Polycythemia

Definition

Classification

Spurious polycythemia (Gaisböck syndrome): Red cell mass is often high-normal, plasma volume is low-normal. Seen predominantly in obese, hypertensive men who smoke.

• Robbins, Cotran & Kumar Pathologic Basis of Disease, Table 14.8
• Henry's Clinical Diagnosis and Management by Laboratory Methods, Box 33.4

Polycythemia Vera (PV)

Pathogenesis

• JAK2 V617F (exon 14): Found in >95% of PV cases. This point mutation in the pseudokinase domain (JH2) removes the auto-inhibitory function of JAK2, constitutively activating JAK-STAT signaling independent of EPO.
• JAK2 exon 12 mutations: Found in JAK2 V617F-negative PV patients.

JAK2 gene domains. V617F occurs in the pseudokinase domain (JH2); exon 12 mutations occur nearby. Both lead to constitutive kinase activation. (Goldman-Cecil Medicine)

Morphology / Pathology

• Bone marrow: Hypercellular - increased erythroid, myeloid, and megakaryocytic forms (panmyelosis); 10% have marrow fibrosis at diagnosis
• Spleen: Mildly enlarged (250-300 g) from vascular congestion; foci of extramedullary hematopoiesis
• Liver: Enlarged with foci of extramedullary hematopoiesis
• Thromboses and infarctions: Common in heart, spleen, and kidneys (due to hyperviscosity and vascular stasis)
• Hemorrhages: Occur in ~one-third of patients (GI tract, oropharynx, brain)
• Peripheral blood: Basophilia is characteristic; dysfunctional giant platelets; megakaryocyte fragments
• Robbins & Kumar Basic Pathology, p. 407

Clinical Features

Laboratory Findings

WHO Diagnostic Criteria (2016/2022)

1. Hb >16.5 g/dL (men) or >16.0 g/dL (women), OR Hct >49% (men) or >48% (women), OR increased red cell mass
2. Bone marrow biopsy: hypercellular (panmyelosis) with pleomorphic mature megakaryocytes
3. Presence of JAK2 V617F or JAK2 exon 12 mutation

• Subnormal serum erythropoietin level

Natural History and Complications

1. Thrombotic/hemorrhagic complications: The main causes of morbidity and mortality
2. Spent phase (post-PV myelofibrosis): 15-20% of cases after ~10 years; bone marrow fibrosis, massive splenomegaly, worsening cytopenias. JAK2 inhibitors (ruxolitinib) are approved for this phase.
3. Blast crisis / AML transformation: Less common than in CML; more rare overall

Treatment

Secondary Polycythemia - Key Points

• EPO is elevated (unlike PV where it is suppressed)
• Physiologic/compensatory: High altitude (RBC count rises to 6-7 million/mm³), chronic lung disease, cyanotic congenital heart disease - all due to tissue hypoxia stimulating renal EPO production
• Paraneoplastic: Renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma produce EPO autonomously
• HIF pathway mutations (Chuvash polycythemia - homozygous VHL mutation; prolyl hydroxylase mutations) stabilize HIF-1α, which constitutively upregulates EPO transcription even at normal oxygen tension
• Rarely, high-affinity hemoglobin mutants (impaired O2 unloading) or 2,3-BPG deficiency cause secondary polycythemia

Measurement of Red Cell Mass

• Red cell volume: ⁵¹Cr-labeled autologous RBCs
• Plasma volume: ¹²⁵I-labeled albumin

• Henry's Clinical Diagnosis and Management by Laboratory Methods
• Guyton and Hall Textbook of Medical Physiology

Polycythemia Due to Smoking

Mechanism 1: Absolute Secondary Polycythemia - "Smoker's Polycythemia"

Pathophysiology

1. Reduces functional O2-carrying capacity - the hemoglobin bound to CO cannot carry oxygen
2. Shifts the oxygen-hemoglobin dissociation curve to the left - even the remaining oxyhemoglobin releases O2 less readily to tissues
3. Together, these produce functional tissue hypoxia despite a normal arterial PO2
4. The kidneys sense reduced O2 delivery and respond by increasing EPO secretion
5. Elevated EPO drives compensatory erythroid proliferation in the marrow - true absolute polycythemia

Key point: O2 saturation measured by standard pulse oximetry is falsely normal in smokers because it cannot distinguish COHb from oxyhemoglobin. Arterial blood gas with co-oximetry is needed to measure true COHb levels.

Mechanism 2: Relative Polycythemia - Gaisböck Syndrome

• Red cell mass is high-normal (not truly elevated)
• Plasma volume is reduced (hemoconcentration)
• The net result is an elevated hematocrit without a true increase in total circulating RBCs

• Henry's Clinical Diagnosis and Management by Laboratory Methods

Summary: How Smoking Causes Both Types

Diagnostic Approach (Harrison's)

Harrison's Principles of Internal Medicine, 22e - Differential diagnosis of polycythemia

1. Check O2 saturation - may be falsely normal in smokers by pulse oximetry
2. Measure serum EPO - will be elevated in smoker's polycythemia (unlike PV where it is low)
3. If EPO is elevated and O2 saturation appears normal, measure COHb by co-oximetry
4. High COHb + elevated EPO + smoking history = "Smoker's polycythemia" - diagnosis confirmed

Management

"Such patients should be urged to stop smoking. Those who cannot stop smoking require phlebotomy to control their polycythemia." - Harrison's Principles of Internal Medicine, 22e

Why Smoking Polycythemia Matters Clinically

• The elevated hematocrit increases blood viscosity -> thrombotic risk (stroke, MI, DVT)
• It can mimic polycythemia vera on initial labs - the key distinguishing feature is elevated (not low) serum EPO in smoker's polycythemia
• Standard pulse oximetry will miss the underlying hypoxia - you must use co-oximetry to detect COHb

Distinguishing Smoker's Polycythemia from Polycythemia Vera: Lab Comparison

The Core Logic

• In PV: the bone marrow proliferates autonomously, EPO is suppressed, all cell lines are involved
• In smoker's polycythemia: the marrow responds normally to a CO-driven hypoxic signal; only red cells increase

Side-by-Side Lab Comparison

The Decisive Tests - In Order of Priority

Step 1: Serum EPO

• Low EPO -> strongly suggests PV -> proceed to JAK2 testing
• Elevated EPO -> suggests secondary polycythemia (smoking, hypoxia, tumour) -> check COHb

Step 2: JAK2 V617F mutation assay

• Positive (VAF ≥5%) -> PV confirmed (no further workup needed if other criteria met)
• Negative -> consider JAK2 exon 12, renal disease, tumours, or other causes

Step 3: COHb by co-oximetry (arterial blood gas)

• Elevated COHb + smoking history + elevated EPO = smoker's polycythemia
• Do not rely on pulse oximetry alone - it reads COHb as oxyhaemoglobin and gives a falsely normal SpO2

Step 4: CBC differential

• Leukocytosis + thrombocytosis + basophilia accompany the erythrocytosis
• In smoker's polycythemia, WBC and platelets are normal - EPO only drives the erythroid lineage

"As erythropoietin stimulates only the red cell pathway, WBC and platelet counts should be unchanged [in secondary polycythemia]." - Rosen's Emergency Medicine

WHO Diagnostic Criteria for PV (2016) - for Reference

1. Hb >16.5 g/dL (men) or >16.0 g/dL (women), OR Hct >49%/48%, OR elevated red cell mass
2. Bone marrow: trilineage proliferation with pleomorphic mature megakaryocytes
3. JAK2 V617F or exon 12 mutation

• Subnormal serum EPO

Quick Summary Table

• Harrison's Principles of Internal Medicine, 22e
• Rosen's Emergency Medicine, WHO Box 109.16
• Robbins & Kumar Basic Pathology

Approach to a Case of Polycythemia

When to Suspect It

• Hb >17 g/dL (men) or >15 g/dL (women)
• Hct >50% (men) or >45% (women)
• Hct >60% (men) or >55% (women) is almost invariably a true elevated red cell mass

Step 1: History and Physical Examination

• Ruddy (plethoric) complexion - hallmark of polycythemia
• Splenomegaly - strongly favours PV (extramedullary haematopoiesis)
• Cyanosis - suggests right-to-left shunt or severe hypoxia
• Signs of chronic lung disease (clubbing, barrel chest, wheeze)
• Hypertension - common in both PV and Gaisböck syndrome

Step 2: Confirm True (Absolute) vs. Relative Polycythemia

In practice, ⁵¹Cr red cell mass measurement is rarely performed now. Instead, confirm persistence on repeat CBC after adequate hydration, and proceed to EPO measurement if Hb/Hct remains elevated.

• Acute dehydration (vomiting, diarrhoea, burns)
• Diuretic therapy
• Gaisböck (spurious/stress) polycythemia - obese, hypertensive, smoking men with chronically contracted plasma volume

Step 3: Check O₂ Saturation First

• If O₂ sat <92-93% -> patient is hypoxic -> secondary polycythemia likely -> investigate for heart/lung disease or high altitude
• If O₂ sat is normal (≥93%) -> proceed to EPO measurement

Caveat for smokers: Standard pulse oximetry is unreliable - it cannot distinguish COHb from oxyHb and will read falsely normal. Use ABG with co-oximetry to get the true O₂ saturation and measure COHb directly.

Step 4: Measure Serum Erythropoietin (EPO) - The Pivotal Test

Harrison's Principles of Internal Medicine 22e - Approach to the differential diagnosis of polycythemia

If EPO is LOW or Undetectable

1. Test for JAK2 V617F mutation (and exon 12 if V617F negative)
   • JAK2 VAF ≥5% -> Polycythemia Vera confirmed
   • JAK2 negative -> still possible PV (check exon 12), or rare EPO receptor mutation
2. Abdominal ultrasound - assess spleen size (splenomegaly supports PV)
3. Supporting labs for PV: leukocytosis, thrombocytosis, absolute basophilia, elevated LDH, elevated uric acid
4. Bone marrow biopsy (if needed to complete WHO criteria): trilineage hyperplasia (panmyelosis), pleomorphic megakaryocytes

If EPO is ELEVATED

Step 5: Elevated EPO - Narrow the Cause

Elevated EPO
     |
     ├── O₂ sat LOW (<92%)
     │        └── Lung disease, cyanotic heart disease, high altitude,
     │            sleep apnoea, right-to-left shunt
     │            -> Treat/investigate the underlying condition
     │
     └── O₂ sat NORMAL (≥93%)
              |
              ├── SMOKER? -> Check COHb (co-oximetry on ABG)
              │        COHb elevated -> "Smoker's polycythemia"
              │        -> Smoking cessation; phlebotomy if can't quit
              │
              ├── High O₂ affinity haemoglobin?
              │        -> P50 assay (reduced), haemoglobin electrophoresis
              │
              └── Autonomous EPO secretion (tumour/renal)?
                       -> CT abdomen/pelvis
                       -> Renal cell carcinoma, hepatocellular carcinoma,
                          Wilms tumour, cerebellar haemangioblastoma,
                          uterine leiomyoma, renal cysts
                       -> MRI brain/cerebellum if neurologic signs

Step 6: Complete the Workup Based on the Branch

Summary Algorithm

Elevated Hb/Hct on CBC
        |
        v
[1] HISTORY + EXAM
  (smoking, altitude, drugs, aquagenic pruritus, splenomegaly)
        |
        v
[2] REPEAT CBC AFTER HYDRATION
  -> If normalises: Relative polycythemia - manage cause
  -> If persists: True absolute polycythemia
        |
        v
[3] CHECK O₂ SATURATION (ABG + co-oximetry, NOT just pulse ox)
  -> <92%: Hypoxic secondary polycythemia
  -> ≥93%: Proceed to EPO
        |
        v
[4] SERUM EPO LEVEL  <--- THE PIVOTAL TEST
    /                   \
  LOW                  HIGH
  (PV likely)         (Secondary)
    |                   |
    v                   v
[5] JAK2 V617F     O₂ sat normal?
   + exon 12        |         |
   Abdo U/S        Smoker?  No
   BM biopsy        COHb↑   -> CT abdomen (tumour)
                    -> Smoker's Poly   P50 (high-affinity Hb)
                                       VHL gene (Chuvash)

Red Flags Requiring Urgent Action

• Harrison's Principles of Internal Medicine 22e, pp. 494-495
• Rosen's Emergency Medicine, Box 109.15-109.16
• Tintinalli's Emergency Medicine
• Murray & Nadel's Textbook of Respiratory Medicine

1. Trigger - Hb/Hct thresholds that prompt workup
2. Step 1 - History & physical (key clues: aquagenic pruritus, splenomegaly, smoking, drugs)
3. Step 2 - Repeat CBC after hydration to rule out relative polycythemia / Gaisböck syndrome
4. Step 3 - ABG + co-oximetry (not just pulse ox) to check for hypoxic cause
5. Step 4 (Pivotal) - Serum EPO level branches the entire workup:
   • Low EPO → PV pathway (JAK2, bone marrow biopsy, WHO criteria)
   • High EPO → Secondary pathway (smoker's polycythemia via COHb, paraneoplastic tumours, genetic/high-affinity Hb causes)
6. Red alert box - Urgent indications for immediate phlebotomy and complications to watch for

How Testosterone and SGLT2 Inhibitors Cause Polycythemia

Part 1: Testosterone-Induced Polycythemia

Epidemiology

Mechanisms - Multiple Pathways

1. EPO Stimulation (Indirect - via kidneys)

• Testosterone acts on renal peritubular cells to stimulate EPO gene transcription
• This raises the homeostatic EPO "set point" - more EPO is produced at any given oxygen level
• EPO then acts on CFU-E (Colony Forming Unit-Erythroid) progenitors to drive red cell proliferation, differentiation, and survival
• Note: The EPO level in testosterone-induced polycythemia is variable - it may be transiently elevated, then suppressed once Hb rises (normal feedback), making it an unreliable marker

2. Hepcidin Suppression -> Increased Iron Availability

• Testosterone suppresses hepcidin, the master regulator of iron metabolism
• Low hepcidin increases ferroportin activity on enterocytes and macrophages -> more iron released into circulation
• Greater iron bioavailability removes the rate-limiting step for haemoglobin synthesis and erythropoiesis
• This is now considered one of the most important mechanisms

3. Direct Bone Marrow Stimulation

• Testosterone (and its active metabolite dihydrotestosterone/DHT) acts directly on androgen receptors on erythroid precursors in the bone marrow
• Increases the number of EPO-responsive cells (BFU-E and CFU-E progenitors) in the marrow
• This is EPO-independent - erythropoiesis is amplified even without a rise in EPO

4. Aromatization to Estradiol -> Erythroid Stimulation

• In adipose tissue (especially in obese patients), testosterone is aromatized to estradiol
• Estradiol stimulates hematopoietic stem cell proliferation via estrogen receptor alpha (ERα)
• This explains why higher BMI is an independent risk factor for testosterone-induced erythrocytosis

5. IGF-1 Mediation

• Testosterone may increase insulin-like growth factor 1 (IGF-1), which has direct erythropoietic effects

Physiologic Basis

"Erythropoiesis increases [at puberty], resulting in higher hematocrit and hemoglobin concentrations in men than boys or women." - Goodman & Gilman's Pharmacological Basis of Therapeutics

Clinical Management of Testosterone-Induced Erythrocytosis

• Risk is highest with injectable esters (peak-trough fluctuations); lower with transdermal gels; lowest with pellets

Part 2: SGLT2 Inhibitor-Induced Erythrocytosis

The Debate: Hemoconcentration vs. True Erythropoiesis

The True Mechanism: Amelioration of Renal Hypoxia

1. The diabetic/CKD kidney is chronically hypoxic
   • High glucose load forces the proximal tubule to work overtime reabsorbing glucose via SGLT2, consuming excessive oxygen
   • The proximal tubule sits in a borderline hypoxic zone of the renal cortex even normally (low O₂ tension, high metabolic demand)
   • In diabetes + CKD, this hypoxia is worsened
2. SGLT2 inhibition reduces proximal tubular workload
   • By blocking SGLT2, glucose reabsorption in the proximal tubule is reduced -> less oxygen consumed per nephron
   • Renal cortex hypoxia is ameliorated
3. Improved renal oxygenation -> more efficient EPO production
   • EPO is produced by peritubular fibroblasts in the renal cortex, triggered by HIF-1α/HIF-2α when O₂ tension falls
   • Paradoxically, restoring normal O₂ sensing (by reducing the pathological hypoxia suppressing EPO in diseased kidneys) allows EPO to rise back toward normal
   • This increased EPO drives genuine erythropoiesis - a true increase in red cell mass
4. Additional: Iron metabolism improvement
   • SGLT2i may reduce inflammation (lowering hepcidin indirectly) -> improved iron bioavailability for erythropoiesis

Why This Matters Clinically

"The increase in hematocrit with SGLT2i treatment is not due to hemoconcentration, but to an increase in erythropoiesis due to amelioration of hypoxia and more efficient erythropoietin production." - Ekanayake & Mudaliar, Diabetes Metab Syndr, 2023

Is This "Polycythemia" Clinically Concerning?

Summary Comparison

• Harrison's Principles of Internal Medicine 22e
• Goodman & Gilman's Pharmacological Basis of Therapeutics
• Ekanayake & Mudaliar, Diabetes Metab Syndr 2023, PMID 36657305
• Cases et al., Nefrologia 2024, PMID 38604895

Why LDH and Uric Acid Are Raised in Polycythemia Vera

Raised LDH - The Mechanism

What is LDH?

Why Does It Rise in PV?

• Many of these cells undergo ineffective haematopoiesis - they proliferate but are destroyed in the marrow before reaching the circulation (intramedullary cell death)
• Mature cells have a normal lifespan, but with greatly expanded numbers, the absolute daily cell death is far higher
• Splenic sequestration and destruction is increased due to splenomegaly
• Vascular thromboses cause local cell necrosis

LDH as a Marker in MPNs

• Elevated LDH at diagnosis correlates with higher disease burden and more aggressive disease
• A rising LDH in PV can signal progression to spent-phase myelofibrosis or blast crisis (AML transformation) - both involve massive cell turnover/necrosis

The general principle: LDH rises in any condition of rapid cell turnover or cell death - haemolysis, leukaemia, lymphoma, solid tumours, and tissue infarction. In PV it is the neoplastic cell proliferation + turnover that drives it.

Raised Uric Acid (Hyperuricaemia) - The Mechanism

The Purine Pathway

Cell DNA/RNA (adenine, guanine)
         |
         | [Cell death -> nucleic acid release]
         ↓
    Purines (AMP, GMP)
         |
         | Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
         ↓
    Hypoxanthine / Xanthine
         |
         | Xanthine oxidase
         ↓
      URIC ACID  <--- accumulates in plasma

Why Does It Rise in PV?

• Every dividing cell contains purine-rich DNA and RNA (adenine + guanine bases)
• In PV, the JAK2 clone continuously produces and destroys enormous numbers of cells
• As these cells die and their nuclei are degraded, huge quantities of purines are released
• These are catabolised through the xanthine oxidase pathway to uric acid
• The rate of uric acid production overwhelms renal excretory capacity -> secondary hyperuricaemia

• Erythroid cells (most numerous) - large nuclear DNA during precursor stages
• Granulocytes - rich in nuclear DNA
• Megakaryocytes - polyploid (massively enlarged nuclei with multiple genome copies), releasing huge purine loads when they fragment

• Textbook of Family Medicine 9e, Table 14-18: "Polycythemia vera" explicitly listed under Overproduction causes of hyperuricaemia (alongside myeloproliferative disorders, malignancies, haemolytic anaemia)

Summary: Common Root Cause

Why Platelets Are Dysfunctional in Polycythemia Vera

The Core Problem

Mechanism 1: Intrinsic Receptor Defects (Clonal Origin)

Mechanism 2: Arachidonic Acid / Thromboxane Pathway Defect

• The AA -> TxA2 signalling pathway is constitutively hyperactivated at baseline (due to JAK2-driven signalling), leading to chronic low-grade platelet activation
• This chronic pre-activation depletes platelets of their activation machinery - they become "exhausted" and cannot respond to a fresh stimulus properly
• Giant platelets and megakaryocyte fragments seen in PV blood have abnormal cytoskeletal organisation, further impairing shape change and release reactions

Mechanism 3: Granule Abnormalities

• Dense granules (δ-granules): contain ADP, ATP, serotonin, Ca²⁺ - amplify aggregation
• Alpha granules (α-granules): contain fibrinogen, VWF, P-selectin, coagulation factors - promote adhesion and clot formation

• Dense granule content is reduced or depleted (partial dense granule deficiency)
• Alpha granule release is impaired
• This means the normal positive-feedback amplification of platelet plug formation is blunted -> bleeding tendency

Mechanism 4: Acquired von Willebrand Syndrome (AvWS) - The Key to the Bleeding Paradox

Normal VWF Function

How Extreme Thrombocytosis Destroys HMW VWF Multimers

Massive thrombocytosis in PV/ET
         |
         ↓
Enormous total platelet surface area
(GPIb receptors on each platelet)
         |
         ↓
In vivo adsorption of HMW VWF multimers
onto platelet surface GPIb receptors
         |
         ↓
HMW multimers are rapidly cleared
from circulation (along with platelets)
         |
         ↓
Selective loss of HMW VWF multimers
(similar pattern to Type 2A VWD)
         |
         ↓
Impaired platelet adhesion at high shear
(mucocutaneous bleeding: epistaxis,
GI bleeding, bruising, menorrhagia)

This is why PV can cause both thrombosis (from activated clonal platelets + hyperviscosity) AND bleeding (from AvWS + platelet dysfunction) - sometimes in the same patient.

Mechanism 5: JAK2-Driven Paradoxical Hyperactivation -> Thrombosis

• JAK2 V617F in platelets causes constitutive JAK-STAT signalling even without external stimulation
• This produces a basally hyperactivated state: increased P-selectin expression, increased platelet-leukocyte aggregates, increased tissue factor expression
• The viscous, hypercellular blood has slow flow -> amplifies thrombotic risk further
• Result: thrombosis in unusual sites - hepatic vein (Budd-Chiari syndrome), portal vein, mesenteric veins, cerebral sinus

The Paradox Explained: Same Platelets, Opposite Outcomes

"Platelets produced from the neoplastic clone are often dysfunctional, a derangement that contributes to the elevated risk of thrombosis and bleeding." - Robbins & Kumar Basic Pathology

• Robbins & Kumar Basic Pathology (Robbins Pathology)
• Robbins, Cotran & Kumar Pathologic Basis of Disease
• Michiels et al., Semin Thromb Hemost 2006 - The paradox of platelet activation and impaired function in ET and PV
• AvWS in myeloproliferative neoplasms, Cancers (Basel) 2020, PMC7407619