Myeloproliferative Neoplasms: Too Many Cells, and the Drugs That Rein Them In
Most blood cancers make too few working cells. This family does the opposite: the marrow gets stuck in the "on" position and floods the blood with red cells, or platelets, or scar tissue. The result is blood too thick to be safe. Learn three diseases that share one broken switch — and why the cure includes an aspirin, a centuries-old bloodletting, and a modern pill that turns the switch back off.
A ruddy, plethoric man of 62 sits in the clinic looking almost sunburnt — his face and palms are a deep red. His complaint is strange: every time he steps out of a warm shower, an unbearable itch crawls over his skin, no rash to show for it. He mentions headaches and a odd fullness under his left ribs. His blood count is the giveaway: a haematocrit that has climbed so high the blood is running thick and sluggish, quietly raising his risk of a stroke. The remedies that will keep him safe are almost poetic in their range: a bloodletting older than modern medicine, a daily baby aspirin, and a tablet that quiets the overactive marrow.
One broken switch: JAK-STAT stuck "on"
The myeloproliferative neoplasms are cancers of overproduction. The myeloproliferative neoplasms (Myeloproliferative neoplasms, MPNs) are clonal disorders in which a single mutated stem cell in the bone marrow keeps churning out mature blood cells with no off-signal. This chapter covers the classic BCR-ABL-NEGATIVE trio — polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. They are the cousins of chronic myeloid leukaemia (CML), but CML is defined by the BCR-ABL fusion gene and is covered in its own chapter; these three are BCR-ABL-NEGATIVE and are driven by a different broken switch.
That broken switch is the JAK-STAT signalling pathway. Normally the hormones that command blood production (erythropoietin for red cells, thrombopoietin for platelets) bind a receptor, which activates a Janus kinase (JAK2), which relays the "make more cells" message inward. In these MPNs a mutation — most famously JAK2 V617F, and in others CALR or MPL — jams that relay permanently in the on state. The marrow behaves as if it is being flooded with growth signal even when no hormone is present. Over 95% of polycythaemia vera carries JAK2 V617F; about half of essential thrombocythaemia and primary myelofibrosis do, with most of the rest carrying CALR or MPL.
Remember the unifying idea and the rest falls into place: one overactive JAK-STAT pathway explains all three diseases AND the newest drug class. If the switch is stuck on, a JAK inhibitor (like ruxolitinib) is the rational answer. And because thick, cell-crowded blood clots easily, low-dose aspirin runs through the whole family as clot insurance.
Polycythaemia vera: too many red cells
The core problem is a raised red cell mass. Polycythaemia vera (Polycythaemia vera, PV) overproduces red cells — and frequently white cells and platelets too. The rising haematocrit thickens the blood (hyperviscosity), producing headache, dizziness, visual disturbance, a plethoric red face, and the characteristic aquagenic pruritus — an intense itch after a hot bath or shower. The spleen is often enlarged. The real danger is thrombosis: strokes, heart attacks, and clots in unusual sites. A helpful clue is a LOW serum erythropoietin — the body isn't asking for red cells; the marrow is making them on its own.
The backbone is regular VENESECTION (phlebotomy): literally removing blood to bring the haematocrit down to target (below 0.45 / 45%), which directly cuts viscosity and clot risk. Add LOW-DOSE ASPIRIN (75–100 mg daily) to reduce arterial thrombosis. For higher-risk patients (older, prior clot, very high counts), add cytoreduction — HYDROXYUREA (hydroxycarbamide) is first-line to quiet the marrow; interferon-alpha is preferred in younger or pregnant patients because it avoids the small leukaemogenic worry and is pregnancy-friendly. For disease resistant to or intolerant of hydroxyurea, RUXOLITINIB (a JAK inhibitor) is licensed and targets the very pathway at fault.
- PV = raised red cell mass (± high WBC/platelets); over 95% carry JAK2 V617F.
- Hyperviscosity → headache, plethora, aquagenic pruritus (itch after a hot bath).
- Main threat is thrombosis; serum erythropoietin is characteristically LOW.
- Treat: venesection to a target haematocrit + low-dose aspirin.
- Cytoreduce with hydroxyurea (interferon in young/pregnant); ruxolitinib if resistant.
Essential thrombocythaemia: too many platelets
Essential thrombocythaemia (Essential thrombocythaemia, ET) is the platelet-dominant member: a persistently high platelet count from clonal overproduction. The paradox students must hold in mind is that ET causes BOTH thrombosis (the usual worry — clots, transient ischaemic attacks, erythromelalgia, a burning redness of the hands and feet) AND, at very high counts, bleeding — because the excess platelets are dysfunctional and can mop up von Willebrand factor (acquired von Willebrand syndrome). Diagnosis demands first excluding a reactive thrombocytosis — a high platelet count driven by infection, inflammation, iron deficiency, bleeding or a splenectomy — which is far commoner and is not a neoplasm.
Low-risk patients may need only LOW-DOSE ASPIRIN to lower thrombotic risk (used cautiously, and often withheld at extreme platelet counts because of the bleeding paradox). Higher-risk patients get cytoreduction: HYDROXYUREA is first-line. ANAGRELIDE is a platelet-specific option that selectively lowers the platelet count by impairing megakaryocyte maturation — useful when a targeted platelet drop is wanted. Interferon-alpha is again the choice in younger or pregnant patients.
- ET = sustained high platelets from clonal overproduction (JAK2, CALR or MPL).
- Causes BOTH thrombosis AND, at very high counts, paradoxical bleeding.
- Always exclude reactive thrombocytosis (infection, inflammation, iron deficiency).
- Aspirin ± cytoreduction; anagrelide selectively lowers the platelet count.
Primary myelofibrosis: the marrow scars over
Here the overactive marrow ends in fibrosis. In primary myelofibrosis (Primary myelofibrosis, PMF) the clonal cells drive the marrow to lay down scar tissue (fibrosis), progressively crowding out normal production. Blood-making moves out to the spleen and liver (extramedullary haematopoiesis), producing massive splenomegaly. The blood film is classic — teardrop-shaped red cells (dacrocytes) and a leukoerythroblastic picture (immature red and white precursors spilling into the blood). Patients suffer cytopenias (especially anaemia) and heavy constitutional symptoms: drenching sweats, weight loss, fever and fatigue, plus dragging abdominal discomfort from the huge spleen. PMF carries the worst prognosis of the three.
RUXOLITINIB, a JAK1/JAK2 inhibitor, is the landmark drug: it dramatically shrinks the enlarged spleen and relieves the constitutional symptoms (sweats, weight loss, fatigue), markedly improving quality of life — though it does not reverse the fibrosis. Much of care is SUPPORTIVE: transfusions for anaemia, and drugs for symptom control. The only potentially curative option is an ALLOGENEIC STEM CELL TRANSPLANT, reserved for selected younger, higher-risk patients who can tolerate its considerable risks.
- PMF = marrow fibrosis + massive splenomegaly + cytopenias + constitutional symptoms.
- Film: teardrop red cells (dacrocytes) and a leukoerythroblastic picture.
- Ruxolitinib (JAK1/2 inhibitor) shrinks the spleen and relieves symptoms.
- Allogeneic stem cell transplant is the only potential cure — selected patients only.
- PMF carries the worst prognosis of the three MPNs.
These diseases don't sit in a silo. Notice how much of this toolkit you already know from elsewhere. The BCR-ABL-POSITIVE cousin, CML, and its tyrosine kinase inhibitors live in the previous CML chapter — the contrast (positive vs negative) is the whole reason we grouped these three. JAK inhibitors are not confined to blood: the same JAK-STAT logic makes drugs like tofacitinib and baricitinib useful in rheumatoid arthritis, which you meet in the Inflammation section. Low-dose aspirin as antithrombotic prophylaxis threads straight into the Cardiovascular section. And hydroxyurea reappears in the Sickle cell chapter, where it raises fetal haemoglobin — same drug, entirely different rationale.
- Forgetting low-dose aspirin for thrombosis prevention in PV and ET — it is a core, cheap intervention, not an afterthought.
- Giving iron to a polycythaemia patient. Iron fuels red-cell production — the opposite of the goal; the (often iron-deficient) picture from repeated venesection is intentional.
- Mistaking a reactive thrombocytosis (infection, inflammation, iron deficiency, bleeding) for essential thrombocythaemia — the reactive cause is far commoner and must be excluded first.
- Assuming ET only clots. At very high platelet counts it can paradoxically bleed via acquired von Willebrand syndrome.
A 62-year-old man has a raised haematocrit, a plethoric face, itching after hot showers, and a low serum erythropoietin. Alongside venesection, which drug most directly reduces his main risk (thrombosis)?
- MPNs are BCR-ABL-NEGATIVE overproduction cancers driven by JAK-STAT stuck on (JAK2 V617F, CALR, MPL).
- PV = too many red cells → venesection + low-dose aspirin, hydroxyurea/interferon, ruxolitinib if resistant.
- ET = too many platelets (clots AND paradoxical bleeding) → aspirin, hydroxyurea, anagrelide.
- PMF = marrow fibrosis, big spleen, cytopenias → ruxolitinib for spleen/symptoms; transplant can cure.
- Hoffbrand AV, Moss PAH. Hoffbrand's Essential Haematology — The myeloproliferative neoplasms: polycythaemia vera, essential thrombocythaemia & myelofibrosis.
- British Society for Haematology (BSH) Guideline — Diagnosis and management of polycythaemia vera, essential thrombocythaemia and primary myelofibrosis.
- Bain BJ, Bates I, Laffan MA. Dacie and Lewis Practical Haematology — Blood film features of myeloproliferative neoplasms.
- WHO Classification of Haematolymphoid Tumours — Myeloproliferative neoplasms (JAK2/CALR/MPL driver mutations).
- Katzung BG. Basic & Clinical Pharmacology — Hydroxyurea, ruxolitinib (JAK inhibitors) and interferon-alpha.
