmoscopy.

Musculoskeletal and Joint Findings

Gouty arthritis or tophi

• Elevated cell turnover in PV increases uric acid levels.
• Can present as joint inflammation (e.g., first metatarsophalangeal joint) or visible tophi.

Neurological Clues on Examination

Visual disturbances

• Transient amaurosis fugax or scotomata may prompt suspicion.
• These are often reversible with haematocrit control.
• Fluorescein angiography (in studies) shows slowed retinal/choroidal flow in affected patients.

Other Findings Suggesting Haemorrhagic Tendency

Mucosal bleeding or bruising

• Suggests underlying acquired von Willebrand syndrome, especially in patients with extreme thrombocytosis (>1 million/μL).
• Important to assess in patients being considered for aspirin therapy.

Systemic Symptoms with Examination Correlates

Excessive sweating (hyperhidrosis)

• Often reported but may have no specific exam correlate.
• Part of systemic symptom complex shared with other myeloproliferative neoplasms

Initial Screening and Haematological Parameters

Haemoglobin and Haematocrit

• Elevated haemoglobin and/or haematocrit are essential for suspecting PV.
• WHO diagnostic thresholds:
  • Men: Haemoglobin >165 g/L or Haematocrit >49%
  • Women: Haemoglobin >160 g/L or Haematocrit >48%
• British standards may use slightly higher cut-offs.
• In high-altitude dwellers or hypoxic states, interpret with caution.
• “Masked PV” refers to patients with diagnostic marrow and molecular findings but without overt erythrocytosis; often misdiagnosed as essential thrombocythaemia.

White Blood Cell and Platelet Counts

• Modest leukocytosis and thrombocytosis are frequently observed.
• WBC ≥15 × 10⁹/L is associated with worse prognosis.
• Thrombocytosis is not a predictor of thrombosis but may suggest PV when in context with erythrocytosis.

Mean Corpuscular Volume (MCV) and Peripheral Blood Smear

• MCV often low due to iron deficiency, which may mask polycythaemia.
• Blood smear: typically normocytic, normochromic RBCs; microcytosis may suggest iron depletion.
• Presence of leukoerythroblastic features may indicate disease progression.

Biochemistry and Inflammatory Markers

Serum Ferritin and Iron Studies

• Assess for iron deficiency, which can obscure diagnosis.
• Low MCV with low ferritin and normal haemoglobin may indicate PV with masked erythrocytosis.

Liver Function Tests

• Generally normal unless hepatic vein thrombosis (e.g. Budd-Chiari syndrome) is present.

Serum Uric Acid

• Commonly elevated due to high cell turnover; associated with gout.

Vitamin B12 and Binding Capacity

• Frequently elevated due to increased transcobalamin from high white cell burden.

Molecular and Bone Marrow Testing

JAK2 Mutation Testing

• JAK2 V617F mutation found in ~95% of PV cases.
• JAK2 exon 12 mutations account for ~3% of JAK2 V617F-negative PV.
• Quantitative V617F allele burden may offer prognostic information.

Bone Marrow Biopsy

• Required in most cases, except where erythrocytosis is unequivocal and both JAK2 mutation and low erythropoietin are confirmed.
• Diagnostic findings:
  • Hypercellularity for age
  • Trilineage panmyelosis (erythroid, granulocytic, megakaryocytic proliferation)
  • Pleomorphic megakaryocytes
  • Reticulin fibrosis may indicate a higher risk of progression.

Erythropoietin and Red Cell Mass Studies

Serum Erythropoietin (EPO)

• Typically low in PV.
• Helps distinguish from secondary causes of erythrocytosis (which show elevated or normal EPO).

Red Cell Mass Measurement

• Rarely used; no longer part of WHO criteria.
• May be helpful when diagnosis remains unclear and in cases of suspected masked PV.

Advanced Molecular and Cytogenetic Studies

Further Mutation Panels (NGS)

• CALR and MPL mutations are generally absent in PV but present in essential thrombocythaemia and primary myelofibrosis.
• Mutations in ASXL1, SRSF2, IDH2 may predict worse survival and higher transformation risk.

Cytogenetics

• Abnormal karyotypes (e.g., del(5q), del(20q), trisomy 8/9) seen in up to 30% of untreated PV and more commonly after cytotoxic therapy.

Other Laboratory and Functional Tests

Leukocyte Alkaline Phosphatase (LAP) Score

• Elevated in most PV cases, though now largely replaced by molecular markers.

Coagulation Studies

• May show artefactual abnormalities due to sample collection issues in polycythaemic patients.
• Adjust anticoagulant-to-blood ratios appropriately.

Platelet Function Tests

• May show spontaneous aggregation or abnormal response to agonists, indicating thrombotic tendency.

Oxygen Saturation and Carboxyhaemoglobin

• Helps exclude secondary polycythaemia due to hypoxia or smoking.

Abdominal Imaging

• Evaluate for splenomegaly or splanchnic vein thrombosis if suspected clinically or via lab findings.

WHO Diagnostic Criteria for PV (2022 Revision)

Diagnosis requires

• All 3 major criteria, or
• First 2 major + minor criterion

Major Criteria

• Elevated haemoglobin/haematocrit or red cell mass
• Bone marrow hypercellularity with trilineage growth
• Presence of JAK2 V617F or exon 12 mutation

Minor Criterion

• Subnormal serum erythropoietin

Myeloproliferative Neoplasms (MPNs)

Essential Thrombocythaemia (ET)

• May resemble masked PV but is typically characterised by:
  • Persistent isolated thrombocytosis with normal haemoglobin, red cell mass, and erythropoietin (EPO) levels.
  • Absence of aquagenic pruritus and marked facial or conjunctival plethora.
  • Splenomegaly is less common, occurring in only 10–20% of cases.
     Molecular profile
• CALR or MPL mutations are commonly identified and usually exclude PV.
• JAK2 mutations occur in ~60% of ET cases, overlapping with PV but without associated erythrocytosis.
   Bone marrow
• Shows predominant megakaryocytic proliferation with large, hyperlobulated megakaryocytes.
• Trilineage hyperplasia is absent.
• Differentiating ET from masked PV often requires combined assessment of haemoglobin/haematocrit thresholds and marrow histology.

Primary Myelofibrosis (PMF)

• Characterised by:
  • Anaemia, marked splenomegaly, and systemic symptoms such as weight loss and night sweats.
  • Peripheral smear findings of tear-drop poikilocytes and nucleated red blood cells.
     Histopathology
• Reveals marrow fibrosis, abnormal megakaryocyte clustering, and absence of trilineage hyperplasia.
• JAK2, CALR, or MPL mutations may be present, but erythrocytosis is not a feature.

Chronic Myeloid Leukaemia (CML)

• Defined by marked granulocytosis and the presence of the Philadelphia chromosome (BCR::ABL1 fusion gene).
• Thrombosis is uncommon.
• Diagnosis is confirmed by FISH or PCR detection of BCR::ABL1.

Reactive (Secondary) Causes of Polycythaemia

Hypoxia-driven erythrocytosis

• Chronic hypoxaemia leads to increased EPO production.
• Common causes include chronic obstructive pulmonary disease (COPD), cyanotic congenital heart disease, high altitude, and obstructive sleep apnoea.
   Smoking-related erythrocytosis
• Caused by carbon monoxide exposure; assess using carboxyhaemoglobin levels.
   Investigations
• Oxygen saturation <92% may indicate significant tissue hypoxia.
• Arterial blood gas analysis, overnight oximetry, and pulmonary function testing assist in diagnosis.
• EPO levels are elevated or normal; red cell mass may be increased, but white cell and platelet counts remain normal.

Erythropoietin-secreting tumours

• Include renal cell carcinoma, hepatocellular carcinoma, and cerebellar haemangioblastoma.
• Clues:
  • Paraneoplastic syndromes, systemic symptoms, or abdominal masses.
  • Diagnosis involves imaging (renal ultrasound, CT, MRI) and detecting elevated serum EPO levels.

Exogenous erythropoietin or androgen use

• A history of testosterone or anabolic steroid administration may explain erythrocytosis.
• Haemoglobin levels usually normalise following drug cessation.
• No clonal haematopoiesis or bone marrow abnormalities are present.

Inherited and Congenital Polycythaemias

Congenital causes of erythrocytosis

• Usually present in childhood or early adulthood and may follow autosomal dominant or recessive inheritance.
• Underlying mechanisms include:
  • EPOR gain-of-function mutations
  • Mutations in oxygen-sensing genes: VHL, HIF2α, and PHD2
  • Haemoglobin variants with increased oxygen affinity (evident as low P50 on oxygen dissociation testing)
     Diagnostic approach
• Includes detailed family history, genetic testing, and oxygen dissociation studies.

Masked PV and Diagnostic Challenges

• Defined by patients who fulfil molecular and bone marrow criteria for PV but lack overt erythrocytosis.
• More frequently observed in men and often misclassified as ET.
• Associated with higher platelet counts, increased thrombotic risk, and worse prognosis.
• Accurate diagnosis requires careful interpretation of haemoglobin/haematocrit thresholds, bone marrow findings, and JAK2 mutation status.

Treatment Objectives

Primary Goals

• Prevent major thrombotic events.
• Alleviate disease-related symptoms such as pruritus and erythromelalgia.
• Maintain haematocrit below 45%.
• Minimise transformation to post-PV myelofibrosis or acute leukaemia (although no current therapy is proven to reduce this risk).

Additional Aims

• Address cardiovascular comorbidities: hypertension, diabetes, hyperlipidaemia, smoking.
• Improve quality of life through symptom control and supportive care.
• Tailor management to special populations, including pregnant women and children.

Risk Stratification

Low Risk

• Age <60 years
• No history of thrombosis

High Risk

• Age ≥60 years or prior thrombotic event

Modifying Factors

• Coexistent cardiovascular risk factors
• Haematocrit not controlled with phlebotomy alone
• Marked leukocytosis or thrombocytosis

Core Treatment Modalities

Low-Dose Aspirin

• Recommended for all patients unless contraindicated.
• Reduces risk of thrombosis and relieves microvascular symptoms.
• Twice-daily dosing may benefit those with persistent symptoms or high thrombotic risk.
• Caution: Assess for acquired von Willebrand syndrome (evaluate ristocetin cofactor activity) before use in patients with thrombocytosis.

Phlebotomy

• First-line in both low- and high-risk patients to reduce haematocrit quickly.
• Target: Haematocrit <45%.
• Regimen: 250–500 mL removed twice weekly or on alternate days if haematocrit ≥60%.
• Induces iron deficiency, which can alleviate symptoms but may also cause fatigue or cognitive impairment.
• Iron supplementation is generally avoided unless severely symptomatic.

Cytoreductive Therapy

Indications for Use

• Routinely used in high-risk patients.
• Considered in low-risk patients with:
  • New thrombotic or haemorrhagic events
  • Progressive cytoses or symptomatic disease
  • Intolerance or insufficient response to phlebotomy alone

First-Line Agents

 Hydroxycarbamide

• Oral antimetabolite.
• Lowers thrombotic risk.
• Teratogenic and possibly leukaemogenic with long-term use.
• Requires regular monitoring for cytopenias.

Ropeginterferon alfa-2b

• Long-acting pegylated interferon.
• Reduces JAK2 V617F allele burden over time.
• Non-inferior to hydroxycarbamide; may offer better long-term control.
• Contraindicated in autoimmune, hepatic, or psychiatric disorders.

Peginterferon alfa-2a

• Preferred in younger patients and during pregnancy.
• Higher side-effect burden but may induce molecular remission.

Second-Line and Salvage Therapy

Ruxolitinib (JAK1/2 inhibitor)

• Indicated in patients resistant or intolerant to hydroxycarbamide.
• Effective in controlling haematocrit, reducing splenomegaly, and alleviating symptoms.
• Monitor for herpes zoster and non-melanoma skin cancers.

Busulfan

• Used in elderly or frail patients not candidates for other therapies.
• Increased risk of secondary malignancies with long-term use.
• Not endorsed by current NCCN guidelines.

Contraindicated Agents

• Radioactive phosphorus, chlorambucil, and pipobroman—linked to high rates of leukaemic transformation.

Special Considerations

Patients with Leukocytosis or Thrombocytosis

• Cytoreduction may be considered in high-risk patients.
• If platelet count ≥1000 × 10⁹/L, test for von Willebrand factor deficiency.
• Anagrelide may be added for refractory thrombocytosis.

Pregnancy

• Lower haematocrit target (<41%) recommended in the first trimester.
• Use phlebotomy cautiously.
• Low-dose aspirin combined with low-molecular-weight heparin (LMWH) postpartum for 6 weeks is standard.
• Peginterferon alfa-2a is the cytoreductive agent of choice.
• Hydroxycarbamide is contraindicated during pregnancy and lactation.

Paediatric Patients

• Rarely treated; management is based on expert consensus.
• Phlebotomy and low-dose aspirin used for symptom or risk control.
• Cytoreduction is uncommon but interferon may be cautiously considered.

Monitoring and Response Assessment

• Routine surveillance includes haematocrit, full blood count, and symptom evaluation.
• Bone marrow biopsy or JAK2 allele burden testing is reserved for suspected disease progression or transformation.

Response Criteria (European LeukemiaNet/MPN-RT)

 Complete Response (CR)

• Haematocrit <45% without phlebotomy
• White cell count ≤10 × 10⁹/L
• Platelets ≤400 × 10⁹/L
• ≥10-point reduction in MPN-SAF symptom score
• No vascular events or disease progression

Partial Response (PR)

• Meets all clinical and haematological criteria of CR but not histological criteria

Progressive Disease

• Evolution to myelofibrosis, myelodysplastic syndrome, or acute leukaemia

Overall Survival

Survival in Treated Patients

• Modern therapies have extended median survival to approximately 14 years, with up to 24 years in patients under 60.
• A registry-based analysis (10,725 patients, median follow-up 5.8 years) reported an overall median survival of 11.9 years.
• Stratified estimates suggest:
  • ≤40 years: 37 years
  • 41–60 years: 22 years
  • 60 years: 10 years

Survival in Untreated Patients

• Historically poor, with average survival reported as 1.5–3 years without treatment.

Five-Year Survival

• Approximatey 79.5%, but notably wolrse than the age- and sex-matched general population.

Major Causes of Morbidity and Mortality

Thrombosis

• Leading cause of death in 10–40% of cases.
• Venous and arterial thrombotic events include:
  • Pulmonary embolism
  • Mesenteric vein thrombosis
  • Renal vein/artery thrombosis
  • Stroke and peripheral arterial occlusions

Haemorrhage

• Occurs in 15–35% of patients, leading to death in 6–30% of those affected.
• Often related to vascular compromise from thrombosis or hyperviscosity.

Leukaemic Transformation and Myelodysplasia

• Acute leukaemia develops in 1–5.9% depending on treatment modality:
  • Phlebotomy alone: ~1.5%
  • Chlorambucil: 13.5% (within 5 years)
  • Phosphorus-32: 10.2% (within 6–10 years)
  • Hydroxyurea: 5.9% at 15 years
• Time to acute myeloid leukaemia (AML) transformation is typically around 7.3 years.

Myelofibrosis

• Occurs in 3–10% of cases, representing the “spent phase” of PV.
• Leads to pancytopenia, increased transfusion needs, and higher infection and bleeding risk.

Gastrointestinal Complications

• Peptic ulcer disease incidence is 3–5 times higher than in the general population.
• Attributed to elevated histamine levels.

Progression Risk and Disease Transformation

Transformation to AML

• Occurs in ~1% of patients over a median of 4.4 years post-diagnosis.
• Risk influenced by patient age, cytoreductive therapy, and molecular profile.

Post-PV Myelofibrosis

• Treated with ruxolitinib (JAK1/2 inhibitor) or fedratinib (JAK2 inhibitor), both FDA approved.

Prognostic Factors

Clinical Factors

• Advanced age
• History of thrombosis
• Leukocytosis (WBC ≥15 × 10⁹/L)
• High lactate dehydrogenase (LDH) level
• Elevated JAK2 mutant allele burden
• Increased bone marrow reticulin fibrosis

Genetic Mutations

• Mutations in SRSF2, ASXL1, and IDH2 associated with inferior outcomes.
• SRSF2 independently predicts poor survival even when adjusted for age and thrombosis.

Masked PV

• Presents without overt erythrocytosis but with molecular and histological evidence of PV.
• Associated with:
  • Worse prognosis (particularly in older adults with leukocytosis)
  • Higher transformation rates
  • Delayed diagnosis and under-treatment

Prognostic Scoring Systems

International Prognostic Score (Age, WBC, Thrombosis History)

• Low Risk: Median survival ~27.8 years
• Intermediate Risk: ~18.9 years
• High Risk: ~10.9 years
  • Points assigned:
    • Age ≥67: 5 points
    • Age 57–66: 2 points
    • WBC ≥15 × 10⁹/L: 1 point
    • Venous thrombosis history: 1 point

Mutation-Enhanced International Prognostic Scoring System (MIPSS)

• Factors:
  • Age >67 (2 points)
  • Thrombosis history (1 point)
  • WBC ≥15 × 10⁹/L (1 point)
  • SRSF2 mutation (3 points)
• Risk Tiers and Median Survival:
  • Low (0–1 points): 24 years
  • Intermediate (2–3 points): 13.1 years
  • High (≥4 points): 3.2 years

Thrombosis

Overview

• Thrombosis is a leading cause of morbidity and mortality in PV.
• Events may be arterial (e.g., myocardial infarction, stroke) or venous (e.g., deep vein thrombosis, splanchnic vein thrombosis).
• Thrombotic risk correlates with hyperviscosity and may be influenced by leukocytosis, though this relationship remains controversial.

Management

• Standard anticoagulation should be administered for all thrombotic events.
• Concomitant cytoreduction is recommended under the guidance of a haematologist.
• Aspirin use is contraindicated in patients with acquired von Willebrand’s disease due to increased bleeding risk.

Haemorrhage

Epidemiology

• Major bleeding occurs in 1.7% to 20% of PV patients, though life-threatening events are rare.

Contributors

• Elevated platelet counts (≥1000 × 10⁹/L) may contribute through acquired von Willebrand’s disease.
• Aspirin or anticoagulants can exacerbate bleeding, particularly in those with abnormal coagulation profiles.

Management

• Discontinue antiplatelet/anticoagulant therapy if bleeding is suspected.
• Perform ristocetin cofactor activity testing in the context of unexplained bleeding.
• Cytoreductive therapy is indicated when platelet counts are excessively high.

Post-PV Myelofibrosis

Natural History

• Occurs in 4.9–6% at 10 years and up to 14% at 15 years.
• Features include anaemia, reduced need for phlebotomy, marrow fibrosis, and splenomegaly.

Risk Factors

• High JAK2 V617F allele burden.
• Baseline reticulin fibrosis in the bone marrow.

Management

• Primarily palliative
• Allogeneic stem cell transplantation is the only curative option, reserved for select patients.

Acute Leukaemia and Myelodysplastic Syndrome

Risk Estimates

• Transformation to AML or MDS occurs in 2.3–14.4% by 10 years and 5.5–18.7% by 15 years.

Treatment-Related Risks

• Chlorambucil and phosphorus-32 are associated with higher leukaemic transformation rates.
• Hydroxycarbamide has a reported 5.9% risk over 15 years, though causality is debated.

Prognosis

• Poor; post-PV AML is resistant to conventional chemotherapy.
• Allogeneic stem cell transplant may be an option for fit individuals.

Drug-Related Complications

Busulfan

• Leukaemogenicity is unclear; some studies suggest increased risk when used sequentially with hydroxycarbamide.
• Not recommended by current NCCN guidelines.

Hydroxycarbamide

• Pancytopenia is the most serious adverse effect.
• Associated with potential transformation to myelofibrosis or leukaemia, particularly in patients developing cytopenias.

Pegylated Interferon

• High discontinuation rate due to toxicity.
• Common side effects: flu-like symptoms, depression, cardiovascular symptoms, autoimmune disease.
• Requires careful patient screening and thyroid monitoring.

Other Complications

Pruritus

• Common and often severe; may be refractory to standard antihistamines.
• Responds to pegylated interferon or ruxolitinib.
• Preliminary evidence supports potential use of omalizumab.

Severe Erythromelalgia

• Painful, burning erythema of extremities or face/neck.
• Generally responds to low-dose aspirin unless contraindicated.

Peptic Ulcer Disease

• Observed at a rate 3–5 times that of the general population.
• Attributed to elevated serum histamine.

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