Blood & Lymphoreticular

Polycythemia vera: diagnosis and management

Clinical Overview and When to Suspect Polycythemia Vera

When to suspect PV on Step 3:

— Men: Hgb >16.5 g/dL or Hct >49%

— Women: Hgb >16.0 g/dL or Hct >48%

Step 3 management mindset: PV is an outpatient hematology longitudinal disease. Your job is recognize → confirm JAK2 → risk stratify → start phlebotomy + aspirin → add cytoreduction when indicated → monitor for transformation. Vignettes typically embed in primary care visits, pre-op evaluations, or workup of unprovoked splanchnic thrombosis.

Board pearl: Any patient with Budd-Chiari syndrome or unprovoked portal vein thrombosis must be tested for JAK2 V617F, even if the CBC looks normal — masked PV can present with thrombosis before erythrocytosis is obvious due to iron deficiency or splenic sequestration.

Polycythemia vera (PV) is a chronic BCR-ABL-negative myeloproliferative neoplasm (MPN) driven by clonal hematopoietic stem cell proliferation, almost always due to a JAK2 mutation (V617F in ~95%, exon 12 in ~3%).

Median age at diagnosis is ~60 years; slight male predominance. Incidence ~1–2 per 100,000/year.

Core pathophysiology: JAK2 gain-of-function → cytokine-independent erythropoiesis → panmyelosis (erythrocytosis ± leukocytosis ± thrombocytosis), low erythropoietin (EPO), and high thrombosis risk from hyperviscosity and qualitative platelet/leukocyte dysfunction.

Persistently elevated hemoglobin/hematocrit without obvious secondary cause:

Constellation symptoms — aquagenic pruritus after hot showers, erythromelalgia (burning red hands/feet relieved by aspirin), facial plethora, headache, dizziness, visual blurring, tinnitus.

Unexplained thrombosis in unusual sites: hepatic vein (Budd-Chiari), portal/splenic/mesenteric vein, cerebral venous sinus — always check JAK2.

Splenomegaly on exam or imaging.

Low or low-normal serum EPO with elevated red cell mass.

Incidental CBC abnormalities in a hypertensive smoker — but smoking causes secondary erythrocytosis, so don't anchor.

Presentation Patterns and Key History

— Arterial: stroke, TIA, MI, peripheral arterial occlusion.

— Venous: DVT/PE, but classically splanchnic vein thrombosis (Budd-Chiari, portal, mesenteric) and cerebral venous sinus thrombosis.

Key history questions to ask in the vignette:

Key distinction: Relative (spurious) erythrocytosis (Gaisböck syndrome) — hypertensive, obese, diuretic-using middle-aged man with elevated Hct from plasma volume contraction. EPO and red cell mass are normal; no JAK2. Don't phlebotomize.

Board pearl: Aquagenic pruritus + erythromelalgia + splanchnic thrombosis is the PV triad on board questions; any single component should make you order JAK2 V617F PCR and serum EPO before pursuing expensive secondary workups.

Hyperviscosity symptoms dominate: headache, dizziness, blurred vision, tinnitus, paresthesias, fatigue, "brain fog." These reflect sluggish microcirculation when Hct rises above ~55%.

Aquagenic pruritus: intense itching minutes after warm water exposure (shower, bath), often without rash. Present in ~40%; mediated by mast cell/basophil degranulation. Highly suggestive of PV.

Erythromelalgia: burning erythema of digits, soles, or palms triggered by warmth, dramatically relieved by low-dose aspirin — a near-pathognomonic clue on the exam.

Thrombotic presentations (often the initial event in 20–30%):

Bleeding paradox: GI bleeding, epistaxis, mucocutaneous bruising — from acquired von Willebrand syndrome when platelets >1,000–1,500 × 10⁹/L (large multimers absorbed by platelets).

Constitutional: night sweats, weight loss, early satiety (splenomegaly), bone pain, gout/hyperuricemia from high cell turnover.

Smoking, OSA symptoms, chronic lung disease, high-altitude residence, EPO/androgen use → screen out secondary erythrocytosis.

Family history of MPN, prior unexplained clots, miscarriages.

Medications (testosterone, diuretics causing hemoconcentration).

Pruritus pattern, erythromelalgia, headaches.

Prior surgeries with unexpected clotting or bleeding.

Physical Exam Findings and Hemodynamic Assessment

— Excoriations from chronic pruritus.

— Erythromelalgia: warm, tender, dusky red digits; rarely digital ischemia/necrosis.

— Petechiae or ecchymoses if acquired vWD or aspirin-related.

Hemodynamic considerations:

CCS pearl: A patient admitted for stroke or MI found incidentally to have Hct 62% and JAK2+ → order CBC with differential, JAK2 V617F, serum EPO, LDH, uric acid, ferritin, comprehensive metabolic panel, abdominal ultrasound (spleen size), start aspirin 81 mg, perform therapeutic phlebotomy 500 mL with concurrent isotonic saline, and consult hematology. Avoid heparin until platelet count and vWD activity are clarified if extreme thrombocytosis.

Board pearl: Plethora + splenomegaly + pruritus after shower in a 60-year-old = PV until proven otherwise — go straight to JAK2.

Facial plethora / ruddy complexion: deep red-purple coloration of cheeks, nose, lips, ears, and conjunctivae — reflects engorged dermal capillaries with high Hct.

Conjunctival injection and engorged retinal veins on funduscopy; occasional retinal hemorrhages if hyperviscosity is severe.

Splenomegaly in ~70% at diagnosis — palpate carefully; massive splenomegaly suggests post-PV myelofibrosis transformation.

Hepatomegaly in ~40%.

Skin findings:

Cardiovascular: hypertension is common (~50%); listen for bruits suggesting arterial atherosclerosis accelerated by hyperviscosity.

Neurologic: focal deficits suggesting prior stroke/TIA; gait/coordination issues from cerebellar venous sinus thrombosis.

Gouty arthritis: tophi or monoarthritis from urate overproduction.

Hypertension from increased blood viscosity and volume; treat per usual JNC/ACC targets, but recognize that reducing Hct often improves BP.

Volume status can be deceiving — patients are plethoric but not necessarily volume overloaded; avoid aggressive diuresis, which worsens hyperviscosity.

In acute thrombotic crisis with very high Hct (>60%), consider therapeutic phlebotomy + IV isotonic saline simultaneously to drop Hct while preserving plasma volume.

Diagnostic Workup — Initial Labs and Imaging

— Elevated Hgb/Hct (cardinal feature).

— Leukocytosis (neutrophil predominant) in ~40%.

— Thrombocytosis in ~50%.

— Smear: usually unremarkable early; later may show teardrop cells (myelofibrosis transformation) or basophilia.

Imaging:

ECG: if symptomatic, look for ischemia or atrial fibrillation (adds thrombotic risk).

Key distinction: PV = low EPO + JAK2+. Secondary erythrocytosis = high EPO (hypoxia, EPO-secreting tumor — renal cell carcinoma, hepatocellular, cerebellar hemangioblastoma, uterine leiomyoma). Relative erythrocytosis = normal red cell mass, normal EPO (volume contraction).

Board pearl: Order JAK2 V617F and serum EPO together as your two highest-yield tests — this pairing resolves >95% of erythrocytosis workups without needing a red cell mass study.

CBC with differential and peripheral smear:

Serum erythropoietin (EPO): low or low-normal in PV (the JAK2 clone suppresses EPO via feedback). A high EPO essentially rules out PV and points to secondary erythrocytosis.

JAK2 V617F mutation by PCR — first-line molecular test; positive in ~95%.

JAK2 exon 12 mutation — order if V617F negative but PV strongly suspected (isolated erythrocytosis, very low EPO); positive in additional ~3%.

Ferritin and iron studies: often low because expanded erythropoiesis consumes iron; don't supplement — replacing iron worsens erythrocytosis.

LDH, uric acid, B12: often elevated (high cell turnover, transcobalamin from neutrophils).

CMP: assess renal/hepatic function before cytoreduction.

Coagulation studies + von Willebrand activity (ristocetin cofactor): if platelets >1,000 × 10⁹/L, screen for acquired vWD before starting aspirin.

Abdominal ultrasound or CT: assess spleen size, screen for splanchnic vein thrombosis if symptoms or LFT abnormalities.

Pulse oximetry / ABG: rule out hypoxia-driven secondary erythrocytosis (COPD, OSA, R-to-L shunt).

Consider sleep study if OSA features.

Diagnostic Workup — Advanced and Confirmatory Studies (WHO 2016 Criteria)

WHO 2016 diagnostic criteria for PV — diagnosis requires all 3 major OR first 2 major + minor:

Major criteria:

1. Hgb >16.5 g/dL (men) / >16.0 g/dL (women) OR Hct >49%/>48% OR increased red cell mass >25% above mean predicted.

2. Bone marrow biopsy showing hypercellularity for age with trilineage proliferation (panmyelosis) — prominent pleomorphic, mature megakaryocytes.

3. JAK2 V617F or JAK2 exon 12 mutation.

Minor criterion:

Bone marrow biopsy:

Additional studies in select scenarios:

CCS pearl: In the JAK2-negative patient with persistent erythrocytosis and low EPO, send JAK2 exon 12 next, then bone marrow biopsy. Do not order red cell mass studies as a first-line test on the exam.

Board pearl: A low EPO + JAK2 V617F+ in a patient meeting Hgb/Hct thresholds is enough to establish PV; bone marrow biopsy adds prognostic information but is not required for diagnosis in this scenario.

Subnormal serum EPO.

Not strictly required if Hgb >18.5 (men)/>16.5 (women) + JAK2+ + low EPO — but recommended in most cases for prognostic information (baseline reticulin fibrosis predicts myelofibrosis transformation).

Confirms diagnosis in ambiguous cases and distinguishes from essential thrombocythemia (ET) and primary myelofibrosis (PMF).

Red cell mass by radiolabeled chromium (⁵¹Cr): historically gold standard; now rarely needed given Hct thresholds in WHO criteria.

Cytogenetics and next-generation sequencing: abnormal karyotype (~20%) and additional mutations (ASXL1, SRSF2, IDH1/2, TP53) confer higher risk of myelofibrosis/AML transformation.

Doppler of hepatic/portal veins: if splanchnic thrombosis suspected.

Renal/abdominal imaging: rule out EPO-secreting tumors when EPO is high.

CO-oximetry, carboxyhemoglobin: smokers can have spurious erythrocytosis from elevated COHb.

Risk Stratification and First-Line Management Logic

Conventional risk stratification (drives therapy intensity):

(Cardiovascular risk factors — HTN, DM, smoking, hyperlipidemia — and leukocytosis >11 × 10⁹/L modify risk but don't reclassify on basic Step 3 schemes.)

Universal treatment goals (ALL patients):

1. Therapeutic phlebotomy to maintain Hct <45% (both sexes — based on landmark CYTO-PV trial showing >4-fold reduction in CV death/major thrombosis vs Hct 45–50% target).

2. Low-dose aspirin 81 mg daily — unless contraindicated (active bleeding, acquired vWD with platelets >1,000–1,500 × 10⁹/L).

3. Aggressive cardiovascular risk factor control: BP, lipids, glucose, smoking cessation.

Add cytoreductive therapy for high-risk patients OR low-risk patients with:

First-line cytoreductive agents:

Second-line:

Step 3 management: A 55-year-old man with newly diagnosed PV and no thrombosis history → phlebotomy to Hct <45% + aspirin 81 mg + CV risk control, no cytoreduction yet. A 68-year-old with prior TIA → add hydroxyurea from the start.

Board pearl: Hct target is <45% in both men and women — the older "<42% for women" rule is outdated; CYTO-PV established the unified <45% threshold.

Low risk: age <60 AND no prior thrombosis.

High risk: age ≥60 OR prior arterial/venous thrombosis.

Symptomatic/progressive splenomegaly.

Progressive leukocytosis or thrombocytosis.

Poor tolerance of frequent phlebotomy.

Severe disease-related symptoms (intractable pruritus, constitutional).

New thrombosis on aspirin + phlebotomy.

Hydroxyurea — most common first-line.

Pegylated interferon-α (ropeginterferon alfa-2b, peginterferon alfa-2a) — preferred in younger patients and pregnancy; potentially disease-modifying (reduces JAK2 allele burden).

Ruxolitinib (JAK1/2 inhibitor) — for hydroxyurea intolerance/resistance, severe pruritus, symptomatic splenomegaly.

Busulfan — rarely, in elderly intolerant of others (leukemogenic risk).

Pharmacotherapy — First-Line Drug Regimens

Aspirin (81 mg PO daily):

Hydroxyurea (HU):

Pegylated interferon-α (ropeginterferon alfa-2b — Besremi; peginterferon alfa-2a):

Ruxolitinib (JAK1/2 inhibitor):

Adjuncts:

Board pearl: Pegylated interferon is the cytoreductive agent of choice in pregnancy and in young patients, while hydroxyurea remains first-line in the typical older PV patient.

Indicated in virtually all PV patients for thrombosis prevention and erythromelalgia.

Contraindications: active bleeding, acquired vWD (check ristocetin cofactor if platelets >1,000 × 10⁹/L), aspirin allergy.

Twice-daily low-dose aspirin (81 mg BID) considered in high-risk patients with prior arterial thrombosis or persistent microvascular symptoms.

Starting dose: 500–1,000 mg/day PO; titrate to maintain Hct <45%, WBC 4–10, platelets <400 × 10⁹/L without cytopenias.

Adverse effects: cytopenias, oral/leg ulcers, mucositis, nail hyperpigmentation, photosensitivity, macrocytosis (expected and benign — confirms compliance), rare AML risk (controversial, low).

Monitoring: CBC every 2 weeks during titration, then every 3 months. CMP every 6–12 months. Skin exams yearly (squamous cell skin cancer risk).

Hydroxyurea resistance/intolerance (ELN criteria): need phlebotomy to keep Hct <45%, uncontrolled myeloproliferation, failure to reduce massive splenomegaly, or cytopenias at lowest effective dose.

Preferred in younger patients (<60), pregnant patients, those desiring fertility, hydroxyurea intolerance.

Disease-modifying potential: reduces JAK2 V617F allele burden, may induce molecular remission.

Adverse effects: flu-like symptoms, depression (screen and avoid in active psychiatric disease), autoimmune flares (thyroid, hepatitis), injection-site reactions, fatigue.

Subcutaneous every 2 weeks (ropeg).

FDA-approved for HU-resistant/intolerant PV.

Excellent for refractory pruritus, splenomegaly, constitutional symptoms.

Watch for opportunistic infections (zoster, TB reactivation), weight gain, lipid increases, cytopenias. Screen for latent TB/HBV before starting. Do not stop abruptly — cytokine rebound.

Allopurinol for hyperuricemia/gout.

Antihistamines, SSRIs (paroxetine), phototherapy for pruritus refractory to systemic therapy.

Procedures — Therapeutic Phlebotomy and Special Procedural Considerations

Therapeutic phlebotomy is the cornerstone procedure of PV management.

— Remove 450–500 mL whole blood per session via large-bore peripheral IV.

— Concurrent isotonic saline infusion of equal volume in elderly, hypotensive, or volume-depleted patients to prevent post-procedure orthostasis.

— Frequency: weekly or every 2 weeks initially until target Hct reached, then every 1–3 months maintenance.

Perioperative management of PV (high-yield Step 3):

Allogeneic stem cell transplant:

Splenectomy:

CCS pearl: Newly diagnosed PV with Hct 58% in clinic → schedule therapeutic phlebotomy 500 mL today, start aspirin 81 mg, check JAK2 if not done, order CBC, EPO, CMP, LDH, uric acid, ferritin, counsel on hydration, schedule repeat phlebotomy in 1 week, and follow Hct weekly until <45%.

Board pearl: Iron deficiency from chronic phlebotomy is expected and desired — never prescribe iron to a PV patient unless cytoreduction is being substituted.

Indication: Hct above target (<45%) in all PV patients.

Technique:

Goal: induce iron deficiency — this is therapeutic, not a complication. Do not replace iron unless symptomatic severe deficiency (then reconsider cytoreduction instead).

Contraindications/cautions: severe cardiovascular disease (consider isovolemic exchange or smaller volumes 250 mL), elderly (slower, with fluids).

Adverse effects: vasovagal episodes, iron deficiency symptoms (restless legs, pica, fatigue, hair changes), worsening reactive thrombocytosis.

PV patients have markedly increased peri-op thrombotic AND bleeding risk.

Elective surgery: defer until Hct <45% and platelets controlled for at least 2–3 months. Continue cytoreduction.

Aspirin: typically continue for most surgeries; hold 5–7 days only for neurosurgery, posterior eye, or high-bleed-risk procedures, balancing thrombosis risk.

VTE prophylaxis: mechanical + pharmacologic (LMWH) post-op unless bleeding precludes.

Avoid dehydration peri-op.

Only curative therapy; reserved for post-PV myelofibrosis or AML transformation in suitable candidates.

Rarely indicated; high morbidity. Considered for massive symptomatic splenomegaly refractory to medical therapy, typically in post-PV myelofibrosis phase.

Special Populations — Elderly and Renal/Hepatic Impairment

Elderly patients (≥60, especially ≥75):

Renal impairment:

Hepatic impairment:

Step 3 management: A 78-year-old with PV, CKD stage 3b (CrCl 35), and prior stroke → phlebotomy to Hct <45% (slow, 250 mL with saline), aspirin 81 mg, hydroxyurea at reduced dose 500 mg every other day with biweekly CBC, allopurinol if hyperuricemic (renal-dosed), and tight BP control.

Board pearl: In any PV patient with abnormal LFTs or ascites, image the hepatic and portal veins — splanchnic thrombosis is the dominant hepatic complication and often the index event leading to PV diagnosis.

Automatically classified as high risk → cytoreduction indicated alongside phlebotomy + aspirin.

Hydroxyurea is first-line; well-tolerated in elderly.

Tighter monitoring for cytopenias — start lower (500 mg/day), titrate slowly.

Phlebotomy: use smaller volumes (250–300 mL) with isotonic saline replacement to avoid orthostasis, falls, and cardiac decompensation in those with CAD/CHF.

Higher bleeding risk with aspirin — verify CrCl, GI history; consider PPI if prior ulcer or concurrent NSAID/anticoagulant.

Screen for polypharmacy interactions (warfarin, DOACs, NSAIDs).

Higher baseline thrombotic risk from comorbid AFib, CAD, immobility — keep Hct strictly <45%.

Hydroxyurea is renally cleared: reduce dose if CrCl <60 mL/min; substantial dose reduction or avoidance if CrCl <30. Some guidelines: ~50% dose if CrCl 30–60; ~20% if <30; avoid if on dialysis if alternatives exist.

Allopurinol: dose-adjust for renal function.

Ruxolitinib: reduce dose if CrCl <60 mL/min; specific dosing per platelet count and renal function.

Watch contrast nephropathy in patients undergoing imaging — they're already hyperviscous.

Common in PV due to Budd-Chiari syndrome or portal vein thrombosis.

Hydroxyurea: use cautiously; no strict hepatic dose adjustment but monitor LFTs.

Ruxolitinib: dose reduce in moderate-severe hepatic impairment.

Pegylated interferon: avoid in decompensated cirrhosis, autoimmune hepatitis.

Manage portal hypertension complications (varices, ascites) per standard hepatology care; anticoagulation often required for splanchnic thrombosis despite varices — gastroenterology co-management.

Special Populations — Pregnancy and Other Demographic Subgroups

Pregnancy in PV:

Antepartum management:

Postpartum:

Pediatric PV:

Other subgroups:

Board pearl: In a pregnant PV patient, the trifecta is phlebotomy + aspirin + pegylated interferon (if cytoreduction needed) + postpartum LMWH for 6 weeks. Hydroxyurea is contraindicated.

Key distinction: Erythrocytosis on testosterone therapy in a hypogonadal man = secondary, not PV. Check EPO (normal/high) and JAK2 (negative) before phlebotomizing repeatedly.

Pregnancy is high-risk: increased miscarriage (1st-trimester loss ~20–40%), IUGR, preeclampsia, placental abruption, maternal thrombosis (including cerebral and splanchnic veins).

Pre-conception counseling: optimize Hct, switch teratogenic agents.

Avoid hydroxyurea (teratogenic — Category D). Discontinue ≥3 months before conception in both partners.

Avoid ruxolitinib in pregnancy.

Therapeutic phlebotomy to maintain Hct <45% (some experts target the upper-normal pregnancy range, <37% during pregnancy due to physiologic hemodilution and placental flow considerations).

Low-dose aspirin 81 mg daily throughout pregnancy (also reduces preeclampsia risk).

Pegylated interferon-α is the cytoreductive agent of choice when needed — does not cross placenta significantly, no teratogenicity signal.

Prophylactic LMWH indicated in high-risk patients (prior thrombosis, prior pregnancy loss) — continue 6 weeks postpartum (peak VTE risk window).

Continue LMWH 6 weeks postpartum in all PV patients (some recommend in everyone given peripartum VTE risk).

Breastfeeding: hydroxyurea and ruxolitinib contraindicated; interferon generally considered compatible.

Extremely rare; most "polycythemia" in children is secondary (cyanotic CHD, high-altitude, EPO-secreting tumors). Confirm with JAK2 and EPO; refer to pediatric hematology.

Athletes/altitude residents: secondary erythrocytosis — high EPO, JAK2 negative.

Testosterone supplementation: a frequent Step 3 distractor — causes secondary erythrocytosis with high or normal EPO; manage by reducing/discontinuing testosterone, occasional phlebotomy.

Smokers: COHb-driven secondary erythrocytosis; smoking cessation is the management.

Complications and Adverse Outcomes

Thrombotic complications (leading cause of morbidity/mortality):

Hemorrhagic complications:

Disease transformation:

Other complications:

Step 3 management: A PV patient develops progressive anemia, increasing splenomegaly, and teardrop cells on smear → post-PV myelofibrosis. Re-stage with bone marrow biopsy, consider ruxolitinib for symptom control, evaluate for allogeneic SCT if young/fit, and address transfusion needs.

Board pearl: AML transformation in PV has the worst prognosis of all PV complications and is promoted by alkylator chemotherapy — this is why busulfan and ³²P are reserved for elderly patients with limited life expectancy.

Arterial (~60% of thrombotic events): stroke, TIA, MI, peripheral arterial disease, retinal artery occlusion.

Venous: DVT/PE, splanchnic vein thrombosis (hepatic = Budd-Chiari; portal, splenic, mesenteric), cerebral venous sinus thrombosis.

Microvascular: erythromelalgia, transient visual disturbances, acral paresthesias.

Risk peaks at extreme Hct, with poorly controlled disease, leukocytosis, or off aspirin.

Acquired von Willebrand syndrome with platelets >1,000–1,500 × 10⁹/L — paradoxical mucocutaneous and GI bleeding.

Aspirin or anticoagulant-related bleeding, especially in elderly with HTN.

Post-PV myelofibrosis (post-PV MF): occurs in ~10–20% at 15–20 years. Features: progressive splenomegaly, cytopenias (especially anemia), leukoerythroblastic smear with teardrop cells, increased LDH, marrow fibrosis on biopsy. Treat with ruxolitinib, transfusion support, allo-SCT if eligible.

Acute myeloid leukemia (AML) transformation: ~5–10% lifetime risk; very poor prognosis (median survival <6 months). Risk increased by prior alkylator exposure (busulfan, chlorambucil, ³²P), advanced age, abnormal karyotype, high-risk mutations (ASXL1, SRSF2, IDH, TP53).

Hyperuricemia/gout from high cell turnover — manage with allopurinol; hydration.

Pruritus — refractory in some; SSRIs, antihistamines, phototherapy, ruxolitinib.

Iron deficiency from chronic phlebotomy — expected; do not supplement iron.

Squamous cell skin cancer with chronic hydroxyurea — annual skin exams, sun protection counseling.

Pulmonary hypertension in subset of patients.

When to Escalate Care — ICU, Consult, and Triage

Immediate hematology consultation:

Admit (inpatient) for:

ICU triage:

Multidisciplinary consults:

CCS pearl: A patient presents to the ED with abdominal pain, ascites, and elevated LFTs; ultrasound shows hepatic vein obstruction (Budd-Chiari). Order CBC (Hct 56%, platelets 680), JAK2 V617F (positive), start IV heparin, therapeutic phlebotomy with saline, hematology and hepatology consults, CT abdomen with contrast, evaluate for TIPS if refractory. Transition to long-term anticoagulation + aspirin + cytoreduction.

Board pearl: Unprovoked splanchnic or cerebral venous sinus thrombosis = inpatient anticoagulation + JAK2 testing + hematology consult, regardless of CBC at presentation.

Any newly suspected PV — outpatient hematology referral within 1–2 weeks for diagnosis confirmation, treatment planning, and longitudinal care.

Hydroxyurea intolerance/resistance.

Suspected transformation to myelofibrosis or AML.

Pregnancy planning or pregnancy in PV.

Acute thrombotic event: stroke, MI, PE, Budd-Chiari, mesenteric thrombosis — admit, anticoagulate (heparin/LMWH), urgent phlebotomy, hematology consult.

Hct >60% with hyperviscosity symptoms: aggressive phlebotomy with saline replacement; consider isovolemic exchange (erythrocytapheresis) if available for rapid Hct reduction.

Major bleeding (especially with platelets >1,000 × 10⁹/L): hold aspirin, check vWF activity, transfuse as needed, plasma/cryo for vWD, urgent cytoreduction.

Severe symptomatic splenomegaly with infarction or rupture (rare).

Suspected leukemic transformation (blasts on smear, rising LDH, cytopenias).

Acute massive PE with hemodynamic compromise, large stroke requiring close monitoring, hepatic failure from Budd-Chiari, splenic infarction with hemodynamic instability, AML with tumor lysis or DIC.

Gastroenterology/Hepatology: splanchnic thrombosis, portal hypertension management.

Interventional radiology: TIPS for Budd-Chiari; thrombolysis in select cases.

Neurology/Stroke team: CVA, CVST.

OB-MFM: pregnant patient with PV.

Transplant hematology: allo-SCT evaluation for post-PV MF or AML transformation.

Key Differentials — Same-Category Causes (Other MPNs and Erythrocytoses)

Within the MPN family:

— Platelets persistently >450 × 10⁹/L; mild or no erythrocytosis.

— JAK2 V617F in ~50%, CALR in ~25%, MPL in ~5%.

— Bone marrow: large hyperlobated megakaryocytes, no significant erythroid hyperplasia.

— Risk stratification: IPSET-thrombosis (age, prior thrombosis, JAK2 status, CV risk factors).

— Treatment: aspirin ± hydroxyurea (high-risk).

— Cytopenias, massive splenomegaly, leukoerythroblastic smear with teardrop cells, marrow fibrosis.

— JAK2/CALR/MPL mutations.

— Ruxolitinib, transfusion support, allo-SCT.

— BCR-ABL1 positive; basophilia, marked leukocytosis with full myeloid spectrum.

— Distinct from PV by molecular testing.

Other erythrocytoses (non-MPN):

— Hypoxia: COPD, OSA, high altitude, cyanotic congenital heart disease, smoking (CO).

— EPO-secreting tumors: renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma, uterine leiomyoma, pheochromocytoma, parathyroid adenoma.

— Exogenous: testosterone/anabolic steroids, EPO doping.

— Post-renal transplant erythrocytosis.

— High-oxygen-affinity hemoglobinopathies (left-shifted O₂ dissociation curve, low P50).

— VHL mutations (Chuvash polycythemia), EPO receptor mutations, 2,3-BPG deficiency, HIF-2α mutations.

— Plasma volume contraction (diuretics, dehydration, obesity, smoking).

— Normal red cell mass; normal EPO; JAK2 negative.

Key distinction: PV: low EPO + JAK2+. Secondary: high EPO + JAK2−. Relative: normal EPO, normal red cell mass. This trichotomy resolves virtually every erythrocytosis vignette on Step 3.

Board pearl: Cerebellar mass + erythrocytosis = hemangioblastoma (often VHL syndrome) — secondary, not PV.

Essential thrombocythemia (ET):

Primary myelofibrosis (PMF):

Post-PV myelofibrosis: as described — fibrotic progression of established PV.

Chronic myeloid leukemia (CML):

Secondary erythrocytosis (high EPO):

Congenital erythrocytosis:

Relative (spurious) erythrocytosis (Gaisböck):

Key Differentials — Other-Category Causes

Hyperviscosity mimics:

Pruritus mimics:

Splanchnic thrombosis differentials:

Constitutional symptoms / splenomegaly:

Erythromelalgia mimics:

Step 3 management: Pruritus + splenomegaly + B symptoms + lymphadenopathy → don't anchor on PV; pursue lymphoma workup with imaging and biopsy. PV pruritus is aquagenic and unaccompanied by adenopathy or B symptoms (early on).

Board pearl: When the vignette gives hyperviscosity symptoms with anemia and elevated total protein, think Waldenström, not PV — the Hct is low, opposite of PV's mechanism.

Waldenström macroglobulinemia / IgM gammopathy: hyperviscosity from monoclonal IgM, not red cells. SPEP/IFE shows M-spike; Hct often low (anemia). Treat with plasmapheresis acutely.

Multiple myeloma: occasionally hyperviscous with high IgA or IgG3; bone pain, hypercalcemia, renal failure, anemia.

Sickle cell disease, leukemic blast crisis: viscosity from cell rigidity/leukostasis, not Hct.

Cholestasis (PBC, PSC, drug-induced): pruritus + elevated alk phos, bilirubin, GGT.

Uremia, hypothyroidism, iron deficiency: itch without rash.

Cutaneous T-cell lymphoma (mycosis fungoides): rash present.

Atopic dermatitis, scabies, dermatographism: visible skin findings.

Hodgkin lymphoma: classic paraneoplastic pruritus with B symptoms, adenopathy.

Cirrhosis with portal hypertension (chicken-or-egg with PV).

Antiphospholipid syndrome, factor V Leiden, prothrombin G20210A, protein C/S deficiency, antithrombin deficiency.

Paroxysmal nocturnal hemoglobinuria (PNH) — flow cytometry for CD55/CD59 absent.

Behçet disease.

Oral contraceptives, pregnancy.

Hematologic malignancies: CML, CLL, lymphomas, hairy cell leukemia.

Infections: TB, malaria, visceral leishmaniasis, infective endocarditis, EBV/CMV.

Storage disorders: Gaucher disease.

Congestive splenomegaly from portal hypertension.

Raynaud phenomenon (usually pallor → cyanosis, cold-induced, opposite trigger).

Peripheral neuropathy with burning (diabetic, alcoholic).

Complex regional pain syndrome.

Secondary Prevention, Discharge Medications, and Long-Term Plan

Lifelong management framework (every PV patient):

— BP <130/80 in most; ACE-I/ARB if comorbidities.

— Statin per ASCVD risk calculator and primary/secondary prevention guidelines.

— Diabetes: A1c per ADA targets.

— Smoking cessation — counsel at every visit; nicotine replacement, varenicline, bupropion.

— Weight management, Mediterranean diet, exercise.

Post-thrombosis (secondary prevention):

Vaccinations:

Discharge checklist after PV-related admission:

Step 3 management: A 65-year-old PV patient discharged after first DVT → lifelong anticoagulation (warfarin INR 2–3 or DOAC), continue aspirin only if separate arterial indication, hydroxyurea for cytoreduction, phlebotomy to Hct <45%, statin, BP control, hematology follow-up in 2 weeks.

Board pearl: Unprovoked VTE in a PV patient = indefinite anticoagulation, not 3–6 months.

Phlebotomy as needed to maintain Hct <45% indefinitely.

Aspirin 81 mg daily lifelong (unless contraindicated).

Cytoreduction (hydroxyurea or interferon) for high-risk patients lifelong; for low-risk patients with progressive disease features.

Aggressive cardiovascular risk factor optimization:

Allopurinol if hyperuricemic or symptomatic gout.

Arterial event: aspirin (often consider clopidogrel or aspirin BID per cardiology/neurology), statin, optimize CV risk factors, ensure tight Hct control and cytoreduction.

Venous thrombosis: indefinite anticoagulation (warfarin or DOAC) given high recurrence risk in unprovoked MPN-associated thrombosis. DOACs increasingly accepted; warfarin remains preferred in splanchnic thrombosis per some guidelines. Add aspirin only if also arterial indication — generally avoid aspirin + full anticoagulation due to bleeding.

Splanchnic thrombosis: indefinite anticoagulation; manage portal hypertension complications.

Annual influenza, pneumococcal (PCV20 or PCV15+PPSV23), zoster (especially if on ruxolitinib), COVID-19, hepatitis B if on interferon, Tdap.

Medication reconciliation: aspirin, cytoreductive agent, anticoagulant if indicated, allopurinol, statin, antihypertensive.

Phlebotomy schedule arranged.

Hematology follow-up within 1–2 weeks.

Primary care follow-up within 1–2 weeks for chronic disease management.

Patient education materials on symptoms of thrombosis, bleeding, transformation.

Follow-Up, Monitoring Parameters, and Counseling

Routine monitoring intervals:

— Every 2 weeks during phlebotomy induction and dose titration of cytoreduction.

— Every 2–3 months once stable (Hct <45%, controlled counts).

Monitoring of specific therapies:

Counseling priorities:

Patient resources: MPN Research Foundation, Leukemia & Lymphoma Society.

Step 3 management: Stable PV at 6-month visit: Hct 43%, platelets 380, on hydroxyurea 1 g/day and aspirin → continue current regimen, recheck CBC in 3 months, annual skin exam, reinforce sun protection and hydration, update vaccines.

Board pearl: A rising LDH with new cytopenias and teardrop cells in a stable PV patient should trigger bone marrow biopsy to evaluate for post-PV myelofibrosis — don't wait for massive splenomegaly.

CBC with differential:

Peripheral smear annually or with any unexplained count change — screen for teardrops, blasts, leukoerythroblastic picture (transformation).

Spleen exam at each visit; imaging if changing.

CMP, LDH, uric acid, ferritin every 6–12 months.

JAK2 V617F allele burden (optional, useful with interferon therapy to assess molecular response).

Bone marrow biopsy if clinical features of transformation (worsening cytopenias, increasing splenomegaly, rising LDH, blasts on smear, new cytogenetic-suspect findings).

Hydroxyurea: CBC q2–4 weeks during titration → q3 months. Annual skin exam (squamous cell skin cancer risk), foot exam (leg ulcers).

Interferon: monthly TSH, LFTs, depression screening (PHQ-9), CBC.

Ruxolitinib: CBC q2 weeks initially → q3 months; lipid panel, weight, signs of infection (zoster, TB reactivation), avoid abrupt discontinuation.

Hydration: avoid dehydration which worsens hyperviscosity.

Smoking cessation: critical (CV risk, worsens hyperviscosity).

Sun protection (especially on hydroxyurea).

Recognize alarm symptoms: new headache, focal weakness, chest pain, abdominal pain, calf swelling, vision changes, unusual bruising/bleeding — present immediately.

Medication adherence: PV is chronic; thrombosis risk returns rapidly if therapy lapses.

Pregnancy planning: women of childbearing age should discuss preconception planning early; switch off hydroxyurea ≥3 months before conception.

Family screening: PV is rarely familial; routine family screening not recommended, but counsel about MPN family clusters.

Ethical, Legal, and Patient Safety Considerations

Informed consent issues:

Patient safety / transitions of care (high-yield Step 3):

Mandatory reporting / public health:

Driving and disability:

Health equity considerations:

Board pearl: A patient on hydroxyurea undergoing emergency surgery — do not stop hydroxyurea abruptly without a cytoreduction bridge plan and Hct optimization; this is a classic Step 3 transition-of-care safety scenario.

Hydroxyurea and leukemia risk: discuss the low but real potential leukemogenic concern (less than alkylators), particularly for younger patients facing decades of therapy — this informs the choice between hydroxyurea and pegylated interferon.

Interferon and depression/suicide: screen for psychiatric history; documented warning required. Mandatory baseline PHQ-9; immediate evaluation for suicidal ideation.

Cytoreduction in pregnancy: counsel on teratogenicity of hydroxyurea (Category D); document discussion. Discuss contraception with women on hydroxyurea and male partners on hydroxyurea (sperm DNA effects).

Allogeneic SCT for transformation: complex consent regarding mortality (~20–40% TRM), GVHD, and curative intent.

Transition from hospital to outpatient: ensure phlebotomy follow-up scheduled before discharge — gaps in phlebotomy after a thrombotic admission directly increase recurrence risk. Verify pharmacy has cytoreductive agent; bridge anticoagulation properly.

Medication reconciliation: NSAIDs and aspirin doubling at discharge can cause bleeding; common error.

Anticoagulation safety: confirm INR follow-up or DOAC adherence after PV-related VTE; bleeding risk with thrombocytosis + acquired vWD.

Preoperative communication: surgeons may not appreciate PV's dual thrombotic/bleeding risk — hematology should formally communicate peri-op plan. Failure-mode: stopping cytoreduction without bridging plan → rebound thrombocytosis and thrombosis.

PV is not reportable to public health authorities.

Cancer registry reporting required for myeloid neoplasms in most US states once diagnosis is established.

Post-stroke or post-seizure (rare): comply with state driving restrictions; document counseling.

Phlebotomy access barriers (transportation, infusion center hours) disproportionately affect underserved patients — proactively connect to social work for transportation, home health phlebotomy where available.

Cost of newer agents (ropeginterferon, ruxolitinib) — verify insurance/patient assistance programs early.

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: If the vignette mentions a cerebellar hemangioblastoma with high Hgb and Hct, the answer is VHL syndrome with EPO-secreting tumor, NOT PV — and EPO will be high, not low.

Key distinction: PV → low EPO + JAK2 positive. Memorize this pair above all else for Step 3 erythrocytosis vignettes.

JAK2 V617F: 95% of PV; also 50% of ET and 50% of PMF.

JAK2 exon 12: 3% of PV; presents with isolated erythrocytosis.

Hct target <45% in both men and women (CYTO-PV trial).

Aspirin 81 mg daily universally indicated.

Aquagenic pruritus after hot showers — highly specific.

Erythromelalgia — burning red extremities, dramatic aspirin response.

Budd-Chiari, portal vein thrombosis, cerebral venous sinus thrombosis → always test JAK2.

Low serum EPO = PV; high EPO = secondary.

Iron deficiency from phlebotomy is desired — never replace iron.

Hydroxyurea: first-line cytoreduction for high-risk PV.

Pegylated interferon: preferred in pregnancy and young patients.

Ruxolitinib: HU-resistant/intolerant; refractory pruritus and splenomegaly.

Busulfan/³²P/chlorambucil: avoid in young — leukemogenic.

Acquired vWD at platelets >1,000–1,500 — paradoxical bleeding; check ristocetin cofactor.

Hyperuricemia/gout: treat with allopurinol.

Post-PV myelofibrosis: teardrop cells, leukoerythroblastic smear, marrow fibrosis.

AML transformation: ~5–10% lifetime; worst with prior alkylators.

VHL mutations: cerebellar hemangioblastoma, renal cell carcinoma, pheochromocytoma — secondary erythrocytosis.

Chuvash polycythemia: VHL R200W homozygous; congenital.

High-affinity hemoglobin variants: low P50.

CYTO-PV trial: established Hct <45% target.

ECLAP trial: established low-dose aspirin benefit.

PROUD-PV / CONTINUATION-PV: ropeginterferon non-inferior to hydroxyurea.

MAJIC-PV / RESPONSE trials: ruxolitinib for HU resistance.

Median survival in PV: ~14–20 years with modern management.

Pregnancy in PV: aspirin + phlebotomy + peg-interferon + 6 weeks postpartum LMWH.

WHO Hgb thresholds: M >16.5, F >16.0; Hct M >49%, F >48%.

Board Question Stem Patterns

Pattern 1 — Classic presentation:

"A 62-year-old man presents with headaches, dizziness, and intense itching after hot showers. Exam: facial plethora, spleen tip palpable. Hgb 19.2, Hct 58%, WBC 13, platelets 520."

→ Next best test: JAK2 V617F PCR and serum EPO. Treatment: phlebotomy + aspirin + hydroxyurea (age ≥60 = high-risk).

Pattern 2 — Budd-Chiari unmasking PV:

"A 45-year-old woman with new-onset ascites and hepatomegaly; imaging shows hepatic vein occlusion. Hgb 14.5, Hct 43%, platelets 480."

→ Despite "normal" CBC: test JAK2 — likely masked PV with iron deficiency.

Pattern 3 — Erythromelalgia clue:

"A 55-year-old man with burning red feet relieved by aspirin; Hgb 17.8, platelets 750."

→ PV (or ET) — confirm JAK2; aspirin + phlebotomy.

Pattern 4 — Secondary erythrocytosis distractor:

"A 58-year-old smoker with COPD has Hgb 18.0. EPO is elevated. JAK2 negative."

→ Secondary erythrocytosis; address hypoxia (smoking cessation, supplemental O₂ if qualifying), not PV management.

Pattern 5 — Testosterone-induced erythrocytosis:

"A 60-year-old man on testosterone replacement has Hgb 18.5. EPO normal, JAK2 negative."

→ Reduce or discontinue testosterone; occasional phlebotomy if symptomatic; not PV.

Pattern 6 — Pregnancy in PV:

"A 32-year-old G2P0 with known PV on hydroxyurea is now pregnant."

→ Stop hydroxyurea, start pegylated interferon if cytoreduction needed, aspirin throughout pregnancy, phlebotomy, postpartum LMWH × 6 weeks.

Pattern 7 — Transformation:

"A patient with 15-year history of PV now has Hgb 9.5, platelets 90, massive splenomegaly, teardrop cells on smear."

→ Post-PV myelofibrosis; bone marrow biopsy, consider ruxolitinib, transplant evaluation.

Pattern 8 — Acquired vWD bleeding:

"PV patient with platelets 1,800, mucocutaneous bleeding on aspirin."

→ Check ristocetin cofactor activity (acquired vWD); hold aspirin, initiate cytoreduction.

Pattern 9 — Hct target trap:

The answer is <45% for both men and women — not 42% for women.

Pattern 10 — Iron deficiency trap:

PV patient with low ferritin and microcytosis from chronic phlebotomy.

→ Do NOT supplement iron — this is expected and therapeutic.

Board pearl: When given a vignette of unexplained thrombosis in an unusual location, the highest-yield single test is JAK2 V617F PCR — regardless of how "normal" the CBC appears.

One-Line Recap

Polycythemia vera is a JAK2-driven myeloproliferative neoplasm diagnosed by elevated Hct/Hgb + JAK2 mutation + low EPO, managed lifelong with phlebotomy to Hct <45%, low-dose aspirin, cytoreduction (hydroxyurea first-line; pegylated interferon in young/pregnant patients) for high-risk disease, and aggressive cardiovascular risk modification — with vigilance for thrombosis, acquired von Willebrand bleeding, and transformation to myelofibrosis or AML.

Rapid-fire high-yield recap:

Board pearl: Low EPO + JAK2-positive + Hct above threshold = polycythemia vera — this single triad resolves nearly every Step 3 PV vignette.

Diagnosis: Hgb >16.5 (M)/>16.0 (F) or Hct >49%/>48% + JAK2 V617F (95%) or exon 12 (3%) + low serum EPO; bone marrow biopsy for prognosis and ambiguous cases. WHO 2016 criteria.

Risk stratification: Low risk = age <60 and no prior thrombosis (phlebotomy + aspirin); High risk = age ≥60 or prior thrombosis (add cytoreduction). Universal Hct target <45% in both sexes (CYTO-PV).

First-line therapy: phlebotomy + aspirin 81 mg + CV risk control ± hydroxyurea (or pegylated interferon in young/pregnant); ruxolitinib for HU-resistant/intolerant or refractory pruritus/splenomegaly. Iron deficiency from phlebotomy is therapeutic — do not replace iron.

Complications: arterial and venous thrombosis (including splanchnic/cerebral venous sinus — always test JAK2 in unusual-site clots), acquired von Willebrand syndrome with platelets >1,000–1,500, post-PV myelofibrosis (teardrop cells, fibrotic marrow), and AML transformation (worst prognosis, promoted by alkylators).

Special populations: avoid hydroxyurea in pregnancy (use interferon + aspirin + phlebotomy + postpartum LMWH); reduce hydroxyurea dose in CKD; high-risk elderly require cytoreduction; testosterone- and hypoxia-driven erythrocytoses are secondary (high EPO, JAK2 negative) and treated by addressing the cause, not PV protocols.