Myeloproliferative Disorders and Erythromelalgia
Myeloproliferative disorders (MPNs) are clonal stem cell disorders characterized by excessive production of mature blood cells, while erythromelalgia is a neurovascular pain syndrome that can occur as a complication of these disorders, particularly in essential thrombocythemia.
Myeloproliferative Disorders
Classification and Characteristics
Myeloproliferative neoplasms (MPNs) are classified as Philadelphia chromosome-negative classical MPNs, which include:
Polycythemia Vera (PV):
- Characterized by increased red cell mass
- Diagnostic criteria include hemoglobin >16.5 g/dL in men or >16 g/dL in women
- Bone marrow shows hypercellularity with trilineage myeloproliferation
- Presence of JAK2 mutation is required for diagnosis 1
Essential Thrombocythemia (ET):
Primary Myelofibrosis (PMF):
- Characterized by bone marrow fibrosis
- Megakaryocyte proliferation and atypia
- Can present as pre-PMF or overt PMF 1
Molecular Pathophysiology
- JAK2V617F mutation is detected in:
- ~95% of PV cases
- ~60% of ET cases
- ~60% of PMF cases 1
- CALR and MPL mutations are found in JAK2-negative ET and PMF 1
- These mutations lead to constitutive activation of cytokine signaling pathways 1
Risk Stratification
Risk stratification is primarily designed to estimate thrombotic complications:
- High-risk: Age >60 years or history of thrombosis
- Low-risk: Absence of both risk factors 1
Additional risk factors include:
- Leukocytosis (>11 × 10^9/L)
- Extreme thrombocytosis (>1,000 × 10^9/L) - associated with bleeding risk due to acquired von Willebrand syndrome 3
Erythromelalgia
Definition and Characteristics
Erythromelalgia is a neurovascular pain syndrome characterized by:
- Burning pain in extremities (primarily feet and hands)
- Redness (erythema)
- Increased temperature in the affected areas 4, 5
Types and Association with MPNs
- Primary erythromelalgia: Occurs independently
- Secondary erythromelalgia: Associated with underlying conditions, particularly MPNs 6
Association with Myeloproliferative Disorders
- Most commonly associated with ET and PV
- Can occur in all variants of chronic myeloproliferative disorders with sufficient platelet counts 4
- Often precedes the diagnosis of MPNs by a median of 2.5 years 6
- Caused by platelet-mediated acral inflammation and arteriolar thrombosis in thrombocythemia 4
Diagnosis
- Clinical presentation: burning pain, redness, and warmth in extremities
- Symptoms provoked by heat, exercise, and dependency
- Symptoms relieved by cold exposure and elevation of the extremity
- Infrared thermography can help visualize the hyperthermal area 5
- Diagnostic hallmark: Prompt and lasting relief of burning pain with low-dose aspirin 4
Treatment
For secondary erythromelalgia associated with MPNs:
For high-risk ET patients with erythromelalgia:
Clinical Implications and Monitoring
Important Clinical Considerations
- All patients with erythromelalgia should be monitored with periodic blood counts, as it may precede MPNs by years 6
- Abnormal blood counts should prompt investigation for underlying MPNs 6
- In ET patients with vasomotor/microvascular disturbances like erythromelalgia, aspirin is recommended if not contraindicated 1
Disease Progression and Prognosis
- 10-year risk of leukemic/fibrotic transformation is <1%/1% in ET and <3%/10% in PV 3
- Risk of thrombosis exceeds 20% in untreated high-risk patients 3
- Risk factors for shortened survival include advanced age, leukocytosis, and history of thrombosis 3