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{{CMG}}{{AE}} {{MJK}}; {{shyam}} | {{CMG}}{{AE}} {{MJK}}; {{shyam}} | ||
==Overview== | ==Overview== | ||
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]]. | 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]]. | ||
==Pathophysiology== | ==Pathophysiology== | ||
===Normal erythrocyte physiology=== | ===Normal erythrocyte physiology=== | ||
In order to understand the pathophysiology of polycythemia vera, one must first understand the normal physiology of [[red blood cell]] production. Under normal circumstances, [[erythrocytes]] are produced at a basal rate in response to [[erythropoietin]]. [[Erythropoietin]] is a hormone produced by the peritubular capillaries of the kidneys and serves as a signal for expansion of the erythrocyte pool. This process is normally tightly controlled. The Janus kinase JAK2 is the receptor for [[erythropoietin]], and this receptor (in the wild-type form) becomes activated when [[erythropoietin]] is present. JAK2 is a protein of the Janus kinase family, located on chromosome 9.<ref name="pmid21120186">{{cite journal| author=Means RT| title=JAK2 V617F and the evolving paradigm of polycythemia vera. | journal=Korean J Hematol | year= 2010 | volume= 45 | issue= 2 | pages= 90-4 | pmid=21120186 | doi=10.5045/kjh.2010.45.2.90 | pmc=2983020 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21120186 }} </ref> JAK2 signals through STAT molecules, which are signal transducers and activators of transcription. Under conditions of low oxygen content, such as high altitude or smoking, erythropoietin production increases, and red blood cell production increases. This is the normal physiologic response to hypoxia, and this response serves to ensure adequate oxygen delivery to tissues. | In order to understand the pathophysiology of polycythemia vera, one must first understand the normal [[physiology]] of [[red blood cell]] production. Under normal circumstances, [[erythrocytes]] are produced at a basal rate in response to [[erythropoietin]]. [[Erythropoietin]] is a hormone produced by the peritubular [[capillaries]] of the kidneys and serves as a signal for expansion of the [[erythrocyte]] pool. This process is normally tightly controlled. The Janus kinase JAK2 is the receptor for [[erythropoietin]], and this receptor (in the wild-type form) becomes activated when [[erythropoietin]] is present. JAK2 is a protein of the Janus kinase family, located on chromosome 9.<ref name="pmid21120186">{{cite journal| author=Means RT| title=JAK2 V617F and the evolving paradigm of polycythemia vera. | journal=Korean J Hematol | year= 2010 | volume= 45 | issue= 2 | pages= 90-4 | pmid=21120186 | doi=10.5045/kjh.2010.45.2.90 | pmc=2983020 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21120186 }} </ref> JAK2 signals through STAT molecules, which are signal transducers and activators of transcription. Under conditions of low oxygen content, such as high altitude or smoking, [[erythropoietin]] production increases, and red blood cell production increases. This is the normal physiologic response to [[hypoxia]], and this response serves to ensure adequate oxygen delivery to tissues. | ||
===Pathogenesis of polycythemia vera=== | ===Pathogenesis of polycythemia vera=== | ||
The pathophysiology of polycythemia vera is founded upon the presence of a [[JAK2]] mutation within a [[hematopoietic stem cell]] (and therefore within an [[erythroid]] precursor). A point mutation that converts [[valine]] to [[phenylalanine]] at the 617th position within the JAK2 gene is found in more than 95% of polycythemia vera. The JAK2 V617F point mutation is an activating mutation that resulting in autonomous activity of the [[JAK2]] pathway, resulting in excess [[red blood cell]] production in an [[erythropoietin]]-independent manner.<ref name="pmid21120186">{{cite journal| author=Means RT| title=JAK2 V617F and the evolving paradigm of polycythemia vera. | journal=Korean J Hematol | year= 2010 | volume= 45 | issue= 2 | pages= 90-4 | pmid=21120186 | doi=10.5045/kjh.2010.45.2.90 | pmc=2983020 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21120186 }} </ref> The JAK2 exon 12 mutation results in a similar phenotype. The JAK2 exon 12 mutation is found in only 2-3% of patients with polycythemia vera.<ref name="pmid26324368">{{cite journal| author=Stein BL, Oh ST, Berenzon D, Hobbs GS, Kremyanskaya M, Rampal RK et al.| title=Polycythemia Vera: An Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F. | journal=J Clin Oncol | year= 2015 | volume= 33 | issue= 33 | pages= 3953-60 | pmid=26324368 | doi=10.1200/JCO.2015.61.6474 | pmc=4979103 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26324368 }} </ref> The most rare mutation involves LNK, which is an inhibitor of the JAK-STAT signaling pathway. | The pathophysiology of polycythemia vera is founded upon the presence of a [[JAK2]] mutation within a [[hematopoietic stem cell]] (and therefore within an [[erythroid]] precursor). A point mutation that converts [[valine]] to [[phenylalanine]] at the 617th position within the JAK2 gene is found in more than 95% of polycythemia vera. The JAK2 V617F point mutation is an activating mutation that resulting in autonomous activity of the [[JAK2]] pathway, resulting in excess [[red blood cell]] production in an [[erythropoietin]]-independent manner.<ref name="pmid21120186">{{cite journal| author=Means RT| title=JAK2 V617F and the evolving paradigm of polycythemia vera. | journal=Korean J Hematol | year= 2010 | volume= 45 | issue= 2 | pages= 90-4 | pmid=21120186 | doi=10.5045/kjh.2010.45.2.90 | pmc=2983020 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21120186 }} </ref> The JAK2 exon 12 mutation results in a similar phenotype. The JAK2 exon 12 [[mutation]] is found in only 2-3% of patients with polycythemia vera.<ref name="pmid26324368">{{cite journal| author=Stein BL, Oh ST, Berenzon D, Hobbs GS, Kremyanskaya M, Rampal RK et al.| title=Polycythemia Vera: An Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F. | journal=J Clin Oncol | year= 2015 | volume= 33 | issue= 33 | pages= 3953-60 | pmid=26324368 | doi=10.1200/JCO.2015.61.6474 | pmc=4979103 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26324368 }} </ref> The most rare mutation involves LNK, which is an inhibitor of the JAK-STAT signaling pathway. | ||
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]].<ref name="pmid25162887">{{cite journal| author=Spivak JL, Considine M, Williams DM, Talbot CC, Rogers O, Moliterno AR et al.| title=Two clinical phenotypes in polycythemia vera. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 9 | pages= 808-17 | pmid=25162887 | doi=10.1056/NEJMoa1403141 | pmc=4211877 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25162887 }} </ref> In essential thrombocythemia, for example, the [[JAK2]] mutation is found in ~50% of patients.<ref name="pmid26324368">{{cite journal| author=Stein BL, Oh ST, Berenzon D, Hobbs GS, Kremyanskaya M, Rampal RK et al.| title=Polycythemia Vera: An Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F. | journal=J Clin Oncol | year= 2015 | volume= 33 | issue= 33 | pages= 3953-60 | pmid=26324368 | doi=10.1200/JCO.2015.61.6474 | pmc=4979103 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26324368 }} </ref> These diseases have overlapping clinical features.<ref name="pmid25162887">{{cite journal| author=Spivak JL, Considine M, Williams DM, Talbot CC, Rogers O, Moliterno AR et al.| title=Two clinical phenotypes in polycythemia vera. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 9 | pages= 808-17 | pmid=25162887 | doi=10.1056/NEJMoa1403141 | pmc=4211877 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25162887 }} </ref> | 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]].<ref name="pmid25162887">{{cite journal| author=Spivak JL, Considine M, Williams DM, Talbot CC, Rogers O, Moliterno AR et al.| title=Two clinical phenotypes in polycythemia vera. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 9 | pages= 808-17 | pmid=25162887 | doi=10.1056/NEJMoa1403141 | pmc=4211877 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25162887 }} </ref> In essential thrombocythemia, for example, the [[JAK2]] [[mutation]] is found in ~50% of patients.<ref name="pmid26324368">{{cite journal| author=Stein BL, Oh ST, Berenzon D, Hobbs GS, Kremyanskaya M, Rampal RK et al.| title=Polycythemia Vera: An Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F. | journal=J Clin Oncol | year= 2015 | volume= 33 | issue= 33 | pages= 3953-60 | pmid=26324368 | doi=10.1200/JCO.2015.61.6474 | pmc=4979103 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26324368 }} </ref> These diseases have overlapping clinical features.<ref name="pmid25162887">{{cite journal| author=Spivak JL, Considine M, Williams DM, Talbot CC, Rogers O, Moliterno AR et al.| title=Two clinical phenotypes in polycythemia vera. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 9 | pages= 808-17 | pmid=25162887 | doi=10.1056/NEJMoa1403141 | pmc=4211877 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25162887 }} </ref> | ||
===Other pathogenic mutations in polycythemia vera=== | ===Other pathogenic mutations in polycythemia vera=== | ||
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===Pathophysiology leading to thrombosis=== | ===Pathophysiology leading to thrombosis=== | ||
In polycythemia vera, the erythrocyte count can be as high as 8 to 9 million erythrocytes per cubic millimeter of blood (normal is 3 million per cubic millimeter). The [[hematocrit]] may be as high as 70 to 80% (normal is 45% for men and 43% for women). In addition, the total blood volume sometimes increases to as much as twice the normal values. These lab abnormalities arise from autonomous [[red blood cell]] production triggered by the JAK2 mutation in erythroid precursors. The entire vascular system can become markedly engorged with blood, and the blood circulation time throughout the body can increase up to twice the normal value. The increased numbers of [[erythrocyte]]s causes a five time increase in blood [[viscosity]]. Capillaries can become plugged by the very viscous blood which results in an extremely sluggish flow of blood.<ref name="pmid16827884">{{cite journal |author=Thurmes PJ, Steensma DP |title=Elevated serum erythropoietin levels in patients with Budd-Chiari syndrome secondary to polycythemia vera: clinical implications for the role of JAK2 mutation analysis |journal=Eur. J. Haematol. |volume=77 |issue=1 |pages=57–60 |date=July 2006 |pmid=16827884 |doi=10.1111/j.1600-0609.2006.00667.x |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0902-4441&date=2006&volume=77&issue=1&spage=57}}</ref><ref name="wikipedia">National Cancer Institute. Polycythemia vera.https://en.wikipedia.org/wiki/Polycythemia_vera</ref> This represents the pathophysiology of thrombosis in polycythemia vera. Plugging of capillaries within the cerebral vasculature can result in stroke. Plugging of capillaries within the coronary vasculature can result in myocardial infarction. Plugging of capillaries within the pulmonary circulation can result in pulmonary embolism. | In polycythemia vera, the erythrocyte count can be as high as 8 to 9 million erythrocytes per cubic millimeter of blood (normal is 3 million per cubic millimeter). The [[hematocrit]] may be as high as 70 to 80% (normal is 45% for men and 43% for women). In addition, the total blood volume sometimes increases to as much as twice the normal values. These lab abnormalities arise from autonomous [[red blood cell]] production triggered by the JAK2 mutation in erythroid precursors. The entire vascular system can become markedly engorged with blood, and the blood circulation time throughout the body can increase up to twice the normal value. The increased numbers of [[erythrocyte]]s causes a five time increase in blood [[viscosity]]. Capillaries can become plugged by the very viscous blood which results in an extremely [[sluggish]] flow of blood.<ref name="pmid16827884">{{cite journal |author=Thurmes PJ, Steensma DP |title=Elevated serum erythropoietin levels in patients with Budd-Chiari syndrome secondary to polycythemia vera: clinical implications for the role of JAK2 mutation analysis |journal=Eur. J. Haematol. |volume=77 |issue=1 |pages=57–60 |date=July 2006 |pmid=16827884 |doi=10.1111/j.1600-0609.2006.00667.x |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0902-4441&date=2006&volume=77&issue=1&spage=57}}</ref><ref name="wikipedia">National Cancer Institute. Polycythemia vera.https://en.wikipedia.org/wiki/Polycythemia_vera</ref> This represents the [[pathophysiology]] of [[thrombosis]] in polycythemia vera. Plugging of capillaries within the cerebral [[vasculature]] can result in stroke. Plugging of capillaries within the coronary vasculature can result in [[myocardial infarction]]. Plugging of [[capillaries]] within the [[pulmonary]] circulation can result in pulmonary embolism. | ||
==Genetics== | ==Genetics== | ||
Gene involved in the pathogenesis of polycythemia vera include ''[[JAK2]]'' kinase (V617F).<ref>{{cite journal | author=Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR | title=Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders | journal=Lancet | year=2005 | pages=1054-61 | volume=365 | issue=9464 | id=PMID 15781101}}</ref><ref>{{cite journal | author=Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG | title=Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis | journal=Cancer Cell | year=2005 | pages=387-97 | volume=7 | issue=4 | id=PMID 15837627}}</ref> | Gene involved in the [[pathogenesis]] of polycythemia vera include ''[[JAK2]]'' kinase (V617F).<ref>{{cite journal | author=Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR | title=Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders | journal=Lancet | year=2005 | pages=1054-61 | volume=365 | issue=9464 | id=PMID 15781101}}</ref><ref>{{cite journal | author=Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG | title=Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis | journal=Cancer Cell | year=2005 | pages=387-97 | volume=7 | issue=4 | id=PMID 15837627}}</ref> | ||
==References== | ==References== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]; Shyam Patel [3]
Overview
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.
Pathophysiology
Normal erythrocyte physiology
In order to understand the pathophysiology of polycythemia vera, one must first understand the normal physiology of red blood cell production. Under normal circumstances, erythrocytes are produced at a basal rate in response to erythropoietin. Erythropoietin is a hormone produced by the peritubular capillaries of the kidneys and serves as a signal for expansion of the erythrocyte pool. This process is normally tightly controlled. The Janus kinase JAK2 is the receptor for erythropoietin, and this receptor (in the wild-type form) becomes activated when erythropoietin is present. JAK2 is a protein of the Janus kinase family, located on chromosome 9.[1] JAK2 signals through STAT molecules, which are signal transducers and activators of transcription. Under conditions of low oxygen content, such as high altitude or smoking, erythropoietin production increases, and red blood cell production increases. This is the normal physiologic response to hypoxia, and this response serves to ensure adequate oxygen delivery to tissues.
Pathogenesis of polycythemia vera
The pathophysiology of polycythemia vera is founded upon the presence of a JAK2 mutation within a hematopoietic stem cell (and therefore within an erythroid precursor). A point mutation that converts valine to phenylalanine at the 617th position within the JAK2 gene is found in more than 95% of polycythemia vera. The JAK2 V617F point mutation is an activating mutation that resulting in autonomous activity of the JAK2 pathway, resulting in excess red blood cell production in an erythropoietin-independent manner.[1] The JAK2 exon 12 mutation results in a similar phenotype. The JAK2 exon 12 mutation is found in only 2-3% of patients with polycythemia vera.[2] The most rare mutation involves LNK, which is an inhibitor of the JAK-STAT signaling pathway. 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.[3] In essential thrombocythemia, for example, the JAK2 mutation is found in ~50% of patients.[2] These diseases have overlapping clinical features.[3]
Other pathogenic mutations in polycythemia vera
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).[2] These mutations are also common to myelodysplastic syndrome.
Pathophysiology leading to thrombosis
In polycythemia vera, the erythrocyte count can be as high as 8 to 9 million erythrocytes per cubic millimeter of blood (normal is 3 million per cubic millimeter). The hematocrit may be as high as 70 to 80% (normal is 45% for men and 43% for women). In addition, the total blood volume sometimes increases to as much as twice the normal values. These lab abnormalities arise from autonomous red blood cell production triggered by the JAK2 mutation in erythroid precursors. The entire vascular system can become markedly engorged with blood, and the blood circulation time throughout the body can increase up to twice the normal value. The increased numbers of erythrocytes causes a five time increase in blood viscosity. Capillaries can become plugged by the very viscous blood which results in an extremely sluggish flow of blood.[4][5] This represents the pathophysiology of thrombosis in polycythemia vera. Plugging of capillaries within the cerebral vasculature can result in stroke. Plugging of capillaries within the coronary vasculature can result in myocardial infarction. Plugging of capillaries within the pulmonary circulation can result in pulmonary embolism.
Genetics
Gene involved in the pathogenesis of polycythemia vera include JAK2 kinase (V617F).[6][7]
References
- ↑ 1.0 1.1 Means RT (2010). "JAK2 V617F and the evolving paradigm of polycythemia vera". Korean J Hematol. 45 (2): 90–4. doi:10.5045/kjh.2010.45.2.90. PMC 2983020. PMID 21120186.
- ↑ 2.0 2.1 2.2 Stein BL, Oh ST, Berenzon D, Hobbs GS, Kremyanskaya M, Rampal RK; et al. (2015). "Polycythemia Vera: An Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F". J Clin Oncol. 33 (33): 3953–60. doi:10.1200/JCO.2015.61.6474. PMC 4979103. PMID 26324368.
- ↑ 3.0 3.1 Spivak JL, Considine M, Williams DM, Talbot CC, Rogers O, Moliterno AR; et al. (2014). "Two clinical phenotypes in polycythemia vera". N Engl J Med. 371 (9): 808–17. doi:10.1056/NEJMoa1403141. PMC 4211877. PMID 25162887.
- ↑ Thurmes PJ, Steensma DP (July 2006). "Elevated serum erythropoietin levels in patients with Budd-Chiari syndrome secondary to polycythemia vera: clinical implications for the role of JAK2 mutation analysis". Eur. J. Haematol. 77 (1): 57–60. doi:10.1111/j.1600-0609.2006.00667.x. PMID 16827884.
- ↑ National Cancer Institute. Polycythemia vera.https://en.wikipedia.org/wiki/Polycythemia_vera
- ↑ Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR (2005). "Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders". Lancet. 365 (9464): 1054–61. PMID 15781101.
- ↑ Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG (2005). "Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis". Cancer Cell. 7 (4): 387–97. PMID 15837627.