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

• 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.
  
  

• 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.
  
  

• 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

• 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.
  
  

• 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

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

• 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

• PV originates from a multipotent haematopoietic stem cell acquiring a somatic mutation, most commonly in JAK2.
• The JAK2 V617F mutation:
  • Occurs in >95% of PV patients.
  • Substitutes valine for phenylalanine at position 617, leading to constitutive activation of the JAK-STAT signalling pathway.
  • Drives cytokine-independent proliferation of red cells, white cells, and platelets (trilineage hyperplasia).
• Exon 12 mutations (seen in ~3–4%):
  • Also promote erythrocytosis but are typically restricted to the erythroid lineage.
    
    

Bone Marrow Findings and Growth Characteristics

• Bone marrow biopsy shows:
  • Age-inappropriate hypercellularity.
  • Trilineage expansion (panmyelosis), with increased erythroid, granulocytic, and megakaryocytic precursors.
• Erythroid progenitors in PV:
  • Exhibit autonomous growth in vitro without erythropoietin.
  • Suggest a downstream defect in cytokine receptor signalling, affecting multiple growth factor pathways.
    
    

JAK2 Allele Burden and Clinical Implications

• Homozygosity for JAK2 V617F is more frequent in males.
• Higher JAK2 V617F allele frequency (>50%) is associated with:
  • Increased risk of venous thrombosis.
  • Higher rates of progression to post-PV myelofibrosis.
  • Elevated leukocyte and platelet counts.
    
    

Haemostatic Disruption and Thrombosis

• Hyperviscosity due to elevated red cell mass contributes to:
  • Microvascular symptoms (e.g. headache, dizziness, erythromelalgia).
  • Increased risk of arterial and venous thromboses.
• Thrombotic mechanisms include:
  • Enhanced leukocyte activation and tissue factor expression.
  • Platelet-derived microparticles promoting coagulation.
  • Elevated platelet counts with abnormal function.
• Neutrophil extracellular traps (NETs):
  • Formed by activated neutrophils.
  • Contribute to thrombosis in PV.
  • May be suppressed by JAK inhibitors in preclinical models.
    
    

Leukocytosis and Thrombotic Risk

• While high white cell counts are common, evidence linking leukocytosis to thrombosis is inconsistent:
  • Some studies show correlation.
  • Others suggest leukocytosis is not independently predictive.
    
    

Platelet Count and Thrombotic Risk

• Thrombocytosis is not an independent risk factor for thrombosis.
• Extremely high platelet counts (>1,000 × 10⁹/L) may cause:
  • Acquired von Willebrand syndrome.
  • Increased bleeding tendency due to vWF adsorption onto platelets.
    
    

Bleeding Complications

• Haemorrhage may result from:
  • Acquired von Willebrand syndrome (seen in up to 15% of PV patients).
  • Platelet dysfunction and microvascular damage.
    
    

Inflammatory and Metabolic Factors

• Hyperhomocystinaemia:
  • Present in over half of PV patients.
  • Considered an additive thrombotic risk factor.
• Inflammatory cytokines and oxidative stress may also contribute to endothelial dysfunction.
  
  

PV Genomic and Expression Profiles

• Gene expression profiling distinguishes PV phenotypes:
  • Independent of age, sex, or JAK2 allele burden.
  • Associated with differences in disease duration, splenomegaly, thrombosis frequency, treatment history, and risk of transformation.
• Expression signatures may vary by age and sex:
  • Some profiles correlate with adverse outcomes or differential progression rates.
    
    
    
    

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

• 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.

• 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.
  
  

• 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.
  
  

• 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.
  
  
  

• 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

• 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.
  
  

• 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

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

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

• 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

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

• 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

• 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.
  
  

• 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

• 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.
  
  

• 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

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

Musculoskeletal and Joint Findings

• 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

• 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

• 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

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

Initial Screening and Haematological Parameters

• 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.
  
  

• 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.
  
  

• 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

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

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

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

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

Molecular and Bone Marrow 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.
  
  
  

• 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

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

• 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

• 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.
  
  

• 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

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

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

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

• Helps exclude secondary polycythaemia due to hypoxia or smoking.
  
  

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

WHO Diagnostic Criteria for PV (2022 Revision)

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

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

• Subnormal serum erythropoietin

Myeloproliferative Neoplasms (MPNs)

• ET may resemble masked PV but is distinguished by:
  • Persistent isolated thrombocytosis with normal haemoglobin, red cell mass, and EPO levels.
  • Absence of aquagenic pruritus and marked plethora.
  • Splenomegaly is less common (10–20%) than in PV.
• Molecular profile:
  • CALR or MPL mutations are frequently found and typically exclude PV.
  • JAK2 mutations may be present in ~60%, overlapping with PV but lacking erythrocytosis.
• Bone marrow:
  • Proliferation primarily in the megakaryocytic lineage with large, hyperlobulated megakaryocytes.
  • Trilineage hyperplasia is absent.
• Distinguishing ET from masked PV may require evaluating haemoglobin/haematocrit thresholds and bone marrow features.
  
  

• PMF presents with:
  • Anaemia, marked splenomegaly, and systemic symptoms (e.g. weight loss, night sweats).
  • Peripheral smear may reveal tear-drop poikilocytes and nucleated red blood cells.
• Histopathology:
  • Bone marrow fibrosis, abnormal megakaryocyte clustering, and absence of trilineage hyperplasia.
• May carry JAK2, CALR, or MPL mutations, but erythrocytosis is generally absent.
  
  

• Characterised by marked granulocytosis and the presence of the Philadelphia chromosome (BCR::ABL1 fusion gene).
• Thrombosis is rare.
• Confirmed by FISH or PCR testing for BCR::ABL1.
  
  
  

Reactive (Secondary) Causes of Polycythaemia

• Chronic hypoxic states stimulate EPO production:
  • Causes include COPD, cyanotic heart disease, high altitude, and sleep apnoea.
  • Smoking-related carbon monoxide exposure must be assessed (carboxyhaemoglobin levels).
• Investigations:
  • Oxygen saturation <92% suggests tissue hypoxia.
  • Arterial blood gas, overnight oximetry, and pulmonary function tests assist in diagnosis.
• EPO levels are elevated or normal; red cell mass may be increased, but white cells and platelets are normal.
  
  

• Include renal cell carcinoma, hepatocellular carcinoma, cerebellar haemangioblastoma.
• Clues:
  • Paraneoplastic syndromes, constitutional symptoms, or abdominal masses.
• Confirm with imaging (e.g. renal ultrasound, CT, MRI) and elevated EPO levels.
  
  

• History of testosterone or anabolic steroid use may explain erythrocytosis.
• Cessation typically normalises haemoglobin levels.
• No clonal markers or marrow abnormalities.
  
  
  

Inherited and Congenital Polycythaemias

• Often autosomal dominant or recessive, usually present in childhood or early adulthood.
• May involve:
  • EPO receptor (EPOR) gain-of-function mutations.
  • Mutations in oxygen-sensing genes: VHL, HIF2α, PHD2.
  • Haemoglobin variants with increased oxygen affinity (e.g. low P50 on dissociation curve).
• Diagnostic approach:
  • Detailed family history.
  • Genetic testing and oxygen dissociation studies.
    
    

Masked PV and Diagnostic Challenges

• Some patients meet molecular and histological criteria for PV but lack classical erythrocytosis.
• More frequently seen in men and often misdiagnosed as ET.
• Associated with higher platelet counts, higher risk of thrombosis, and poorer prognosis.
• Requires careful interpretation of haemoglobin/haematocrit, bone marrow biopsy, and JAK2 mutation status.
  
  

Treatment Objectives

• Prevent major thrombotic events.
• Alleviate disease-related symptoms (e.g. pruritus, erythromelalgia).
• Maintain haematocrit below 45%.
• Minimise transformation to post-PV myelofibrosis or acute leukaemia (although no current treatment has been proven to reduce this risk).
  
  

• Address cardiovascular risk factors (hypertension, diabetes, hyperlipidaemia, smoking).
• Optimise quality of life with symptom control and supportive care.
• Adapt therapy for specific populations such as pregnant women and children.
  
  

Risk Stratification

• Age <60 years and no history of thrombosis.

• Age ≥60 years or history of thrombosis.

• Presence of cardiovascular risk factors.
• Uncontrolled haematocrit despite phlebotomy.
• Marked leukocytosis or thrombocytosis.
  
  

Core Treatment Modalities

• Recommended for all patients unless contraindicated.
• Reduces thrombotic risk and relieves microvascular symptoms (e.g. erythromelalgia, pruritus).
• Twice-daily dosing may benefit patients with refractory symptoms or high thrombotic risk.
• Caution advised in patients with acquired von Willebrand syndrome (evaluate ristocetin cofactor activity).
  
  

• Indicated in all low-risk and high-risk patients to promptly reduce haematocrit.
• Target: Haematocrit <45%.
• Typical schedule: 250–500 mL removed twice weekly or on alternate days if haematocrit ≥60%.
• Phlebotomy induces iron deficiency, contributing to symptom control but may cause fatigue or cognitive slowing.
• Iron replacement is generally avoided unless severe symptoms emerge.
  
  

Cytoreductive Therapy

• Routinely for high-risk patients.
• Considered in low-risk patients with:
  • New thrombotic or bleeding events.
  • Progressive cytoses or symptomatic disease.
  • Intolerance or failure of phlebotomy alone.

• Hydroxycarbamide:
  • Oral antimetabolite.
  • Decreases thrombotic events.
  • Teratogenic and potentially leukaemogenic (especially with long-term use).
  • Requires regular monitoring for cytopenias.
• Ropeginterferon alfa-2b:
  • Long-acting pegylated interferon.
  • Shown to reduce JAK2 V617F allele burden over time
  • Non-inferior to hydroxycarbamide; superior in maintaining response long-term.
  • Contraindicated in autoimmune, hepatic, or psychiatric disorders.
• Peginterferon alfa-2a:
  • Favoured in younger patients and those who are pregnant.
  • High response rates but more adverse effects.
  • May induce molecular remission in some cases.
    
    

Second-Line and Salvage Therapy

• Ruxolitinib (JAK1/2 inhibitor):
  • Used in hydroxycarbamide-resistant or -intolerant patients.
  • Benefits include haematocrit control, spleen reduction, symptom relief.
  • Requires monitoring for herpes zoster and non-melanoma skin cancers.
• Busulfan:
  • Reserved for elderly or frail patients intolerant to other agents.
  • Long-term use associated with increased risk of secondary malignancies.
  • Not recommended by NCCN guidelines.
• Contraindicated agents:
  • Radioactive phosphorus, chlorambucil, and pipobroman—associated with leukaemic transformation.
    
    

Special Considerations

• Cytoreduction may be used in high-risk patients to control elevated counts.
• Platelet counts ≥1000 × 10⁹/L warrant testing for von Willebrand factor deficiency.
• Anagrelide may be added for refractory thrombocytosis.
  
  

• Lower haematocrit target (e.g. <41% in first trimester).
• Phlebotomy used cautiously if needed.
• Low-dose aspirin plus LMWH (postpartum for 6 weeks) is standard.
• Peginterferon alfa-2a is the cytoreductive agent of choice.
• Hydroxycarbamide is contraindicated during pregnancy and breastfeeding.
  
  

• Treatment is rare and based on expert consensus.
• Phlebotomy and low-dose aspirin for symptom or risk control.
• Cytoreduction is rarely used but interferon may be considered with caution.
  
  

Monitoring and Response Assessment

• Regular monitoring of haematocrit, full blood count, and symptom burden.
• Routine bone marrow biopsy or JAK2 allele burden testing not indicated unless transformation is suspected.
  
  

• Complete Response (CR):
  • Haematocrit <45% without phlebotomy.
  • WBC ≤10 × 10⁹/L, Platelets ≤400 × 10⁹/L.
  • Symptom improvement (≥10-point MPN-SAF score drop).
  • No vascular events or disease progression.
• Partial Response (PR):
  • Meets all but histologic criteria of CR.
• Progressive Disease:
  • Transformation to myelofibrosis, myelodysplastic syndrome, or acute leukaemia.
    
    

Overall Survival

• 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
    
    

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

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

Major Causes of Morbidity and Mortality

• 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
    
    

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

• 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.
  
  

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

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

Progression Risk and Disease Transformation

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

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

Prognostic 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
  
  

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

• 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

• 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
      
      

• 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

• 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.

• 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

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

• 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.
  
  

• 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

• 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.
  
  

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

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

Acute Leukaemia and Myelodysplastic Syndrome

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

• 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.
  
  

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

Drug-Related Complications

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

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

• 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

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

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

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

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