Polycythemia Vera and Other Myeloproliferative Neoplasms¶
Chapter 108 | Part 12: Hematology
KEY CLINICAL POINTS¶
- Polycythemia Vera (PV), Primary Myelofibrosis (PMF), and Essential Thrombocythosis (ET) are clonal myeloproliferative neoplasms (MPNs) driven by mutations in JAK2, CALR, or MPL.
- JAK2 V617F mutation is central to PV pathogenesis, while CALR and MPL mutations are more common in PMF and ET.
- Diagnosis requires exclusion of reactive causes of erythrocytosis, thrombocytosis, or myelofibrosis using WHO classification and scoring systems (IPSS/DIPSS).
- Management includes phlebotomy for PV, ruxolitinib for splenomegaly in PMF, and cytoreductive agents for ET.
- Prognosis varies by disease: PV is indolent, PMF has a shorter survival with risk stratification, and ET is generally benign unless thrombosis occurs.
1. DEFINITION & OVERVIEW¶
Polycythemia Vera (PV), Primary Myelofibrosis (PMF), and Essential Thrombocythosis (ET) are clonal MPNs characterized by overproduction of blood cells, myelofibrosis, and risk of leukemic transformation. PV is marked by erythrocytosis, PMF by marrow fibrosis and extramedullary hematopoiesis, and ET by thrombocytosis.
Table 108-1: World Health Organization Classification of Chronic Myeloproliferative Neoplasms¶
| Chronic Myeloid Leukemia | Chronic Ne utrophilic Leukemia | Chronic Eo sinophilic Leukemia | Polycythe mia Vera | Primary M yelofibrosi s | Essential T hrombocyt osis | Mastocyto sis | Myeloprolif erative Ne oplasms, U nclassifiab le |
|---|---|---|---|---|---|---|---|
| BCR-ABL– positive | |||||||
| CSF3R mutation, t(15;19) | |||||||
| PDGFRa, F IP1L1-PDG FbB | |||||||
| JAK2 V617F |
| Chronic Myeloid Leukemia | Chronic Ne utrophilic Leukemia | Chronic Eo sinophilic Leukemia | Polycythe mia Vera | Primary M yelofibrosi s | Essential T hrombocyt osis | Mastocyto sis | Myeloprolif erative Ne oplasms, U nclassifiab le |
|---|---|---|---|---|---|---|---|
| JAK2, MPL, CALR mutations | |||||||
| JAK2, CALR, MPL mutations | |||||||
| KIT mutations | |||||||
| Unclassifia ble |
1.1 Myeloproliferative Neoplasms (MPNs)¶
MPNs are a group of disorders involving clonal proliferation of hematopoietic stem cells, leading to increased production of one or more blood cell lines. They include PV, PMF, and ET, which share common pathogenic mechanisms but distinct clinical features.
1.2 WHO Classification¶
The WHO classification includes eight MPNs, with PV, PMF, and ET being the most clinically relevant. Other entities include chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), and chronic eosinophilic leukemia (CEL).
2. EPIDEMIOLOGY¶
PV occurs in 2.5/100,000, increasing with age. PMF is rare, with a median age of 60. ET has an incidence of 1–2/100,000, with female predominance. Risk factors include age, family history, and comorbidities like tuberculosis or HIV.
2.1 Demographics¶
PV affects all adult age groups, with higher incidence in women <50. PMF primarily affects men in their sixth decade. ET shows female predominance, though no sex difference in PMF or reactive thrombocytosis.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
JAK2 V617F mutation (95% PV), CALR (36% PMF), and MPL (4% PMF) drive MPNs. JAK2 activation leads to constitutive signaling, erythropoiesis, and resistance to apoptosis. PMF involves fibroblast proliferation and extramedullary hematopoiesis.
Table 108-2: Causes of Erythrocytosis¶
| Relative Erythrocytosis | Absolute Erythrocytosis |
|---|---|
| Hemoconcentration (dehydration, diuretics, tobacco) | Hypoxia (tumors, COPD, CO poisoning) |
| Androgens, ethanol abuse | Hypernephroma, hepatoma |
| Sleep apnea, renal disease | High altitude, pulmonary disease |
| Relative Erythrocytosis | Absolute Erythrocytosis |
|---|---|
| Postrenal transplantation, SGLT2 inhibitors | Right-to-left shunts, meningioma |
| Focal glomerulonephritis, recombinant EPO | Hepatopulmonary syndrome, pheochromocytoma |
| Bartter’s syndrome, VHL mutations | 2,3-BPG mutation, PHD2/HIF2a mutations |
| LNK mutations | Polycythemia Vera |
3.1 Genetic Mutations¶
JAK2 V617F (PV, PMF), CALR (PMF, ET), and MPL (PMF) mutations are central. ASXL1, EZH2, and IDH1/2 mutations worsen prognosis in PMF.
3.2 Pathogenesis¶
JAK2 activation disrupts erythropoietin/thrombopoietin signaling, leading to uncontrolled cell proliferation. PMF involves fibroblast proliferation and marrow fibrosis, while ET is driven by thrombopoietin/MPL signaling.
4. CLINICAL FEATURES¶
PV presents with erythrocytosis, splenomegaly, and thrombosis. PMF features splenomegaly, marrow fibrosis, and constitutional symptoms. ET is often asymptomatic but may cause thrombosis or erythromelalgia.
4.1 PV Symptoms¶
Hyperviscosity (headache, TIA, visual disturbances), pruritus, splenomegaly, and thrombosis. Acute leukemia transformation is rare.
4.2 PMF Features¶
Splenomegaly, marrow fibrosis, anemia, and constitutional symptoms (weight loss, night sweats). Extramedullary hematopoiesis causes teardrop RBCs and nucleated RBCs.
4.3 ET Presentation¶
Incidental thrombocytosis, erythromelalgia, ocular migraine, or bleeding. Asymptomatic patients require no therapy unless thrombosis occurs.
5. DIFFERENTIAL DIAGNOSIS¶
Reactive erythrocytosis (dehydration, CO poisoning), secondary myelofibrosis (tumors, infections), and other MPNs (CML, PMF). Exclude reactive thrombocytosis (inflammation, malignancy).
5.1 Reactive Causes¶
Hemoconcentration, hypoxia, or tumors. Distinguish from PV using JAK2/CALR/MPL mutations and plasma volume/erythrocyte mass measurements.
6. INVESTIGATIONS & DIAGNOSIS¶
Laboratory tests include CBC, reticulocyte count, JAK2/CALR/MPL mutation analysis, and plasma volume/erythrocyte mass. Bone marrow biopsy confirms myelofibrosis. Flow cytometry and cytogenetics exclude CML.
Table 108-3: Disorders Causing Myelofibrosis¶
| Malignant | Nonmalignant |
|---|---|
| Acute leukemia, CML, PMF, myelodysplasia | HIV, tuberculosis, systemic lupus, renal osteodystrophy |
| Hairy cell leukemia, Hodgkin’s disease, lymphoma | Vitamin D deficiency, thorium dioxide exposure |
| Multiple myeloma, metastatic carcinoma | Gray platelet syndrome, polycythemia vera |
| Systemic mastocytosis | Hepatopulmonary syndrome |
6.1 Diagnostic Criteria¶
Erythrocytosis (hemoglobin ≥ 18.5 g/dL, hematocrit ≥ 55%) with JAK2/CALR/MPL mutations. PMF requires marrow fibrosis and exclusion of CML. ET is diagnosed by thrombocytosis with no reactive cause.
7. MANAGEMENT & TREATMENT¶
Phlebotomy for PV, ruxolitinib for splenomegaly in PMF, and cytoreductive agents (hydroxyurea, interferon) for ET. Aspirin for thrombosis prevention. Allogeneic transplant is curative for PMF.
7.1 PV Treatment¶
Phlebotomy to maintain hemoglobin <140 g/L in men, <120 g/L in women. Ruxolitinib for refractory cases. Avoid chemotherapy due to leukemogenic risk.
7.2 PMF Management¶
Ruxolitinib for splenomegaly and constitutional symptoms. Pegylated IFN- α for early disease. Splenectomy for refractory cases with significant complications.
7.3 ET Therapy¶
Aspirin for thrombosis prevention. Hydroxyurea or anagrelide for symptomatic thrombocytosis. Avoid 32P or alkylating agents due to leukemogenic risk.
8. PROGNOSIS & COMPLICATIONS¶
PV has a long survival with low leukemic transformation. PMF prognosis is stratified by IPSS/DIPSS scores, with high-risk patients having median survival <5 years. ET is generally benign but carries thrombotic risk.
Table 108-4: Scoring Systems for PMF Prognosis¶
| Risk Factor | IPSS (2009) | DIPSS (2010) | DIPSS PLUS (2011) |
|---|---|---|---|
| Anemia (<10 g/dL) | X | X | X |
| Leukocytosis (>25,000/mL) | X | X | X |
| Peripheral blasts (‡1%) | X | X | X |
| Constitutional symptoms | X | X | X |
| Age (>65 years) | X | X | X |
| Unfavorable karyotype | X | X | X |
| Platelet count (<100,000/mL) | X | X | X |
| Risk Factor | IPSS (2009) | DIPSS (2010) | DIPSS PLUS (2011) |
|---|---|---|---|
| Transfusion dependence | X | X | X |
8.1 PMF Prognosis¶
IPSS/DIPSS scores guide risk stratification. High-risk PMF has 5-year survival <50%. Leukemic transformation occurs in ~10% of patients.
8.2 Complications¶
Thrombosis, hemorrhage, splenic infarction, and myelofibrosis. PV may cause hepatic venous thrombosis (Budd-Chiari syndrome).
9. SPECIAL CONSIDERATIONS¶
Pregnancy requires careful monitoring of blood counts and anticoagulation. Elderly patients may need lower-dose therapies. Iron deficiency from phlebotomy requires supplementation. Splenectomy increases leukemic risk.
9.1 Pregnancy¶
Monitor hemoglobin and platelet counts. Avoid anticoagulants unless thrombosis risk is high. Phlebotomy may be needed to prevent hyperviscosity.
10. KEY POINTS & CLINICAL PEARLS¶
- JAK2 V617F is central to PV, while CALR/MPL mutations are more common in PMF and ET. 2. Distinguish reactive from clonal erythrocytosis using plasma volume/erythrocyte mass measurements. 3. Ruxolitinib is effective for splenomegaly in PMF and refractory PV. 4. Aspirin is first-line for thrombosis prevention in ET. 5. IPSS/DIPSS scores guide PMF prognosis and treatment decisions.