Erythrocytosis (Polycythemia)

A comprehensive overview for clinicians, students, and curious patients

1. Definition and Basic Concepts

Term	Core idea	Key laboratory hallmark	Typical drivers
Absolute erythrocytosis	True expansion of total red‑cell mass (RCM)	↑ RBC mass on isotope study or markedly elevated hematocrit/hemoglobin	Primary bone‑marrow disorders or sustained erythropoietin (EPO) stimulation
Relative (spurious) erythrocytosis	Normal RCM but ↓ plasma volume (hemoconcentration)	High hematocrit but normal red‑cell mass	Dehydration, diuretics, stress‑polycythemia (“Gaisböck syndrome”)

A hematocrit (Hct) > 52 % in men or > 48 % in women (or hemoglobin > 18.5 g/dL and > 16.5 g/dL, respectively) should prompt a structured evaluation.

2. Classification

Primary (EPO‑independent) erythrocytosis
- Polycythemia vera (PV): Chronic myeloproliferative neoplasm driven by JAK2 mutations (≈ 95 % V617F, ≈ 3 % exon 12).
- Primary familial/congenital polycythemias (rare): Germ‑line defects in EPO receptor, VHL, EPAS1 (HIF‑2α).
Secondary (EPO‑driven) erythrocytosis
- Hypoxia‑mediated – COPD, obstructive sleep apnea (OSA), cyanotic heart disease, chronic high‑altitude exposure, heavy smoking (carbon‑monoxide binding).
- Pathologic EPO secretion – Renal cell carcinoma, hepatocellular carcinoma, uterine fibroids, cerebellar hemangioblastoma, pheochromocytoma, adrenal adenoma.
- Drug‑ or hormone‑related – Exogenous EPO, testosterone or anabolic‑androgenic steroids, SGLT2 inhibitors (mild).
Relative (spurious) erythrocytosis – Plasma‑volume contraction (burns, dehydration, diuretics, severe vomiting).

3. Pathophysiology Snapshot

Elevated red‑cell mass → ↑ whole‑blood viscosity
Hyperviscosity slows microvascular flow → tissue hypoxia and thrombogenesis
In PV, excessive platelets and leukocytes add a prothrombotic milieu and chronic inflammatory signaling (JAK‑STAT activation).

4. Clinical Presentation

“Hyper‑viscosity” symptoms	Thrombotic/vascular events	PV‑specific clues
Headache, dizziness, tinnitus	Deep‑vein thrombosis, stroke, MI, Budd–Chiari syndrome, portal‑splenic thrombosis	Aquagenic pruritus (itch after warm shower), erythromelalgia (burning hands/feet), facial plethora, splenomegaly
Visual blurring, choreiform movements	Microvascular angina, claudication	Gout, peptic ulcers (histamine release), leukocytosis

5. Step‑wise Diagnostic Approach

Confirm erythrocytosis
- CBC repeat × 2, consider plasma‑volume/RBC‑mass study if results are borderline or suspicion of relative polycythemia.
Rule out primary PV
- JAK2 V617F (first‑line), if negative test exon 12.
- Bone‑marrow biopsy if mutation‑negative but strong clinical suspicion.
Assess for secondary drivers
- Serum EPO: Low/normal → suggests PV; High → secondary.
- Arterial oxygen saturation, carboxyhemoglobin (smokers), overnight oximetry or polysomnography, chest X‑ray/CT, abdominal ultrasound/CT (renal masses), serum testosterone level.
Additional labs: Ferritin (PV is often iron‑deficient), LDH, uric acid, basic metabolic panel, coagulation profile.

6. Management Principles

Scenario	First‑line measures	Additional / special situations
Polycythemia vera	Therapeutic phlebotomy to keep Hct < 45 % (men) or < 42 % (women); low‑dose aspirin 81 mg daily (unless contraindicated)	Cytoreduction when high‑risk (age ≥ 60 y or prior thrombosis): hydroxyurea; alternatives—interferon‑α (preferred in pregnancy or younger pts), busulfan (elderly), ruxolitinib (JAK inhibitor) for HU‑intolerant/resistant
Secondary erythrocytosis	Treat underlying cause: optimize COPD/OSA therapy (CPAP), resect EPO‑secreting tumor, adjust exogenous testosterone/EPO	Phlebotomy only if symptomatic hyperviscosity or Hct > 56 % despite correction of driver; avoid iron deficiency
Relative erythrocytosis	Re‑hydrate, stop offending diuretics, manage stress

Lifestyle counseling
Strict smoking cessation, maintain hydration, regular exercise within guidelines, control cardiovascular risk factors (BP, lipids, glucose), avoid iron supplementation unless deficient.

7. Complications & Prognosis

Thrombosis – leading morbidity/mortality cause in PV (arterial > venous).
Hemorrhage – paradoxical bleeding in 5–10 % of PV (acquired von Willebrand disease when Hct very high).
Myelofibrotic or leukemic transformation – PV → post‑PV myelofibrosis (≈ 10‑15 % at 15 y) or AML (≈ 3–10 % lifetime).
Quality‑of‑life issues – chronic pruritus, fatigue, concentration difficulties.

Hemorrhage in polycythemia vera?

Can polycythemia vera cause acquired von Willebrand disease?

AVWS associated with myeloproliferative neoplasia (MPN) primarily results from adsorption of VWF to transformed blood cells, in particular platelets. It has been reported in essential thrombocythemia and polycythemia vera, but also in chronic myeloid leukemia, primary myelofibrosis, and sometimes in acute leukemia.
What is the function of ADAMTS13? The enzyme ADAMTS13 breaks down von Willebrand factor into smaller pieces to regulate its interaction with platelets.

With modern risk‑adapted therapy, median survival in PV now exceeds 18–20 years; patients achieving strict Hct control have stroke/MI rates comparable to the general population.

8. Follow‑up & Monitoring

Parameter	Interval	Notes
CBC, differential	Every 3 mo while titrating; q6–12 mo when stable	Watch for iron deficiency (falling MCV) or leukocytosis
Ferritin, iron studies	At diagnosis, then if MCV ↓ or fatigue ↑	Iron store repletion in PV is individualized
Symptom assessment (pruritus, microvascular)	Every visit	MPN‑SAF TSS questionnaire can help quantify burden
JAK2 allele burden (PV)	Baseline, then if considering cytoreduction change	Rising burden may herald disease progression
Bone‑marrow biopsy	At diagnosis (optional); if cytopenias, splenomegaly, or ↑ LDH	Evaluate for post‑PV myelofibrosis

9. Special Situations

Pregnancy – Aim Hct < 45 % via phlebotomy; low‑dose aspirin; consider interferon‑α if cytoreduction needed.
High‑altitude residents – “Chronic mountain sickness” can mimic PV; treatment centers on acclimatization breaks, supplemental oxygen over 3,000 m.
Athletes – Distinguish physiologic “sports polycythemia” (↑ plasma volume + modest RBC mass) from doping with EPO/testosterone; look for suppressed EPO level in the former.

10. Key Take‑Home Messages

Always verify true red‑cell mass; do not mistake dehydration for PV.
Low EPO + JAK2 mutation = PV until proven otherwise.
Target hematocrit ≤ 45 % saves lives—confirmed by CYTO‑PV RCT.
Treat the root cause in secondary erythrocytosis; phlebotomy is supportive, not curative.
Regular follow‑up is crucial to prevent thrombosis and detect progression early.

Disclaimer: This educational article is not a substitute for individualized medical care. Patients should discuss diagnosis and treatment options with their qualified healthcare professional.

References:

Polycythemia: https://www.ncbi.nlm.nih.gov/books/NBK526081/

Polycythemia: https://www.testmottagningen.se/en/symtom/hjart-och-karlsjukdomar/polycytemi/#:~:text=Polycythemia%20%2D%20too%20many%20red%20blood%20cells,cells%20%2D%20an%20increased%20amount%20of%20erythrocytes.

High red blood cell count: https://www.altru.org/health-library/symptoms/high-red-blood-cell-count

Red Blood Cell Disorders: https://health.ucdavis.edu/conditions/blood-disorders/red-blood-cell-disorders

Red Blood Cell (RBC) Count: https://www.healthline.com/health/rbc-count

Polycythemia Everything you need to know: https://www.medicalnewstoday.com/articles/polycythemia

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