Write a short note on the myeloproliferative neoplasms, including polycythaemia vera.

Definition

The myeloproliferative neoplasms (MPNs) are clonal disorders of the pluripotent haematopoietic stem cell characterised by excessive proliferation of one or more mature myeloid lineages with retained differentiation — in contrast to acute leukaemia, where differentiation is arrested. They share a tendency to splenomegaly, thrombosis, marrow fibrosis, and transformation to acute leukaemia.

The JAK2 V617F mutation causes constitutive activation of JAK-STAT signalling, rendering progenitors hypersensitive to (or independent of) growth factors — it is the unifying molecular lesion of the BCR-ABL1-negative MPNs.

Polycythaemia Vera

Definition: a clonal MPN with autonomous overproduction of red cells (and often granulocytes and platelets), independent of erythropoietin.

Distinguish from other causes of a raised haematocrit:

Clinical features:

• Hyperviscosity: headache, dizziness, tinnitus, visual disturbance, poor concentration, fatigue.
• Plethoric facies with conjunctival suffusion; ruddy cyanosis.
• Aquagenic pruritus — intense itching after a hot bath or shower, a highly characteristic symptom caused by histamine release from basophils.
• Splenomegaly (in about 70%) and hepatomegaly.
• Thrombosis — arterial and venous, and the leading cause of morbidity and death: stroke, myocardial infarction, deep vein thrombosis, and thrombosis at unusual sites — Budd–Chiari syndrome and portal vein thrombosis (a raised haematocrit in a patient with Budd–Chiari should always prompt JAK2 testing).
• Bleeding paradoxically, from acquired platelet dysfunction and acquired von Willebrand disease at very high platelet counts.
• Erythromelalgia — burning pain and redness of hands and feet, relieved by aspirin.
• Gout from high cell turnover; peptic ulceration.

Investigations:

• CBC: raised haemoglobin and haematocrit, often with leucocytosis and thrombocytosis — the involvement of all three lineages strongly favours a primary process.
• JAK2 V617F mutation testing — the key diagnostic test, positive in over 95%; JAK2 exon 12 in most of the remainder.
• Serum erythropoietin — LOW, distinguishing it from secondary causes.
• Bone marrow: hypercellular with panmyelosis and clustered pleomorphic megakaryocytes; reticulin staining to assess fibrosis.
• Raised serum uric acid, LDH and vitamin B12; low or normal ferritin; arterial oxygen saturation and abdominal ultrasound to exclude secondary causes.

Management:

• Venesection (phlebotomy) to maintain the haematocrit below 45% — the primary intervention, with clear evidence of reduced thrombotic events.
• Low-dose aspirin in all patients unless contraindicated, to reduce thrombosis and relieve erythromelalgia.
• Cytoreductive therapy for high-risk patients (age over 60, or previous thrombosis), poor tolerance of venesection, symptomatic splenomegaly or progressive thrombocytosis: hydroxyurea first-line; interferon-alpha (preferred in younger patients and in pregnancy); ruxolitinib (a JAK inhibitor) for hydroxyurea-resistant or intolerant disease.
• Control cardiovascular risk factors; allopurinol for gout; antihistamines or interferon for pruritus.
• Monitor for transformation to myelofibrosis (post-polycythaemic) or acute myeloid leukaemia, which occurs in a minority over years.

Essential Thrombocythaemia

Sustained thrombocytosis (platelets > 450 × 10⁹/L) with clonal marrow proliferation, after exclusion of reactive causes — infection, inflammation, iron deficiency, malignancy, post-splenectomy, haemorrhage (which together account for the great majority of raised platelet counts). Features include thrombosis, erythromelalgia, and paradoxical bleeding at very high counts. Marrow shows large hyperlobulated ("staghorn") megakaryocytes in clusters. Management follows the same risk-stratified principles: aspirin for all, hydroxyurea or interferon (or anagrelide) for high-risk disease.

Primary Myelofibrosis

Clonal proliferation with cytokine-driven reactive marrow fibrosis and extramedullary haemopoiesis. Features: massive splenomegaly (often the largest spleens in medicine), constitutional symptoms (fever, weight loss, drenching night sweats), progressive anaemia and cytopenias, and portal hypertension.

Investigations:

• leucoerythroblastic blood picture with tear-drop poikilocytes (dacrocytes) — highly characteristic
• "dry tap" on marrow aspiration with trephine showing fibrosis
• JAK2/CALR/MPL mutation.

Management: supportive transfusion, ruxolitinib for splenomegaly and constitutional symptoms, androgens or erythropoietin for anaemia, splenectomy or splenic irradiation in selected cases, and allogeneic stem cell transplantation as the only curative option. It carries the highest risk of leukaemic transformation among the MPNs.