Vannucchi AM, Guglielmelli P, Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach. Curr Opin Hematol. 2018 Mar;25(2):112-119. doi: 10.1097/MOH.0000000000000402. Review. PubMed PMID: 29194068.
Mesa R, Jamieson C, Bhatia R, et al. Myeloproliferative Neoplasms, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016 Dec;14(12):1572-1611. PubMed PMID: 27956542.
Definition, Etiology, PathogenesisTop
Clinical Features And Natural HistoryTop
1. Signs and symptoms depend on the stage of the disease as well as the number and severity of functional abnormalities in the platelets; they include features of both small-vessel and large-vessel occlusion: paresthesias, transient visual impairment, seizures, hemiparesis, symptoms of ischemic heart disease, erythromelalgia, headache, and vertigo or dizziness. Rare symptoms include mucosal and gastrointestinal bleeding caused by abnormalities of platelet function, acquired von Willebrand disease, or both. Splenomegaly is seen in <50% of patients. Constitutional symptoms may also occur. Many patients have asymptomatic disease discovered on routine complete blood cell analysis that demonstrates thrombocytosis with or without elevations or other cell lines.
2. Natural history: The disease may remain asymptomatic for many years before the development of thrombotic (most frequently), hemorrhagic complications, or both. In ~8% of patients transformation to myelofibrosis occurs. Transformation to acute leukemia or myelodysplastic syndrome (MDS) is less frequent (~1%).
1. Complete blood count (CBC): Persistent elevation of platelet counts (≥450×109/L), abnormal platelet shape and size, and various abnormalities of platelet function (most frequently impaired aggregation) can be seen.
2. Bone marrow examination: Bone marrow aspiration and/or trephine biopsy reveal increased marrow cellularity with proliferation of the megakaryocytic lineage and an increased proportion of large, mature megakaryocytes. No proliferation or immature cells of granulocytic or erythropoietic lineages are observed. Bone marrow aspiration and biopsy are important to confirm the diagnosis of ET and to distinguish it from other myeloproliferative neoplasms, particularly prefibrotic myelofibrosis.
3. Molecular studies: Most patients are found to harbor the JAK2 V617F mutation or other clonal genetic markers (MPL or CALR mutations).
To establish the diagnosis of ET, all the following criteria must be fulfilled:
1) Persistently elevated platelet counts ≥450×109/L.
2) Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant left shift of neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers is seen.
3) Exclusion of polycythemia vera (PV), primary myelofibrosis, chronic myelogenous leukemia (CML), MDS, and other myeloid neoplasms.
4) Presence of the JAK2 V617F mutation or other clonal genetic markers; if these are absent, exclude reactive thrombocytosis.
2. Reactive thrombocytosis: Solid tumors (mainly lung or pancreatic cancers), iron deficiency anemia, chronic inflammatory or infectious conditions, acute hemorrhage, splenectomy, chronic alcohol abuse, frequent blood donations, as well as hemolytic or drug-induced anemias.
3. Familial thrombocytosis: For instance, due to mutations of the thrombopoietin gene.
4. Apparent thrombocytosis: Cryoglobulinemia, fragmented erythrocytes, or malignant cells in peripheral blood.
The choice of treatment depends on the presence of risk factors for thrombotic complications: age >60 years, mutational status, and prior thrombosis (arterial or venous). Patients who are <60 years, have no thrombosis history, and do not harbor the JAK2 mutation (very low risk) are treated with observation alone unless cardiovascular risk factors or vasomotor symptoms are present, in which case acetylsalicylic acid (ASA) may be used. All other patients should receive ASA unless they are receiving therapeutic anticoagulation or have acquired von Willebrand disease. In patients >60 years or with a history of thrombosis add cytoreductive treatment. This may also be considered in patients with platelet counts >1500×109/L, progressive myeloproliferation (eg, progressive enlargement of the spleen), uncontrolled systemic symptoms, or evidence of microcirculatory impairment due to platelet clumping that is clinically resistant to ASA.
1. Cytoreductive treatment: Hydroxyurea (INN hydroxycarbamide) is the first-line drug. Second-line treatments are used in:
1) Patients in whom no significant reduction of platelet counts has been achieved using adequate hydroxyurea doses.
2) Patients with intolerance of hydroxyurea.
2) Interferon alpha.
3) Busulfan (consider these in patients with short life expectancy).
2. Antiplatelet agents: ASA 50 mg to 100 mg once daily (bid administration may be considered in higher-risk patients or in those not responding to the once-daily treatment) in all patients with microcirculation abnormalities (eg, erythromelalgia), except for patients with acquired von Willebrand disease. The second-line agents are clopidogrel 75 mg once daily or ticlopidine 250 mg bid. Patients requiring therapeutic anticoagulation (eg, atrial fibrillation, venous thrombosis) do not require ASA unless there are compelling indications (eg, recent coronary artery stenting).
3. Appropriate preventative measures should be used in patients with either additional risk factors for thrombosis or a history of thrombosis: see Prevention of Cardiovascular Diseases; see Venous Thromboembolism.
Examination of platelet counts as required to monitor cytoreductive therapy (to ensure that underdosing or overdosing does not occur). The frequency at which monitoring is required in asymptomatic patients is unknown but should be increased as the platelet count rises >1000×109/L.
Prognosis is established on the basis of International Prognostic Score for ET (IPSET):
1) Age >60 years: Score 2.
2) White blood cell count >11×109/L: Score 1.
3) A previous thrombotic event: Score 1.
The mean survival in patients without the above risk factors is similar to that of general population; in patients with scores 1 or 2, the mean survival is 25 years; and in patients with score 3, it is 14 years. A separate IPSET-thrombosis score can be used to predict the annual risk of thrombosis (range, 0.5%-2.25% per year).