Hematology & Internal Medicine & Family Medicine
Polycythemia (polycythemia)
Polycythemia—also known as polyglobulia—is defined by an abnormal increase in circulating red blood cell mass, which is reflected in laboratory tests by elevated levels of serum hemoglobin, hematocrit, and red blood cell count beyond the normal range adjusted for gender. The current diagnostic thresholds for polycythemia vera (PV—see below) according to the 2022 WHO criteria are a hemoglobin level > 165 g/L in men and > 160 g/L in women, or a hematocrit > 49% in men and > 48% in women—thresholds lower than the 2016 WHO criteria to improve early detection. It is essential to distinguish between two major mechanisms of polycythemia with radically different diagnostic and therapeutic implications: absolute polycythemia—in which the total red blood cell mass is actually increased due to bone marrow overproduction (polycythemia vera, polycythemia secondary to erythropoietin overproduction)—and relative or concentration polycythemia—in which the red blood cell mass is normal but a reduction in plasma volume (dehydration, diuretics, vomiting) concentrates the red blood cells and makes hemoglobin and hematocrit appear elevated. Relative polycythemia is much more common than absolute polycythemia in general practice and resolves spontaneously with correction of dehydration. Polycythemia vera (PV) is the primary and most severe form—a clonal myeloproliferative neoplasm of hematopoietic stem cells characterized by a somatic mutation in the JAK2 gene (primarily JAK2 V617F in 95% of cases) that confers increased sensitivity and constitutional activation of EPO and other cytokine signaling pathways, leading to uncontrolled autonomous proliferation of the three bone marrow lineages (erythrocytes, leukocytes, and platelets) with a predominance of the red blood cell lineage. Its major thrombotic risk (arterial and venous thrombosis—stroke, myocardial infarction, portal vein thrombosis) is the leading cause of mortality and warrants early antiproliferative and antithrombotic treatment.
Classification and etiologies
| Category | Mechanism and main etiologies | Distinctive biological characteristics |
|---|---|---|
| Relative polycythemia (false polycythemia) | Reduced plasma volume → RBC concentration + dehydration (vomiting + diarrhea + excessive diuresis + heat) + diuretics + extensive burns + smoking (CO → chronic hemoconcentration) + Gaisbock's syndrome (obesity + hypertension + stress + smoking in middle-aged men) | Elevated hemoglobin and hematocrit + but NORMAL red blood cell mass (measurable by Cr51 scintigraphy - rarely performed) + normal or low EPO + negative JAK2 + normalization with rehydration |
| Polycythemia Vera (PV) - Primary Polycythemia | Somatic JAK2 V617F (95 %) or JAK2 exon 12 (3–5 %) mutation → constitutive activation of EPO-independent JAK-STAT pathways → autonomous proliferation of all three cell lines + predominantly erythrocytosis + frequent leukocytosis and thrombocytosis | Low or undetectable EPO + JAK2 V617F positive + polycythemia + often leukocytosis + thrombocytosis + splenomegaly + aquagenic pruritus (pathognomonic) + increased red blood cell mass |
| Appropriate secondary polycythemia (chronic hypoxia) | Chronic tissue hypoxia → stimulation of EPO production by renal peritubular cells → increased erythropoiesis + severe COPD (chronic SpO₂ < 90 %) + right heart failure + high-altitude exposure (mountaineers + inhabitants of the Andean and Tibetan highlands) + severe obstructive sleep apnea syndrome | Elevated EPO + JAK2 negative + low O₂ saturation + low PaO₂ on ABG + isolated polycythemia (without leukocytosis or thrombocytosis) + treatment of the cause → progressive normalization |
| Inappropriate secondary polycythemia (ectopic EPO overproduction) | Autonomous, unregulated production of EPO by a tumor or a diseased kidney + clear cell renal cell carcinoma +++ (20 % of CCRs produce EPO) + cerebellar hemangioblastoma (VHL) + hepatocellular carcinoma + adrenal carcinoma + polycystic kidney disease + renal artery stenosis (focal renal hypoxia) | Elevated EPO + JAK2 negative + normal O₂ saturation + abdominal and cerebral CT scan + searching for EPO-producing tumor + treatment = tumor resection |
| Polycythemia due to EPO receptor (EPOR) mutation | Gain-of-function mutation of the erythropoietin receptor → hypersensitivity to normal EPO concentrations → pure erythrocytosis + hereditary + autosomal dominant + normal or low EPO + no leukocytosis or thrombocytosis + often familial | Low or normal EPO + JAK2 negative + isolated polycythemia + family history + EPOR genetic analysis + the champion cyclist Eero Mäntyranta had this mutation (natural sporting advantage) |
Polycythemia Vera — Clinical Presentation and 2022 WHO Diagnostic Criteria
- Clinical manifestations aquagenic pruritus (intense itching following exposure to hot water—pathognomonic and present in 40–70% of patients → mechanism: degranulation of basophils and mast cells upon contact with hot water) + facial erythrosis (purplish-red face) + erythromelalgia (burning pain and redness of the extremities due to microthrombosis of small distal vessels + relieved by aspirin) + headaches + dizziness + tinnitus + visual disturbances (hyperviscosity) + splenomegaly + thromboses (stroke + MI + Budd-Chiari + portal vein thrombosis) + paradoxical hemorrhages (acquired von Willebrand disease) + constitutional symptoms (fatigue + night sweats + weight loss = high MPN-10 score)
- WHO Criteria 2022 — Major Diagnoses: Criterion 1: hemoglobin > 165 g/L (men) or > 160 g/L (women) or hematocrit > 49% (men) or > 48% (women) Criterion 2: bone marrow biopsy = trilineage hypercellularity with pleomorphic megakaryocyte proliferation + criterion 3: presence of the JAK2 V617F mutation + or JAK2 exon 12
- WHO 2022 Minor Criterion: Subnormal serum EPO (low or undetectable)
- Diagnostic PV: The 3 major criteria OR the first 2 major criteria + the minor criterion → diagnosis of polycythemia vera confirmed + the JAK2 V617F mutation alone (criterion 3) with low EPO is sufficient for diagnosis without bone marrow biopsy in typical cases
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Aquagenic pruritus—intense itching following skin contact with water (shower, bath, or swimming pool)—is a nearly pathognomonic sign of polycythemia vera. Although not 100% specific (it can occur in other myeloproliferative neoplasms and in certain liver diseases), its presence in a patient with polycythemia and facial erythema should immediately prompt testing for JAK2 V617F and EPO. Pruritus in PV can be highly debilitating and may precede diagnosis by several years.
Treatment of polycythemia vera
- Thrombotic risk stratification low risk: age < 60 years old + no history of thrombosis + low JAK2 allele burden + high risk: age ≥ 60 years old + or history of thrombosis (arterial or venous) → risk guides treatment intensity
- Phlebotomies (therapeutic bloodletting) — universal treatment: phlebotomy of 450 mL of blood every 1 to 2 weeks until the target hematocrit is achieved< 45 % in men + < 42 % in women — CYTO-PV trial (2013) + followed by maintenance phlebotomy as frequently as necessary + mechanism: erythrocyte depletion + induction of relative iron deficiency (inhibits erythropoiesis) + reduction in blood viscosity and thrombotic risk + standard treatment for all PV patients regardless of risk
- Low-dose aspirin — universal treatment: Aspirin 81–100 mg/day by mouth (unless contraindicated—anticoagulation + allergy) + reduces the risk of arterial thrombosis + particularly indicated for erythromelalgia (rapid relief) + ECLAP study: 59% reduction in major thrombotic events vs. placebo
- Hydroxyurea (hydroxycarbamide — Hydrea®) — first-line cytoreductive treatment: 500 mg to 2 g/day orally depending on response + reduces hemoglobin, platelets, and white blood cells + indicated in cases of high risk (age ≥ 60 years + history of thrombosis) + or if hematocrit is difficult to control with phlebotomy alone + adverse effects: leg ulcers + long-term leukemogenic potential (cumulative risk of transformation to AML estimated at 1–5% over 10 years)
- Ruxolitinib (Jakafi® + Jakavi®) — JAK1/JAK2 inhibitor: 10 to 20 mg twice daily orally + indicated if resistance or intolerance to hydroxyurea + trials RESPONSE and RESPONSE-2 (Vannucchi 2015 — NEJM): hematocrit control + reduction of splenomegaly + improvement of symptoms (pruritus ++) + superior to standard second-line therapies + adverse effects: anemia + thrombocytopenia + reactivated herpes infections + reimbursed by the RAMQ after failure of hydroxyurea
- Pegylated interferon alpha (Besremi® — ropeginterferon alfa-2b): approved by Health Canada for PV + SC injection every 2 weeks → reduction of JAK2 allele burden (disease-modifying effect) + indicated for first-line therapy in young patients ((< 60 years old) to spare hydroxyurea +/- or in case of hydroxyurea intolerance
Situations requiring urgent hematological consultation
A hematocrit greater than 55–60% with headache + dizziness + visual disturbances + or acute thrombosis (stroke + TIA + Budd-Chiari syndrome + portal vein thrombosis in a young patient) constitutes a hematologic emergency—an urgent therapeutic phlebotomy of 450 mL must be performed within hours to reduce blood viscosity, concurrently with diagnostic testing (JAK2 + EPO + CBC). Any polycythemia with JAK2 V617F positivity must be referred to hematology within days of diagnosis to initiate treatment.
For the evaluation of polycythemia (elevated hemoglobin or hematocrit), serum EPO and JAK2 V617F mutation testing, phlebotomy decisions, and hematological management, Clinique Omicron offers medical consultations at its service points in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
Consult at Clinique Omicron
Clinique Omicron's physicians and registered nurse practitioners (RNPs) assess patients with high hemoglobin or hematocrit levels, prescribe serum EPO levels and the JAK2 V617F mutation test along with a complete blood count (CBC) to differentiate relative polycythemia from absolute primary (PV) or secondary forms, perform maintenance therapeutic phlebotomies for patients with known PV, and refer to hematology for initiation of cytoreductive therapy and specialized follow-up. Consultations are available at several service points in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not substitute for advice from a physician or hematologist. Polycythemia vera is a chronic myeloproliferative neoplasm requiring indefinite treatment and regular hematologic monitoring to prevent thrombotic complications and monitor for progression to myelofibrosis or acute leukemia.
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