Etiology
The cause of polycythemia vera (PV) is unknown, but genetic mutations affecting hematopoietic stem cells are known to play a role.
The Janus kinase 2 (JAK2) V617F somatic driver mutation is present in approximately 95% of patients with PV.[3][4][5][6] JAK2 exon 12 mutations are present in approximately 3% to 4% of patients.[28] JAK2 is a cytoplasmic tyrosine protein kinase that is required for hematopoietic cytokine receptor signal transduction.[29] Other mutations (e.g., LNK mutations) are present in approximately 1% of patients.[30]
PV is the classic phenotypic consequence of the JAK2 V617F mutation. However, this mutation is not specific for PV as it is present in other myeloproliferative neoplasms (essential thrombocythemia, primary myelofibrosis), chronic myelomonocytic leukemia, and acute myeloid leukemia.[31] It is hypothesized that the JAK2 V617F mutation arises as a secondary genetic event, subsequent to mutations in other genes (e.g., epigenetic regulator genes or transcriptional genes), which leads to clonal hematopoiesis in PV.[29][32] Where the JAK2 46/1 haplotype is present it greatly increases the risk of acquiring a V617F mutation, and may also increase the risk of other mutations associated with PV.[33][34][35]
Several sequence variations other than JAK2 (i.e., nondriver mutations) have been implicated in PV. In one study involving 133 patients, targeted gene sequencing identified nondriver mutations in approximately 50% of patients, with the epigenetic regulators TET2 and ASXL1 being the most common.[36] In this study, ASXL1, SRSF2, and IDH2 were associated with a poor prognosis. In a similar study, nondriver mutations were identified in approximately 27% of patients with PV (n=130), with mutations to TET2, DNMT3A, and ASXL1 most commonly observed.[37] TET2, DNMT3A, and ASXL1 are the three genes most frequently mutated in clonal hematopoiesis of indeterminate potential.[38][39] The presence of one or more of these mutations significantly increased the risk of thrombosis in patients with PV in one case control study.[40]
Considering that mutations in epigenetic regulators may precede the acquisition of JAK2 V617F, as well as follow it, there has been interest in studying the effects of mutation order in myeloproliferative neoplasms.[32] Studies have shown that acquisition of JAK2 V617F prior to mutations in TET2 or DNMT3A favors a PV rather than an essential thrombocythemia phenotype.[41][42]
Familial PV and early driver mutation acquisition
Familial PV does occur, but the majority of cases are sporadic. Even in familial cases, PV is usually not congenital but is acquired (that is, blood counts at birth are normal). Epidemiologic data do, however, suggest an increased risk of PV in people who have an affected family member.[43] This association may be caused by inherited genetic mutations that predispose to a PV phenotype.[44] Neonatal polycythemia is almost never caused by PV.
JAK V617F mutations appear to occur during childhood (including in utero) in patients with myeloproliferative neoplasms. This is followed by clonal expansion and evolution of phenotype-driving clones, with clinical features only becoming apparent later in life. The rate of clonal expansion appears to occur at variable rates over a lifetime, suggesting that additional factors may influence the consequences of JAK2V 617F mutation.[45]
As in many hematologic malignancies, unrecognized environmental factors may be contributory.[46] At present, however, there are no clearly identified etiologic agents or circumstances.
Pathophysiology
PV is a clonal hematopoietic stem cell disorder. Mutations in bone marrow hematopoietic stem cells endow their progeny with a proliferative advantage. The JAK2 V617F mutation results in the activation of biochemical pathways involved in erythropoietin receptor signaling. In PV, this causes a trilineage expansion of morphologically normal red blood cells (RBC), white blood cells (WBC), and platelets.[47] Patients with a higher JAK2 V617F allele burden appear to be at greater risk for thrombosis and myelofibrotic progression.[48][49][50] One cohort study found that JAK2 V617F variant allele frequency >50% was associated with a higher risk of venous thrombosis in both low-risk and high-risk patients with PV.[48]
Plethoric symptoms appear to be related to hyperviscosity. The increased risk of thrombosis has also been attributed to hyperviscosity, as manifested by an increased RBC mass and/or hematocrit.[51][52][53] However, studies have suggested that thrombosis may be independent of hematocrit, and may be influenced by the WBC count.[54][55] Activated WBCs release several inflammatory markers that may be prothrombotic.[56] Neutrophil extracellular traps (NETs) have been implicated in the pathophysiology of thrombosis in the myeloproliferative neoplasms, and NET formation can be inhibited, at least preclinically, by pharmacologic JAK inhibition.[57] These conclusions are based on association and are not established; not all studies have demonstrated a relationship between leukocytosis and thrombosis.[58][59]
The collective evidence across multiple studies in PV and essential thrombocythemia suggests that thrombocytosis is not an independent risk factor for thrombosis.[60][61][62]
PV genomic profiles
Gene expression profiling may allow two clinical phenotypes of PV to be distinguished, independent of known sex-specific differences.[63] Thus, patients who did not differ significantly with respect to age, JAK2 V617F allele burden, leukocyte count, platelet count, or clonal dominance could be accurately separated by molecular methods into groups that differed significantly in terms of disease duration, hemoglobin level, frequency of thromboembolic events, palpable splenomegaly and splenectomy, chemotherapy exposure, leukemic transformation, and survival.[63] Genomic profiles in PV may also differ based on age at diagnosis.[64]
Classification
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