Materiały źródłowe

• #1 Erythrocytosis: genes and pathways involved in disease development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8580782/

  Erythrocytosis is a blood disorder characterised by an increased red blood cell mass. The most common causes of erythrocytosis are acquired and caused by diseases and conditions that are accompanied by hypoxaemia or overproduction of erythropoietin. More rarely, erythrocytosis has a known genetic background, such as for polycythaemia vera and familial erythrocytosis. The majority of cases of polycythaemia vera are associated with acquired variants in JAK2, while familial erythrocytosis is a group of congenital disorders. Familial erythrocytosis type 1 is associated with hypersensitivity to erythropoietin (variants in EPOR), types 25 with defects in oxygen-sensing pathways (variants in VHL, EGLN1, EPAS1, EPO), and types 68 with an increased affinity of haemoglobin for oxygen (variants in HBB, HBA1, HBA2, BPGM). Due to a heterogenic genetic background, the causes of disease are not fully discovered and in more than 70% of patients the condition remains labelled idiopathic.

• #2 Erythrocytosis (Polycythaemia): Definition, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/23468-erythrocytosis

  Erythrocytosis involves having a higher-than-normal concentration of red blood cells (erythrocytes) in your blood. […] Erythrocytosis causes you to have high levels of hematocrit and/or hemoglobin. […] Too many red blood cells can impact your body in a variety of ways depending on whats causing your erythrocytosis. […] More serious causes of erythrocytosis can cause your blood to become too thick, putting you at risk of blood clots, heart attacks or strokes. […] Erythrocytosis is classified based on the blood composition that causes the high concentration of red blood cells. […] Primary erythrocytosis results from problems in the spongy tissue inside of your bones called bone marrow. […] With primary erythrocytosis, red blood cell production increases in your bone marrow because of a genetic defect in the cells that eventually mature into red blood cells.

• #3 Erythrocytosis (Polycythaemia): Definition, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/23468-erythrocytosis

  Secondary erythrocytosis results from problems outside of your bone marrow. […] Most secondary erythrocytosis involves your body producing too much of a hormone called erythropoietin (EPO). […] EPO tells your bone marrow to make more red blood cells. […] Secondary erythrocytosis usually involves high levels of EPO. […] Conditions that deprive your tissues of oxygen can cause your body to have too little oxygen. […] In response, EPO levels rise, so more red blood cells are made. […] Some tumors secrete excess EPO. […] Erythrocytosis can also occur after a kidney transplant. […] Your levels of EPO can help your provider determine whether you have primary or secondary erythrocytosis. […] EPO levels are low with primary erythrocytosis and high with secondary erythrocytosis. […] Most causes of erythrocytosis cant be cured.

• #4 Erythrocytosis (Polycythaemia): Definition, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/23468-erythrocytosis

  Erythrocytosis involves having a higher-than-normal concentration of red blood cells (erythrocytes) in your blood. […] Erythrocytosis causes you to have high levels of hematocrit and/or hemoglobin. […] Too many red blood cells can impact your body in a variety of ways depending on whats causing your erythrocytosis. […] More serious causes of erythrocytosis can cause your blood to become too thick, putting you at risk of blood clots, heart attacks or strokes. […] Erythrocytosis is classified based on the blood composition that causes the high concentration of red blood cells. […] Primary erythrocytosis results from problems in the spongy tissue inside of your bones called bone marrow. […] With primary erythrocytosis, red blood cell production increases in your bone marrow because of a genetic defect in the cells that eventually mature into red blood cells.

• #5 Erythrocytosis | eClinpath

  https://eclinpath.com/hematology/polycythemia/

  Erythrocytosis is defined as an increase in red blood cell (RBC) mass, usually absolute, and is also associated with an increased hematocrit (HCT) and hemoglobin concentration. […] An increased HCT or RBC count can be relative (proportional changes of RBC numbers in relation to plasma water) or absolute (a true increase in RBC numbers due to erythropoiesis, i.e. erythrocytosis). […] Absolute increase in HCT or RBC mass (erythrocytosis): This is due to increased erythropoiesis and can be primary (a bone marrow disorder) or secondary, due to appropriate or inappropriate production of the erythropoietic cytokine, erythropoietin. […] Primary erythrocytosis: This can be a familial disorder or neoplastic. […] Polycythemia vera: This is a chronic myeloproliferative disorder (chronic erythroid leukemia) and is a neoplastic condition in which RBC production is autonomous and independent of erythropoietin concentrations.

• #6 Secondary Erythrocytosis – Hematology and Oncology – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/hematology-and-oncology/myeloproliferative-disorders/secondary-erythrocytosis

  Secondary erythrocytosis is erythrocytosis that develops secondary to disorders that cause tissue hypoxia, inappropriately increased erythropoietin production, or increased sensitivity to erythropoietin. […] Common causes of secondary erythrocytosis include smoking, chronic arterial hypoxemia, tumors (tumor-associated erythrocytosis), use of androgenic steroids, and surreptitious erythropoietin use. […] Patients with chronic hypoxemia (arterial hemoglobin oxygen concentration 92%), typically due to lung disease, right-to-left intracardiac shunts, renal transplantation, prolonged exposure to high altitudes, or hypoventilation syndromes, often develop erythrocytosis. […] Tumor-associated erythrocytosis can occur when renal tumors, cysts, hepatomas, cerebellar hemangioblastomas, or uterine leiomyomas secrete erythropoietin. […] Serum erythropoietin level is elevated in patients with hypoxia-induced erythrocytosis (or level is inappropriately normal for their elevated hematocrit) and in patients with tumor-associated erythrocytosis. […] Treatment of secondary erythrocytosis is directed at the underlying disorder.

• #7 Molecular pathogenesis of congenital erythrocytoses and polycythemia vera – UpToDate

  https://www.uptodate.com/contents/molecular-pathogenesis-of-congenital-erythrocytoses-and-polycythemia-vera/print

  Molecular pathogenesis of congenital erythrocytoses and polycythemia vera […] Erythrocytosis can result from increased red blood cell (RBC) mass (absolute erythrocytosis) and/or decreased intravascular volume (relative or spurious erythrocytosis). Absolute erythrocytosis can be caused by a disorder of erythroid progenitor cells (primary erythrocytosis) or in response to elevated levels of erythropoietin (EPO), cobalt, and other causes (secondary erythrocytosis) (table 1). […] Most cases of primary erythrocytosis are due to PV, a myeloproliferative neoplasm caused by acquired (ie, not inherited) somatic mutations of JAK2 in bone marrow stem cells. Rare inherited (germline) conditions can cause erythrocytosis due to inherited gene variants that cause augmented hypoxia sensing, increased affinity of Hb for oxygen (O2), and other causes. […] This topic discusses molecular mechanisms associated with inherited (congenital) causes of erythrocytosis and PV.

• #8 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.

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

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

  Progenitors of the blood cells in these patients display abnormal responses to growth factors, suggesting the presence of a defect in a signaling pathway common to different growth factors. The observation that in vitro erythroid colonies grow when no endogenous erythropoietin (Epo) is added to the culture and the presence of a truncated Epo receptor in familial erythrocytosis indicate that the defect is in the transmission of the signal. The sensitivity of PV progenitors to multiple cytokines suggests that the defect may lie in a common pathway downstream from multiple receptors. Increased expression of BCLX suggests an additional decrease in cellular apoptosis. […] A mutation of the Janus kinase2 gene (JAK2) is the most likely source of PV pathogenesis, as JAK2 is directly involved in the intracellular signaling following exposure to cytokines to which PV progenitor cells display hypersensitivity.

• #10 Polycythemia vera pathophysiology – wikidoc

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

  Normal physiology of red blood cell production involves the stimulation of the erythropoietin receptor on erythroid cells by the hormone erythropoietin. This process is normally tightly regulated. In polycythemia vera, there is autonomous production of red blood cells in an erythropoietin-independent manner due to an activating JAK2 mutation. The mutation is usually a point mutation (V617F). The JAK2 mutation causes hyperactivity of the red blood cell production process. Other mutations that are associated with the pathophysiology of polycythemia vera include mutations in TET2, SF3B1, and ASXL1. The resulting elevation of hemoglobin and red blood cell mass predisposes patients to thrombosis. […] The presence of a JAK2 mutation within a hematopoietic stem cell and therefore within an erythroid precursor.

• #11 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.

• #12 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. […] 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. […] In polycythemia vera, iron absorption is increased due to suppression of hepcidin production. […] Although patients with iron deficiency from other causes become anemic, patients with polycythemia vera have increased RBC production and thus, even when iron-deficient initially patients with polycythemia vera can have a normal hematocrit level but an elevated red cell count and microcytic RBC indices; this combination of findings is a hallmark of polycythemia vera. […] Mutations of the Janus kinase 2 (JAK2) gene are responsible in most cases of polycythemia vera. […] These mutations lead to sustained activation of the JAK2 kinase, which causes excess blood cell production independent of erythropoietin.

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

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

  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. […] 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.

• #14 Erythrocytosis: genes and pathways involved in disease development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8580782/

  Activation of the EPO-EPOR signalling pathway in erythroblasts results in the transcription of various genes that are involved in cell proliferation, differentiation, prevention of apoptosis, and iron regulation, leading to RBC maturation. […] The disease mechanism is based on inactivation of the JAK2 pseudokinase autoinhibitory domain, which is responsible for inhibition of JAK2 self-activation. Two variants in exon 13 have been associated with erythrocytosis, and heterozygous variants in JAK2 and EGLN1 with familial erythrocytosis. Variants of the JAK2 gene may be present in several other diseases, such as essential thrombocythaemia and primary myelofibrosis, although the symptoms of affected patients can be very different. […] Familial erythrocytosis type 1 (ECYT1) is an autosomal dominant genetic disorder that is associated with more than 28 germline EPOR variants. Different frameshift variants in exon 8 have been identified in families in which several members show symptoms of the disease. The mechanism underlying the frameshift variants is a truncation of the EPOR intracellular C-terminal region, which is responsible for negative feedback regulation of the receptor. These variants enable EPO-EPOR signal transduction even at low serum EPO levels, and they prevent feedback inhibition through the SH2B3 and PTPN6/SOCS-3 inhibitory domain. […] The disease mechanism underlying these variants is inactivation of the EGLN1 and VHL enzymes, EPAS1 stabilisation, or increased EPO transcription activation, all of which result in increased EPO production under normoxic conditions and, consequently, RBC overproduction.

• #15

  https://haematologica.org/article/view/8411

  Primary familial and congenital polycythemia is characterized by erythropoietin hypersensitivity of erythroid progenitors due to germline nonsense or frameshift mutations in the erythropoietin receptor gene. […] Here we provide evidence for a new mechanism whereby the presence of novel sequences generated by frameshift mutations is required for the phenotype rather than just extensive truncation resulting from nonsense mutations. […] We show that the erythropoietin hypersensitivity induced by a new erythropoietin receptor mutant, p.Gln434Profs*11, could not be explained by the loss of negative signaling and of the internalization domains, but rather by the appearance of a new C-terminal tail. […] These results suggest a new mechanism that might be common to erythropoietin receptor frameshift mutations.

• #16

  https://haematologica.org/article/view/8411

  In summary, we show that primary familial and congenital polycythemia is more complex than expected since distinct mechanisms are involved in the erythropoietin hypersensitivity phenotype, according to the type of erythropoietin receptor mutation. […] We identified and extensively studied a new germline frameshift EPOR mutation, c.1300dup (p.Gln434Profs*11), responsible for marked erythropoietin hypersensitivity as in JAK2-positive polycythemia vera. […] Our results highlight that a different mechanism underlies erythropoietin hypersensitivity due to frameshift EPOR mutations. […] Thus, confirming previous reports, we showed that extensive truncations lacking all EPOR negative regulatory sites are sufficient in themselves to induce the PFCP phenotype. […] The greater erythropoietin hypersensitivity induced by EPOR p.Gln434Profs*11 cannot, therefore, be explained by the receptor truncation itself and the loss of the two SHP-1 and SOCS3 binding sites which are responsible for a persistent activation, but rather by the appearance of a new C-terminal tail that confers spontaneous signaling. […] Collectively these results show that p.Gln434Profs*11 increases EPOR stability, dimerization and localization at the cell surface without modifying internalization of the receptor.

• #17 Secondary Erythrocytosis – Hematology and Oncology – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/hematology-and-oncology/myeloproliferative-disorders/secondary-erythrocytosis

  Secondary erythrocytosis is erythrocytosis that develops secondary to disorders that cause tissue hypoxia, inappropriately increased erythropoietin production, or increased sensitivity to erythropoietin. […] Common causes of secondary erythrocytosis include smoking, chronic arterial hypoxemia, tumors (tumor-associated erythrocytosis), use of androgenic steroids, and surreptitious erythropoietin use. […] Patients with chronic hypoxemia (arterial hemoglobin oxygen concentration 92%), typically due to lung disease, right-to-left intracardiac shunts, renal transplantation, prolonged exposure to high altitudes, or hypoventilation syndromes, often develop erythrocytosis. […] Tumor-associated erythrocytosis can occur when renal tumors, cysts, hepatomas, cerebellar hemangioblastomas, or uterine leiomyomas secrete erythropoietin. […] Serum erythropoietin level is elevated in patients with hypoxia-induced erythrocytosis (or level is inappropriately normal for their elevated hematocrit) and in patients with tumor-associated erythrocytosis. […] Treatment of secondary erythrocytosis is directed at the underlying disorder.

• #18 Erythrocytosis | eClinpath

  https://eclinpath.com/hematology/polycythemia/

  Secondary erythrocytosis: This is usually due to increased erythropoietin production. The physiologic stimulus for erythropoietin production is hypoxia, therefore erythropoietin production can be appropriate (in response to hypoxia), albeit excessive, or inappropriate (independent of hypoxia). […] Inappropriate secondary erythrocytosis: This is due to enhanced erythropoiesis that is independent of a hypoxic stimulus, and is usually mediated via erythropoietin.

• #19 Secondary Polycythemia: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/205039-overview

  In secondary polycythemia, the number of red blood cells (RBCs) is increased as a result of an underlying condition. […] Secondary polycythemia most often develops as a response to chronic hypoxemia, which triggers increased production of erythropoietin by the kidneys. […] Elevated hemoglobin levels due to chronic hypoxia in patients with chronic lung disorders such as COPD or sleep apnea are the result of an increased production of erythropoietin, which in turn causes increased production of red blood cells. […] Secondary polycythemia is defined as an absolute increase in red blood cell mass that is caused by enhanced stimulation of red blood cell production. […] Enhanced erythroid stimulation can be a physiologic response to generalized or localized tissue hypoxia. […] Inappropriate stimulation of EPO production may occur in the following settings: Benign renal lesions, such as hydronephrosis and cysts, can stimulate EPO production, possibly due to compromised renal blood flow by compressive or vasoconstrictive mechanisms.

• #20 Insights into the Pathophysiology and Therapeutic Targets of Consequences Induced by Polycythemia in COPD – Biosciences Biotechnology Research Asia

  https://www.biotech-asia.org/vol20no4/insights-into-the-pathophysiology-and-therapeutic-targets-of-consequences-induced-by-polycythemia-in-copd/

  Polycythemia, characterized by an excess of red blood cells (RBCs), is a common occurrence in individuals with chronic obstructive pulmonary disease (COPD) due to chronic hypoxia resulting from impaired lung function. […] The elevated red blood cell count can thicken the blood, increasing the risk of blood clots and cardiovascular complications. […] Polycythemia, a condition where the body produces many red blood cells, has been identified as an independent risk factor for death in COPD patients who also have pulmonary embolism. […] Secondary polycythemia, is a common occurrence in individuals with COPD due to chronic hypoxia, characterized by low oxygen levels resulting from impaired lung function. […] In COPD, the damaged lungs hinder proper airflow and gas exchange, leading to a reduced supply of oxygen to the body’s tissues.

• #21 JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views | Leukemia

  https://www.nature.com/articles/s41375-021-01290-6

  Conversely, under hypoxic conditions, PHD2 enzymatic activity is reduced, resulting in diminished hydroxylation and degradation of HIF2A, in other words stabilization of HIF2A following which the HIF complex binds hypoxia responsive elements within the EPO gene and turns on its transcription. This constitutes the pathogenetic basis for hypoxia-induced acquired erythrocytosis associated with chronic obstructive pulmonary disease (COPD), cyanotic heart disease with right to left shunt, and high-altitude habitat. Amelioration of tissue hypoxia reverses the process resulting in compensated normal EPO in such conditions, consistent with the assertion that regulation of erythropoiesis by HIF is exquisitely sensitive to oxygen levels. In addition, HIF2A expression is also controlled by iron regulatory proteins 1 and 2 (Irps) via its iron-responsive elements, and deletion of Irp1 in murine studies has been found to increase HIF2A expression, which in turn stimulates EPO, leading to erythrocytosis.

• #22 Insights into the Pathophysiology and Therapeutic Targets of Consequences Induced by Polycythemia in COPD – Biosciences Biotechnology Research Asia

  https://www.biotech-asia.org/vol20no4/insights-into-the-pathophysiology-and-therapeutic-targets-of-consequences-induced-by-polycythemia-in-copd/

  In response, the body initiates a compensatory mechanism by increasing the production of red blood cells to enhance oxygen-carrying capacity. […] This response is triggered by the hormone erythropoietin, which is produced by the kidneys in response to low oxygen levels. […] Consequently, higher levels of red blood cells lead to polycythemia. […] However, this condition can thicken the blood, increasing the risk of blood clots and cardiovascular complications. […] Polycythemic COPD is a subtype of COPD characterized by an increase in hematocrit count in response to chronic hypoxemia. […] The onset of secondary polycythemia can be influenced by elevated carboxyhemoglobin (COHb) levels in individuals who smoke and persistent hypoxemia, or low oxygen levels in the blood, in those with COPD.

• #23 Benefit of Theophylline on COPD-Related Erythrocytosis | AAFP

  https://www.aafp.org/pubs/afp/issues/1998/0215/p791.html

  Patients with chronic obstructive pulmonary disease (COPD) tend to develop erythrocytosis to compensate for the chronic hypoxic state. […] Theophylline is effective in reducing hematocrit and erythropoietin levels in patients with erythrocytosis following renal transplantation. […] In the retrospective study, hematocrit levels were found to be significantly lower in the 50 patients receiving theophylline, compared with the levels in the 61 patients not receiving this drug. […] In the prospective study, arterial oxygen saturation did not significantly increase during theophylline therapy. However, hematocrit levels declined significantly in seven of eight patients after three months of theophylline therapy. […] Serum erythropoietin levels declined by 21 to 91 percent in five of the seven patients in whom this variable was studied. […] The authors believe that, although the side effects of theophylline may limit its use in some patients, the possible beneficial effects demonstrated in this study may outweigh the side effects. They encourage the use of theophylline in patients with COPD-related erythrocytosis.

• #24 Secondary Polycythemia: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/205039-overview

  In secondary polycythemia, the number of red blood cells (RBCs) is increased as a result of an underlying condition. […] Secondary polycythemia most often develops as a response to chronic hypoxemia, which triggers increased production of erythropoietin by the kidneys. […] Elevated hemoglobin levels due to chronic hypoxia in patients with chronic lung disorders such as COPD or sleep apnea are the result of an increased production of erythropoietin, which in turn causes increased production of red blood cells. […] Secondary polycythemia is defined as an absolute increase in red blood cell mass that is caused by enhanced stimulation of red blood cell production. […] Enhanced erythroid stimulation can be a physiologic response to generalized or localized tissue hypoxia. […] Inappropriate stimulation of EPO production may occur in the following settings: Benign renal lesions, such as hydronephrosis and cysts, can stimulate EPO production, possibly due to compromised renal blood flow by compressive or vasoconstrictive mechanisms.

• #25 Secondary Polycythemia: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/205039-overview

  Hemoglobin mutants associated with tight binding to oxygen and a failure to deliver oxygen in the venous blood can cause high EPO levels. […] A von Hippel-Lindau gene mutation results in polycythemia by altering the von Hippel-Lindau protein, which plays an important role in sensing hypoxia and binds to hydroxylated HIF1-alpha to serve as a recognition site of an E3-ubiquitin ligase complex. […] Chuvash polycythemia is caused by an autosomal recessive gene mutation on the von Hippel-Lindau gene, which results in the upregulation of the HIF1-alpha target gene and causes elevations in EPO levels. […] The administration of androgen esters to hypogonadal men can lead to polycythemia. […] Secondary polycythemia has been reported as a paraneoplastic phenomenon in patients with testicular cancer.

• #26 Testosterone therapy-induced erythrocytosis: can phlebotomy be justified? in: Endocrine Connections Volume 13 Issue 10 (2024)

  https://ec.bioscientifica.com/view/journals/ec/13/10/EC-24-0283.xml

  Erythrocytosis, or elevated hematocrit, is a common side effect of testosterone therapy (TTh) in male hypogonadism. Testosterone stimulates erythropoiesis through an initial rise in erythropoietin (EPO), the establishment of a new EPO/hemoglobin set point, and a parallel decrease in the master iron regulator protein hepcidin, as well as several other potential mechanisms. […] Evidence shows an increased thrombotic risk associated with TTh-induced erythrocytosis. […] However, evidence supporting the efficacy or safety of therapeutic phlebotomy in lowering hematocrit in TTh-induced erythrocytosis is lacking. […] The persistent suppression of hematocrit follows after depletion of iron stores as it puts the proverbial brakes on erythropoiesis by lack of substrate and lowers tissue oxygen partial pressure (pO2), thereby triggering various biological pathways. Some of these pathways might affect thrombotic risk.

• #27 Testosterone therapy-induced erythrocytosis: can phlebotomy be justified? in: Endocrine Connections Volume 13 Issue 10 (2024)

  https://ec.bioscientifica.com/view/journals/ec/13/10/EC-24-0283.xml

  While significant progress has been made, our understanding of the mechanism of action behind the stimulation of erythropoiesis by testosterone remains incomplete. […] Several mechanisms have been proposed, including increased EPO production, stimulation of colony-forming unit-erythroids (CFU-E: erythroid progenitors which differentiate into proerythroblasts), and increased incorporation of iron into erythrocytes. […] An increase in HIF, in particular HIF-2, increases EPO production, which would establish a new EPO/hemoglobin set point and could be the underlying mechanism for testosterone’s recalibration of the EPO/hemoglobin set point. […] The question that remains is whether decreased tissue pO2 in response to therapeutic phlebotomy in TTh-induced erythrocytosis increases HIF activity sufficiently to also confer a thrombotic risk that might offset or override the potential benefit of correcting increased hematocrit. […] In summary, the practice of therapeutic phlebotomy for treating TTh-induced erythrocytosis might potentially increase, rather than decrease, thrombotic risk through the HIF pathway by the combined action of depleting iron stores and decreasing tissue pO2.

• #28 JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views | Leukemia

  https://www.nature.com/articles/s41375-021-01290-6

  Germline mutations in the oxygen-sensing (VHL-HIF2A-PHD) pathway genes are relatively rare but when present may result in erythrocytosis with elevated or inappropriately normal EPO. It is to be noted that interrogation of this pathway is an evolving area of investigation with recent identification of novel zinc finger domain PHD2 mutations and splicing mutations in VHL. In chronological order, in 1997, Chuvash polycythemia (CP), an autosomal recessive condition with homozygous VHL (R200W) mutation was initially described in Chuvashia (Russia) and subsequently noted in the Italian island of Ischia and worldwide. Functionally, VHL-HIF2A interaction is disrupted with impaired ability of VHL to target hydroxylated HIF2A for proteasomal degradation, resulting in increased HIF2A and EPO levels under normoxic conditions. In addition, mutant VHL exhibits altered affinity for suppressor of cytokine signaling 1, impeding formation of a heterodimeric E3 ligase involved in targeting phosphorylated JAK2 for ubiquitin-mediated proteasomal degradation. Accordingly, erythroid progenitors in affected patients also displayed hypersensitivity to EPO, which is an inherent feature shared by PV.

• #29 The role of PHD2 mutations in the pathogenesis of erythrocytosis | HP

  https://www.dovepress.com/the-role-of-phd2-mutations-in-the-pathogenesis-of-erythrocytosis-peer-reviewed-fulltext-article-HP

  The transcription of the erythropoietin (EPO) gene is tightly regulated by the hypoxia response pathway to maintain oxygen homeostasis. Elevations in serum EPO level may be reflected in an augmentation in the red cell mass, thereby causing erythrocytosis. […] Sequence analysis of the genes encoding the PHDs in patients with erythrocytosis has revealed heterozygous germline mutations only occurring in Egl nine homolog 1 (EGLN1, also known as PHD2), the gene that encodes PHD2. […] The exact mechanism of a potential tumor-suppressor role for PHD2 still needs to be elucidated. A knockin mouse model expressing the first reported PHD2-P317R mutation recapitulates the phenotype observed in humans (erythrocytosis with inappropriately normal serum EPO levels) and demonstrates that haploinsufficiency and partial deregulation of PHD2 is sufficient to cause erythrocytosis.

• #30 The role of PHD2 mutations in the pathogenesis of erythrocytosis | HP

  https://www.dovepress.com/the-role-of-phd2-mutations-in-the-pathogenesis-of-erythrocytosis-peer-reviewed-fulltext-article-HP

  Germline defects in some of the genes encoding proteins in red blood cells, including ones in the EPO signal transduction pathway, have been identified in hereditary erythrocytosis. […] Mutations in the receptor of EPO (EPOR) (responsible for ECYT1 [erythrocytosis type1]) induce the loss of the negative feedback control by SHP and the constitutive activation of the EPO signaling pathway. […] The absence of mutations in both the EGLN2 and EGLN3 genes (which encode PHD1 and PHD3, respectively) in individuals with erythrocytosis and the detection of an increasing number of heterozygous EGLN1 mutations pointed to the potential involvement of PHD2 in the regulation of the HIF- subunit and the development of erythrocytosis. […] PHD2 may also have an important role in facilitating adaptation to high altitude. […] The hydroxylase activity of PHD2 may not necessarily be the only functionally relevant target of the mutations. […] The EPO pathway is sensitive to modest changes in PHD2 activity, such that even a heterozygous PHD2 mutation was sufficient to induce erythrocytosis.

• #31 Erythrocytosis: genes and pathways involved in disease development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8580782/

  Activation of the EPO-EPOR signalling pathway in erythroblasts results in the transcription of various genes that are involved in cell proliferation, differentiation, prevention of apoptosis, and iron regulation, leading to RBC maturation. […] The disease mechanism is based on inactivation of the JAK2 pseudokinase autoinhibitory domain, which is responsible for inhibition of JAK2 self-activation. Two variants in exon 13 have been associated with erythrocytosis, and heterozygous variants in JAK2 and EGLN1 with familial erythrocytosis. Variants of the JAK2 gene may be present in several other diseases, such as essential thrombocythaemia and primary myelofibrosis, although the symptoms of affected patients can be very different. […] Familial erythrocytosis type 1 (ECYT1) is an autosomal dominant genetic disorder that is associated with more than 28 germline EPOR variants. Different frameshift variants in exon 8 have been identified in families in which several members show symptoms of the disease. The mechanism underlying the frameshift variants is a truncation of the EPOR intracellular C-terminal region, which is responsible for negative feedback regulation of the receptor. These variants enable EPO-EPOR signal transduction even at low serum EPO levels, and they prevent feedback inhibition through the SH2B3 and PTPN6/SOCS-3 inhibitory domain. […] The disease mechanism underlying these variants is inactivation of the EGLN1 and VHL enzymes, EPAS1 stabilisation, or increased EPO transcription activation, all of which result in increased EPO production under normoxic conditions and, consequently, RBC overproduction.

• #32 JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views | Leukemia

  https://www.nature.com/articles/s41375-021-01290-6

  Recently, mutations in the EPO gene itself have been identified in relation to familial erythrocytosis whereby a single base pair deletion in exon 2 caused a frameshift that truncated translation of the main EPO messenger RNA (mRNA), but converted a typically noncoding mRNA, which was transcribed from an alternative promoter within intron 1, to produce excess functional EPO mainly through the liver. In addition, in a five-generation kindred with erythrocytosis, a novel heterozygous 5UTR EPO variant has been newly discovered; the mutated 5UTR of EPO augments interaction with HIF2, leading to increased production of EPO. […] Structurally, Hgb is a tetramer, comprising of two alpha and beta globin subunits (an 11 dimer and an 22 dimer in Hgb A) with two conformationally stable states; the relaxed (R), high-oxygen affinity state and tense (T), low-oxygen affinity state. Oxygen binding to Hgb subunits demonstrates cooperativity, resulting in a sigmoidal oxygen dissociation curve which is left-shifted (low p50) with high-affinity variants. The R-T transition is impacted by mutations in critical regions of the globin chain in high-affinity variants. Oxygen delivery is compromised at the tissue capillary level, resulting in hypoxia which serves as a stimulus for EPO production and subsequent erythrocytosis. Almost, 100 high-oxygen affinity Hgb variants have been reported; a review of the Mayo Clinic Hgb variant database (1974-2018) identified 762 patients with 80 distinct variants (61 , 20). These mutations were mostly missense impacting the heme pocket, 12 contact sites, 2, 3 BPG binding sites and C-terminal conformation stabilization regions, with the most common variants being Hb Tarrant (chain variant) and Hb Malmo (chain variant). Only one-third of high-affinity variants give rise to erythrocytosis, likely a result of either low-level expression of the variant or concomitant hemolysis. Within red cells, 2, 3, BPGM catalyzes conversion of 1, 2 BPG to 2, 3 BPG, the latter binds deoxy Hgb tetramer and allosterically converts it to a low-oxygen affinity state, prompting release of oxygen. However, with 2, 3 BPGM deficiency, conversion of 1, 2 BPG to 2, 3 BPG is impaired, which enables the Hgb tetramer to assume a high-oxygen affinity state. Erythrocytosis resulting from 2, 3 BPG deficiency is relatively uncommon with limited cases described in the literature.

• #33 Erythrocytosis: genes and pathways involved in disease development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8580782/

  Less often, erythrocytosis has a genetic background, acquired in polycythaemia vera (PV), the most common myeloproliferative neoplasm, and congenital or familial erythrocytosis (ECYT), a rare genetic disorder. Acquired variants in the Janus tyrosine kinase 2 gene (JAK2) are indicative of PV. Congenital ECYT has a heterogeneous genetic background and it has been divided into eight types, based on the genes affected. Primary erythrocytoses, PV and ECYT1, are the consequences of constant activation of the EPO-EPOR signalling pathway due to variants in the JAK2 or EPOR genes, with the levels of serum EPO usually being below normal. Secondary congenital erythrocytoses (i.e., ECYT2-8) develop due to a mechanism extrinsic of the erythroid cells, and here the levels of serum EPO are usually normal or elevated. The mechanism underlying ECYT2-5 is an altered hypoxia inducible factor (HIF)-EPO oxygen-sensing pathway which is due to inherited variants in the VHL, EGLN1, EPAS1, or EPO genes. Finally, the mechanism that leads to ECYT6-8 is an increased affinity of haemoglobin for oxygen, due to variants in the HBB, HBA1, HBA2, and/or BPGM genes.

• #34 JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views | Leukemia

  https://www.nature.com/articles/s41375-021-01290-6

  Recently, mutations in the EPO gene itself have been identified in relation to familial erythrocytosis whereby a single base pair deletion in exon 2 caused a frameshift that truncated translation of the main EPO messenger RNA (mRNA), but converted a typically noncoding mRNA, which was transcribed from an alternative promoter within intron 1, to produce excess functional EPO mainly through the liver. In addition, in a five-generation kindred with erythrocytosis, a novel heterozygous 5UTR EPO variant has been newly discovered; the mutated 5UTR of EPO augments interaction with HIF2, leading to increased production of EPO. […] Structurally, Hgb is a tetramer, comprising of two alpha and beta globin subunits (an 11 dimer and an 22 dimer in Hgb A) with two conformationally stable states; the relaxed (R), high-oxygen affinity state and tense (T), low-oxygen affinity state. Oxygen binding to Hgb subunits demonstrates cooperativity, resulting in a sigmoidal oxygen dissociation curve which is left-shifted (low p50) with high-affinity variants. The R-T transition is impacted by mutations in critical regions of the globin chain in high-affinity variants. Oxygen delivery is compromised at the tissue capillary level, resulting in hypoxia which serves as a stimulus for EPO production and subsequent erythrocytosis. Almost, 100 high-oxygen affinity Hgb variants have been reported; a review of the Mayo Clinic Hgb variant database (1974-2018) identified 762 patients with 80 distinct variants (61 , 20). These mutations were mostly missense impacting the heme pocket, 12 contact sites, 2, 3 BPG binding sites and C-terminal conformation stabilization regions, with the most common variants being Hb Tarrant (chain variant) and Hb Malmo (chain variant). Only one-third of high-affinity variants give rise to erythrocytosis, likely a result of either low-level expression of the variant or concomitant hemolysis. Within red cells, 2, 3, BPGM catalyzes conversion of 1, 2 BPG to 2, 3 BPG, the latter binds deoxy Hgb tetramer and allosterically converts it to a low-oxygen affinity state, prompting release of oxygen. However, with 2, 3 BPGM deficiency, conversion of 1, 2 BPG to 2, 3 BPG is impaired, which enables the Hgb tetramer to assume a high-oxygen affinity state. Erythrocytosis resulting from 2, 3 BPG deficiency is relatively uncommon with limited cases described in the literature.

• #35 Erythrocytosis: genes and pathways involved in disease development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8580782/

  The prime regulator of erythropoiesis is EPO, which is a protein hormone that is produced mainly by the kidney. The HIF transcription factor family regulates EPO expression. In humans there are three alpha subunit paralogues: HIF1A, EPAS1 (HIF2A), and HIF3A. All three HIFA paralogues form a transcription complex with HIF beta subunit, aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF1B). ARNT is constitutively expressed, while HIFA are regulated through sensing of the oxygen concentrations in the cell cytoplasm. The main regulator of EPO production in the kidneys is endothelial Per-Arnt-Sim (PAS)-domain-containing protein 1 (EPAS1, also known as HIF2A). Two additional proteins are crucial for this HIF-EPO pathway regulation: the Egl nine homolog 1 (EGLN1, also known as prolyl hydroxylase domain-containing protein 2; PHD2); and von Hippel-Lindau disease tumour suppressor (VHL). Under normal oxygen conditions, HIFA is hydroxylated by EGLN1, with this hydroxylation being recognised by VHL, which leads to HIFA ubiquitination and degradation in the proteasome. Under low oxygen concentrations, EGLN1 is not active, and HIFA is translocated into the nucleus, where it forms a transcription complex with ARNT and CREBBP/p300 HAT; this results in the transcription of numerous hypoxia-inducible genes, including EPO, which influence the growth of erythroid progenitor cells. Once EPO is released into the bloodstream and transported to the bone marrow, it binds to EPOR on the surface of erythroblasts, thus leading to activation of the EPO-EPOR signalling pathway.

• #36 Erythrocytosis: genes and pathways involved in disease development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8580782/

  The prime regulator of erythropoiesis is EPO, which is a protein hormone that is produced mainly by the kidney. The HIF transcription factor family regulates EPO expression. In humans there are three alpha subunit paralogues: HIF1A, EPAS1 (HIF2A), and HIF3A. All three HIFA paralogues form a transcription complex with HIF beta subunit, aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF1B). ARNT is constitutively expressed, while HIFA are regulated through sensing of the oxygen concentrations in the cell cytoplasm. The main regulator of EPO production in the kidneys is endothelial Per-Arnt-Sim (PAS)-domain-containing protein 1 (EPAS1, also known as HIF2A). Two additional proteins are crucial for this HIF-EPO pathway regulation: the Egl nine homolog 1 (EGLN1, also known as prolyl hydroxylase domain-containing protein 2; PHD2); and von Hippel-Lindau disease tumour suppressor (VHL). Under normal oxygen conditions, HIFA is hydroxylated by EGLN1, with this hydroxylation being recognised by VHL, which leads to HIFA ubiquitination and degradation in the proteasome. Under low oxygen concentrations, EGLN1 is not active, and HIFA is translocated into the nucleus, where it forms a transcription complex with ARNT and CREBBP/p300 HAT; this results in the transcription of numerous hypoxia-inducible genes, including EPO, which influence the growth of erythroid progenitor cells. Once EPO is released into the bloodstream and transported to the bone marrow, it binds to EPOR on the surface of erythroblasts, thus leading to activation of the EPO-EPOR signalling pathway.

• #37 JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views | Leukemia

  https://www.nature.com/articles/s41375-021-01290-6

  The HIF pathway regulates erythropoiesis and EPO production within renal peritubular cells, in an oxygen-dependent manner. HIF transcription factor is a heterodimer with alpha and beta subunits, the latter is constitutively expressed, while hypoxia affects the function of the former. HIF-A has three known isoforms (HIF-1A, HIF2A, HIF-3A), amongst which HIF2A is mainly involved in regulation of EPO synthesis; HIF2A knockout mice demonstrate a hypocellular marrow and anemia as a result of inadequate EPO production. In the presence of oxygen, HIF2A undergoes hydroxylation at two critical proline residues, Pro405 and Pro531, mediated by PHD2, following which it undergoes degradation by the ubiquitin proteasomal pathway, a process mediated by VHL, a tumor suppressor protein, serving as the substrate recognition component of an E3 ubiquitin ligase complex. In addition, a 2-oxoglutarate dependent oxygenase, factor inhibiting HIF (FIH), catalyzes hydroxylation of a specific arginine residue within HIF which inhibits HIF binding to p300, a transcriptional co-activator. The end result is reduced transcriptional activation of EPO; a HIF target gene.

• #38 JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views | Leukemia

  https://www.nature.com/articles/s41375-021-01290-6

  The HIF pathway regulates erythropoiesis and EPO production within renal peritubular cells, in an oxygen-dependent manner. HIF transcription factor is a heterodimer with alpha and beta subunits, the latter is constitutively expressed, while hypoxia affects the function of the former. HIF-A has three known isoforms (HIF-1A, HIF2A, HIF-3A), amongst which HIF2A is mainly involved in regulation of EPO synthesis; HIF2A knockout mice demonstrate a hypocellular marrow and anemia as a result of inadequate EPO production. In the presence of oxygen, HIF2A undergoes hydroxylation at two critical proline residues, Pro405 and Pro531, mediated by PHD2, following which it undergoes degradation by the ubiquitin proteasomal pathway, a process mediated by VHL, a tumor suppressor protein, serving as the substrate recognition component of an E3 ubiquitin ligase complex. In addition, a 2-oxoglutarate dependent oxygenase, factor inhibiting HIF (FIH), catalyzes hydroxylation of a specific arginine residue within HIF which inhibits HIF binding to p300, a transcriptional co-activator. The end result is reduced transcriptional activation of EPO; a HIF target gene.

• #39 Erythrocytosis: genes and pathways involved in disease development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8580782/

  The prime regulator of erythropoiesis is EPO, which is a protein hormone that is produced mainly by the kidney. The HIF transcription factor family regulates EPO expression. In humans there are three alpha subunit paralogues: HIF1A, EPAS1 (HIF2A), and HIF3A. All three HIFA paralogues form a transcription complex with HIF beta subunit, aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF1B). ARNT is constitutively expressed, while HIFA are regulated through sensing of the oxygen concentrations in the cell cytoplasm. The main regulator of EPO production in the kidneys is endothelial Per-Arnt-Sim (PAS)-domain-containing protein 1 (EPAS1, also known as HIF2A). Two additional proteins are crucial for this HIF-EPO pathway regulation: the Egl nine homolog 1 (EGLN1, also known as prolyl hydroxylase domain-containing protein 2; PHD2); and von Hippel-Lindau disease tumour suppressor (VHL). Under normal oxygen conditions, HIFA is hydroxylated by EGLN1, with this hydroxylation being recognised by VHL, which leads to HIFA ubiquitination and degradation in the proteasome. Under low oxygen concentrations, EGLN1 is not active, and HIFA is translocated into the nucleus, where it forms a transcription complex with ARNT and CREBBP/p300 HAT; this results in the transcription of numerous hypoxia-inducible genes, including EPO, which influence the growth of erythroid progenitor cells. Once EPO is released into the bloodstream and transported to the bone marrow, it binds to EPOR on the surface of erythroblasts, thus leading to activation of the EPO-EPOR signalling pathway.

• #40 JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views | Leukemia

  https://www.nature.com/articles/s41375-021-01290-6

  EPO binds to its receptor (EPOR) on the erythroid progenitor surface, which is part of the cytokine class I receptor superfamily; the receptor subsequently undergoes dimerization and activates JAK2, which in turn leads to tyrosine phosphorylation of its distal region. EPO-induced JAK2 activation leads to intracellular activation of the Ras/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt pathways, and signal transducer and activator of transcription (STAT 1, 3, 5A, 5B), which turn on numerous target genes that promote red cell survival, proliferation and maturation. In essence, EPO in synergy with several growth factors (SCF, GM-CSF, IL-3, and IGF-1) enhances red cell survival by inhibition of apoptosis together with maturation and proliferation of erythroid progenitor cells. Germline heterozygous nonsense and frameshift mutations in exon 8 of EPOR have been described causing truncation of the C-terminal distal portion of the receptor which contains several tyrosine residues that serve as docking sites for SHP1, SOCS3 that are negative regulators of EPO signaling. This results in hypersensitivity to EPO via excessive activation of the EPO receptor.

• #41 JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views | Leukemia

  https://www.nature.com/articles/s41375-021-01290-6

  EPO binds to its receptor (EPOR) on the erythroid progenitor surface, which is part of the cytokine class I receptor superfamily; the receptor subsequently undergoes dimerization and activates JAK2, which in turn leads to tyrosine phosphorylation of its distal region. EPO-induced JAK2 activation leads to intracellular activation of the Ras/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt pathways, and signal transducer and activator of transcription (STAT 1, 3, 5A, 5B), which turn on numerous target genes that promote red cell survival, proliferation and maturation. In essence, EPO in synergy with several growth factors (SCF, GM-CSF, IL-3, and IGF-1) enhances red cell survival by inhibition of apoptosis together with maturation and proliferation of erythroid progenitor cells. Germline heterozygous nonsense and frameshift mutations in exon 8 of EPOR have been described causing truncation of the C-terminal distal portion of the receptor which contains several tyrosine residues that serve as docking sites for SHP1, SOCS3 that are negative regulators of EPO signaling. This results in hypersensitivity to EPO via excessive activation of the EPO receptor.

• #42 Erythrocytosis: genes and pathways involved in disease development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8580782/

  Activation of the EPO-EPOR signalling pathway in erythroblasts results in the transcription of various genes that are involved in cell proliferation, differentiation, prevention of apoptosis, and iron regulation, leading to RBC maturation. […] The disease mechanism is based on inactivation of the JAK2 pseudokinase autoinhibitory domain, which is responsible for inhibition of JAK2 self-activation. Two variants in exon 13 have been associated with erythrocytosis, and heterozygous variants in JAK2 and EGLN1 with familial erythrocytosis. Variants of the JAK2 gene may be present in several other diseases, such as essential thrombocythaemia and primary myelofibrosis, although the symptoms of affected patients can be very different. […] Familial erythrocytosis type 1 (ECYT1) is an autosomal dominant genetic disorder that is associated with more than 28 germline EPOR variants. Different frameshift variants in exon 8 have been identified in families in which several members show symptoms of the disease. The mechanism underlying the frameshift variants is a truncation of the EPOR intracellular C-terminal region, which is responsible for negative feedback regulation of the receptor. These variants enable EPO-EPOR signal transduction even at low serum EPO levels, and they prevent feedback inhibition through the SH2B3 and PTPN6/SOCS-3 inhibitory domain. […] The disease mechanism underlying these variants is inactivation of the EGLN1 and VHL enzymes, EPAS1 stabilisation, or increased EPO transcription activation, all of which result in increased EPO production under normoxic conditions and, consequently, RBC overproduction.

• #43 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.

• #44 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.

• #45 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).

• #46 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.

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

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

  A unique valine-to-phenylalanine substitution at position 617 (V617F) in the pseudokinase JAK2 domain has been identified. The substitution, called JAK2V617F, leads to a permanently turned-on signaling at the affected cytokine receptors. […] The JAK2V617F mutation is present in more than 95% of PV cases, but is also found in 50-60% of essential thrombocytosis and primary myelofibrosis cases. […] Thrombosis and bleeding are frequent in persons with PV, as a result of the disruption of hemostatic mechanisms because of (1) increased numbers of red blood cells and (2) elevation of the platelet count. There are findings that indicate the additional roles of tissue factor and polymorphonuclear leukocytes (PMLs) in clotting, the platelet surface as a contributor to phospholipid-dependent coagulation reactions, and the entity of platelet microparticles. Tissue factor is also synthesized by blood leukocytes, the level of which is increased in persons with MPD, which can contribute to thrombosis.

• #48 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.

• #49 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).

• #50 Erythrocytosis: ED Focused Evaluation and Management – emDocs

  https://www.emdocs.net/erythrocytosis-ed-focused-evaluation-management/

  Erythrocytosis, also known as polycythemia, refers to an increase in red blood cell mass. It can be relative or absolute. In relative polycythemia there is a decrease in plasma volume making it appear that there is an increase in red blood cells. There are three categories of absolute polycythemia. […] Primary Polycythemia: Occurs when there is an inherited or acquired mutation in erythroid progenitors that lead to proliferation. This can be seen in polycythemia vera (PV), a myeloproliferative disorder, or in rare polycythemias that lead to an activation of the erythropoietin (EPO) receptor like in primary familial and congenital polycythemia as in the case of Mäntyranta. […] Pathogenesis: PV develops from a point mutation in the JAK-2 leading to tyrosine kinase activation. The mutated tyrosine kinase leads to growth factor independent proliferation of red blood cells. […] Hyperviscosity syndrome presents with a triad of bleeding, visual disturbances, and focal neurologic signs and can be a complication of erythrocytosis.

• #51 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). […] Splenomegaly may produce secondary symptoms (eg, abdominal pain, early satiety, weight loss, and nausea) and can cause abdominal organ compression and portal hypertension.

• #52 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). […] Splenomegaly may produce secondary symptoms (eg, abdominal pain, early satiety, weight loss, and nausea) and can cause abdominal organ compression and portal hypertension.

• #53 Polycythemia: Definition, causes, symptoms, and more

  https://www.medicalnewstoday.com/articles/polycythemia

  Treatment for PV aims to manage the condition by reducing both the red blood cell count and the risk of complications, such as blood clots. […] To help manage the condition, doctors will look to reduce the red blood cell count through a process called phlebotomy, which manually removes blood through one of the veins. […] Sometimes, phlebotomy is not enough to control blood cell growth. […] In cases where a person does not respond well to other medications, doctors may recommend drugs that inhibit the JAK2 enzyme, which the JAK2 gene is responsible for producing. […] Polycythemia can be managed with treatment. However, certain complications can turn into a life-threatening condition. […] In about 5% of cases, polycythemia may progress to difficult-to-treat leukemia.

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

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

  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. […] Their team saw resolution of pain and reversal of microvascular complications with aspirin and indomethacin but not other therapeutic agents, thereby highlighting the important role of platelet-mediated inflammation and microcirculatory occlusion in the pathogenesis of erythromelalgia. […] 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. […] There has been a correlation between higher mutant allele burden, often characterized as homozygous versus heterozygous, and worse disease outcomes. […] Overall, study authors conclude that mutant allele burden significantly correlated with the risk of MF transformation.

• #55 JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views | Leukemia

  https://www.nature.com/articles/s41375-021-01290-6

  Erythrocytosis refers to either a true or apparent increase in hemoglobin (Hgb)/hematocrit (Hct); distinction requires familiarity with sex-, race- and altitude-adjusted normal values, together with an appreciation of extreme normal values that exceed the 95th percentile (2 SD) of reference range and attention to clinical factors associated with plasma volume depletion (relative erythrocytosis) […] The diagnostic workup of JAK2 unmutated erythrocytosis lacks uniformity, and often includes investigations for rare hereditary conditions and several acquired entities known to be associated with secondary erythrocytosis. In a substantial proportion (up to 70%) of patients, despite extensive testing, erythrocytosis remains uncharacterized and sometimes labeled as idiopathic, which is often a diagnosis of exclusion […] Herein, we outline our systematic diagnostic and therapeutic approach in JAK2 unmutated erythrocytosis; our review also includes illustrative cases and a discussion on underlying pathogenetic mechanisms.

• #56 Erythrocytosis: genes and pathways involved in disease development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8580782/

  Erythrocytosis is a blood disorder characterised by an increased red blood cell mass. The most common causes of erythrocytosis are acquired and caused by diseases and conditions that are accompanied by hypoxaemia or overproduction of erythropoietin. More rarely, erythrocytosis has a known genetic background, such as for polycythaemia vera and familial erythrocytosis. The majority of cases of polycythaemia vera are associated with acquired variants in JAK2, while familial erythrocytosis is a group of congenital disorders. Familial erythrocytosis type 1 is associated with hypersensitivity to erythropoietin (variants in EPOR), types 25 with defects in oxygen-sensing pathways (variants in VHL, EGLN1, EPAS1, EPO), and types 68 with an increased affinity of haemoglobin for oxygen (variants in HBB, HBA1, HBA2, BPGM). Due to a heterogenic genetic background, the causes of disease are not fully discovered and in more than 70% of patients the condition remains labelled idiopathic.

• #57 Polycythemia: Definition, causes, symptoms, and more

  https://www.medicalnewstoday.com/articles/polycythemia

  Treatment for PV aims to manage the condition by reducing both the red blood cell count and the risk of complications, such as blood clots. […] To help manage the condition, doctors will look to reduce the red blood cell count through a process called phlebotomy, which manually removes blood through one of the veins. […] Sometimes, phlebotomy is not enough to control blood cell growth. […] In cases where a person does not respond well to other medications, doctors may recommend drugs that inhibit the JAK2 enzyme, which the JAK2 gene is responsible for producing. […] Polycythemia can be managed with treatment. However, certain complications can turn into a life-threatening condition. […] In about 5% of cases, polycythemia may progress to difficult-to-treat leukemia.

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