On this page
Study tools
Write your answer
Saved on this device. No marking — you are the marker.
Q1: Definition, classification and the molecular spine (2 min)
- Define the myeloproliferative neoplasms (MPN): clonal disorders of haematopoietic stem cells causing overproduction of one or more mature myeloid lineages.
- Name the classic BCR-ABL-negative trio: polycythaemia vera (PV) — red cells; essential thrombocythemia (ET) — platelets; primary myelofibrosis (PMF) — fibrosis/ineffective extramedullary haematopoiesis. Chronic myeloid leukaemia is BCR-ABL-positive and separate.
- State the shared molecular lesion: JAK2 V617F (constitutive JAK-STAT signalling) in ~95 percent of PV and 50 to 60 percent of ET/PMF; CALR and MPL cover most JAK2-negative ET/PMF.
- Note that the three overlap: PV/ET may evolve into post-PV/post-ET myelofibrosis, and all may transform to acute myeloid leukaemia.
Q2: Pathophysiology and mechanism (3 min)
- JAK2 V617F (valine-to-phenylalanine, position 617) makes the JAK2 kinase constitutively active, so the clone proliferates without EPO/TPO stimulus — hence EPO-independent erythroid colonies and low serum EPO in PV.
- PV — hyperviscosity: raised red-cell mass increases viscosity, causing sluggish flow, endothelial activation and thrombosis (cerebral, coronary, splanchnic).
- ET — thrombosis and bleeding: large dysfunctional platelets plus leukocyte activation cause thrombosis; platelets over 1500 cause acquired von Willebrand disease (adsorption of large vWF multimers) and bleeding.
- PMF — fibrosis: abnormal megakaryocytes secrete TGF-beta, PDGF, bFGF, stimulating fibroblasts to lay down reticulin/collagen. Haematopoiesis shifts to the spleen and liver (extramedullary) → massive splenomegaly, tear-drop (dacrocyte) cells, leukoerythroblastic film.
Q3: Investigations and the discriminating tests (3 min)
- PV: raised haematocrit (over 0.52 M / over 0.48 F), low serum EPO, JAK2 V617F positive, hypercellular marrow. The single best discriminator of primary from secondary polycythaemia is serum EPO (low in PV, high in secondary).
- ET: sustained platelets over 450 x10^9/L, megakaryocytic hyperplasia on trephine, exclusion of reactive causes (CRP, ferritin, infection, iron deficiency), JAK2/CALR/MPL screen.
- PMF: blood film — tear-drop cells, nucleated red cells, leukoerythroblastic film, raised LDH/urate; bone-marrow trephine with reticulin stain shows fibrosis; driver mutation screen.
- Pitfall: splanchnic vein thrombosis (Budd-Chiari, portal) → test JAK2 even with a normal blood count (occult MPN).
- Reproduce IPSET-thrombosis (ET) and DIPSS / DIPSS-plus (PMF) as the risk scores guiding cytoreduction and transplant.
Q4: Management — definitive and stepwise (3 min)
- PV: venesection to haematocrit below 0.45 (ECLAP target) + low-dose aspirin 75 mg; hydroxycarbamide first-line if high-risk (over 60, prior thrombosis); interferon-alpha in younger patients/pregnancy; ruxolitinib in resistant disease.
- ET: low-dose aspirin for microvascular symptoms (erythromelalgia); cytoreduction with hydroxycarbamide if high-risk (over 60, prior thrombosis, platelets over 1500); anagrelide or interferon as alternatives; interferon-alpha is safe in pregnancy (avoid hydroxycarbamide/anagrelide).
- PMF: ruxolitinib (JAK1/2 inhibitor) for splenomegaly and symptoms; allogeneic stem-cell transplant is the only curative option for younger fit high-risk patients; supportive care (transfusion, allopurinol, antibiotics); fedratinib/pacritinib/momelotinib as alternative JAK inhibitors.
- Name doses: hydroxycarbamide oral ~15 to 20 mg/kg/day titrated; aspirin 75 mg oral; interferon-alpha subcutaneous; ruxolitinib oral.
Q5: Complications, prognosis and the single biggest killer (2 min)
- Thrombosis is the leading cause of death in PV and ET (stroke, MI, Budd-Chiari); the only cure for PMF is allogeneic stem-cell transplant.
- Transformation: PV/ET → post-PV/post-ET myelofibrosis; any MPN → acute myeloid leukaemia (risk highest in PMF, ~10 to 20 percent).
- Treatment toxicities: hydroxycarbamide — cytopenias, oral/leg ulcers; anagrelide — palpitations, fluid retention, headache; interferon — flu-like illness, depression, thyroid dysfunction; ruxolitinib — cytopenias, infection (TB/herpes zoster), withdrawal syndrome on stopping.
- High-yield: aquagenic pruritus and gout are clues to PV; platelets over 1500 in ET cause bleeding, not thrombosis; interferon-alpha is safe in pregnancy.