Myeloproliferative Neoplasms & Secondary Erythrocytosis

Approach to a high hematocrit

Define it. Erythrocytosis means Hb above 16.5 g/dL or Hct above 49% in men, or Hb above 16.0 g/dL or Hct above 48% in women. First exclude relative erythrocytosis — a contracted plasma volume from dehydration, diuretics, vomiting, or diarrhea with a normal red cell mass — by repeating the CBC once the patient is euvolemic. Stress (Gaisböck) erythrocytosis in obese, hypertensive, smoking men is also relative.

EPO first. Send a serum EPO level with JAK2 V617F. A low EPO with the mutation means polycythemia vera. A normal or high EPO means secondary erythrocytosis: check pulse oximetry, carboxyhemoglobin, a sleep study when OSA is suspected, renal and hepatic imaging, and the medication list. A low EPO with negative V617F calls for JAK2 exon 12 testing.

Treating secondary erythrocytosis. Treat the cause: smoking cessation, CPAP for OSA, oxygen for hypoxemic lung disease, resection of an EPO-secreting tumor, a lower testosterone dose, or an ACE inhibitor/ARB for post-transplant erythrocytosis. Pulse oximetry misreads carboxyhemoglobin as oxyhemoglobin, so smokers need co-oximetry. The PV hematocrit target does not apply here; phlebotomy is reserved for symptomatic hyperviscosity, as in cyanotic heart disease.

Polycythemia vera

Mechanism. JAK2 is the kinase behind the EPO, thrombopoietin, and G-CSF receptors. The V617F mutation (about 95% of PV) or an exon 12 mutation switches it on permanently, so erythropoiesis proceeds without EPO. Serum EPO is low, and leukocytosis, thrombocytosis, and splenomegaly are common.

Clinical clues. Aquagenic pruritus after warm showers; erythromelalgia (burning, red, warm hands and feet that respond to aspirin); facial plethora; headache, dizziness, and visual symptoms; gout from high cell turnover; and arterial or venous thrombosis, including Budd–Chiari syndrome and other splanchnic vein thromboses.

MPNs are the leading cause of Budd–Chiari syndrome. Test JAK2 in any splanchnic vein thrombosis even when the CBC is normal — hypersplenism and iron deficiency can mask high counts.

Treatment for everyone. Phlebotomy to a hematocrit below 45% — a target that lowered cardiovascular death and major thrombosis compared with 45–50% — plus low-dose aspirin (81–100 mg daily) and tight control of cardiovascular risk factors, including smoking. Phlebotomy makes patients iron deficient on purpose; replacing iron would drive the hematocrit back up.

High risk: age ≥60 or prior thrombosis. Add cytoreduction. Hydroxyurea is first-line (watch for cytopenias, macrocytosis, oral and leg ulcers, and skin cancers). Interferon-α (ropeginterferon or pegylated interferon) suits younger patients and pregnancy, because hydroxyurea is teratogenic. Ruxolitinib is used when hydroxyurea fails or is not tolerated.

Essential thrombocythemia

Reactive first. Most platelet counts above 450,000/μL are reactive: iron deficiency, infection or inflammation, splenectomy, malignancy, and blood loss. Check ferritin, CRP/ESR, and the smear, and treat the cause — iron-deficiency thrombocytosis resolves with iron. Reactive thrombocytosis itself carries little thrombotic risk. Persistent unexplained thrombocytosis prompts JAK2, CALR, MPL, and BCR-ABL1 testing.

Diagnosis. ET requires a sustained platelet count ≥450,000/μL, usually a driver mutation (JAK2 in about half, CALR in about a quarter, MPL in a few percent), and a marrow with enlarged, hyperlobulated megakaryocytes, once CML, PV, primary myelofibrosis, and MDS are excluded.

Clinical course. Many patients are asymptomatic. Others have vasomotor symptoms (headache, erythromelalgia, visual disturbance), arterial or venous thrombosis, or pregnancy loss. At extreme counts, typically above 1,000,000/μL, platelets adsorb and clear large vWF multimers, producing acquired von Willebrand syndrome with mucocutaneous bleeding.

Check vWF activity (ristocetin cofactor) before starting aspirin in extreme thrombocytosis; if it is low, withhold aspirin and cytoreduce first.

Treatment. Low-dose aspirin for most, especially with vasomotor symptoms, a JAK2 mutation, or cardiovascular risk factors. Hydroxyurea for high-risk disease (revised IPSET-thrombosis: prior thrombosis at any age, or age over 60 with JAK2 V617F); age over 60 alone without JAK2 is intermediate risk, where cytoreduction is optional. Anagrelide, a PDE3 inhibitor that blocks megakaryocyte maturation, is second-line; it causes palpitations, headache, and fluid retention and prevented arterial events less well than hydroxyurea plus aspirin. Interferon-α is preferred for young women and in pregnancy.

Primary myelofibrosis and disease evolution

Pathophysiology. Clonal megakaryocytes release fibrogenic cytokines (TGF-β, PDGF) that scar the marrow, pushing hematopoiesis into the spleen and liver.

Presentation. Older adults with massive splenomegaly (early satiety, left upper quadrant pain, splenic infarcts), hepatomegaly, anemia, bone pain, and constitutional symptoms — fever, night sweats, weight loss. The smear shows teardrop cells and leukoerythroblastosis (nucleated RBCs, immature granulocytes); the aspirate is a dry tap, and the core biopsy shows reticulin and collagen fibrosis with atypical megakaryocytes. Most patients carry a JAK2, CALR, or MPL mutation.

Treatment. The JAK1/2 inhibitor ruxolitinib shrinks the spleen and relieves constitutional symptoms but does not eradicate the clone; it causes dose-related anemia and thrombocytopenia, raises infection risk (herpes zoster), and should be tapered rather than stopped abruptly. Anemia is supported with transfusions. Allogeneic HSCT, for fit higher-risk patients, is the only cure.

Exclude CML. Every MPN workup includes BCR-ABL1 testing for the Philadelphia chromosome, because CML can present with thrombocytosis and mimic ET, and it is treated with tyrosine kinase inhibitors instead.

Transformation. Over years, PV and ET can progress to post-PV or post-ET myelofibrosis (falling counts, enlarging spleen), and any MPN can transform to AML (≥20% blasts), which carries a dismal prognosis.