Borderline High Hemoglobin (15.5–17 g/dL): Work‑up and Management
Your hemoglobin levels of 15.5–16.5 g/dL (with one reading at 17 g/dL) do not meet the standard WHO diagnostic thresholds for polycythemia vera and likely represent normal physiologic variation or mild secondary erythrocytosis that requires only watchful waiting with periodic monitoring rather than aggressive investigation. 1
Understanding Your Hemoglobin Values in Context
Your hemoglobin range sits in a gray zone that warrants clarification:
For men: The WHO major criterion for polycythemia vera requires hemoglobin ≥18.5 g/dL, or alternatively ≥17 g/dL with a documented sustained increase of ≥2 g/dL from your personal baseline 2, 1. Your single reading of 17 g/dL does not meet criteria unless you can document a prior baseline at least 2 g/dL lower (e.g., 15 g/dL or less) that was sustained 1.
For women: The WHO major criterion requires hemoglobin ≥16.5 g/dL, or alternatively ≥15 g/dL with a documented sustained increase of ≥2 g/dL from baseline 2, 1. If you are female and your hemoglobin fluctuates between 15.5–16.5 g/dL with one peak at 17 g/dL, this does exceed the standard threshold and warrants JAK2 mutation testing 1, 3.
Normal reference ranges: Adult males typically have hemoglobin 15.5 ± 2.0 g/dL (range 13.5–17.5 g/dL) and post-menopausal females 14.0 ± 2.0 g/dL (range 12–16 g/dL) 4. Your values are at the upper end of normal or just above, depending on sex.
When to Pursue Further Work‑up
Proceed with diagnostic evaluation if any of the following apply:
Sex-specific thresholds are met: Women with hemoglobin ≥16.5 g/dL or men with hemoglobin ≥18.5 g/dL should undergo JAK2 mutation testing immediately 1, 3.
Sustained rise from baseline: If you have documented hemoglobin values ≥2 g/dL lower than current levels (e.g., prior baseline 14–15 g/dL, now consistently 16.5–17 g/dL), this meets alternative WHO criteria and warrants JAK2 testing 1, 3.
Associated clinical features: Presence of thrombocytosis (platelets ≥450 × 10⁹/L), leukocytosis (WBC ≥12 × 10⁹/L), splenomegaly, aquagenic pruritus (itching after warm showers), unusual thrombosis, or erythromelalgia (burning pain in hands/feet) should prompt immediate hematology referral 3.
Progressive trend: If serial measurements over 6–12 months show a steady upward trajectory (e.g., 15.5 → 16.0 → 16.5 → 17.0 g/dL), this warrants investigation even if absolute thresholds are not yet met 4, 3.
Initial Laboratory Work‑up (If Indicated)
Order the following tests to differentiate primary from secondary causes:
JAK2 V617F mutation (exon 14): First-line molecular test that detects >90% of polycythemia vera cases 1, 3. If negative, consider JAK2 exon 12 mutation testing, which captures an additional 3–5% of cases 2, 1.
Complete blood count with differential: Assess for thrombocytosis (platelets ≥450 × 10⁹/L) and leukocytosis (WBC ≥12 × 10⁹/L), which support polycythemia vera diagnosis 3.
Serum erythropoietin level: Low or low-normal EPO suggests primary polycythemia vera, whereas elevated EPO indicates secondary erythrocytosis 4, 3.
Serum ferritin and transferrin saturation: Iron deficiency can mask polycythemia vera by lowering hemoglobin; ferritin <30 ng/mL or transferrin saturation <20% indicates iron depletion that must be corrected before formal diagnosis 1, 4.
Reticulocyte count and peripheral blood smear: Evaluate bone marrow response and red cell morphology 4.
Systematic Evaluation for Secondary Causes
If JAK2 mutation is negative, investigate the following secondary causes in order of likelihood:
Hypoxia-Driven Causes
Obstructive sleep apnea: Order polysomnography (sleep study) if you have snoring, witnessed apneas, daytime somnolence, or obesity 4, 3. Nocturnal hypoxemia drives EPO production and resolves with CPAP therapy 4.
Chronic obstructive pulmonary disease (COPD): Obtain pulmonary function tests and chest imaging if you have smoking history, chronic cough, or dyspnea 4, 3.
Smoking: Carbon monoxide from smoking causes tissue hypoxia and stimulates EPO production ("smoker's polycythemia") 4. This resolves with smoking cessation 4.
High altitude residence: Physiologic adaptation to altitude increases hemoglobin by 0.2–4.5 g/dL depending on elevation (1000–4500 meters) 4, 3. At 4000 meters, normal male hemoglobin averages 17.3 g/dL (range 13–21 g/dL) 3.
Non-Hypoxia-Driven Causes
Testosterone therapy: Prescribed or unprescribed testosterone causes erythrocytosis in 6–11% of patients undergoing JAK2 testing 5. Review all medications and supplements 4, 3.
SGLT2 inhibitors: Sodium-glucose cotransporter-2 inhibitors (e.g., empagliflozin, dapagliflozin) are an increasingly common cause of elevated hemoglobin, accounting for 2–19% of cases in recent series 5. Stopping SGLT2 inhibitors decreases hemoglobin by an average of 14.7 g/dL 5.
Erythropoietin-producing tumors: Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce EPO autonomously 4. Obtain renal ultrasound or CT if EPO is elevated without hypoxia 4.
Renal disease: Hydronephrosis, polycystic kidney disease, and post-renal transplant erythrocytosis can elevate EPO 2, 4.
Relative Polycythemia (Plasma Volume Depletion)
- Dehydration, diuretic use, burns, or stress polycythemia (Gaisböck syndrome): These cause hemoconcentration without true increase in red cell mass 4. Confirm with repeat testing after adequate hydration 4.
Management Based on Etiology
If Polycythemia Vera is Confirmed
Polycythemia vera requires aggressive management to prevent life-threatening thrombotic complications:
Therapeutic phlebotomy: Maintain hematocrit strictly <45% through regular phlebotomy to reduce thrombotic risk 2, 1, 4. The CYTO-PV trial demonstrated that hematocrit <45% reduces thrombotic events from 9.8% to 2.7% (P=0.007) 4.
Low-dose aspirin: Initiate aspirin 81–100 mg daily as the second cornerstone of therapy for thrombosis prevention 4, 3.
Hematology referral: All patients with confirmed polycythemia vera require specialist management for consideration of cytoreductive therapy (hydroxyurea, interferon-alpha, or ruxolitinib) if high-risk features are present 2, 3.
If Secondary Erythrocytosis is Identified
Treat the underlying condition rather than the elevated hemoglobin:
- CPAP therapy for obstructive sleep apnea 4, 3
- Smoking cessation 4, 3
- Management of COPD or other pulmonary disease 4, 3
- Dose adjustment or discontinuation of testosterone 4, 3
- Discontinuation of SGLT2 inhibitors (if safe from glycemic standpoint) 5
- Surgical resection of erythropoietin-producing tumors 4
Therapeutic phlebotomy is contraindicated in secondary erythrocytosis unless hemoglobin >20 g/dL and hematocrit >65% with documented hyperviscosity symptoms after confirming adequate hydration and excluding iron deficiency 4. Routine phlebotomy in secondary erythrocytosis causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk 4.
If No Cause is Identified (Idiopathic Erythrocytosis)
For borderline elevations without clear etiology:
Serial monitoring: Repeat complete blood count every 3–6 months to assess for progressive rise 4.
Reassess if hemoglobin rises: If hemoglobin increases to meet WHO diagnostic thresholds (≥18.5 g/dL men, ≥16.5 g/dL women) or shows sustained rise ≥2 g/dL from baseline, repeat JAK2 testing and consider hematology referral 1, 3.
No intervention required: Hemoglobin values in the 15.5–17 g/dL range without progressive rise, associated symptoms, or secondary causes do not require treatment 4.
Common Pitfalls to Avoid
Do not perform aggressive phlebotomy for borderline hemoglobin elevations, as this depletes iron stores and worsens oxygen delivery 4.
Do not overlook iron deficiency: Coexisting iron deficiency can mask polycythemia vera by lowering hemoglobin; always check ferritin and transferrin saturation before excluding the diagnosis 1, 4.
Do not use hematocrit alone for diagnosis: Hematocrit can falsely increase by 2–4% with prolonged sample storage and is affected by hyperglycemia, whereas hemoglobin remains stable 4. Hemoglobin is the preferred measurement 4.
Do not ignore medication history: Testosterone and SGLT2 inhibitors are increasingly common causes of erythrocytosis that are easily reversible 5.
Do not apply standard thresholds at high altitude: Physiologic adaptation to altitude can increase hemoglobin by up to 4.5 g/dL; use altitude-adjusted reference ranges 4, 3.