Materiały źródłowe

• #1 Polycythemia Vera: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/205114-overview

  Polycythemia vera (PV) is a stem cell disorder characterized as a panhyperplastic, malignant, and neoplastic marrow disorder. Its most prominent feature is an elevated absolute red blood cell mass because of uncontrolled red blood cell production. This is accompanied by increased white blood cell (myeloid) and platelet (megakaryocytic) production, which is due to an abnormal clone of the hematopoietic stem cells with increased sensitivity to the different growth factors for maturation. […] The bone marrow of patients with polycythemia vera (PV) contains normal stem cells but also contains abnormal clonal stem cells that interfere with or suppress normal stem cell growth and maturation. The panmyelosis in PV appears to result from unregulated neoplastic proliferation. The origin of the stem cell transformation remains unknown.

• #2 Polycythemia vera – Wikipedia

  https://en.wikipedia.org/wiki/Polycythemia_vera

  In oncology, polycythemia vera (PV) is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells. The majority of cases are caused by mutations in the JAK2 gene, most commonly resulting in a single amino acid change in its protein product from valine to phenylalanine at position 617. […] Polycythemia vera (PV), being a primary polycythemia (increase in the fraction of volume occupied by red cells in the blood), is caused by neoplastic proliferation and maturation of erythroid, megakaryocytic and granulocytic elements to produce what is referred to as panmyelosis. In contrast to secondary polycythemias, PV is associated with a low serum level of the hormone erythropoietin (EPO). Instead, PV cells often carry activating mutation in a tyrosine kinase encoding gene, JAK2, which acts in signaling pathways of the EPO receptor, making those cells proliferate independently from EPO.

• #3 Polycythemia Vera (PV) – MPN Research Foundation

  https://mpnresearchfoundation.org/polycythemia-vera-pv/

  Polycythemia vera (PV) is a chronic, progressive myeloproliferative neoplasm (MPN) primarily characterized by an elevation of the red blood cells. […] The trigger for polycythemia vera (PV) and other myeloproliferative neoplasms (MPNs) isn’t known. However, researchers have discovered that PV and other MPNs may be caused by non-inherited genetic mutations affecting proteins that work in signaling pathways in cells. […] Nearly all PV patients have a mutation called JAK2V617F (found in the JAK2 gene) in their blood-forming cells. This mutation is one of the ways that JAK (Janus kinase) pathway signaling can become dysregulated and cause the body to produce too many blood cells. […] Approximately 95% of all PV patients have a mutation of the JAK2 gene in their blood-forming cells. This mutation leads to hyperactive JAK (Janus kinase) signaling, causing the body to make the wrong number of blood cells.

• #4 Polycythemia Vera – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557660/

  Polycythemia vera is a myeloproliferative disorder associated with a Janus kinase-2 (JAK2) mutation that causes the neoplastic proliferation of the hematopoietic progenitor cells. It causes elevated red blood cell production along with secondary white blood cell and platelet production. […] The current understanding of pathophysiology involves increased sensitivity to growth factors due to an abnormal hematopoietic cell clone. […] The Janus kinase-2 (JAK2) gene involved with intracellular signaling is mutated in 90% of cases of polycythemia vera (PV). […] The cause of panmyelosis is unregulated neoplastic proliferation. JAK2 kinase mutation likely leads to the signaling derangements resulting in PV. A valine to phenylalanine substitution at position 617 of the JAK2 gene, or JAK2V617F, leads to constitutively active cytokine receptors. […] This process leads to increased production of red blood cells and platelets with associated complications of thrombosis and bleeding.

• #5 Polycythemia vera: historical oversights, diagnostic details, and therapeutic views | Leukemia

  https://www.nature.com/articles/s41375-021-01401-3

  Polycythemia vera (PV) is a relatively indolent myeloid neoplasm with median survival that exceeds 35 years in young patients, but its natural history might be interrupted by thrombotic, fibrotic, or leukemic events, with respective 20-year rates of 26%, 16%, and 4%. […] Damesheks concept of MPN was genetically ratified in 2005 by the seminal discovery, across these three clincopathologic entities, of a JAK2 gain of-function mutation (JAK2V617F; a G to T somatic mutation at nucleotide 1849, in exon 14, resulting in the substitution of valine to phenylalanine at codon 617). […] Laboratory studies examining the pathogenetic role of JAK2 mutations are highlighted by its origin at the stem cell level and the demonstration of heightened JAK-STAT activation and induction of mutant JAK2-driven PV phenotype in mice.

• #6 Polycythemia vera pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Polycythemia_vera_pathophysiology

  The mutation that occurs is a point mutation that induces conversion of valine to phenylalanine at the 617th position within the JAK2 gene (JAK2 V617F). […] The JAK2 V617F point mutation is an activating mutation that results in autonomous activity of the JAK2 pathway, resulting in excess red blood cell production in an erythropoietin-independent manner. […] The JAK2 V617F mutation has been established to be positive in about 96% of people with polycythemia vera. […] There could also be a mutation in exon 12 of JAK2 which results in a similar phenotype as JAK2 V617F. It is seen in about 2-3% of people with polycythemia vera. […] A very few patients with erythrocytosis and low erythropoietin (EPO) levels may have mutations in LNK (SH2B3), which is an inhibitor of the JAK-STAT signaling pathway.

• #7 Polycythemia Vera (PV)

  https://atlasgeneticsoncology.org/haematological/1103/polycythemia-vera-(pv)

  The disease is a chronic myeloproliferative disorder originating from a mutated pluripotent stem cell capable of producing red blood cells, granulocytes and megakaryocytes. […] A valine to phenylalanine substitution at position 617 (JAK2 V617F mutation) is present in 65-97% of the patients, leading to constitutive kinase activity. The mutation is acquired and occurs at the level of a pluripotent stem cell originating myeloid and lymphoid cells. […] The mutated JAK2 protein binds to the cytoplasmic domain of Epo-R and promotes signalling independent of Epo stimulation. […] JAK2 signalling involves the phosphorylation of several Y residues at the Epo receptor with activation of STAT, MAP kinase PI-3-kinase and AKT. These events lead to survival and proliferation of erythroid progenitors. […] JAK2 is involved in intracellular signalling following stimulation by IL3, TPO and GM-CSF, and erythroid progenitors in PV are hypersensitive to stimulation by these cytokines.

• #8 Polycythemia Vera – Hematology and Oncology – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hematology-and-oncology/myeloproliferative-disorders/polycythemia-vera

  Polycythemia vera involves increased production of red blood cells (RBCs), white blood cells (WBCs), and platelets. Thus, polycythemia vera is a panmyelosis because of increases of all 3 peripheral blood components. Increased production confined to the RBC line is termed erythrocytosis; isolated erythrocytosis may occur with polycythemia vera but is more commonly due to other causes (see secondary erythrocytosis). In polycythemia vera, RBC production proceeds independently of the serum erythropoietin level, which is usually low but can be normal. However, because the thrombopoietin receptor is the only growth factor receptor in hematopoietic stem cells, thrombocytosis can occur before erythrocytosis. […] Polycythemia vera is caused by a mutation in an hematopoietic stem cell. Mutations of the Janus kinase 2 (JAK2) gene are responsible in most cases of polycythemia vera. JAK2 is a member of the class I type of tyrosine kinase family of enzymes and is involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF) receptors. Specifically, the JAK2V617F mutation or the JAK2 exon12 mutation is present in 95% of patients with polycythemia vera. Calreticulin (CALR) mutations have been found rarely in patients with polycythemia vera who lack a JAK2 mutation, and lymphocytic adaptor protein (LNK) mutations have been found in patients with isolated erythrocytosis. These mutations lead to sustained activation of the JAK2 kinase, which causes excess blood cell production independent of erythropoietin. […] Polycythemia vera is due to mutations involving JAK2, or rarely the CALR or LNK mutations in hematopoietic stem cells that lead to sustained activation of JAK2 kinase, which causes excess blood cell production.

• #9 The Role of JAK2 Inhibition in Polycythemia Vera

  https://www.targetedonc.com/view/the-role-of-jak2-inhibition-in-polycythemia-vera

  Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by clonal hematopoiesis and an absolute increase in the red blood cell mass, with an associated leukocytosis and thrombocytosis. Virtually all patients with PV harbor a mutation in the nonreceptor tyrosine kinase JAK2, with the majority of patients harboring the classic JAK2 (V617F). This point mutation inactivates the pseudokinase domain, resulting in constitutive enzymatic activity and intracellular signal transduction, ultimately leading to uncontrolled cellular proliferation. […] The mutated JAK2 codes for a nonreceptor tyrosine kinase that belongs to the Janus kinase family of proteins, which phosphorylate cytoplasmic targets such as signal transducers and regulators of downstream transcription (STATs). This phosphorylation cascade ultimately results in the upregulation of genes responsible for cellular proliferation and differentiation. The V617F mutation is located within the auto-inhibitory domain of the tyrosine kinase, which helps explain why the JAK2 V617F mutation is associated with a loss of autoregulation and subsequent uncontrolled cellular proliferation. In contrast to the loss of regulation accompanying the V617F mutation, mutations in exon 12 act as gain-of-function aberrations through a pathway that remains incompletely elucidated.

• #10 Take a look at the Recent articles

  https://www.oatext.com/Immunotherapy-and-polycythemia-vera.php

  Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by abnormal growth of erythroid precursors in the bone marrow. Almost all patients with PV, around 97%, have a mutation in Janus kinase 2 (JAK2). It is through the activation of JAK/Signal Transducers and Activators of Transcription (STAT) protein signaling pathway that the JAK2 mutation is thought to induce cellular proliferation, growth, hematopoiesis and immune response in PV patients. […] Additional genetic mutations have been implicated in PV pathogenesis. In this perspective, targeting different pathways might be required. […] A mutation in a specific gene, Janus kinase 2 (JAK2) is found in a large percentage of people with MPDs. […] The JAK/STAT pathway plays a vital role in the initiation of signal transduction through hematopoietic growth factor receptors. JAK/STAT is also a target for identifying the molecular abnormalities in PV. Furthermore, in erythropoietin-independent differentiation of erythroid progenitors in PV, where constitutive activation of STAT3 has been reported, STAT3 was found to be repressed by inhibitors of JAK2. Recently, several groups have identified a consistent, single somatic activating mutation in the JAK2 gene in the majority of patients with PV.

• #11

  https://haematologica.org/article/view/1055

  Polycythemia vera (PV) is an acquired clonal myeloproliferative disorder characterized by increased production of mature red cells. […] We still lack a molecular target responsible for this disorder; however, recent investigations have focused on a number of molecules involved in signal transduction pathways mediated by erythropoietin (Epo) and other growth factors. […] Overproduction of erythroid cells in PV is particular in that it occurs in the absence of a recognizable physiologic stimulus, since circulating serum levels of Epo are normal or lower than normal. […] Genetic analysis as well as in vitro studies, have established an essential role for Epo in the survival and maturation of committed erythroid progenitors. […] Epo initiates its cellular response by binding to the Epo receptor (EpoR) expressed on the surface of immature erythroblasts.

• #12 Polycythemia vera pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Polycythemia_vera_pathophysiology

  In addition to the JAK2 point mutation, epigenetic factors also contribute to the pathogenesis of polycythemia vera. This conclusion was made after it was determined that the same JAK2 activating mutation could contribute to the pathogenesis of essential thrombocythemia and primary myelofibrosis. […] On average, patients with polycythemia vera harbor 6-7 mutations. Besides the JAK2 mutation, other mutations occur in genes such as TET2 (found in 8.3% of patients), SF3B1 (involved in RNA splicing), DNMT3A (involved in epigenetic regulation), and ASXL1 (associated with a poor prognosis).

• #13

  https://omim.org/entry/263300

  A number sign (#) is used with this entry because of evidence that most cases of polycythemia vera (PV) are associated with a somatic mutation in the JAK2 gene (147796) on chromosome 9p24. […] Somatic mutations in the TET2 gene (612839) and the NFE2 gene (601490) have also been found in cases of polycythemia vera. […] Polycythemia vera (PV), the most common form of primary polycythemia, is caused by somatic mutation in a single hematopoietic stem cell leading to clonal hematopoiesis. […] Chen et al. (1998) presented results indicating that amplification of a gene or genes on 9p play a crucial role in the pathogenesis of PV. […] Sozer et al. (2009) identified somatic homozygous JAK2 V617F mutations in liver venule endothelial cells and hematopoietic cells from 2 unrelated PV patients who developed Budd-Chiari syndrome. However, analysis of endothelial cells from a third PV patient with Budd-Chiari syndrome and in 2 patients with hepatoportal sclerosis without PV showed only wildtype JAK2. Endothelial and hematopoietic cells are believed to come from a common progenitor called the hemangioblast. Sozer et al. (2009) concluded that finding V617F-positive endothelial cells and hematopoietic cells from PV patients who developed Budd-Chiari syndrome indicates that endothelial cells are involved by the PV malignant process, and suggested that the disease might originate from a common cell of origin in some patients. […] Spivak et al. (2014) used gene expression profiling to identify several molecular pathways in PV outside the canonical JAK2 pathway.

• #14 Polycythemia Vera-Associated Complications: Pathogenesis, Clinical Man | JBM

  https://www.dovepress.com/polycythemia-vera-associated-complications-pathogenesis-clinical-manif-peer-reviewed-fulltext-article-JBM

  Polycythemia vera is a Philadelphia-negative chronic myeloproliferative neoplasm, characterized by erythrocytosis, which is unique, compared to essential thrombocytosis and primary myelofibrosis. […] Three key driver mutations have been subsequently described in MPNs JAK2, CALR and MPL all of which act to constitutively activate the JAK-STAT pathway. […] JAK2 V617F is most prevalent in PV, compared to ET and PMF (99% vs 60%). […] Thrombosis has multifactorial contributors, including but not limited to gender, and inflammatory stress; investigators have recently hypothesized that microparticles and Neutrophil Extracellular Trap Formations may add to thrombotic burden. […] The mechanisms involved in the pathogenesis of thrombosis are multifaceted, and involve several cell types, prothrombotic factors and inflammatory markers.

• #15 The Evolving Landscape of Polycythemia Vera Treatment

  https://www.pharmacytimes.com/view/the-evolving-landscape-of-polycythemia-vera-treatment

  Another serious complication of PV is the risk of progression to MF or transformation to acute myeloid leukemia (AML). Approximately 20% of patients with PV progress to MF or an aggressive form of AML known as MPN blast phase (MPN-BP). […] Elevated hematocrit (HCT) is a hallmark of PV, indicating overproduction of RBCs and high blood viscosity. Other lab abnormalities include increased hemoglobin (HGB), abnormal red cell morphology (mean corpuscular volume, mean corpuscular hemoglobin), increased lactate dehydrogenase, decreased erythropoietin, and iron deficiency. […] The main goals of treatment are to reduce the risk of thrombosis, which is the most common cause of mortality, prevent transformation to MF or MPN-BP, and to treat symptoms. […] The mainstays of PV treatment are low-dose aspirin and therapeutic phlebotomy (bloodletting) to mitigate thrombotic risk. The purpose of phlebotomy is to reduce the red cell mass and subsequent hyperviscosity, which can directly lead to thrombosis.

• #16 Polycythemia Vera-Associated Complications: Pathogenesis, Clinical Manifestations, And Effects On Outcomes

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6805785/

  Polycythemia vera is a Philadelphia-negative chronic myeloproliferative neoplasm, characterized by erythrocytosis, which is unique, compared to essential thrombocytosis and primary myelofibrosis. […] Thrombosis has multifactorial contributors, including but not limited to gender, and inflammatory stress; investigators have recently hypothesized that microparticles and Neutrophil Extracellular Trap Formations may add to thrombotic burden. […] The mechanisms involved in the pathogenesis of thrombosis are multifaceted, and involve several cell types, prothrombotic factors and inflammatory markers. […] Some of the well-established risk factors for PV-associated thrombosis include advanced age, disease duration, prior history of thrombosis, erythrocytosis, leukocytosis, and JAK2 V617F allele burden.

• #17 New Perspectives on Polycythemia Vera: From Diagnosis to Therapy

  https://www.mdpi.com/1422-0067/21/16/5805

  Polycythemia vera (PV) is mainly characterized by elevated blood cell counts, thrombotic as well as hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. […] The understanding of MPN pathophysiology dramatically improved following the description of recurrent molecular abnormalities. In particular, compared with both ET and MF, PV is molecularly more homogeneous, being driven by JAK2 mutations in virtually all cases; about 97% of such mutations are represented by JAK2V617F, which results from a somatic G to T mutation involving JAK2 exon 14, leading to a nucleotide change at position 1849 and the substitution of valine to phenylalanine at codon 617. […] Furthermore, JAK2V617F mutation has been proven to play a crucial role in thrombotic complications. In detail, the pathogenesis of blood clotting activation in this disease is multifactorial, and involves various anomalies of platelets, erythrocytes, and leukocytes, as well as dysfunction of endothelial cells.

• #18 Polycythemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Polycythemia_pathophysiology

  The main mechanism by which polycythemia vera develops is a valine to phenylalanine substitution, precisely the JAK2V617F leading to constitutive activation of cytokine receptors. This mutation is present in over 90% of patients with PV, 50% to 60% in patients with primary myelofibrosis, and 50% with patients with essential thrombocythemia. […] Other factors contributing to the pathophysiology of polycythemia (amongst other myeloproliferative neoplasms) are blood cells, plasma factors, and the endothelial compartment. […] Several studies in people and in mouse models have shown the increase in platelet activation and coagulation by factors such as cell surface proteins namely; P-selectin (CD62P), or tissue factor(CD142), and circulating leuco-platelets aggregates. […] An increased expression of CD11, CD14, and leukocyte alkaline phosphatase, which is further amplified in the event of a JAK2V617F mutation.

• #19 Polycythemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Polycythemia_pathophysiology

  The Cytoreductive therapy in PV (CYTO-PV) clinical trial showed there is an increase in the risk of cardiovascular events in patients with 45% hematocrit; consequences depend on arterial or venous territory involvement. […] Activation of endothelial cells leading to increased levels of thrombomodulin, von Willebrand factor, both E and P selectins, and circulating endothelial cells. […] D-dimers, thrombin-anti-thrombin complexes, F1 and F2 fibrinogen fragments are found to be in increased quantities.

• #20 Polycythemia Vera-Associated Complications: Pathogenesis, Clinical Manifestations, And Effects On Outcomes

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6805785/

  Microparticles are typically released into the circulation after being activated by different cell types, especially platelets and endothelial cells. […] Their role has been implicated in the pathophysiology of disease states including sepsis, acute respiratory distress syndrome, glomerulonephritis and cystic fibrosis. […] Overall, study authors conclude that MPs result in TM-resistance in patients, thereby supporting its role as a procoagulant. […] Neutrophil Extracellular Traps (NETs) are key entities of the innate immune systems that defend host organisms against bacteria and other pathogens. […] They found that neutrophils from individuals with all subtypes of MPN had significantly higher levels of NETs compared to controls. […] Overall, JAK2 V617F mutated mice (n=11) have an increased propensity for NETs formation and higher rates of thrombosis after two hours compared to wild-type (n=8) mice.

• #21 New Perspectives on Polycythemia Vera: From Diagnosis to Therapy

  https://www.mdpi.com/1422-0067/21/16/5805

  Indeed, abnormalities of blood cells arising from the clonal hematopoietic stem cells’ proliferation also involve qualitative changes that characterize the switch of these cells from a resting to a procoagulant phenotype. […] Prothrombotic features include blood cells’ expression of procoagulant and proteolytic properties, inflammatory cytokines secretion, and the expression of adhesion molecules. […] The adhesion of platelets to leukocytes and the formation of platelet–leukocyte aggregates mediate the crosstalk between platelets, neutrophils, and monocytes, suggesting that aspirin may inhibit the interaction between neutrophils and platelets. […] Finally, several factors, such as ROS and intracellular proteases, may perturb the physiological state of endothelium in MPN patients and turn it into a pro-adhesive and procoagulant surface.

• #22 Pediatric Polycythemia Vera: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/957470-overview

  The highest JAK2 V617F levels at diagnosis predicted which patients were more likely to have splenomegaly, develop aquagenic pruritus, have higher risk of progression to postpolycythemia vera myelofibrosis, and eventually require chemotherapy. […] In fact, a multivariate analysis that included age, leukocytosis, hematocrit, platelet count, and therapies indicated that the JAK2 V617F/JAK2 wild-type ratio is an independent risk factor for major vascular events.

• #23 Polycythemia Vera-Associated Complications: Pathogenesis, Clinical Man | JBM

  https://www.dovepress.com/polycythemia-vera-associated-complications-pathogenesis-clinical-manif-peer-reviewed-fulltext-article-JBM

  Some of the well-established risk factors for PV-associated thrombosis include advanced age, disease duration, prior history of thrombosis, erythrocytosis, leukocytosis, and JAK2 V617F allele burden. […] These microcirculatory disturbances may be explained by increased blood viscosity or platelet hypersensitivity. […] Erythromelalgia is a vasomotor complication of PV that manifests as warmth, erythema and burning pain in the extremities. […] The pathogenesis is incompletely understood, it is thought to be partially mediated by platelet hypersensitivity. […] The JAK/STAT pathway plays an integral role in normal hematopoiesis. However, a gain-of-function mutation in JAK2 leads to constitutively activated JAK/STAT signaling, thereby giving rise to myeloid neoplasms. […] This hypersensitivity mutation is a hallmark feature of PV, with 99% of patients harboring the JAK2 V617F mutation.

• #24 Polycythemia Vera-Associated Complications: Pathogenesis, Clinical Manifestations, And Effects On Outcomes

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6805785/

  Fibrotic evolution to MF highlights an important disease transformation with significant impacts on morbidity and mortality among PV patients. […] There have been several prognostic factors associated with disease transformation to MF among PV patients, including age, leukocytosis, JAK2 V617F allele burden, and non-driver mutational status. […] Overall, study authors conclude that these sequence variants possess important prognostic relevance for PV patients.

• #25 Polycythemia Vera-Associated Complications: Pathogenesis, Clinical Man | JBM

  https://www.dovepress.com/polycythemia-vera-associated-complications-pathogenesis-clinical-manif-peer-reviewed-fulltext-article-JBM

  There have been several prognostic factors associated with disease transformation to MF among PV patients, including age, leukocytosis, JAK2 V617F allele burden, and non-driver mutational status. […] Overall, study authors conclude that mutant allele burden significantly correlated with the risk of MF transformation.

• #26 Dysregulated iron metabolism in polycythemia vera: etiology and consequences | Leukemia

  https://www.nature.com/articles/s41375-018-0207-9

  Polycythemia vera (PV) is a chronic myeloproliferative neoplasm. Virtually all PV patients are iron deficient at presentation and/or during the course of their disease. […] Insufficiently suppressed hepcidin given the degree of iron deficiency in PV patients strongly suggests that disordered iron metabolism is an important component of the pathobiology of PV. […] The genesis of iron deficiency in PV and its effect on disease manifestations and natural history have been explored to a limited extent. In this review, we focus on what is known about iron metabolism and erythropoiesis in PV. […] The genetic basis of PV was largely speculative until the discovery of driver mutations involving janus kinase 2 (JAK2). JAK2 is a non-receptor tyrosine kinase that transduces erythropoietin receptor (EpoR) signaling. Activation of JAK2 triggers multiple signaling pathways regulating erythroid precursor survival, proliferation, and differentiation.

• #27 Mechanism and Benefits of Rusfertide in Polycythemia Vera

  https://www.targetedonc.com/view/mechanism-and-benefits-of-rusfertide-in-polycythemia-vera

  In patients with polycythemia vera, research has shown that hepcidin levels are typically low. This deficiency leads to the continuous export of iron from the body’s iron stores, which in turn contributes to uncontrolled erythropoiesis. This excessive red blood cell production is primarily driven by the JAK2 V617F mutation. The dysregulation of iron homeostasis exacerbates the condition, making it essential to find effective treatments that address this underlying mechanism. […] Rusfertide is a hepcidin mimetic therapeutic peptide. The way it works is it blocks ferroportin, the channel that exports iron from its stores. A study had shown that in patients with PV, the hepcidin levels are low, leading to continuous export of iron from the iron stores to enable uncontrolled erythropoiesis, which is being driven primarily by the JAK2 V617F mutation. […] Based on this preclinical data, the phase 2 randomized study was conducted in patients with PV who required phlebotomies with or without cytoreductive treatment.

• #28 Dysregulated iron metabolism in polycythemia vera: etiology and consequences | Leukemia

  https://www.nature.com/articles/s41375-018-0207-9

  Hepcidin down-regulates iron release into the plasma by binding to and functionally down-regulating ferroportin, the sole iron exporter. […] Hepcidin suppression as a consequence of increased erythropoietic activity, irrespective of the degree of anemia, hypoxia, or Epo levels, has been repeatedly postulated to explain iron overload in diseases of ineffective erythropoiesis. […] We anticipate that the cause of iron deficiency in PV is a composite of multiple concurrent factors, most likely an aberrant iron restriction response in conjunction with altered hypoxia regulation of iron absorption.

• #29 Emerging agents and regimens for polycythemia vera and essential thrombocythemia | Biomarker Research | Full Text

  https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-021-00298-5

  Limiting the enthusiasm for frontline ruxolitinib or other JAK inhibitor therapy for PV or ET is the lack of evidence for disease course modification including long-term risk of secondary (post-PV and post-ET myelofibrosis). […] The histone deacetylase inhibitors (HDACis) are theorized to reverse histone/DNA complex compaction and thus open the chromatin structure to restore pro-apoptotic gene transcription. […] The iron metabolism pathway has been the subject of recent and unique targeting for the management of PV, which is essentially treated by either inducing or exacerbating iron deficiency with serial therapeutic phlebotomies targeting a hematocrit goal of 45% based on the CYTO-PV study results.

• #30 Polycythemia vera and its neurologic manifestations | MedLink Neurology

  https://www.medlink.com/articles/polycythemia-vera-and-its-neurologic-manifestations

  Polycythemia vera is a clonal myeloproliferative disorder originating from a hematopoietic stem cell in the bone marrow. […] Genomic studies of polycythemia and related myeloproliferative disorders have identified a mutation in the genetic sequence of a specific tyrosine kinase called Janus kinase 2 (JAK2) that induces a growth factor-independent proliferation of cell lines and leads to unregulated hematopoiesis. […] The neurologic complications of polycythemia result primarily from the hyperviscosity of blood due to increased red blood cell mass, and the main consequence of hyperviscosity is thromboembolism; hyperviscosity-induced thromboembolism may be venous or arterial and is seen in about a third of the patients. […] The most frequent types of major thrombosis include stroke; transient ischemic attack; myocardial infarction; peripheral arterial thrombosis; deep venous thrombosis; and thromboembolism, portal vein thrombosis, and thrombosis of the hepatic veins (ie, Budd-Chiari syndrome).

• #31

• #31 Polycythemia vera and its neurologic manifestations | MedLink Neurology

  https://www.medlink.com/articles/polycythemia-vera-and-its-neurologic-manifestations

  Hyperviscosity also causes microvascular sludging, which can cause or contribute to various symptoms, including headaches, dizziness, visual disturbances, distal paresthesias, acrocyanosis, and erythromelalgia. […] The mechanism for pruritus in polycythemia vera, and particularly for water-induced or aquagenic pruritis, is still obscure, and conflicting reports have suggested it is due to abnormal histamine release or prostaglandin production, or to other mechanisms. […] Fatigue in polycythemia vera has been attributed to circulating cytokines (ie, tumor necrosis factor alpha, interleukin-1, and interleukin-6). […] The acquired JAK2 mutation (V617F) is seen in more than 95% to 96% of patients with polycythemia vera, and JAK2 exon 12 mutations occur in about 3%.

• #32 Acute Coronary Syndrome (ACS) in Polycythemia Vera: A Case Report with Review of Literature

  https://www.jcardiac.com/full-text/acute-coronary-syndrome-acs-in-polycythemia-vera-a-case-report-with-review-of-literature

  Polycythemia Vera (PV) is a chronic bone marrow disorder which causes hyper viscosity of blood thereby, increasing the risk of coronary thrombosis and acute myocardial infarction (MI). […] This disorder is marked by increased bleeding and thrombotic occlusion of coronary arteries leading to morbidity and mortality in 40% to 60% of the patients. […] Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm, involving a multipotent hematopoietic progenitor cell lines resulting increased production of RBCs, granulocytes and platelets. Erythrocytosis with increased hematocrit (high blood viscosity) and platelet count generate microparticles (0.1 m to 1 m) with platelet dysfunction and leucocyte-platelet conglomerates that leads to thrombus formation. […] MI can occur in PV patients in the absence of any cardiac risk factors.

• #33 Pediatric Polycythemia Vera: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/957470-overview

  The 9p region contains a gene that encodes for the JAK2 tyrosine kinase. The JAK family of kinases is critical in cytokine receptor signaling and transmits the activating signal in the Epo-EpoR signaling pathway. […] The JAK2 V617F mutation leads to constitutive phosphorylation and thus constitutive activity and STAT (signal transducer and activator of transcription) recruitment, providing the proliferative advantage seen in polycythemia vera. […] However, compelling data strongly argue that this mutation is not a disease-initiating mutation. […] There is familial clustering of polycythemia vera and other myeloproliferative neoplasms, suggesting that the predisposition to polycythemia vera development is inherited. […] The quantitative allele burden (ratio of mutant to wild-type expression) of JAK2 V617F has a clinical impact.

• #34 Take a look at the Recent articles

  https://www.oatext.com/Immunotherapy-and-polycythemia-vera.php

  Several studies showed that the majority of patients (65%-97%) with PV have the JAK2-V617F mutation. A report by Kralovics et al. showed that patients with JAK2-V617F had a significantly longer duration of disease, more treatment with cyto-reducing agents and higher rates of complications (i.e., myelofibrosis, thrombosis and bleeding) than those with wild-type JAK2. […] Other biologic and epigenetic markers present in PV patients are deregulated expression of Bcl-x (B-cell lymphoma-extra, an inhibitor of apoptosis), overexpression of the PRV-1 (polycythemia rubra vera 1) and transcription factor NF-E2 (nuclear factor erythroid-derived 2) genes, and impaired expression of Tpo-R (thrombopoietin receptor). No mutations have yet been detected in these genes and recent evidence indicates that altered expression of these markers is due to activation of the JAK/STAT pathway through the JAK2V617F mutation. Therefore, abnormal expression of these molecules appears to be a secondary consequence of the primary JAK2 mutation.

• #35 Polycythemia Vera: A Researcher’s View – Longer Life Foundation

  http://longerlife.org/meet-the-investigators/polycythemia-vera-a-researchers-view/

  It also reflected the evolving understanding of the genetic basis of these conditions, signifying that the presence of the mutation is a diagnostic criterion for PV, and underscoring that the transition from these conditions to secondary acute myeloid leukemia (sAML) is from one blood cancer to another, not from a pre-cancer to a cancer state. […] For patients under age 45, only the JAK2 mutation is usually present, whereas older patients will present with at least one additional mutation. […] This may be due in part to the fact that as people age, clonal hematopoiesis of indeterminate potential (CHIP) can occur, meaning hematopoietic stem cells or other early blood cell progenitors will contribute to the formation of a genetically distinct subpopulation of blood cells. […] PV disease, no matter its cause, seems to operate via similar genetic pathways.

• #36 Paper: Dysregulated Complement Activation in Polycythemia Vera: A Novel Mechanism for Thrombosis in Myeloproliferative Neoplasms Uncovered By Proteomic Analysis

  https://ash.confex.com/ash/2024/webprogram/Paper206614.html

  Myeloproliferative neoplasms (MPNs) are a group of disorders associated with an increased risk of thrombosis, with polycythemia vera (PV) considered to carry the highest risk. […] This study aims to investigate potential mechanisms underlying the increased thrombotic risk in MPNs through mass spectrometry-based proteomic analysis of bone marrow trephines. […] In PV, there was reduced expression of proteins involved in the regulation of the complement cascade (NES -4.45, adjusted p-value 0.001), complement cascade (-4.28, adjusted p-value 0.001), and initial triggering of the complement cascade (NES -2.69, adjusted p-value 0.01) pathways. […] Soluble complement proteins, including Factor B, Factor D, C1S, C1R, C2, C3, C4A, C5, C6, C7, C9, and components of C1Q, C8, and C4B, were reduced in PV samples compared to controls.

• #37 Paper: Dysregulated Complement Activation in Polycythemia Vera: A Novel Mechanism for Thrombosis in Myeloproliferative Neoplasms Uncovered By Proteomic Analysis

  https://ash.confex.com/ash/2024/webprogram/Paper206614.html

  The underlying mechanisms of thrombosis in MPNs remain incompletely understood. […] In this study, we show a decreased expression of complement regulatory proteins and increased activation and consumption of complement proteins in the bone marrow of PV patients, relative to controls, suggesting heightened thrombo-inflammation in this group. […] In conclusion, we show for the first time that dysregulated complement activation is most pronounced in PV patients. This may help explain the higher rates of thrombosis observed in PV compared to other MPNs.

• #38 Polycythemia Vera: A Researcher’s View – Longer Life Foundation

  http://longerlife.org/meet-the-investigators/polycythemia-vera-a-researchers-view/

  We don’t know yet what drives JAK2-negative PV, and there is nothing specific to guide their treatment. […] Interestingly, some do respond to JAK2 inhibitors. […] As our understanding matures of the impact of gene mutations and age differences, we might be able to tailor therapies for specific patients to achieve better outcomes. […] One avenue we are currently pursuing is improving our understanding of inflammation’s role. PV produces inflammatory cytokines and the inflammatory pathways might steer us to additional targeted therapies.

• #39

  https://www.omim.org/entry/263300

  Spivak et al. (2014) used gene expression profiling to identify several molecular pathways in PV outside the canonical JAK2 pathway. CD34+ peripheral blood cells were isolated from 19 patients with PV and a somatic JAK2 V617F mutation. Men had twice as many up- or down-regulated genes compared to women, but 102 genes with differential regulation compared to controls were identified that were concordant between the sexes, suggesting a potential core set of genes involved in the pathogenesis of PV independent of gender. The pattern of expression of these genes enabled the distinction of 2 clinical subtypes: one with aggressive disease and one with indolent disease. Those with aggressive disease had lower hemoglobin levels, increased number of thromboses, splenomegaly, increased transformation to acute leukemia, and decreased survival compared to those with indolent disease. Pathways involved included histone gene deregulation, activation of the NOTCH (190198) and SHH (600725) signaling pathways, matricellular proteins, and cytokines. The findings reinforced the importance of V617F-independent expression of disease phenotype, since there was no difference in V617F allele burden between the 2 groups. Spivak et al. (2014) suggested that gene expression profiling could have prognostic relevance for patients with PV, and that identification of molecular pathways outside the JAK2 signaling pathway may have therapeutic implications.

• #40 Emerging agents and regimens for polycythemia vera and essential thrombocythemia | Biomarker Research | Full Text

  https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-021-00298-5

  Polycythemia vera (PV) and essential thrombocythemia (ET) are both driven by JAK-STAT pathway activation and consequently much of the recent research efforts to improve the management and outcomes of patients with these neoplasms have centered around inhibition of this pathway. […] Although biologically-distinct diseases, ET and PV share a pathogenesis generally rooted in JAK-STAT activation, which prompts the unregulated proliferation of hematopoietic stem/progenitor cells (HSCs). Ninety nine percent of PV is driven by acquired mutations in the Janus kinase 2 (JAK2) gene, almost always JAK2-V617F. […] The majority of contemporary therapies, including hydroxyurea, busulfan and interferons do not target the principal upstream element of JAK-STAT pathway activation. […] Given the understanding of the role of JAK-STAT pathway activation in ET, JAK inhibition has been studied in this MPN as well.

• #41 The Evolving Landscape of Polycythemia Vera Treatment

  https://www.pharmacytimes.com/view/the-evolving-landscape-of-polycythemia-vera-treatment

  Cytoreductive therapy may be added in the case of frequent phlebotomies, phlebotomy intolerance, disease-related symptoms, progressive thrombocytosis and/or leukocytosis, or splenomegaly. […] Ruxolitinib (Jakafi; Incyte Corporation) is a JAK1/2 inhibitor that is approved for use in patients with PV who are intolerant to or refractory to HU. This drug may especially be useful in those with symptoms of pruritis and splenomegaly. […] Rusfertide, a hepcidin mimetic, is the furthest along in development. Rusfertide binds an iron exporter on key cells involved in iron metabolism called ferroportin, reducing iron availability in the bone marrow that is needed for erythropoiesis. […] Givinostat (Duvyzat; Italfarmaco SpA) is a histone deacetylase inhibitor specific for JAK2 V617F-mutated cells.

• #42 Italfarmaco Announces U.S. FDA Grants Fast Track Designation to Givinostat in Treatment of Polycythemia Vera — TradingView News

  https://www.tradingview.com/news/reuters.com,2025-05-06:newsml_GNX1zSRxm:0-italfarmaco-announces-u-s-fda-grants-fast-track-designation-to-givinostat-in-treatment-of-polycythemia-vera/

  Givinostat is currently being studied for its potential to treat PV, a rare blood cancer characterised by the overproduction of erythroid, myeloid, and megakaryocytic components in the bone marrow. […] By targeting and modulating abnormal gene expression, givinostat may help control excessive cell proliferation driven by mutations such as JAK2V617F, commonly found in PV patients. This mechanism aims to reduce disease burden, alleviate symptoms, and improve long-term outcomes.

• #43 Polycythemia vera therapy | BLCTT

  https://www.dovepress.com/polycythemia-vera-barriers-to-and-strategies-for-optimal-management-peer-reviewed-fulltext-article-BLCTT

  In PV, ruxolitinib is the only JAKi licensed and widely used in intolerance or resistance to HC cases. […] Despite the well-assessed efficacy of ruxolitinib in controlling Hct levels, reducing spleen size, and improving symptom burden, several occurrences and/or adverse effects may limit ruxolitinib use, and its efficiency in reducing thrombosis and later events was unclear. […] A further important and severe effect is the appearance of non-melanoma skin cancers, for which patients should be routinely screened for suspicious skin lesions. […] In addition to the classic and established therapies currently available, there are several molecules (newly or used for different conditions) that are being tested in phase 2/3 trials and which, in the years to come, could represent one more possibility in the management of patients with PV in need of further treatment.

• #44 The Role of JAK2 Inhibition in Polycythemia Vera

  https://www.targetedonc.com/view/the-role-of-jak2-inhibition-in-polycythemia-vera

  Ruxolitinib was approved for the treatment of HU-refractory or -intolerant PV based on the results of the randomized, phase III RESPONSE trial. RESPONSE enrolled 222 phlebotomy-dependent PV patients who had resistance or intolerance to HU as well as palpable splenomegaly of at least 5 cm, and they were randomized to either ruxolitinib (starting dose: 10 mg twice daily) versus best available therapy (BAT). […] The response to ruxolitinib was shown to be durable as well, as an extended follow-up analysis showed that the probabilities of maintaining the primary composite endpoint, and specifically hematocrit control, at the 80-week follow-up point were 92% and 89%, respectively. […] An ongoing follow-up study (RESPONSE-2) randomized 149 PV patients with HU resistance or intolerance, but lacking palpable splenomegaly, to ruxolitinib versus BAT. It demonstrated safety and efficacy results similar to those of the original RESPONSE trial. […] Trials examining the efficacy of other JAK2 inhibitors for PV are ongoing.

• #45 Polycythemia vera: historical oversights, diagnostic details, and therapeutic views | Leukemia

  https://www.nature.com/articles/s41375-021-01401-3

  It is currently assumed that the phenotypic differences between PV and the other two MPN variants are in part contributed by differences in the specific cytokine receptors that are activated by the corresponding driver mutation and interactions with other co-occurring mutations and their order of acquisition.

• #46 Molecular Pathogenesis and Therapy of Polycythemia Induced in Mice by JAK2 V617F | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0000018

  Our results suggest that JAK2 V617F is the primary cause of PV, but not of ET. […] Together, these results indicate that JAK2 V617F expression directly induces polycythemia in mice through Epo-independent overproduction of erythrocytes. The fact that the central erythroid features of PV are recapitulated by expression of JAK2 V617F argues that it is the primary and direct cause of human PV. […] The lack of thrombocytosis suggests that additional events may be required for JAK2 V617F to cause ET, but qualitative platelet abnormalities induced by JAK2 V617F may contribute to the hemostatic complications of PV. […] These results suggest that JAK2 V617F expression induces myelofibrosis, but the resulting impairment of erythropoiesis is due to a defect of the hematopoietic microenvironment, rather than a deficiency of malignant hematopoietic stem cells.

Zobacz więcej