prepare a case for a presentation on polycythemia vera. patient of OSA with secondary polycythemia
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"obstructive sleep apnea" AND "secondary polycythemia" AND "JAK2"
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PMID: 38213957
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"polycythemia vera" AND "WHO criteria" AND diagnosis
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Case Presentation: Polycythemia Vera Unmasked in a Patient with OSA
For Attending Physician Grand Rounds
SECTION 1 - CASE VIGNETTE
Patient: Mr. A.K., 55-year-old male
Setting: Referred from sleep clinic to hematology
Chief Complaint: Incidentally noted elevated hemoglobin on routine blood work.
History of Present Illness:
Mr. A.K. is a morbidly obese (BMI 38) gentleman with a 6-year history of moderate-severe obstructive sleep apnea (OSA), currently on CPAP therapy with reported partial compliance. He was referred after a routine CBC showed persistent erythrocytosis despite months of adequate CPAP use. He reports chronic fatigue, morning headaches, flushing of the face, and occasional pruritus after hot showers (aquagenic pruritus). He denies frank cyanosis, cor pulmonale symptoms, or daytime SaO2 dips on recent monitoring.
Past Medical History:
- Obstructive sleep apnea (on CPAP)
- Hypertension (on amlodipine)
- Gout (on allopurinol)
Medications: Amlodipine 5 mg OD, allopurinol 300 mg OD, CPAP (prescribed 10 cmH2O, compliance ~4.5 hrs/night)
Social History: Non-smoker, occasional alcohol use, desk job
Family History: Father had an unspecified "blood disorder"
Review of Systems: Headaches, tinnitus, transient visual blurring; denies significant snoring (since CPAP), no hemoptysis, no weight loss
SECTION 2 - EXAMINATION FINDINGS
| Finding | Detail |
|---|---|
| Vitals | BP 148/94 mmHg, HR 86, SpO2 96% (room air, awake), BMI 38 |
| General | Plethoric facies, obese |
| Eyes | Conjunctival injection, no icterus |
| Abdomen | Spleen palpable 3 cm below left costal margin (splenomegaly) |
| Extremities | Mild erythema of fingertips bilaterally; no clubbing, no cyanosis |
| Skin | No telangiectasia; aquagenic pruritus reported on history |
SECTION 3 - INITIAL INVESTIGATIONS
| Test | Result | Reference |
|---|---|---|
| Hemoglobin | 19.2 g/dL | Men: normal <16.5 g/dL |
| Hematocrit | 57% | Men: normal <49% |
| WBC | 13,400/µL (neutrophilia) | 4,500-11,000 |
| Platelets | 620,000/µL | 150,000-400,000 |
| MCV | 78 fL (microcytic) | 80-96 |
| RDW | Elevated | - |
| Serum EPO | 4 mIU/mL (subnormal) | 4-26 mIU/mL |
| Uric acid | 9.1 mg/dL | - |
| Overnight oximetry (on CPAP) | Mean SaO2 95%, <3% desaturation index: 5/hr | - |
Key Observation: Despite CPAP, hemoglobin remains markedly elevated. The WBC and platelet counts are also elevated (panmyelosis pattern). EPO is subnormal - the opposite of what is expected in secondary erythrocytosis.
SECTION 4 - THE DIAGNOSTIC DILEMMA (Core Teaching Point)
Why Secondary Polycythemia from OSA Was Initially Assumed
OSA causes recurrent nocturnal hypoxia, which stimulates hypoxia-inducible factor (HIF-1α), leading to increased renal EPO secretion and subsequent erythrocytosis. This is a well-documented cause of secondary (reactive) erythrocytosis. Given this patient's established OSA diagnosis, erythrocytosis was initially attributed to this mechanism by the referring physician.
From the anesthesia literature: "Physiologic abnormalities resulting from OSA include hypoxemia, hypercapnia, pulmonary hypertension, systemic vasoconstriction, hypertension, and secondary polycythemia (from recurrent hypoxemia)." - Barash's Clinical Anesthesia, 9e
Red Flags That Should Have Prompted Further Workup
The following features are inconsistent with a pure secondary erythrocytosis from OSA:
| Feature | Expected in Secondary (OSA) | This Patient |
|---|---|---|
| EPO level | Elevated (stimulus-driven) | Subnormal |
| WBC | Normal | Elevated |
| Platelets | Normal | Elevated |
| Splenomegaly | Absent | Present |
| Aquagenic pruritus | Absent | Present |
| Gout/hyperuricemia | Absent | Present |
| Nocturnal SaO2 on CPAP | Expected to normalize | Near-normal (rules out ongoing hypoxic drive) |
The critical principle here: an elevated EPO level favors secondary erythrocytosis; a subnormal EPO level points strongly toward PV. However, as Harrison's states, "a normal serum erythropoietin level does not exclude PV, but an elevated erythropoietin level is most consistent with a secondary cause for the erythrocytosis." - Harrison's Principles of Internal Medicine, 22e
An analogous case published in 2024 (Afana et al., Case Reports in Oncology, PMID 38213957) describes a 55-year-old morbidly obese man on CPAP in whom PV was unmasked, concluding: "PV can be masked by the assumption of secondary polycythemia based on history. This underscores the importance of screening such cohort through JAK2 and EPO testing to avoid missing PV."
SECTION 5 - FURTHER INVESTIGATIONS
| Test | Result |
|---|---|
| JAK2 V617F mutation (NGS) | POSITIVE |
| Bone marrow biopsy | Hypercellular marrow with trilineage proliferation (panmyelosis); pleomorphic megakaryocytes of varying sizes |
| Bone marrow reticulin | Grade 1 fibrosis |
| Cytogenetics | Normal karyotype |
| Arterial blood gas (awake, room air) | PaO2 82 mmHg, SaO2 96% |
SECTION 6 - DIAGNOSIS
Polycythemia Vera (PV)
Meeting all 3 WHO 2016 Major Criteria:
WHO 2016 Diagnostic Criteria for Polycythemia VeraMajor Criteria (all 3 required)
- Hgb >16.5 g/dL (men) OR Hct >49% (men) - Patient: Hgb 19.2 g/dL, Hct 57% ✓
- Bone marrow hypercellularity with trilineage growth (panmyelosis) with pleomorphic megakaryocytes ✓
- JAK2 V617F or JAK2 exon 12 mutation ✓
Minor Criterion
- Subnormal serum EPO level - Patient: EPO 4 mIU/mL (subnormal) ✓
Source: Washington Manual of Medical Therapeutics; originally Arber DA et al., Blood 2016
This patient satisfies all 3 major criteria, making the diagnosis definitive. The minor criterion (subnormal EPO) further supports it.
SECTION 7 - PATHOPHYSIOLOGY REVIEW
Why PV Causes Panmyeloid Expansion
A point mutation at base pair 1849 (G→T) in the JAK2 gene results in a valine-to-phenylalanine substitution at codon 617 (V617F) in exon 14. This mutation affects the autoinhibitory pseudokinase domain of JAK2, causing constitutive JAK-STAT signaling independent of erythropoietin, thrombopoietin, and other cytokine stimulation.
- JAK2 V617F is found in 95-98% of PV patients
- ~50-60% of essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients also carry it (but different phenotype due to additional genomic context)
- The remaining ~2% of PV patients have JAK2 exon 12 mutations (typically isolated erythrocytosis phenotype)
Sources: Harrison's 22e; Goldman-Cecil Medicine
Why OSA Can Coexist and Confound
Secondary erythrocytosis from OSA operates via a distinct, EPO-dependent mechanism:
- Recurrent nocturnal desaturation → HIF-1α activation → increased EPO secretion → erythroid proliferation only
- This produces isolated erythrocytosis (not trilineage), with elevated or high-normal EPO
- When OSA is present concurrently with PV, the hypoxic stimulus is additive to the already autonomous erythroid drive, potentially masking the degree of the underlying neoplasm
SECTION 8 - DISTINGUISHING PV FROM SECONDARY ERYTHROCYTOSIS: FRAMEWORK
| Feature | Polycythemia Vera | Secondary Erythrocytosis (OSA/Hypoxia) |
|---|---|---|
| Pathophysiology | Clonal JAK2-driven autonomous proliferation | EPO-mediated reactive response |
| EPO level | Subnormal or low-normal | Elevated |
| JAK2 V617F | Positive (95-98%) | Negative |
| WBC | Often elevated | Normal |
| Platelets | Often elevated | Normal |
| Splenomegaly | Present in ~70% | Absent |
| Aquagenic pruritus | Characteristic | Absent |
| Bone marrow | Panmyelosis, megakaryocyte atypia | Normal or mild erythroid hyperplasia |
| Erythromelalgia | Can occur | Absent |
| Budd-Chiari / thrombosis | Elevated risk | Not characteristic |
| SaO2 | Normal (awake) | Low or low-normal |
| Cause | Somatic mutation | Identifiable hypoxic/EPO stimulus |
SECTION 9 - MANAGEMENT
This patient is high-risk PV (age >60 or prior thrombosis; note the elevated platelets and cardiovascular risk factors).
Goals
- Maintain Hct <45% in men (hematocrit target reduces thrombotic risk; CYTOREDUCTION TRIAL)
- Control cardiovascular risk factors
Treatment Approach
1. Phlebotomy
- First-line to reduce hyperviscosity
- Target Hct <45% (men)
- Creates iron deficiency state that limits red cell mass re-expansion
- Once iron-deficient, typically needed every 3 months
2. Low-dose Aspirin 81 mg daily
- Reduces thrombotic risk (microvascular events, erythromelalgia)
- Must avoid if platelet count >900,000/µL (risk of acquired von Willebrand's disease)
3. Cytoreductive Therapy - Hydroxyurea (first-line for high-risk)
- Oral myelosuppressive agent
- Target: normalize WBC, platelets, and maintain Hct <45%
- Note: hydroxyurea is leukemogenic and does not target the JAK2-mutated HSC clone
4. Ruxolitinib (JAK1/2 inhibitor) - second-line or for hydroxyurea-refractory/intolerant
- Effective for pruritus, splenomegaly, symptom burden
- Also available for high-risk patients intolerant of hydroxyurea
5. Pegylated Interferon-α (alternative/preferred in younger patients)
- Targets the involved HSC
- Non-mutagenic
- Can produce complete molecular remissions in ~20% of cases
- Preferred over hydroxyurea in patients of childbearing age
6. Address Comorbidities
- Allopurinol: continue for hyperuricemia/gout (appropriate, already prescribed)
- CPAP: continue for OSA (independent indication; treating OSA will not resolve PV)
- Antihypertensives: optimize BP control
7. Monitor for Transformation
- Post-PV myelofibrosis (~15% over 15 years)
- Acute myeloid leukemia (rare without cytotoxic therapy)
Source: Harrison's Principles of Internal Medicine, 22e; Goldman-Cecil Medicine
SECTION 10 - KEY TEACHING POINTS
-
OSA does not exclude PV. The presence of a secondary cause of erythrocytosis must not halt the diagnostic workup. Clinicians must apply clinical reasoning - a trilineage blood count abnormality with splenomegaly is not explained by OSA alone.
-
EPO level is the single most important discriminating test between primary and secondary erythrocytosis. Subnormal EPO in the setting of erythrocytosis is pathognomonic of an autonomous (clonal) process.
-
JAK2 V617F is positive in 95-98% of PV - its presence essentially confirms the diagnosis in the right clinical context.
-
The WHO 2016 criteria are 3 major + 1 minor; the diagnosis can be made with all 3 major OR with the first 2 major + the minor (subnormal EPO) criterion.
-
Aquagenic pruritus - pruritus after warm water exposure - is a highly specific symptom of PV and should always prompt consideration of the diagnosis.
-
Panmyelosis (elevated Hgb + WBC + platelets) = think MPN, not reactive. Secondary erythrocytosis produces isolated erythrocytosis.
-
Treatment goal is Hct <45% in men. Phlebotomy alone is first-line; cytoreduction is added in high-risk patients.
REFERENCES
- Harrison's Principles of Internal Medicine, 22e (2025), Chapter 108 - Myeloproliferative Neoplasms
- Goldman-Cecil Medicine, International Edition, Chapter 152 - Polycythemia Vera and Related Conditions
- Washington Manual of Medical Therapeutics - WHO 2016 PV Diagnostic Criteria (after Arber DA et al., Blood 2016;127:2391-2405)
- Barash's Clinical Anesthesia, 9e - Respiratory complications of OSA
- Afana MS et al. "Obstructive Sleep Apnea Does Not Exclude Polycythemia Vera: A Case Report." Case Reports in Oncology, 2024. PMID: 38213957
This case is structured for a 20-30 minute attending-level presentation. It works well as a "clinicopathological conference" format: present the case and investigations in Sections 1-4, pause for group discussion on the diagnostic dilemma, then walk through Sections 5-10. The comparison table in Section 8 is particularly useful as a projected slide. Let me know if you would like this converted to a PPTX or DOCX file.
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