Myelofibrosis pathophysiology: Difference between revisions

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{{Myelofibrosis}}
{{Myelofibrosis}}
{{CMG}}{{AE}}{{MJK}}, {{SR}}
{{CMG}}{{AE}}{{Sab}}


==Overview==
==Overview==
Myelofibrosis, a myeloproliferative disorder, is characterized by the proliferation of megakaryocytes in the bone marrow, disrupted cytokine production, and reactive fibrosis resulting in bone marrow failure. The fibrosed and scarred bone marrow produces fewer and fewer normal functioning blood cells leading to pancytopenia and extramedullary hematopoiesis. It can mainly be associated with somatic mutation of the thrombopoietin receptor gene (MPL), the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene but other genes can also be involved and it can also result in the setting of another primary insult.
Myelofibrosis, a [[Myeloproliferative neoplasm|myeloproliferative disorder]], is characterized by the [[proliferation]] of [[Megakaryocyte|megakaryocytes]] in the [[bone marrow]], disrupted [[cytokine]] production, and reactive [[fibrosis]] resulting in [[bone marrow failure]]. The [[Fibrosis|fibrosed]] and scarred [[bone marrow]] produces fewer and fewer normal functioning [[blood cells]] leading to [[pancytopenia]] and [[Extramedullary hematopoiesis|extramedullary hematopoiesis (EMH)]]. It can mainly be associated with [[somatic mutation]] of the [[Myeloproliferative leukemia virus oncogene|myeloproliferative leukemia virus (MPL) oncogene]], the [[Calreticulin|calreticulin (CALR) gene]], or [[Janus kinase 2|Janus kinase 2 (JAK2)]] [[gene]] but other [[Gene|genes]] can also be involved and it can also result in the setting of another primary insult. Associated conditions include [[Cancer|malignancies]], [[Hematology|hematologic]] disorders, [[Infection|infections]], [[Autoimmunity|autoimmune diseases]], and [[Endocrine system|endocrine]] disorders. [[Hepatomegaly]], [[splenomegaly]], and [[lymphadenopathy]] are the positive findings on [[gross pathology]]. On [[microscopic]] [[pathology]], myelofibrosis is characterized by low [[Red blood cell|RBC]] count, [[leukopenia]] - [[leukocytosis]], [[basophilia]], erythroblastosis, [[thrombocytopenia]] - [[thrombocytosis]], [[Megakaryocytes|micromegakaryocytes]], [[Spleen|splenic]] pulp changes, and abnormalities of [[Platelet|platelets]].


==Pathogenesis==
== Pathophysiology ==
*Polyclonal mesenchymal cells of the bone marrow such as, fibroblasts, osteoblasts, pericytes, endothelial cells, adipocytes, and reticular cells create a functional microenvironment, which maintains hematopoiesis. This maintenance takes place through cellular interactions via growth factors, adhesion molecules, cytokines, and extracellular matrix components along with the help of oxygen and calcium.<ref name="pmid24583557">{{cite journal |vauthors=Bedekovics J, Méhes G |title=[Pathomechanism and clinical impact of myelofibrosis in neoplastic diseases of the bone marrow] |language=Hungarian |journal=Orv Hetil |volume=155 |issue=10 |pages=367–75 |date=March 2014 |pmid=24583557 |doi=10.1556/OH.2014.29823 |url=}}</ref>
*Myelofibrosis is the result of pathologic interaction between hematopoietic progenitor and stromal cells leading to the activation and expansion of the stroma and the accumulation of reticulin and collagen fibers produced by mesenchymal cells.<ref name="pmid24583557">{{cite journal |vauthors=Bedekovics J, Méhes G |title=[Pathomechanism and clinical impact of myelofibrosis in neoplastic diseases of the bone marrow] |language=Hungarian |journal=Orv Hetil |volume=155 |issue=10 |pages=367–75 |date=March 2014 |pmid=24583557 |doi=10.1556/OH.2014.29823 |url=}}</ref>
*The development and progression of myelofibrosis involves the activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, which paves the way for the overproduction of abnormal megakaryocytes.<ref name="pmid27756071">{{cite journal |vauthors=Alshemmari SH, Rajan R, Emadi A |title=Molecular Pathogenesis and Clinical Significance of Driver Mutations in Primary Myelofibrosis: A Review |journal=Med Princ Pract |volume=25 |issue=6 |pages=501–509 |date=2016 |pmid=27756071 |pmc=5588514 |doi=10.1159/000450956 |url=}}</ref>
*The abnormally proliferated megakaryocytes produce cytokines such as platelet-derived growth factor (PDGF), transforming growth factor (TGF) beta, and basic fibroblast growth factor (bFGF) which are involved in the abnormal proliferation of fibroblasts, resulting in fibrosis.<ref name="pmid10550553">{{cite journal |vauthors=Le Bousse-Kerdilès MC, Martyré MC |title=Dual implication of fibrogenic cytokines in the pathogenesis of fibrosis and myeloproliferation in myeloid metaplasia with myelofibrosis |journal=Ann. Hematol. |volume=78 |issue=10 |pages=437–44 |date=October 1999 |pmid=10550553 |doi= |url=}}</ref><ref name="pmid17910625">{{cite journal |vauthors=Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP |title=Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres |journal=Br. J. Haematol. |volume=139 |issue=3 |pages=351–62 |date=November 2007 |pmid=17910625 |doi=10.1111/j.1365-2141.2007.06807.x |url=}}</ref>
*Myelofibrosis can result in the setting of somatic mutations in specific genes or it can also be secondary to other primary disorders.
*The somatic mutations driving the disorder can mainly involve the thrombopoietin receptor gene (MPL), the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene.<ref name="pmid27756071">{{cite journal |vauthors=Alshemmari SH, Rajan R, Emadi A |title=Molecular Pathogenesis and Clinical Significance of Driver Mutations in Primary Myelofibrosis: A Review |journal=Med Princ Pract |volume=25 |issue=6 |pages=501–509 |date=2016 |pmid=27756071 |pmc=5588514 |doi=10.1159/000450956 |url=}}</ref>
*The fibrosis of bone marrow leads to extramedullary hematopoiesis involving the reticuloendothelial organs such as the liver and spleen. Rarely, the extramedullary hematopoiesis can also involve ectopic hematopoietic tissue which includes the skin, lymph nodes, pleura, gastrointestinal tract, peritoneum, central nervous system, and genital and urinary tracts.<ref name="pmid11843900">{{cite journal |vauthors=Mak YK, Chan CH, So CC, Chan MK, Chu YC |title=Idiopathic myelofibrosis with extramedullary haemopoiesis involving the urinary bladder in a Chinese lady |journal=Clin Lab Haematol |volume=24 |issue=1 |pages=55–9 |date=February 2002 |pmid=11843900 |doi= |url=}}</ref><ref name="pmid28821362">{{cite journal |vauthors=Philipponnet C, Ronco P, Aniort J, Kemeny JL, Heng AE |title=Membranous Nephropathy and Intrarenal Extramedullary Hematopoiesis in a Patient With Myelofibrosis |journal=Am. J. Kidney Dis. |volume=70 |issue=6 |pages=874–877 |date=December 2017 |pmid=28821362 |doi=10.1053/j.ajkd.2017.06.022 |url=}}</ref><ref name="pmid27883206">{{cite journal |vauthors=Yang M, Roarke M |title=Diffuse pulmonary extramedullary hematopoiesis in myelofibrosis diagnosed with technetium-99m sulfur colloid bone marrow scintigraphy and single photon emission computerized tomography/CT |journal=Am. J. Hematol. |volume=92 |issue=3 |pages=323–324 |date=March 2017 |pmid=27883206 |doi=10.1002/ajh.24616 |url=}}</ref>
*


===Pathogenesis===


*[[Polyclonal]] [[Mesenchymal cell|mesenchymal cells]] of the [[bone marrow]] such as [[fibroblasts]], [[Osteoblast|osteoblasts]], [[Pericyte|pericytes]], [[endothelial cells]], [[Adipocyte|adipocytes]], and [[Reticular cell|reticular cells]] create a functional microenvironment, which maintains [[hematopoiesis]]. This maintenance takes place through [[cellular]] interactions via growth factors, adhesion molecules, [[Cytokine|cytokines]], and [[extracellular matrix]] components along with the help of [[oxygen]] and [[calcium]].<ref name="pmid24583557">{{cite journal |vauthors=Bedekovics J, Méhes G |title=[Pathomechanism and clinical impact of myelofibrosis in neoplastic diseases of the bone marrow] |language=Hungarian |journal=Orv Hetil |volume=155 |issue=10 |pages=367–75 |date=March 2014 |pmid=24583557 |doi=10.1556/OH.2014.29823 |url=}}</ref>
*[[Myelofibrosis]] is the result of [[Pathology|pathologic]] interaction between [[hematopoietic]] [[Progenitor cell|progenitor]] and [[stromal cells]] leading to the activation and expansion of the [[stroma]] and the accumulation of [[reticulin]] and [[collagen]] fibers produced by [[Mesenchymal cell|mesenchymal cells]].<ref name="pmid24583557">{{cite journal |vauthors=Bedekovics J, Méhes G |title=[Pathomechanism and clinical impact of myelofibrosis in neoplastic diseases of the bone marrow] |language=Hungarian |journal=Orv Hetil |volume=155 |issue=10 |pages=367–75 |date=March 2014 |pmid=24583557 |doi=10.1556/OH.2014.29823 |url=}}</ref>
*The development and progression of [[myelofibrosis]] involves the activation of Janus kinase-signal transducer and activator of transcription ([[JAK-STAT signaling pathway|JAK/STAT]]) pathway, which paves the way for the overproduction of abnormal [[megakaryocytes]].<ref name="pmid28028029">{{cite journal |vauthors=Vainchenker W, Kralovics R |title=Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms |journal=Blood |volume=129 |issue=6 |pages=667–679 |date=February 2017 |pmid=28028029 |doi=10.1182/blood-2016-10-695940 |url=}}</ref><ref name="pmid27756071">{{cite journal |vauthors=Alshemmari SH, Rajan R, Emadi A |title=Molecular Pathogenesis and Clinical Significance of Driver Mutations in Primary Myelofibrosis: A Review |journal=Med Princ Pract |volume=25 |issue=6 |pages=501–509 |date=2016 |pmid=27756071 |pmc=5588514 |doi=10.1159/000450956 |url=}}</ref><ref name="pmid26408371">{{cite journal |vauthors=de Freitas RM, da Costa Maranduba CM |title=Myeloproliferative neoplasms and the JAK/STAT signaling pathway: an overview |journal=Rev Bras Hematol Hemoter |volume=37 |issue=5 |pages=348–53 |date=2015 |pmid=26408371 |pmc=4685044 |doi=10.1016/j.bjhh.2014.10.001 |url=}}</ref>
*The abnormally proliferated [[megakaryocytes]] produce [[Cytokine|cytokines]] such as [[Platelet-derived growth factor|platelet-derived growth factor (PDGF)]], [[Transforming growth factor-β|transforming growth factor (TGF) beta]], and [[Basic fibroblast growth factor|basic fibroblast growth factor (bFGF)]] which are involved in the abnormal [[proliferation]] of [[fibroblasts]], resulting in [[fibrosis]].<ref name="pmid10550553">{{cite journal |vauthors=Le Bousse-Kerdilès MC, Martyré MC |title=Dual implication of fibrogenic cytokines in the pathogenesis of fibrosis and myeloproliferation in myeloid metaplasia with myelofibrosis |journal=Ann. Hematol. |volume=78 |issue=10 |pages=437–44 |date=October 1999 |pmid=10550553 |doi= |url=}}</ref><ref name="pmid17910625">{{cite journal |vauthors=Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP |title=Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres |journal=Br. J. Haematol. |volume=139 |issue=3 |pages=351–62 |date=November 2007 |pmid=17910625 |doi=10.1111/j.1365-2141.2007.06807.x |url=}}</ref><ref name="pmid8435338">{{cite journal |vauthors=Reilly JT, Barnett D, Dolan G, Forrest P, Eastham J, Smith A |title=Characterization of an acute micromegakaryocytic leukaemia: evidence for the pathogenesis of myelofibrosis |journal=Br. J. Haematol. |volume=83 |issue=1 |pages=58–62 |date=January 1993 |pmid=8435338 |doi= |url=}}</ref><ref name="pmid12153156">{{cite journal |vauthors=Schmitt A, Drouin A, Massé JM, Guichard J, Shagraoui H, Cramer EM |title=Polymorphonuclear neutrophil and megakaryocyte mutual involvement in myelofibrosis pathogenesis |journal=Leuk. Lymphoma |volume=43 |issue=4 |pages=719–24 |date=April 2002 |pmid=12153156 |doi=10.1080/10428190290016809 |url=}}</ref><ref name="pmid10942376">{{cite journal |vauthors=Schmitt A, Jouault H, Guichard J, Wendling F, Drouin A, Cramer EM |title=Pathologic interaction between megakaryocytes and polymorphonuclear leukocytes in myelofibrosis |journal=Blood |volume=96 |issue=4 |pages=1342–7 |date=August 2000 |pmid=10942376 |doi= |url=}}</ref><ref name="pmid27252511">{{cite journal |vauthors=Zahr AA, Salama ME, Carreau N, Tremblay D, Verstovsek S, Mesa R, Hoffman R, Mascarenhas J |title=Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies |journal=Haematologica |volume=101 |issue=6 |pages=660–71 |date=June 2016 |pmid=27252511 |pmc=5013940 |doi=10.3324/haematol.2015.141283 |url=}}</ref>
*[[Myelofibrosis]] can result in the setting of [[Somatic mutation|somatic mutations]] in specific [[Gene|genes]] or it can also be secondary to other primary disorders.
*The [[Somatic mutation|somatic mutations]] driving the disorder can mainly involve the [[Myeloproliferative leukemia vir|myeloproliferative leukemia virus (MPL) oncogene]], the [[Calreticulin|calreticulin (CALR) gene]], or [[Janus kinase 2|Janus kinase 2 (JAK2)]] [[gene]].<ref name="pmid27756071">{{cite journal |vauthors=Alshemmari SH, Rajan R, Emadi A |title=Molecular Pathogenesis and Clinical Significance of Driver Mutations in Primary Myelofibrosis: A Review |journal=Med Princ Pract |volume=25 |issue=6 |pages=501–509 |date=2016 |pmid=27756071 |pmc=5588514 |doi=10.1159/000450956 |url=}}</ref><ref name="pmid24325356">{{cite journal |vauthors=Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, Them NC, Berg T, Gisslinger B, Pietra D, Chen D, Vladimer GI, Bagienski K, Milanesi C, Casetti IC, Sant'Antonio E, Ferretti V, Elena C, Schischlik F, Cleary C, Six M, Schalling M, Schönegger A, Bock C, Malcovati L, Pascutto C, Superti-Furga G, Cazzola M, Kralovics R |title=Somatic mutations of calreticulin in myeloproliferative neoplasms |journal=N. Engl. J. Med. |volume=369 |issue=25 |pages=2379–90 |date=December 2013 |pmid=24325356 |doi=10.1056/NEJMoa1311347 |url=}}</ref>
*The [[fibrosis]] of [[bone marrow]] leads to [[Extramedullary hematopoiesis|extramedullary hematopoiesis (EMH)]] involving the [[Reticuloendothelial system|reticuloendothelial organs]] such as the [[liver]] and [[spleen]]. Rarely, the [[Extramedullary hematopoiesis|extramedullary hematopoiesis (EMH)]] can also involve [[ectopic]] [[hematopoietic]] [[tissue]] which includes the [[skin]], [[Lymph node|lymph nodes]], [[Lung|lungs]], [[gastrointestinal tract]], [[peritoneum]], [[central nervous system]], [[genital]], and [[urinary tracts]].<ref name="pmid11843900">{{cite journal |vauthors=Mak YK, Chan CH, So CC, Chan MK, Chu YC |title=Idiopathic myelofibrosis with extramedullary haemopoiesis involving the urinary bladder in a Chinese lady |journal=Clin Lab Haematol |volume=24 |issue=1 |pages=55–9 |date=February 2002 |pmid=11843900 |doi= |url=}}</ref><ref name="pmid28821362">{{cite journal |vauthors=Philipponnet C, Ronco P, Aniort J, Kemeny JL, Heng AE |title=Membranous Nephropathy and Intrarenal Extramedullary Hematopoiesis in a Patient With Myelofibrosis |journal=Am. J. Kidney Dis. |volume=70 |issue=6 |pages=874–877 |date=December 2017 |pmid=28821362 |doi=10.1053/j.ajkd.2017.06.022 |url=}}</ref><ref name="pmid27883206">{{cite journal |vauthors=Yang M, Roarke M |title=Diffuse pulmonary extramedullary hematopoiesis in myelofibrosis diagnosed with technetium-99m sulfur colloid bone marrow scintigraphy and single photon emission computerized tomography/CT |journal=Am. J. Hematol. |volume=92 |issue=3 |pages=323–324 |date=March 2017 |pmid=27883206 |doi=10.1002/ajh.24616 |url=}}</ref><ref name="pmid27883206">{{cite journal |vauthors=Yang M, Roarke M |title=Diffuse pulmonary extramedullary hematopoiesis in myelofibrosis diagnosed with technetium-99m sulfur colloid bone marrow scintigraphy and single photon emission computerized tomography/CT |journal=Am. J. Hematol. |volume=92 |issue=3 |pages=323–324 |date=March 2017 |pmid=27883206 |doi=10.1002/ajh.24616 |url=}}</ref><ref name="pmid27521149">{{cite journal |vauthors=Pizzi M, Gergis U, Chaviano F, Orazi A |title=The effects of hematopoietic stem cell transplant on splenic extramedullary hematopoiesis in patients with myeloproliferative neoplasm-associated myelofibrosis |journal=Hematol Oncol Stem Cell Ther |volume=9 |issue=3 |pages=96–104 |date=September 2016 |pmid=27521149 |doi=10.1016/j.hemonc.2016.07.002 |url=}}</ref>
*[[Extramedullary hematopoiesis|Extramedullary hematopoiesis (EMH)]] in the [[spleen]] of patients with [[Primary myelofibrosis|primary myelofibrosis (PMF)]] can lead to abnormal [[angiogenesis]] in the [[Organ (anatomy)|organ]] and it has been documented that [[Monocyte|monocytes]] expressing the angiopoietin-2 receptor (Tie2) play a role in starting/maintaining this [[pathological]] [[angiogenesis]].<ref name="pmid27281335">{{cite journal |vauthors=Campanelli R, Fois G, Catarsi P, Poletto V, Villani L, Erba BG, Maddaluno L, Jemos B, Salmoiraghi S, Guglielmelli P, Abbonante V, Di Buduo CA, Balduini A, Iurlo A, Barosi G, Rosti V, Massa M |title=Tie2 Expressing Monocytes in the Spleen of Patients with Primary Myelofibrosis |journal=PLoS ONE |volume=11 |issue=6 |pages=e0156990 |date=2016 |pmid=27281335 |pmc=4900622 |doi=10.1371/journal.pone.0156990 |url=}}</ref>


===Sites of Extramedullary Hematopoiesis===
*The main sites of [[Extramedullary hematopoiesis|extramedullary hematopoiesis (EMH)]] include the [[spleen]] and [[liver]].<ref name="pmid27521149">{{cite journal |vauthors=Pizzi M, Gergis U, Chaviano F, Orazi A |title=The effects of hematopoietic stem cell transplant on splenic extramedullary hematopoiesis in patients with myeloproliferative neoplasm-associated myelofibrosis |journal=Hematol Oncol Stem Cell Ther |volume=9 |issue=3 |pages=96–104 |date=September 2016 |pmid=27521149 |doi=10.1016/j.hemonc.2016.07.002 |url=}}</ref><ref name="pmid26885416">{{cite journal |vauthors=Mohyuddin GR, Yacoub A |title=Primary Myelofibrosis Presenting as Extramedullary Hematopoiesis in a Transplanted Liver Graft: Case Report and Review of the Literature |journal=Case Rep Hematol |volume=2016 |issue= |pages=9515404 |date=2016 |pmid=26885416 |pmc=4739215 |doi=10.1155/2016/9515404 |url=}}</ref><ref name="pmid23619118">{{cite journal |vauthors=Henry M, Chitlur M, Rajpurkar M, Mastropietro CW, Poulik J, Ravindranath Y |title=Myelofibrosis, hepatic extramedullary hematopoiesis and ascites associated with vitamin D deficiency in early infancy |journal=J. Pediatr. Hematol. Oncol. |volume=36 |issue=4 |pages=319–21 |date=May 2014 |pmid=23619118 |doi=10.1097/MPH.0b013e31828e548a |url=}}</ref><ref name="pmid28895103">{{cite journal |vauthors=Imai K, Aoi T, Kitai H, Endo N, Fujino M, Ichida S |title=A case of perirenal extramedullary hematopoiesis in a patient with primary myelofibrosis |journal=CEN Case Rep |volume=6 |issue=2 |pages=194–199 |date=November 2017 |pmid=28895103 |pmc=5694411 |doi=10.1007/s13730-017-0274-1 |url=}}</ref><ref name="pmid10983698">{{cite journal |vauthors=Kwak HS, Lee JM |title=CT findings of extramedullary hematopoiesis in the thorax, liver and kidneys, in a patient with idiopathic myelofibrosis |journal=J. Korean Med. Sci. |volume=15 |issue=4 |pages=460–2 |date=August 2000 |pmid=10983698 |pmc=3054659 |doi=10.3346/jkms.2000.15.4.460 |url=}}</ref>
*[[Hematopoiesis]] can rarely also occur in the following locations:


Myelofibrosis is a [[Clone (cell biology)|clonal]] neoplastic disorder of [[hematopoiesis]], the formation of blood cellular components.<ref name=causesofmyelofibrosis1wiki1>Causes of myelofibrosis. Wikipedia 2016. https://en.wikipedia.org/wiki/Myelofibrosis. Accessed on March 7, 2016</ref> It is one of the [[myleoproliferative disorders]], diseases of the bone marrow in which excess cells are produced. Production of [[cytokine]]s, such as [[fibroblast growth factor]] by the abnormal hematopoietic cell clone (particularly by [[megakaryocyte]]s, leads to replacement of the hematopoietic tissue of the bone marrow by [[connective tissue]] via collagen [[fibrosis]]. The decrease in hematopoietic tissue impairs the patient's ability to generate new blood cells, resulting in progressive [[pancytopenia]], a shortage of all blood cell types. However, the proliferation of [[fibroblast]]s and deposition of [[collagen]] is a secondary phenomenon, and the fibroblasts themselves are not part of the abnormal cell clone. In primary myelofibrosis, progressive scarring, or [[fibrosis]], of the bone marrow occurs, for the reasons outlined above. In its early phase, myelofibrosis is characterized by elevated numbers of CD34-positive cells in the marrow, while the later phases involve marrow fibrosis with decreasing CD34 cells in the marrow and a corresponding increase in splenic and liver engorgement with CD34 cells.<ref name=diseaseoverviewmf1>Disease overview of primary myelofibrosis. National cancer institute 2016. http://www.cancer.gov/types/myeloproliferative/hp/chronic-treatment-pdq#section/_9. Accessed on March 10, 2016</ref> The result is [[extramedullary hematopoiesis]], or blood cell formation occurring in sites other than the bone marrow, as the hemopoetic cells are forced to migrate to other areas, particularly the [[liver]] and [[spleen]].<ref name=causesofmyelofibrosis1wiki1>Causes of myelofibrosis. Wikipedia 2016. https://en.wikipedia.org/wiki/Myelofibrosis. Accessed on March 7, 2016</ref> This causes an enlargement of these organs. In the liver, the condition is called [[hepatomegaly]]. Enlargement of the spleen is called [[splenomegaly]], which also contributes to causing [[pancytopenia]], particurly [[thrombocytopenia]] and [[anemia]]. Another complication of extramedullary hematopoiesis is [[poikilocytosis]], or the presence of abnormally shaped [[red blood cell]]s. Myelofibrosis can be a late complication of other myeloproliferative disorders, such as [[polycythemia vera]], and less commonly, [[essential thrombocythaemia]]. In these cases, myelofibrosis occurs as a result of [[somatic evolution in cancer|somatic evolution]] of the abnormal hematopoietic stem cell clone that caused the original disorder. In some cases, the development of myelofibrosis following these disorders may be accelerated by the oral [[chemotherapy]] drug [[hydroxycarbamide|hydroxyurea]].<ref name=causesofmyelofibrosis1wiki1>Causes of myelofibrosis. Wikipedia 2016. https://en.wikipedia.org/wiki/Myelofibrosis. Accessed on March 7, 2016</ref>  
:*[[Genitourinary tract]]<ref name="pmid11843900">{{cite journal |vauthors=Mak YK, Chan CH, So CC, Chan MK, Chu YC |title=Idiopathic myelofibrosis with extramedullary haemopoiesis involving the urinary bladder in a Chinese lady |journal=Clin Lab Haematol |volume=24 |issue=1 |pages=55–9 |date=February 2002 |pmid=11843900 |doi= |url=}}</ref><ref name="pmid28821362">{{cite journal |vauthors=Philipponnet C, Ronco P, Aniort J, Kemeny JL, Heng AE |title=Membranous Nephropathy and Intrarenal Extramedullary Hematopoiesis in a Patient With Myelofibrosis |journal=Am. J. Kidney Dis. |volume=70 |issue=6 |pages=874–877 |date=December 2017 |pmid=28821362 |doi=10.1053/j.ajkd.2017.06.022 |url=}}</ref><ref name="pmid10983698">{{cite journal |vauthors=Kwak HS, Lee JM |title=CT findings of extramedullary hematopoiesis in the thorax, liver and kidneys, in a patient with idiopathic myelofibrosis |journal=J. Korean Med. Sci. |volume=15 |issue=4 |pages=460–2 |date=August 2000 |pmid=10983698 |pmc=3054659 |doi=10.3346/jkms.2000.15.4.460 |url=}}</ref>
:*[[Central nervous system]]<ref name="pmid23621819">{{cite journal |vauthors=Singer A, Quencer R |title=Intracranial extramedullary hematopoiesis: a rare cause of headaches |journal=J Neuroimaging |volume=24 |issue=5 |pages=524–7 |date=2014 |pmid=23621819 |doi=10.1111/jon.12029 |url=}}</ref><ref name="pmid28775247">{{cite journal |vauthors=Fareed S, Nashwan AJ, Abu Jarir S, Husain A, Suliman DS, Ibrahim F, Moustafa A, Akhter MS, Yassin MA |title=Spinal Abscess Caused by Salmonella Bacteremia in a Patient with Primary Myelofibrosis |journal=Am J Case Rep |volume=18 |issue= |pages=859–864 |date=August 2017 |pmid=28775247 |pmc=5551928 |doi= |url=}}</ref><ref name="pmid24429645">{{cite journal |vauthors=Hijikata Y, Ando T, Inagaki T, Watanabe H, Ito M, Sobue G |title=[Spinal cord compression due to extramedullary hematopoiesis in a patient with myelofibrosis] |language=Japanese |journal=Rinsho Shinkeigaku |volume=54 |issue=1 |pages=27–31 |date=2014 |pmid=24429645 |doi= |url=}}</ref><ref name="pmid11843900">{{cite journal |vauthors=Mak YK, Chan CH, So CC, Chan MK, Chu YC |title=Idiopathic myelofibrosis with extramedullary haemopoiesis involving the urinary bladder in a Chinese lady |journal=Clin Lab Haematol |volume=24 |issue=1 |pages=55–9 |date=February 2002 |pmid=11843900 |doi= |url=}}</ref>
:*[[Lymph nodes]]<ref name="pmid28895103">{{cite journal |vauthors=Imai K, Aoi T, Kitai H, Endo N, Fujino M, Ichida S |title=A case of perirenal extramedullary hematopoiesis in a patient with primary myelofibrosis |journal=CEN Case Rep |volume=6 |issue=2 |pages=194–199 |date=November 2017 |pmid=28895103 |pmc=5694411 |doi=10.1007/s13730-017-0274-1 |url=}}</ref><ref name="pmid11843900">{{cite journal |vauthors=Mak YK, Chan CH, So CC, Chan MK, Chu YC |title=Idiopathic myelofibrosis with extramedullary haemopoiesis involving the urinary bladder in a Chinese lady |journal=Clin Lab Haematol |volume=24 |issue=1 |pages=55–9 |date=February 2002 |pmid=11843900 |doi= |url=}}</ref>
:*[[Skin]]<ref name="pmid2406300">{{cite journal |vauthors=Mizoguchi M, Kawa Y, Minami T, Nakayama H, Mizoguchi H |title=Cutaneous extramedullary hematopoiesis in myelofibrosis |journal=J. Am. Acad. Dermatol. |volume=22 |issue=2 Pt 2 |pages=351–5 |date=February 1990 |pmid=2406300 |doi= |url=}}</ref>
:*[[Peritoneum]]<ref name="pmid11843900">{{cite journal |vauthors=Mak YK, Chan CH, So CC, Chan MK, Chu YC |title=Idiopathic myelofibrosis with extramedullary haemopoiesis involving the urinary bladder in a Chinese lady |journal=Clin Lab Haematol |volume=24 |issue=1 |pages=55–9 |date=February 2002 |pmid=11843900 |doi= |url=}}</ref>
:*[[Gastrointestinal tract]]<ref name="pmid11843900">{{cite journal |vauthors=Mak YK, Chan CH, So CC, Chan MK, Chu YC |title=Idiopathic myelofibrosis with extramedullary haemopoiesis involving the urinary bladder in a Chinese lady |journal=Clin Lab Haematol |volume=24 |issue=1 |pages=55–9 |date=February 2002 |pmid=11843900 |doi= |url=}}</ref>
:*[[Lung|Lungs]]<ref name="pmid27883206">{{cite journal |vauthors=Yang M, Roarke M |title=Diffuse pulmonary extramedullary hematopoiesis in myelofibrosis diagnosed with technetium-99m sulfur colloid bone marrow scintigraphy and single photon emission computerized tomography/CT |journal=Am. J. Hematol. |volume=92 |issue=3 |pages=323–324 |date=March 2017 |pmid=27883206 |doi=10.1002/ajh.24616 |url=}}</ref><ref name="pmid10983698">{{cite journal |vauthors=Kwak HS, Lee JM |title=CT findings of extramedullary hematopoiesis in the thorax, liver and kidneys, in a patient with idiopathic myelofibrosis |journal=J. Korean Med. Sci. |volume=15 |issue=4 |pages=460–2 |date=August 2000 |pmid=10983698 |pmc=3054659 |doi=10.3346/jkms.2000.15.4.460 |url=}}</ref>


===Sites of Hematopoiesis===
==Genetics==
The principal site of [[extramedullary hematopoiesis]] in myelofibrosis is the [[spleen]], which is usually markedly enlarged, sometimes weighing as much as 4000 g.<ref name=causesofmyelofibrosis1wiki1>Causes of myelofibrosis. Wikipedia 2016. https://en.wikipedia.org/wiki/Myelofibrosis. Accessed on March 7, 2016</ref> As a result of massive [[splenomegaly]], multiple subcapsular [[Splenic infarction|infarcts]] often occur in the spleen, meaning that oxygen supply to the spleen is interrupted, leading to partial or complete tissue death. Histologically, the spleen contains red blood cell precursors, [[granulocyte]] precursors, and [[megakaryocyte]]s, with the megokarycytes prominent in their number and in their bizarre shapes. Megakaryocytes are believed to be involved in causing the secondary fibrosis seen in this condition. This bone marrow fibrosis is a result of inappropriate release of [[PDGF]] and [[TGF beta|TGF-ß]] from these neoplastic megakaryocytes.<ref name=pathologyofmyelofibrosis1>Pathology of myelofibrosis. Dr Henry Knipe and Dr Yuranga Weerakkody et al. Radiopaedia 2016. http://radiopaedia.org/articles/myelofibrosis. Accessed on March 7, 2016</ref> Sometimes, an unusual activity of the [[red blood cell]]s, [[white blood cell]]s, or [[platelet]]s is also observed.<ref name=causesofmyelofibrosis1wiki1>Causes of myelofibrosis. Wikipedia 2016. https://en.wikipedia.org/wiki/Myelofibrosis. Accessed on March 7, 2016</ref> The liver is often moderately enlarged, with foci of extramedullary hematopoiesis. Microscopically, lymph nodes also contain foci of hematopoiesis, but these are insufficient to cause enlargement. There are also reports of hematopoiesis taking place in the [[lungs]]. These cases are associated with [[pulmonary arterial hypertension|hypertension in the pulmonary arteries]]. The [[bone marrow]] in a typical case is hypercellular and diffusely [[fibrotic]]. Both early and late in disease, megakaryocytes are often prominent and are usually [[dysplastic]].<ref name=causesofmyelofibrosis1wiki1>Causes of myelofibrosis. Wikipedia 2016. https://en.wikipedia.org/wiki/Myelofibrosis. Accessed on March 7, 2016</ref>
*Development of [[myelofibrosis]] is the result of multiple [[genetic mutations]].
*[[Gene|Genes]] involved in the [[pathogenesis]] of [[myelofibrosis]] include:<ref name="pmid26124496">{{cite journal |vauthors=Patel KP, Newberry KJ, Luthra R, Jabbour E, Pierce S, Cortes J, Singh R, Mehrotra M, Routbort MJ, Luthra M, Manshouri T, Santos FP, Kantarjian H, Verstovsek S |title=Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib |journal=Blood |volume=126 |issue=6 |pages=790–7 |date=August 2015 |pmid=26124496 |pmc=4528066 |doi=10.1182/blood-2015-03-633404 |url=}}</ref><ref name="TefferiLasho2014">{{cite journal|last1=Tefferi|first1=A|last2=Lasho|first2=T L|last3=Finke|first3=C M|last4=Knudson|first4=R A|last5=Ketterling|first5=R|last6=Hanson|first6=C H|last7=Maffioli|first7=M|last8=Caramazza|first8=D|last9=Passamonti|first9=F|last10=Pardanani|first10=A|title=CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons|journal=Leukemia|volume=28|issue=7|year=2014|pages=1472–1477|issn=0887-6924|doi=10.1038/leu.2014.3}}</ref><ref name="pmid15781101">{{cite journal |author=Baxter EJ, Scott LM, Campbell PJ, ''et al'' |title=Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders |journal=Lancet |volume=365 |issue=9464 |pages=1054–61 |year=2005 |pmid=15781101 |doi=10.1016/S0140-6736(05)71142-9 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(05)71142-9}}</ref><ref name="pmid16834459">{{cite journal |author=Pikman Y, Lee BH, Mercher T, ''et al'' |title=MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia |journal=PLoS Med. |volume=3 |issue=7 |pages=e270 |year=2006 |month=July |pmid=16834459 |pmc=1502153 |doi=10.1371/journal.pmed.0030270 |url=http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0030270}}</ref><ref name="pmid27756071">{{cite journal |vauthors=Alshemmari SH, Rajan R, Emadi A |title=Molecular Pathogenesis and Clinical Significance of Driver Mutations in Primary Myelofibrosis: A Review |journal=Med Princ Pract |volume=25 |issue=6 |pages=501–509 |date=2016 |pmid=27756071 |pmc=5588514 |doi=10.1159/000450956 |url=}}</ref><ref name="pmid27913528">{{cite journal |vauthors=Shammo JM, Stein BL |title=Mutations in MPNs: prognostic implications, window to biology, and impact on treatment decisions |journal=Hematology Am Soc Hematol Educ Program |volume=2016 |issue=1 |pages=552–560 |date=December 2016 |pmid=27913528 |pmc=6142495 |doi=10.1182/asheducation-2016.1.552 |url=}}</ref><ref name="pmid24997152">{{cite journal |vauthors=Li B, Xu J, Wang J, Gale RP, Xu Z, Cui Y, Yang L, Xing R, Ai X, Qin T, Zhang Y, Zhang P, Xiao Z |title=Calreticulin mutations in Chinese with primary myelofibrosis |journal=Haematologica |volume=99 |issue=11 |pages=1697–700 |date=November 2014 |pmid=24997152 |pmc=4222480 |doi=10.3324/haematol.2014.109249 |url=}}</ref><ref name="pmid27037840">{{cite journal |vauthors=Rotunno G, Pacilli A, Artusi V, Rumi E, Maffioli M, Delaini F, Brogi G, Fanelli T, Pancrazzi A, Pietra D, Bernardis I, Belotti C, Pieri L, Sant'Antonio E, Salmoiraghi S, Cilloni D, Rambaldi A, Passamonti F, Barbui T, Manfredini R, Cazzola M, Tagliafico E, Vannucchi AM, Guglielmelli P |title=Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group |journal=Am. J. Hematol. |volume=91 |issue=7 |pages=681–6 |date=July 2016 |pmid=27037840 |doi=10.1002/ajh.24377 |url=}}</ref><ref name="pmid28419183">{{cite journal |vauthors=Song J, Hussaini M, Zhang H, Shao H, Qin D, Zhang X, Ma Z, Hussnain Naqvi SM, Zhang L, Moscinski LC |title=Comparison of the Mutational Profiles of Primary Myelofibrosis, Polycythemia Vera, and Essential Thrombocytosis |journal=Am. J. Clin. Pathol. |volume=147 |issue=5 |pages=444–452 |date=May 2017 |pmid=28419183 |pmc=5402718 |doi=10.1093/ajcp/aqw222 |url=}}</ref><ref name="pmid27870387">{{cite journal |vauthors=Tefferi A |title=Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management |journal=Am. J. Hematol. |volume=91 |issue=12 |pages=1262–1271 |date=December 2016 |pmid=27870387 |doi=10.1002/ajh.24592 |url=}}</ref><ref name="pmid23619563">{{cite journal |vauthors=Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A, Finke C, Score J, Gangat N, Mannarelli C, Ketterling RP, Rotunno G, Knudson RA, Susini MC, Laborde RR, Spolverini A, Pancrazzi A, Pieri L, Manfredini R, Tagliafico E, Zini R, Jones A, Zoi K, Reiter A, Duncombe A, Pietra D, Rumi E, Cervantes F, Barosi G, Cazzola M, Cross NC, Tefferi A |title=Mutations and prognosis in primary myelofibrosis |journal=Leukemia |volume=27 |issue=9 |pages=1861–9 |date=September 2013 |pmid=23619563 |doi=10.1038/leu.2013.119 |url=}}</ref><ref name="pmid26182311">{{cite journal |vauthors=Tefferi A, Pardanani A |title=Myeloproliferative Neoplasms: A Contemporary Review |journal=JAMA Oncol |volume=1 |issue=1 |pages=97–105 |date=April 2015 |pmid=26182311 |doi=10.1001/jamaoncol.2015.89 |url=}}</ref>
===Most Commonly Involved Genes===
*[[Janus kinase 2|Janus kinase 2 (JAK2)]]
*[[Calreticulin|Calreticulin (CALR)]]
*[[Myeloproliferative leukemia virus oncogene|Myeloproliferative leukemia virus (MPL) oncogene]]  
*These [[Mutation|mutations]] are found in approximately 90% of the [[Patient|patients]].
===Less Commonly Involved Genes===
*Additional sex combs-like 1 (ASXL1)
*Slicing factor, serine/arginine-rich 2 (SRSF2)
*[[EZH2|Enhancer of zeste, drosophila, homolog 2 (EZH2)]]
*[[NRAS gene|Neuroblastoma RAS viral oncogene homolog (NRAS)]]
*[[KRAS|Kirsten rat sarcoma viral oncogene homolog (KRAS)]]
*[[PTPN11 gene|Protein-tyrosine phosphatase, non-receptor type 11 (PTPN11)]]
*[[GATA2|GATA-binding protein 2 (GATA2)]]
*[[TP53|Tumor protein p53 (TP53)]]
*[[RUNX1|Runt-related transcription factor 1 (RUNX1)]]
 
==Associated Conditions==
*[[Myelofibrosis]] belongs to a group of disorders collectively called [[Myeloproliferative neoplasm|myeloproliferative disorders]]. Other members of this group include [[Chronic myelogenous leukemia|chronic myelogenous leukemia (CML)]], [[Polycythemia vera|polycythemia vera (PV)]], and [[Essential thrombocythemia|essential thrombocythemia (ET)]].
*[[Myelofibrosis]] can be associated with a variety of medical conditions such as:
 
:*[[Malignancies]] and [[hematologic]] disorders like:<ref name="pmid23787440">{{cite journal |vauthors=Boiocchi L, Mathew S, Gianelli U, Iurlo A, Radice T, Barouk-Fox S, Knowles DM, Orazi A |title=Morphologic and cytogenetic differences between post-polycythemic myelofibrosis and primary myelofibrosis in fibrotic stage |journal=Mod. Pathol. |volume=26 |issue=12 |pages=1577–85 |date=December 2013 |pmid=23787440 |doi=10.1038/modpathol.2013.109 |url=}}</ref><ref name="pmid30159182">{{cite journal |vauthors=Darawshy F, Ben-Yehuda A, Atlan K, Rund D |title=Chronic Lymphocytic Leukemia and Myelofibrosis |journal=Case Rep Hematol |volume=2018 |issue= |pages=7426739 |date=2018 |pmid=30159182 |pmc=6109551 |doi=10.1155/2018/7426739 |url=}}</ref><ref name="pmid28781273">{{cite journal |vauthors=Sakatoku K, Takeoka Y, Araki T, Miura A, Fujitani Y, Yamamura R, Miyagi Y, Senzaki H, Ohta K |title=Lymphocyte-depleted classical Hodgkin lymphoma accompanied by myelofibrosis |language=Japanese |journal=Rinsho Ketsueki |volume=58 |issue=7 |pages=772–775 |date=2017 |pmid=28781273 |doi=10.11406/rinketsu.58.772 |url=}}</ref><ref name="pmid26622707">{{cite journal |vauthors=Fu R, Yu H, Wu YH, Liu H, Shao ZH |title=Hodgkin's lymphoma associated with myelofibrosis: A case report |journal=Oncol Lett |volume=10 |issue=3 |pages=1551–1554 |date=September 2015 |pmid=26622707 |pmc=4533276 |doi=10.3892/ol.2015.3438 |url=}}</ref><ref name="pmid26117015">{{cite journal |vauthors=Liu YL, Wang WJ, Wang XN |title=[Pathological Characteristics of Bone Marrow in Non-Hodgkin's Lymphoma Patients with Secondary Myelofibrosis and Their Relationship with Prognosis] |language=Chinese |journal=Zhongguo Shi Yan Xue Ye Xue Za Zhi |volume=23 |issue=3 |pages=674–8 |date=June 2015 |pmid=26117015 |doi=10.7534/j.issn.1009-2137.2015.03.014 |url=}}</ref><ref name="pmid28239786">{{cite journal |vauthors=Dolgikh TY, Domnikova NP, Tornuev YV, Vinogradova EV, Krinitsyna YM |title=Incidence of Myelofibrosis in Chronic Myeloid Leukemia, Multiple Myeloma, and Chronic Lymphoid Leukemia during Various Phases of Diseases |journal=Bull. Exp. Biol. Med. |volume=162 |issue=4 |pages=483–487 |date=February 2017 |pmid=28239786 |doi=10.1007/s10517-017-3645-x |url=}}</ref><ref name="pmid28823272">{{cite journal |vauthors=Zhao J, Ma L, Guan JH |title=[Pathological Characteristics of Bone Marrow in Multiple Myeloma Patients with Secondary Myelofibrosis and Their Relationship with Prognosis] |language=Chinese |journal=Zhongguo Shi Yan Xue Ye Xue Za Zhi |volume=25 |issue=4 |pages=1080–1085 |date=August 2017 |pmid=28823272 |doi=10.7534/j.issn.1009-2137.2017.04.021 |url=}}</ref><ref name="pmid28561069">{{cite journal |vauthors=Passamonti F, Giorgino T, Mora B, Guglielmelli P, Rumi E, Maffioli M, Rambaldi A, Caramella M, Komrokji R, Gotlib J, Kiladjian JJ, Cervantes F, Devos T, Palandri F, De Stefano V, Ruggeri M, Silver RT, Benevolo G, Albano F, Caramazza D, Merli M, Pietra D, Casalone R, Rotunno G, Barbui T, Cazzola M, Vannucchi AM |title=A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis |journal=Leukemia |volume=31 |issue=12 |pages=2726–2731 |date=December 2017 |pmid=28561069 |doi=10.1038/leu.2017.169 |url=}}</ref><ref name="pmid28601551">{{cite journal |vauthors=Masarova L, Bose P, Daver N, Pemmaraju N, Newberry KJ, Manshouri T, Cortes J, Kantarjian HM, Verstovsek S |title=Patients with post-essential thrombocythemia and post-polycythemia vera differ from patients with primary myelofibrosis |journal=Leuk. Res. |volume=59 |issue= |pages=110–116 |date=August 2017 |pmid=28601551 |pmc=5573611 |doi=10.1016/j.leukres.2017.06.001 |url=}}</ref><ref name="pmid14302719">{{cite journal |vauthors=MARKAND ON |title=SECONDARY MARBLE BONE DISEASE: GENERALISED OSTEOSCLEROSIS AND MYELOFIBROSIS IN CARCINOMA OF PROSTATE WITH A CASE REPORT |journal=J Assoc Physicians India |volume=13 |issue= |pages=349–55 |date=May 1965 |pmid=14302719 |doi= |url=}}</ref><ref name="pmid12897334">{{cite journal |vauthors=Chang JC, Naqvi T |title=Thrombotic thrombocytopenic purpura associated with bone marrow metastasis and secondary myelofibrosis in cancer |journal=Oncologist |volume=8 |issue=4 |pages=375–80 |date=2003 |pmid=12897334 |doi= |url=}}</ref><ref name="pmid5458299">{{cite journal |vauthors=Hiwada K, Sera Y, Nishimura M |title=[Autopsy case of secondary myelofibrosis due to bone marrow metastasis of stomach cancer] |language=Japanese |journal=Iryo |volume=24 |issue=7 |pages=585–90 |date=July 1970 |pmid=5458299 |doi= |url=}}</ref>
::*[[Hodgkin's lymphoma|Hodgkin lymphoma]]
::*[[Non-Hodgkin lymphoma]]
::*[[Chronic lymphocytic leukemia|Chronic lymphocytic leukemia (CLL)]]
::*[[Essential thrombocythemia|Essential thrombocythemia (ET)]]
::*[[Polycythemia vera|Polycythemia vera (PV)]]
::*[[Multiple myeloma|Multiple myeloma (MM)]]
::*[[Malignancies]] with [[metastases]] to the [[bone]]
:*[[Infection|Infections]] such as:<ref name="pmid25745963">{{cite journal |vauthors=Shimono J, Tsutsumi Y, Ohigashi H |title=[Acute renal tubular damage caused by disseminated Trichosporon infection in primary myelofibrosis] |language=Japanese |journal=Rinsho Ketsueki |volume=56 |issue=1 |pages=21–4 |date=January 2015 |pmid=25745963 |doi=10.11406/rinketsu.56.21 |url=}}</ref><ref name="pmid25016180">{{cite journal |vauthors=Qing X, Sun N, Yeh J, Yue C, Cai J |title=Dengue fever and bone marrow myelofibrosis |journal=Exp. Mol. Pathol. |volume=97 |issue=2 |pages=208–10 |date=October 2014 |pmid=25016180 |doi=10.1016/j.yexmp.2014.07.004 |url=}}</ref><ref name="pmid21894472">{{cite journal |vauthors=Lee AC, Fong CM |title=Autoimmune myelofibrosis as the first manifestation of human immunodeficiency virus infection in an infant |journal=Ann. Hematol. |volume=91 |issue=5 |pages=809–810 |date=May 2012 |pmid=21894472 |doi=10.1007/s00277-011-1329-6 |url=}}</ref><ref name="pmid9176580">{{cite journal |vauthors=Hashim MS, Kordofani AY, el Dabi MA |title=Tuberculosis and myelofibrosis in children: a report |journal=Ann Trop Paediatr |volume=17 |issue=1 |pages=61–5 |date=March 1997 |pmid=9176580 |doi= |url=}}</ref><ref name="pmid12032901">{{cite journal |vauthors=Viallard JF, Parrens M, Boiron JM, Texier J, Mercie P, Pellegrin JL |title=Reversible myelofibrosis induced by tuberculosis |journal=Clin. Infect. Dis. |volume=34 |issue=12 |pages=1641–3 |date=June 2002 |pmid=12032901 |doi=10.1086/340524 |url=}}</ref>
::*[[Tuberculosis]] [TB]
::*[[HIV AIDS|HIV infection]]
::*Disseminated [[trichosporon]] [[infection]]
::*[[Dengue fever]]
:*[[Autoimmune diseases]] like:<ref name="pmid27102067">{{cite journal |vauthors=Jain N, Sinha R, Sengupta J, Chakrabartty J |title=A rare case of myelofibrosis secondary to juvenile idiopathic arthritis |journal=Br. J. Haematol. |volume=173 |issue=6 |pages=819 |date=June 2016 |pmid=27102067 |doi=10.1111/bjh.14106 |url=}}</ref><ref name="pmid28293461">{{cite journal |vauthors=Cansu DÜ, Teke HÜ, Korkmaz C |title=A rare cause of cytopenia in a patient with systemic lupus erythematosus: Autoimmune myelofibrosis |journal=Eur J Rheumatol |volume=4 |issue=1 |pages=76–78 |date=March 2017 |pmid=28293461 |pmc=5335895 |doi=10.5152/eurjrheum.2016.011 |url=}}</ref><ref name="pmid24371783">{{cite journal |vauthors=Thorsteinsdottir S, Bjerrum OW, Hasselbalch HC |title=Myeloproliferative neoplasms in five multiple sclerosis patients |journal=Leuk Res Rep |volume=2 |issue=2 |pages=61–3 |date=2013 |pmid=24371783 |pmc=3850374 |doi=10.1016/j.lrr.2013.06.004 |url=}}</ref><ref name="pmid27830539">{{cite journal |vauthors=Abaza Y, Yin CC, Bueso-Ramos CE, Wang SA, Verstovsek S |title=Primary autoimmune myelofibrosis: a case report and review of the literature |journal=Int. J. Hematol. |volume=105 |issue=4 |pages=536–539 |date=April 2017 |pmid=27830539 |doi=10.1007/s12185-016-2129-5 |url=}}</ref><ref name="pmid3146200">{{cite journal |vauthors=el Mouzan MI, Ahmad MA, al Fadel Saleh M, al Sohaibani MO, al Gindan YM |title=Myelofibrosis and pancytopenia in systemic lupus erythematosus |journal=Acta Haematol. |volume=80 |issue=4 |pages=219–21 |date=1988 |pmid=3146200 |doi=10.1159/000205641 |url=}}</ref>
::*[[Systemic lupus erythematosus]] [SLE]
::*[[Multiple sclerosis]] [MS]
::*[[Sjögren's syndrome|Sjogren's syndrome]]
::*[[Juvenile idiopathic arthritis]]
:*[[Endocrine]] disorders such as:
:**[[Primary hyperparathyroidism]]<ref name="pmid17988303">{{cite journal |vauthors=Lim DJ, Oh EJ, Park CW, Kwon HS, Hong EJ, Yoon KH, Kang MI, Cha BY, Lee KW, Son HY, Kang SK |title=Pancytopenia and secondary myelofibrosis could be induced by primary hyperparathyroidism |journal=Int J Lab Hematol |volume=29 |issue=6 |pages=464–8 |date=December 2007 |pmid=17988303 |doi=10.1111/j.1365-2257.2006.00877.x |url=}}</ref>
:*[[SPD|Delta-storage pool deficiency (SPD)]]<ref name="pmid11042524">{{cite journal |vauthors=Mouly S, Youssefian T, Souni F, Cramer E, Lefrere F, Varet B, Hermine O |title=Acquired delta-storage pool deficiency associated with idiopathic myelofibrosis |journal=Leuk. Lymphoma |volume=37 |issue=5-6 |pages=623–7 |date=May 2000 |pmid=11042524 |doi=10.3109/10428190009058516 |url=}}</ref>
:*Ghosal syndrome<ref name="pmid22983925">{{cite journal |vauthors=Datta K, Karmakar M, Hira M, Halder S, Pramanik K, Banerjee G |title=Ghosal hematodiaphyseal dysplasia with myelofibrosis |journal=Indian J Pediatr |volume=80 |issue=12 |pages=1050–2 |date=December 2013 |pmid=22983925 |doi=10.1007/s12098-012-0872-z |url=}}</ref>
:*[[Grey platelet syndrome|Gray platelet syndrome]]<ref name="pmid3615193">{{cite journal |vauthors=Caen JP, Deschamps JF, Bodevin E, Bryckaert MC, Dupuy E, Wasteson A |title=Megakaryocytes and myelofibrosis in gray platelet syndrome |journal=Nouv Rev Fr Hematol |volume=29 |issue=2 |pages=109–14 |date=1987 |pmid=3615193 |doi= |url=}}</ref>
:*[[Chromosome]] 14q32 duplication [[syndrome]], 700-kb<ref name="pmid26280900">{{cite journal |vauthors=Saliba J, Saint-Martin C, Di Stefano A, Lenglet G, Marty C, Keren B, Pasquier F, Valle VD, Secardin L, Leroy G, Mahfoudhi E, Grosjean S, Droin N, Diop M, Dessen P, Charrier S, Palazzo A, Merlevede J, Meniane JC, Delaunay-Darivon C, Fuseau P, Isnard F, Casadevall N, Solary E, Debili N, Bernard OA, Raslova H, Najman A, Vainchenker W, Bellanné-Chantelot C, Plo I |title=Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies |journal=Nat. Genet. |volume=47 |issue=10 |pages=1131–40 |date=October 2015 |pmid=26280900 |doi=10.1038/ng.3380 |url=}}</ref>
:*Revesz syndrome<ref name="pmid17990901">{{cite journal |vauthors=Negrón D, Colón-Castillo L, Morales-Melecio I, Correa-Rivas M |title=Association of extensive brain calcifications, myelofibrosis, and retinopathy in a 12-year-old child |journal=Pediatr. Dev. Pathol. |volume=11 |issue=2 |pages=148–51 |date=2008 |pmid=17990901 |doi=10.2350/06-03-0061.1 |url=}}</ref>
:*[[Dermatomyositis]]<ref name="pmid16642932">{{cite journal |vauthors=Ito A, Umeda M, Koike T, Naruse S, Fujita N |title=[A case of dermatomyositis associated with chronic idiopathic myelofibrosis] |language=Japanese |journal=Rinsho Shinkeigaku |volume=46 |issue=3 |pages=210–3 |date=March 2006 |pmid=16642932 |doi= |url=}}</ref>


==Genetics==
==Gross Pathology==
*Development of myelofibrosis is the result of multiple genetic mutations.<ref name=causesofmyelofibrosis1wiki1>Causes of myelofibrosis. Wikipedia 2016. https://en.wikipedia.org/wiki/Myelofibrosis. Accessed on March 7, 2016</ref>
*On [[gross]] [[pathology]], [[Extramedullary hematopoiesis|extramedullary hematopoiesis (EMH)]], the characteristic finding, is manifested as:<ref name="pmid26891375">{{cite journal |vauthors=Cervantes F, Correa JG, Hernandez-Boluda JC |title=Alleviating anemia and thrombocytopenia in myelofibrosis patients |journal=Expert Rev Hematol |volume=9 |issue=5 |pages=489–96 |date=May 2016 |pmid=26891375 |doi=10.1586/17474086.2016.1154452 |url=}}</ref><ref name="pmid25944376">{{cite journal |vauthors=Hernández-Boluda JC, Martínez-Trillos A, García-Gutiérrez V, Ferrer-Marín F, Xicoy B, Alvarez-Larrán A, Kerguelen A, Barba P, Gómez M, Herrera JC, Correa JG, Cervantes F |title=Long-term results of prednisone treatment for the anemia of myelofibrosis |journal=Leuk. Lymphoma |volume=57 |issue=1 |pages=120–4 |date=2016 |pmid=25944376 |doi=10.3109/10428194.2015.1046866 |url=}}</ref><ref name="pmid26537421">{{cite journal |vauthors=Ungprasert P, Chowdhary VR, Davis MD, Makol A |title=Autoimmune myelofibrosis with pancytopenia as a presenting manifestation of systemic lupus erythematosus responsive to mycophenolate mofetil |journal=Lupus |volume=25 |issue=4 |pages=427–30 |date=April 2016 |pmid=26537421 |doi=10.1177/0961203315615221 |url=}}</ref><ref name="pmid26422082">{{cite journal |vauthors=Tang VK, Huh YO, Tayar JH, Rojas Hernandez CM |title=Primary autoimmune myelofibrosis as etiology of pancytopenia mimicking myelodysplastic syndrome |journal=Leuk. Lymphoma |volume=57 |issue=3 |pages=731–4 |date=2016 |pmid=26422082 |doi=10.3109/10428194.2015.1076931 |url=}}</ref><ref name="pmid27870387" /><ref name="pmid28011890">{{cite journal |vauthors=Panda A, Chandrashekhara SH, Nambirajan A, Mishra P |title=Idiopathic myelofibrosis with disseminated hepatosplenic, mesenteric, renal and pulmonary extramedullary haematopoeisis, portal hypertension and tuberculosis: initial presentation and 2 years follow-up |journal=BMJ Case Rep |volume=2016 |issue= |pages= |date=December 2016 |pmid=28011890 |doi=10.1136/bcr-2016-217854 |url=}}</ref><ref name="pmid14528107">{{cite journal |vauthors=Gruner BA, DeNapoli TS, Elshihabi S, Britton HA, Langevin AM, Thomas PJ, Weitman SD |title=Anemia and hepatosplenomegaly as presenting features in a child with rickets and secondary myelofibrosis |journal=J. Pediatr. Hematol. Oncol. |volume=25 |issue=10 |pages=813–5 |date=October 2003 |pmid=14528107 |doi= |url=}}</ref><ref name="pmid10460376">{{cite journal |vauthors=Guermazi A, de Kerviler E, Cazals-Hatem D, Zagdanski AM, Frija J |title=Imaging findings in patients with myelofibrosis |journal=Eur Radiol |volume=9 |issue=7 |pages=1366–75 |date=1999 |pmid=10460376 |doi=10.1007/s003300050850 |url=}}</ref><ref name="pmid20235305">{{cite journal |vauthors=Merry GM, Aronowitz PB |title=Myelofibrosis with massive hepatosplenomegaly and osteolytic bone lesions |journal=J Hosp Med |volume=5 |issue=3 |pages=E27–8 |date=March 2010 |pmid=20235305 |doi=10.1002/jhm.459 |url=}}</ref>
*Genes involved in the pathogenesis of myelofibrosis include:<ref name="TefferiLasho2014">{{cite journal|last1=Tefferi|first1=A|last2=Lasho|first2=T L|last3=Finke|first3=C M|last4=Knudson|first4=R A|last5=Ketterling|first5=R|last6=Hanson|first6=C H|last7=Maffioli|first7=M|last8=Caramazza|first8=D|last9=Passamonti|first9=F|last10=Pardanani|first10=A|title=CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons|journal=Leukemia|volume=28|issue=7|year=2014|pages=1472–1477|issn=0887-6924|doi=10.1038/leu.2014.3}}</ref><ref name="pmid15781101">{{cite journal |author=Baxter EJ, Scott LM, Campbell PJ, ''et al'' |title=Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders |journal=Lancet |volume=365 |issue=9464 |pages=1054–61 |year=2005 |pmid=15781101 |doi=10.1016/S0140-6736(05)71142-9 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(05)71142-9}}</ref><ref name="pmid16834459">{{cite journal |author=Pikman Y, Lee BH, Mercher T, ''et al'' |title=MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia |journal=PLoS Med. |volume=3 |issue=7 |pages=e270 |year=2006 |month=July |pmid=16834459 |pmc=1502153 |doi=10.1371/journal.pmed.0030270 |url=http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0030270}}</ref>
**[[Lymphadenopathy]]
:* ''[[JAK2]]''
**[[Hepatomegaly]]
:*''[[Calreticulin|CALR]]''
**[[Splenomegaly]]
:*''[[Myeloproliferative leukemia virus oncogene|MPL]]''
==Microscopic Pathology==
* Approximately 90% of those with myelofibrosis have one of these [[mutation]]s. These mutations are not specific to myelofibrosis, and are linked to other myeloproliferative disorders, specifically [[essential thrombocythemia]].<ref name=causesofmyelofibrosis1wiki1>Causes of myelofibrosis. Wikipedia 2016. https://en.wikipedia.org/wiki/Myelofibrosis. Accessed on March 7, 2016</ref>
===On Light Microscopy===
*The ''V617F'' mutation to the [[JAK2]] protein is found in approximately half of individuals with primary myelofibrosis. The ''V617F'' mutation is a change of [[valine]] to [[phenylalanine]] at the 617 position. Janus kinases (JAKs) are '''non-receptor tyrosine kinases''' essential for the activation of signaling that is mediated by cytokine receptors lacking catalytic activity. These include receptors for [[erythropoietin]], [[thrombopoietin]], most [[interleukins]] and [[interferon]]. ''[[JAK2]]'' mutations are significant because ''JAK2'' plays a role in controlling production of blood cells from hematopoietic stem cells. The ''V617F'' mutation appears to make hematopoietic cells more sensitive to growth factors that need JAK2 for signal transduction, which include erythropoietin and thrombopoietin.<ref name=causesofmyelofibrosis1wiki1>Causes of myelofibrosis. Wikipedia 2016. https://en.wikipedia.org/wiki/Myelofibrosis. Accessed on March 7, 2016</ref>
*Low [[Red blood cell|red blood cell (RBC)]] count manifesting as [[anemia]].<ref name="pmid16202684">{{cite journal |vauthors=Thiele J, Kvasnicka HM |title=Hematopathologic findings in chronic idiopathic myelofibrosis |journal=Semin. Oncol. |volume=32 |issue=4 |pages=380–94 |date=August 2005 |pmid=16202684 |doi=10.1053/j.seminoncol.2005.04.010 |url=}}</ref><ref name="pmid26891375">{{cite journal |vauthors=Cervantes F, Correa JG, Hernandez-Boluda JC |title=Alleviating anemia and thrombocytopenia in myelofibrosis patients |journal=Expert Rev Hematol |volume=9 |issue=5 |pages=489–96 |date=May 2016 |pmid=26891375 |doi=10.1586/17474086.2016.1154452 |url=}}</ref><ref name="pmid28009442">{{cite journal |vauthors=Hernández-Boluda JC, Correa JG, García-Delgado R, Martínez-López J, Alvarez-Larrán A, Fox ML, García-Gutiérrez V, Pérez-Encinas M, Ferrer-Marín F, Mata-Vázquez MI, Raya JM, Estrada N, García S, Kerguelen A, Durán MA, Albors M, Cervantes F |title=Predictive factors for anemia response to erythropoiesis-stimulating agents in myelofibrosis |journal=Eur. J. Haematol. |volume=98 |issue=4 |pages=407–414 |date=April 2017 |pmid=28009442 |doi=10.1111/ejh.12846 |url=}}</ref>
*The ''[[Myeloproliferative leukemia virus oncogene|MPL]]'' gene codes for a protein that acts as a receptor for [[thrombopoietin]]. A mutation in that gene, known as a ''W515'' mutation, leads to the production of an abnormal thrombopoietin receptor protein, which results in the overproduction of [[megakaryocyte|abnormal megakaryocytes]]. The abnormal megakaryocytes stimulate other cells, the [[fibroblasts]], to produce [[collagen]] in the bone marrow.<ref name=causesofmyelofibrosis1wiki1>Causes of myelofibrosis. Wikipedia 2016. https://en.wikipedia.org/wiki/Myelofibrosis. Accessed on March 7, 2016</ref>
*[[Erythroblastosis]]<ref name="pmid12412736">{{cite journal |vauthors=Tóth P, Tóth Z |title=Idiopathic myelofibrosis with prominent postsplenectomy erythroblastosis terminating in acute myeloid transformation |journal=Haematologia (Budap) |volume=32 |issue=2 |pages=155–61 |date=2002 |pmid=12412736 |doi= |url=}}</ref><ref name="pmid8638637">{{cite journal |vauthors=Osman Y, Kishi K, Narita M, Saito H, Masuko M, Koike T, Shibata A |title=Idiopathic myelofibrosis with unusually high erythroblastosis in the peripheral blood |journal=Am. J. Hematol. |volume=52 |issue=2 |pages=122–3 |date=June 1996 |pmid=8638637 |doi=10.1002/(SICI)1096-8652(199606)52:2<122::AID-AJH12>3.0.CO;2-J |url=}}</ref>
*Fish-shaped [[Red blood cells|red blood cells (RBCs)]] on [[peripheral blood smear]]<ref name="pmid28731851">{{cite journal |vauthors=Robier C, Körber C, Quehenberger F, Neubauer M, Wölfler A |title=The frequency of occurrence of fish-shaped red blood cells in different haematologic disorders |journal=Clin. Chem. Lab. Med. |volume=56 |issue=2 |pages=323–326 |date=January 2018 |pmid=28731851 |doi=10.1515/cclm-2017-0378 |url=}}</ref>
*Micromegakaryocytes on the [[peripheral blood smear]]<ref name="pmid8435338">{{cite journal |vauthors=Reilly JT, Barnett D, Dolan G, Forrest P, Eastham J, Smith A |title=Characterization of an acute micromegakaryocytic leukaemia: evidence for the pathogenesis of myelofibrosis |journal=Br. J. Haematol. |volume=83 |issue=1 |pages=58–62 |date=January 1993 |pmid=8435338 |doi= |url=}}</ref>
*[[Fibroblast]]-like and [[myofibroblast]]-like [[reticulum]] [[cells]] on [[bone marrow]] study<ref name="pmid2580387">{{cite journal |vauthors=Biagini G, Severi B, Govoni E, Preda P, Pileri S, Martinelli G, Visani G, Finelli C, Castaldini C |title=Stromal cells in primary myelofibrosis: ultrastructural observations |journal=Virchows Arch., B, Cell Pathol. |volume=48 |issue=1 |pages=1–8 |date=1985 |pmid=2580387 |doi= |url=}}</ref>
*[[Teardrop cells]]<ref name="pmid26118701">{{cite journal |vauthors=Egelé A, van Gelder W, Riedl J |title=Automated detection and classification of teardrop cells by a novel RBC module using digital imaging/microscopy |journal=Int J Lab Hematol |volume=37 |issue=6 |pages=e153–6 |date=December 2015 |pmid=26118701 |doi=10.1111/ijlh.12399 |url=}}</ref>
*Increased microvascular [[density]], bizarre [[Blood vessel|vessel]] architecture, and increased number of [[pericytes]] on [[bone marrow]] study<ref name="pmid22250648">{{cite journal |vauthors=Madelung A, Bzorek M, Bondo H, Zetterberg E, Bjerrum OW, Hasselbalch HC, Scheding S, Ralfkiaer E |title=A novel immunohistochemical sequential multi-labelling and erasing technique enables epitope characterization of bone marrow pericytes in primary myelofibrosis |journal=Histopathology |volume=60 |issue=4 |pages=554–60 |date=March 2012 |pmid=22250648 |doi=10.1111/j.1365-2559.2011.04104.x |url=}}</ref><ref name="pmid10880370">{{cite journal |vauthors=Lundberg LG, Lerner R, Sundelin P, Rogers R, Folkman J, Palmblad J |title=Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity |journal=Am. J. Pathol. |volume=157 |issue=1 |pages=15–9 |date=July 2000 |pmid=10880370 |pmc=1850191 |doi=10.1016/S0002-9440(10)64511-7 |url=}}</ref>
*[[Leukocytosis]] and [[thrombocytosis]] (in the initial stages)<ref name="pmid29631428">{{cite journal |vauthors=Magyari F, Bedekovics J, Décsy J, Ilonczai P, Illés Á, Simon Z |title=[Investigation and treatment of prefibrotic/early primary myelofibrosis. A case study] |language=Hungarian |journal=Orv Hetil |volume=159 |issue=15 |pages=603–609 |date=April 2018 |pmid=29631428 |doi=10.1556/650.2018.30995 |url=}}</ref><ref name="pmid27315113">{{cite journal |vauthors=Barraco D, Lasho TL, Gangat N, Finke C, Elala YC, Pardanani A, Tefferi A |title=Leukocytosis and presence of CALR mutation is associated with non-hepatosplenic extramedullary hematopoiesis in primary myelofibrosis |journal=Blood Cancer J |volume=6 |issue= |pages=e436 |date=June 2016 |pmid=27315113 |pmc=5141359 |doi=10.1038/bcj.2016.44 |url=}}</ref><ref name="pmid27293069">{{cite journal |vauthors=Beauverd Y, Alimam S, McLornan DP, Radia DH, Harrison CN |title=Disease characteristics and outcomes in younger adults with primary and secondary myelofibrosis |journal=Br. J. Haematol. |volume=175 |issue=1 |pages=37–42 |date=October 2016 |pmid=27293069 |doi=10.1111/bjh.14173 |url=}}</ref><ref name="pmid25519030">{{cite journal |vauthors=Ota S, Hiramatsu Y, Kondo E, Kasahara A, Takada S, Umena S, Noguchi T, Tanimoto M, Matsumura T |title=Severe case of peripheral leukocytosis initially diagnosed as myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable, but possibly prefibrotic primary myelofibrosis |journal=Acta Med. Okayama |volume=68 |issue=6 |pages=363–8 |date=December 2014 |pmid=25519030 |doi=10.18926/AMO/53025 |url=}}</ref><ref name="pmid29096334">{{cite journal |vauthors=Scotch AH, Kosiorek H, Scherber R, Dueck AC, Slot S, Zweegman S, Boekhorst PAWT, Commandeur S, Schouten H, Sackmann F, Fuentes AK, Hernández-Maraver D, Pahl HL, Griesshammer M, Stegelmann F, Döhner K, Lehmann T, Bonatz K, Reiter A, Boyer F, Etienne G, Ianotto JC, Ranta D, Roy L, Cahn JY, Harrison CN, Radia D, Muxi P, Maldonado N, Besses C, Cervantes F, Johansson PL, Barbui T, Barosi G, Vannucchi AM, Paoli C, Passamonti F, Andreasson B, Ferrari ML, Rambaldi A, Samuelsson J, Birgegard G, Xiao Z, Xu Z, Zhang Y, Sun X, Xu J, Kiladjian JJ, Zhang P, Gale RP, Mesa RA, Geyer HL |title=Symptom burden profile in myelofibrosis patients with thrombocytopenia: Lessons and unmet needs |journal=Leuk. Res. |volume=63 |issue= |pages=34–40 |date=December 2017 |pmid=29096334 |doi=10.1016/j.leukres.2017.10.002 |url=}}</ref><ref name="pmid25521305">{{cite journal |vauthors=Wassie E, Finke C, Gangat N, Lasho TL, Pardanani A, Hanson CA, Ketterling RP, Tefferi A |title=A compendium of cytogenetic abnormalities in myelofibrosis: molecular and phenotypic correlates in 826 patients |journal=Br. J. Haematol. |volume=169 |issue=1 |pages=71–6 |date=April 2015 |pmid=25521305 |doi=10.1111/bjh.13260 |url=}}</ref><ref name="pmid27264006">{{cite journal |vauthors=Guglielmelli P, Rotunno G, Pacilli A, Rumi E, Rosti V, Delaini F, Maffioli M, Fanelli T, Pancrazzi A, Pieri L, Fjerza R, Pietra D, Cilloni D, Sant'Antonio E, Salmoiraghi S, Passamonti F, Rambaldi A, Barosi G, Barbui T, Cazzola M, Vannucchi AM |title=Prognostic impact of bone marrow fibrosis in primary myelofibrosis. A study of the AGIMM group on 490 patients |journal=Am. J. Hematol. |volume=91 |issue=9 |pages=918–22 |date=September 2016 |pmid=27264006 |doi=10.1002/ajh.24442 |url=}}</ref><ref name="pmid28153839">{{cite journal |vauthors=Xu Z |title=MDS/MPN with ring sideroblasts and thrombocytosis masquerading as prefibrotic/early primary myelofibrosis |journal=Blood |volume=129 |issue=5 |pages=657 |date=February 2017 |pmid=28153839 |doi=10.1182/blood-2016-11-749937 |url=}}</ref><ref name="pmid23498669">{{cite journal |vauthors=Cheminant M, Delarue R |title=[Investigation and management of patients presenting with thrombocytosis] |language=French |journal=Rev Med Interne |volume=34 |issue=8 |pages=465–71 |date=August 2013 |pmid=23498669 |doi=10.1016/j.revmed.2013.02.020 |url=}}</ref>
*[[Leukopenia]] and [[thrombocytopenia]] (in the advanced stages)<ref name="pmid29631428">{{cite journal |vauthors=Magyari F, Bedekovics J, Décsy J, Ilonczai P, Illés Á, Simon Z |title=[Investigation and treatment of prefibrotic/early primary myelofibrosis. A case study] |language=Hungarian |journal=Orv Hetil |volume=159 |issue=15 |pages=603–609 |date=April 2018 |pmid=29631428 |doi=10.1556/650.2018.30995 |url=}}</ref><ref name="pmid27315113">{{cite journal |vauthors=Barraco D, Lasho TL, Gangat N, Finke C, Elala YC, Pardanani A, Tefferi A |title=Leukocytosis and presence of CALR mutation is associated with non-hepatosplenic extramedullary hematopoiesis in primary myelofibrosis |journal=Blood Cancer J |volume=6 |issue= |pages=e436 |date=June 2016 |pmid=27315113 |pmc=5141359 |doi=10.1038/bcj.2016.44 |url=}}</ref><ref name="pmid27293069">{{cite journal |vauthors=Beauverd Y, Alimam S, McLornan DP, Radia DH, Harrison CN |title=Disease characteristics and outcomes in younger adults with primary and secondary myelofibrosis |journal=Br. J. Haematol. |volume=175 |issue=1 |pages=37–42 |date=October 2016 |pmid=27293069 |doi=10.1111/bjh.14173 |url=}}</ref><ref name="pmid25519030">{{cite journal |vauthors=Ota S, Hiramatsu Y, Kondo E, Kasahara A, Takada S, Umena S, Noguchi T, Tanimoto M, Matsumura T |title=Severe case of peripheral leukocytosis initially diagnosed as myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable, but possibly prefibrotic primary myelofibrosis |journal=Acta Med. Okayama |volume=68 |issue=6 |pages=363–8 |date=December 2014 |pmid=25519030 |doi=10.18926/AMO/53025 |url=}}</ref><ref name="pmid29096334">{{cite journal |vauthors=Scotch AH, Kosiorek H, Scherber R, Dueck AC, Slot S, Zweegman S, Boekhorst PAWT, Commandeur S, Schouten H, Sackmann F, Fuentes AK, Hernández-Maraver D, Pahl HL, Griesshammer M, Stegelmann F, Döhner K, Lehmann T, Bonatz K, Reiter A, Boyer F, Etienne G, Ianotto JC, Ranta D, Roy L, Cahn JY, Harrison CN, Radia D, Muxi P, Maldonado N, Besses C, Cervantes F, Johansson PL, Barbui T, Barosi G, Vannucchi AM, Paoli C, Passamonti F, Andreasson B, Ferrari ML, Rambaldi A, Samuelsson J, Birgegard G, Xiao Z, Xu Z, Zhang Y, Sun X, Xu J, Kiladjian JJ, Zhang P, Gale RP, Mesa RA, Geyer HL |title=Symptom burden profile in myelofibrosis patients with thrombocytopenia: Lessons and unmet needs |journal=Leuk. Res. |volume=63 |issue= |pages=34–40 |date=December 2017 |pmid=29096334 |doi=10.1016/j.leukres.2017.10.002 |url=}}</ref><ref name="pmid25521305">{{cite journal |vauthors=Wassie E, Finke C, Gangat N, Lasho TL, Pardanani A, Hanson CA, Ketterling RP, Tefferi A |title=A compendium of cytogenetic abnormalities in myelofibrosis: molecular and phenotypic correlates in 826 patients |journal=Br. J. Haematol. |volume=169 |issue=1 |pages=71–6 |date=April 2015 |pmid=25521305 |doi=10.1111/bjh.13260 |url=}}</ref><ref name="pmid27264006">{{cite journal |vauthors=Guglielmelli P, Rotunno G, Pacilli A, Rumi E, Rosti V, Delaini F, Maffioli M, Fanelli T, Pancrazzi A, Pieri L, Fjerza R, Pietra D, Cilloni D, Sant'Antonio E, Salmoiraghi S, Passamonti F, Rambaldi A, Barosi G, Barbui T, Cazzola M, Vannucchi AM |title=Prognostic impact of bone marrow fibrosis in primary myelofibrosis. A study of the AGIMM group on 490 patients |journal=Am. J. Hematol. |volume=91 |issue=9 |pages=918–22 |date=September 2016 |pmid=27264006 |doi=10.1002/ajh.24442 |url=}}</ref><ref name="pmid28153839">{{cite journal |vauthors=Xu Z |title=MDS/MPN with ring sideroblasts and thrombocytosis masquerading as prefibrotic/early primary myelofibrosis |journal=Blood |volume=129 |issue=5 |pages=657 |date=February 2017 |pmid=28153839 |doi=10.1182/blood-2016-11-749937 |url=}}</ref><ref name="pmid23498669">{{cite journal |vauthors=Cheminant M, Delarue R |title=[Investigation and management of patients presenting with thrombocytosis] |language=French |journal=Rev Med Interne |volume=34 |issue=8 |pages=465–71 |date=August 2013 |pmid=23498669 |doi=10.1016/j.revmed.2013.02.020 |url=}}</ref>
*[[Basophilia]]<ref name="pmid25900789">{{cite journal |vauthors=Koumas S, Prokopiou C, Lerni M, Seimeni O, Neokleous N |title=Isochromosome 17q10 associated with basophilia in primary myelofibrosis while with JAK2 inhibitor |journal=Ann. Hematol. |volume=94 |issue=8 |pages=1421–2 |date=August 2015 |pmid=25900789 |doi=10.1007/s00277-015-2380-5 |url=}}</ref><ref name="pmid27874969">{{cite journal |vauthors=Rautenbach Y, Goddard A, Clift SJ |title=Idiopathic myelofibrosis accompanied by peritoneal extramedullary hematopoiesis presenting as refractory ascites in a dog |journal=Vet Clin Pathol |volume=46 |issue=1 |pages=46–53 |date=March 2017 |pmid=27874969 |doi=10.1111/vcp.12430 |url=}}</ref><ref name="pmid9210912">{{cite journal |vauthors=Takimoto Y, Imanaka F, Hayashi Y, Shindo H |title=A patient with basophilic-eosinophilic myeloproliferative disorder showing monosomy 7 and hyperhistaminemia |journal=Acta Haematol. |volume=98 |issue=1 |pages=37–41 |date=1997 |pmid=9210912 |doi=10.1159/000203559 |url=}}</ref>
 
===On Confocal Microscopy===
*Proplatelet (pseudopodia of [[megakaryocyte]] which extend into [[bone marrow]] sinuses to release [[Platelet|platelets]]) formation<ref name="pmid20430444">{{cite journal |vauthors=Muth M, Büsche G, Bock O, Hussein K, Kreipe H |title=Aberrant proplatelet formation in chronic myeloproliferative neoplasms |journal=Leuk. Res. |volume=34 |issue=11 |pages=1424–9 |date=November 2010 |pmid=20430444 |doi=10.1016/j.leukres.2010.03.040 |url=}}</ref>
*[[CD14|CD14+ cells]] and [[Monocyte|monocytes]] expressing the angiopoietin-2 receptor (Tie2) lie close to the [[Blood vessel|vessels]] in the [[spleen]] [[tissue]]<ref name="pmid27281335">{{cite journal |vauthors=Campanelli R, Fois G, Catarsi P, Poletto V, Villani L, Erba BG, Maddaluno L, Jemos B, Salmoiraghi S, Guglielmelli P, Abbonante V, Di Buduo CA, Balduini A, Iurlo A, Barosi G, Rosti V, Massa M |title=Tie2 Expressing Monocytes in the Spleen of Patients with Primary Myelofibrosis |journal=PLoS ONE |volume=11 |issue=6 |pages=e0156990 |date=2016 |pmid=27281335 |pmc=4900622 |doi=10.1371/journal.pone.0156990 |url=}}</ref>
*[[Vessels]] with increased [[density]], [[tortuous]] architecture, and increased branching on [[bone marrow]] study<ref name="pmid10880370">{{cite journal |vauthors=Lundberg LG, Lerner R, Sundelin P, Rogers R, Folkman J, Palmblad J |title=Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity |journal=Am. J. Pathol. |volume=157 |issue=1 |pages=15–9 |date=July 2000 |pmid=10880370 |pmc=1850191 |doi=10.1016/S0002-9440(10)64511-7 |url=}}</ref>
*Thrombospondins (TSP) overexpression<ref name="pmid23259436">{{cite journal |vauthors=Kreipe H, Büsche G, Bock O, Hussein K |title=Myelofibrosis: molecular and cell biological aspects |journal=Fibrogenesis Tissue Repair |volume=5 |issue=Suppl 1 |pages=S21 |date=2012 |pmid=23259436 |pmc=3368793 |doi=10.1186/1755-1536-5-S1-S21 |url=}}</ref>
===On Electron Microscopy===
*Micromegakaryocytes with mature [[cytoplasm]] containing [[alpha granules]] and the associated [[Protein|proteins]]<ref name="pmid8435338">{{cite journal |vauthors=Reilly JT, Barnett D, Dolan G, Forrest P, Eastham J, Smith A |title=Characterization of an acute micromegakaryocytic leukaemia: evidence for the pathogenesis of myelofibrosis |journal=Br. J. Haematol. |volume=83 |issue=1 |pages=58–62 |date=January 1993 |pmid=8435338 |doi= |url=}}</ref>
*[[Megakaryocyte|Megakaryocytes]] in the [[peripheral blood]] with leukoerythroblastosis<ref name="pmid2621794">{{cite journal |vauthors=Shimizu S, Onodera Y, Nakamura Y, Ide K, Ayabe T, Isobe H, Nagoshi H, Someya K |title=[Megakaryocyte proportion versus nucleated cells in the peripheral blood showing leukoerythroblastosis] |language=Japanese |journal=Rinsho Ketsueki |volume=30 |issue=12 |pages=2141–7 |date=December 1989 |pmid=2621794 |doi= |url=}}</ref>
*Significant atypicalities of the [[Neutrophil|neutrophilic]], [[Basophil|basophilic]], and [[Megakaryocyte|megakaryocytic]] [[cell]] lines such as:
 
:*[[Nuclear]]-[[cytoplasmic]] asynchrony<ref name="pmid6935866">{{cite journal |vauthors=Thiele J, Vykoupil KF, Georgii A |title=Ultrastructure of blastic crisis in osteomyelofibrosis. A report of 2 cases with some unusual features |journal=Virchows Arch A Pathol Anat Histol |volume=389 |issue=3 |pages=287–305 |date=1980 |pmid=6935866 |doi= |url=}}</ref>
:*Partial arrest of [[maturation]]
*Ultrastructural abnormalities in [[Platelet|platelets]] such as:
 
:*[[Hypoplasia]] of surface connecting system with few orifices<ref name="pmid1129598">{{cite journal |vauthors=Hattori A, Koike K, Ito S, Matsuoka M |title=Static and functional morphology of the pathological platelets in primary myelofibrosis and myeloproliferative syndrome |journal=Ser Haematol |volume=8 |issue=1 |pages=126–50 |date=1975 |pmid=1129598 |doi= |url=}}</ref>
:*[[Hyperplasia]] of the [[dense]] [[tubular]] system
:*Considerable variety in the number of [[granules]]
*[[Splenic]] findings can consist of the following:
 
:*No alteration in the basic structure<ref name="pmid4793115">{{cite journal |vauthors=Tavassoli M, Weiss L |title=An electron microscopic study of spleen in myelofibrosis with myeloid metaplasia |journal=Blood |volume=42 |issue=2 |pages=267–79 |date=August 1973 |pmid=4793115 |doi= |url=}}</ref>
:*[[Degenerative]] [[Atrophy|atrophic]] changes in the [[white pulp]]
:*Erythropoietic and granulopoietic [[cells]] along with [[Megakaryocyte|megakaryocytes]] in the [[sinuses]] and cords of the [[red pulp]]
:*[[Cytoplasm|Cytoplasmic]] ([[degenerative]] in nature) and [[nuclear]] ([[nuclear]] blebs and loops) changes in the [[Hematopoietic cell|,refhematopoietic cells]]
 
===Images===
[[File:Tear drop poikilocytes in Myelofibrosis.jpg|300px|left|thumb| Histopathological image showing teardrop poikilocytes (yellow arrows) <ref>By Osaretin - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=36814333</ref>]]
[[File:Thrombocytosis.jpg|300px|center|thumb| Histopathological image showing essential thrombocytosis (yellow arrows) <ref>By Erhabor Osaro (Associate Professor) - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=32131622</ref>]]
<br style="clear:left">


==References==
==References==
{{reflist|2}}
{{reflist|2}}


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Latest revision as of 22:50, 29 July 2020

Myelofibrosis Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

Overview

Myelofibrosis, a myeloproliferative disorder, is characterized by the proliferation of megakaryocytes in the bone marrow, disrupted cytokine production, and reactive fibrosis resulting in bone marrow failure. The fibrosed and scarred bone marrow produces fewer and fewer normal functioning blood cells leading to pancytopenia and extramedullary hematopoiesis (EMH). It can mainly be associated with somatic mutation of the myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene but other genes can also be involved and it can also result in the setting of another primary insult. Associated conditions include malignancies, hematologic disorders, infections, autoimmune diseases, and endocrine disorders. Hepatomegaly, splenomegaly, and lymphadenopathy are the positive findings on gross pathology. On microscopic pathology, myelofibrosis is characterized by low RBC count, leukopenia - leukocytosis, basophilia, erythroblastosis, thrombocytopenia - thrombocytosis, micromegakaryocytes, splenic pulp changes, and abnormalities of platelets.

Pathophysiology

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On Light Microscopy

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On Electron Microscopy

  • Ultrastructural abnormalities in platelets such as:
  • Splenic findings can consist of the following:

Images

Histopathological image showing teardrop poikilocytes (yellow arrows) [100]
Histopathological image showing essential thrombocytosis (yellow arrows) [101]


References

  1. ↑ 1.0 1.1 Bedekovics J, Méhes G (March 2014). "[Pathomechanism and clinical impact of myelofibrosis in neoplastic diseases of the bone marrow]". Orv Hetil (in Hungarian). 155 (10): 367–75. doi:10.1556/OH.2014.29823. PMID 24583557.
  2. ↑ Vainchenker W, Kralovics R (February 2017). "Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms". Blood. 129 (6): 667–679. doi:10.1182/blood-2016-10-695940. PMID 28028029.
  3. ↑ 3.0 3.1 3.2 Alshemmari SH, Rajan R, Emadi A (2016). "Molecular Pathogenesis and Clinical Significance of Driver Mutations in Primary Myelofibrosis: A Review". Med Princ Pract. 25 (6): 501–509. doi:10.1159/000450956. PMC 5588514. PMID 27756071.
  4. ↑ de Freitas RM, da Costa Maranduba CM (2015). "Myeloproliferative neoplasms and the JAK/STAT signaling pathway: an overview". Rev Bras Hematol Hemoter. 37 (5): 348–53. doi:10.1016/j.bjhh.2014.10.001. PMC 4685044. PMID 26408371.
  5. ↑ Le Bousse-Kerdilès MC, Martyré MC (October 1999). "Dual implication of fibrogenic cytokines in the pathogenesis of fibrosis and myeloproliferation in myeloid metaplasia with myelofibrosis". Ann. Hematol. 78 (10): 437–44. PMID 10550553.
  6. ↑ Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP (November 2007). "Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres". Br. J. Haematol. 139 (3): 351–62. doi:10.1111/j.1365-2141.2007.06807.x. PMID 17910625.
  7. ↑ 7.0 7.1 7.2 Reilly JT, Barnett D, Dolan G, Forrest P, Eastham J, Smith A (January 1993). "Characterization of an acute micromegakaryocytic leukaemia: evidence for the pathogenesis of myelofibrosis". Br. J. Haematol. 83 (1): 58–62. PMID 8435338.
  8. ↑ Schmitt A, Drouin A, Massé JM, Guichard J, Shagraoui H, Cramer EM (April 2002). "Polymorphonuclear neutrophil and megakaryocyte mutual involvement in myelofibrosis pathogenesis". Leuk. Lymphoma. 43 (4): 719–24. doi:10.1080/10428190290016809. PMID 12153156.
  9. ↑ Schmitt A, Jouault H, Guichard J, Wendling F, Drouin A, Cramer EM (August 2000). "Pathologic interaction between megakaryocytes and polymorphonuclear leukocytes in myelofibrosis". Blood. 96 (4): 1342–7. PMID 10942376.
  10. ↑ Zahr AA, Salama ME, Carreau N, Tremblay D, Verstovsek S, Mesa R, Hoffman R, Mascarenhas J (June 2016). "Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies". Haematologica. 101 (6): 660–71. doi:10.3324/haematol.2015.141283. PMC 5013940. PMID 27252511.
  11. ↑ Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, Them NC, Berg T, Gisslinger B, Pietra D, Chen D, Vladimer GI, Bagienski K, Milanesi C, Casetti IC, Sant'Antonio E, Ferretti V, Elena C, Schischlik F, Cleary C, Six M, Schalling M, Schönegger A, Bock C, Malcovati L, Pascutto C, Superti-Furga G, Cazzola M, Kralovics R (December 2013). "Somatic mutations of calreticulin in myeloproliferative neoplasms". N. Engl. J. Med. 369 (25): 2379–90. doi:10.1056/NEJMoa1311347. PMID 24325356.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 Mak YK, Chan CH, So CC, Chan MK, Chu YC (February 2002). "Idiopathic myelofibrosis with extramedullary haemopoiesis involving the urinary bladder in a Chinese lady". Clin Lab Haematol. 24 (1): 55–9. PMID 11843900.
  13. ↑ 13.0 13.1 Philipponnet C, Ronco P, Aniort J, Kemeny JL, Heng AE (December 2017). "Membranous Nephropathy and Intrarenal Extramedullary Hematopoiesis in a Patient With Myelofibrosis". Am. J. Kidney Dis. 70 (6): 874–877. doi:10.1053/j.ajkd.2017.06.022. PMID 28821362.
  14. ↑ 14.0 14.1 14.2 Yang M, Roarke M (March 2017). "Diffuse pulmonary extramedullary hematopoiesis in myelofibrosis diagnosed with technetium-99m sulfur colloid bone marrow scintigraphy and single photon emission computerized tomography/CT". Am. J. Hematol. 92 (3): 323–324. doi:10.1002/ajh.24616. PMID 27883206.
  15. ↑ 15.0 15.1 Pizzi M, Gergis U, Chaviano F, Orazi A (September 2016). "The effects of hematopoietic stem cell transplant on splenic extramedullary hematopoiesis in patients with myeloproliferative neoplasm-associated myelofibrosis". Hematol Oncol Stem Cell Ther. 9 (3): 96–104. doi:10.1016/j.hemonc.2016.07.002. PMID 27521149.
  16. ↑ 16.0 16.1 Campanelli R, Fois G, Catarsi P, Poletto V, Villani L, Erba BG, Maddaluno L, Jemos B, Salmoiraghi S, Guglielmelli P, Abbonante V, Di Buduo CA, Balduini A, Iurlo A, Barosi G, Rosti V, Massa M (2016). "Tie2 Expressing Monocytes in the Spleen of Patients with Primary Myelofibrosis". PLoS ONE. 11 (6): e0156990. doi:10.1371/journal.pone.0156990. PMC 4900622. PMID 27281335.
  17. ↑ Mohyuddin GR, Yacoub A (2016). "Primary Myelofibrosis Presenting as Extramedullary Hematopoiesis in a Transplanted Liver Graft: Case Report and Review of the Literature". Case Rep Hematol. 2016: 9515404. doi:10.1155/2016/9515404. PMC 4739215. PMID 26885416.
  18. ↑ Henry M, Chitlur M, Rajpurkar M, Mastropietro CW, Poulik J, Ravindranath Y (May 2014). "Myelofibrosis, hepatic extramedullary hematopoiesis and ascites associated with vitamin D deficiency in early infancy". J. Pediatr. Hematol. Oncol. 36 (4): 319–21. doi:10.1097/MPH.0b013e31828e548a. PMID 23619118.
  19. ↑ 19.0 19.1 Imai K, Aoi T, Kitai H, Endo N, Fujino M, Ichida S (November 2017). "A case of perirenal extramedullary hematopoiesis in a patient with primary myelofibrosis". CEN Case Rep. 6 (2): 194–199. doi:10.1007/s13730-017-0274-1. PMC 5694411. PMID 28895103.
  20. ↑ 20.0 20.1 20.2 Kwak HS, Lee JM (August 2000). "CT findings of extramedullary hematopoiesis in the thorax, liver and kidneys, in a patient with idiopathic myelofibrosis". J. Korean Med. Sci. 15 (4): 460–2. doi:10.3346/jkms.2000.15.4.460. PMC 3054659. PMID 10983698.
  21. ↑ Singer A, Quencer R (2014). "Intracranial extramedullary hematopoiesis: a rare cause of headaches". J Neuroimaging. 24 (5): 524–7. doi:10.1111/jon.12029. PMID 23621819.
  22. ↑ Fareed S, Nashwan AJ, Abu Jarir S, Husain A, Suliman DS, Ibrahim F, Moustafa A, Akhter MS, Yassin MA (August 2017). "Spinal Abscess Caused by Salmonella Bacteremia in a Patient with Primary Myelofibrosis". Am J Case Rep. 18: 859–864. PMC 5551928. PMID 28775247.
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  24. ↑ Mizoguchi M, Kawa Y, Minami T, Nakayama H, Mizoguchi H (February 1990). "Cutaneous extramedullary hematopoiesis in myelofibrosis". J. Am. Acad. Dermatol. 22 (2 Pt 2): 351–5. PMID 2406300.
  25. ↑ Patel KP, Newberry KJ, Luthra R, Jabbour E, Pierce S, Cortes J, Singh R, Mehrotra M, Routbort MJ, Luthra M, Manshouri T, Santos FP, Kantarjian H, Verstovsek S (August 2015). "Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib". Blood. 126 (6): 790–7. doi:10.1182/blood-2015-03-633404. PMC 4528066. PMID 26124496.
  26. ↑ Tefferi, A; Lasho, T L; Finke, C M; Knudson, R A; Ketterling, R; Hanson, C H; Maffioli, M; Caramazza, D; Passamonti, F; Pardanani, A (2014). "CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons". Leukemia. 28 (7): 1472–1477. doi:10.1038/leu.2014.3. ISSN 0887-6924.
  27. ↑ Baxter EJ, Scott LM, Campbell PJ; et al. (2005). "Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders". Lancet. 365 (9464): 1054–61. doi:10.1016/S0140-6736(05)71142-9. PMID 15781101.
  28. ↑ Pikman Y, Lee BH, Mercher T; et al. (2006). "MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia". PLoS Med. 3 (7): e270. doi:10.1371/journal.pmed.0030270. PMC 1502153. PMID 16834459. Unknown parameter |month= ignored (help)
  29. ↑ Shammo JM, Stein BL (December 2016). "Mutations in MPNs: prognostic implications, window to biology, and impact on treatment decisions". Hematology Am Soc Hematol Educ Program. 2016 (1): 552–560. doi:10.1182/asheducation-2016.1.552. PMC 6142495. PMID 27913528.
  30. ↑ Li B, Xu J, Wang J, Gale RP, Xu Z, Cui Y, Yang L, Xing R, Ai X, Qin T, Zhang Y, Zhang P, Xiao Z (November 2014). "Calreticulin mutations in Chinese with primary myelofibrosis". Haematologica. 99 (11): 1697–700. doi:10.3324/haematol.2014.109249. PMC 4222480. PMID 24997152.
  31. ↑ Rotunno G, Pacilli A, Artusi V, Rumi E, Maffioli M, Delaini F, Brogi G, Fanelli T, Pancrazzi A, Pietra D, Bernardis I, Belotti C, Pieri L, Sant'Antonio E, Salmoiraghi S, Cilloni D, Rambaldi A, Passamonti F, Barbui T, Manfredini R, Cazzola M, Tagliafico E, Vannucchi AM, Guglielmelli P (July 2016). "Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group". Am. J. Hematol. 91 (7): 681–6. doi:10.1002/ajh.24377. PMID 27037840.
  32. ↑ Song J, Hussaini M, Zhang H, Shao H, Qin D, Zhang X, Ma Z, Hussnain Naqvi SM, Zhang L, Moscinski LC (May 2017). "Comparison of the Mutational Profiles of Primary Myelofibrosis, Polycythemia Vera, and Essential Thrombocytosis". Am. J. Clin. Pathol. 147 (5): 444–452. doi:10.1093/ajcp/aqw222. PMC 5402718. PMID 28419183.
  33. ↑ 33.0 33.1 Tefferi A (December 2016). "Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management". Am. J. Hematol. 91 (12): 1262–1271. doi:10.1002/ajh.24592. PMID 27870387.
  34. ↑ Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A, Finke C, Score J, Gangat N, Mannarelli C, Ketterling RP, Rotunno G, Knudson RA, Susini MC, Laborde RR, Spolverini A, Pancrazzi A, Pieri L, Manfredini R, Tagliafico E, Zini R, Jones A, Zoi K, Reiter A, Duncombe A, Pietra D, Rumi E, Cervantes F, Barosi G, Cazzola M, Cross NC, Tefferi A (September 2013). "Mutations and prognosis in primary myelofibrosis". Leukemia. 27 (9): 1861–9. doi:10.1038/leu.2013.119. PMID 23619563.
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  63. ↑ Negrón D, Colón-Castillo L, Morales-Melecio I, Correa-Rivas M (2008). "Association of extensive brain calcifications, myelofibrosis, and retinopathy in a 12-year-old child". Pediatr. Dev. Pathol. 11 (2): 148–51. doi:10.2350/06-03-0061.1. PMID 17990901.
  64. ↑ Ito A, Umeda M, Koike T, Naruse S, Fujita N (March 2006). "[A case of dermatomyositis associated with chronic idiopathic myelofibrosis]". Rinsho Shinkeigaku (in Japanese). 46 (3): 210–3. PMID 16642932.
  65. ↑ 65.0 65.1 Cervantes F, Correa JG, Hernandez-Boluda JC (May 2016). "Alleviating anemia and thrombocytopenia in myelofibrosis patients". Expert Rev Hematol. 9 (5): 489–96. doi:10.1586/17474086.2016.1154452. PMID 26891375.
  66. ↑ Hernández-Boluda JC, Martínez-Trillos A, García-Gutiérrez V, Ferrer-Marín F, Xicoy B, Alvarez-Larrán A, Kerguelen A, Barba P, Gómez M, Herrera JC, Correa JG, Cervantes F (2016). "Long-term results of prednisone treatment for the anemia of myelofibrosis". Leuk. Lymphoma. 57 (1): 120–4. doi:10.3109/10428194.2015.1046866. PMID 25944376.
  67. ↑ Ungprasert P, Chowdhary VR, Davis MD, Makol A (April 2016). "Autoimmune myelofibrosis with pancytopenia as a presenting manifestation of systemic lupus erythematosus responsive to mycophenolate mofetil". Lupus. 25 (4): 427–30. doi:10.1177/0961203315615221. PMID 26537421.
  68. ↑ Tang VK, Huh YO, Tayar JH, Rojas Hernandez CM (2016). "Primary autoimmune myelofibrosis as etiology of pancytopenia mimicking myelodysplastic syndrome". Leuk. Lymphoma. 57 (3): 731–4. doi:10.3109/10428194.2015.1076931. PMID 26422082.
  69. ↑ Panda A, Chandrashekhara SH, Nambirajan A, Mishra P (December 2016). "Idiopathic myelofibrosis with disseminated hepatosplenic, mesenteric, renal and pulmonary extramedullary haematopoeisis, portal hypertension and tuberculosis: initial presentation and 2 years follow-up". BMJ Case Rep. 2016. doi:10.1136/bcr-2016-217854. PMID 28011890.
  70. ↑ Gruner BA, DeNapoli TS, Elshihabi S, Britton HA, Langevin AM, Thomas PJ, Weitman SD (October 2003). "Anemia and hepatosplenomegaly as presenting features in a child with rickets and secondary myelofibrosis". J. Pediatr. Hematol. Oncol. 25 (10): 813–5. PMID 14528107.
  71. ↑ Guermazi A, de Kerviler E, Cazals-Hatem D, Zagdanski AM, Frija J (1999). "Imaging findings in patients with myelofibrosis". Eur Radiol. 9 (7): 1366–75. doi:10.1007/s003300050850. PMID 10460376.
  72. ↑ Merry GM, Aronowitz PB (March 2010). "Myelofibrosis with massive hepatosplenomegaly and osteolytic bone lesions". J Hosp Med. 5 (3): E27–8. doi:10.1002/jhm.459. PMID 20235305.
  73. ↑ Thiele J, Kvasnicka HM (August 2005). "Hematopathologic findings in chronic idiopathic myelofibrosis". Semin. Oncol. 32 (4): 380–94. doi:10.1053/j.seminoncol.2005.04.010. PMID 16202684.
  74. ↑ Hernández-Boluda JC, Correa JG, García-Delgado R, Martínez-López J, Alvarez-Larrán A, Fox ML, García-Gutiérrez V, Pérez-Encinas M, Ferrer-Marín F, Mata-Vázquez MI, Raya JM, Estrada N, García S, Kerguelen A, Durán MA, Albors M, Cervantes F (April 2017). "Predictive factors for anemia response to erythropoiesis-stimulating agents in myelofibrosis". Eur. J. Haematol. 98 (4): 407–414. doi:10.1111/ejh.12846. PMID 28009442.
  75. ↑ Tóth P, Tóth Z (2002). "Idiopathic myelofibrosis with prominent postsplenectomy erythroblastosis terminating in acute myeloid transformation". Haematologia (Budap). 32 (2): 155–61. PMID 12412736.
  76. ↑ Osman Y, Kishi K, Narita M, Saito H, Masuko M, Koike T, Shibata A (June 1996). "Idiopathic myelofibrosis with unusually high erythroblastosis in the peripheral blood". Am. J. Hematol. 52 (2): 122–3. doi:10.1002/(SICI)1096-8652(199606)52:2<122::AID-AJH12>3.0.CO;2-J. PMID 8638637.
  77. ↑ Robier C, Körber C, Quehenberger F, Neubauer M, Wölfler A (January 2018). "The frequency of occurrence of fish-shaped red blood cells in different haematologic disorders". Clin. Chem. Lab. Med. 56 (2): 323–326. doi:10.1515/cclm-2017-0378. PMID 28731851.
  78. ↑ Biagini G, Severi B, Govoni E, Preda P, Pileri S, Martinelli G, Visani G, Finelli C, Castaldini C (1985). "Stromal cells in primary myelofibrosis: ultrastructural observations". Virchows Arch., B, Cell Pathol. 48 (1): 1–8. PMID 2580387.
  79. ↑ Egelé A, van Gelder W, Riedl J (December 2015). "Automated detection and classification of teardrop cells by a novel RBC module using digital imaging/microscopy". Int J Lab Hematol. 37 (6): e153–6. doi:10.1111/ijlh.12399. PMID 26118701.
  80. ↑ Madelung A, Bzorek M, Bondo H, Zetterberg E, Bjerrum OW, Hasselbalch HC, Scheding S, Ralfkiaer E (March 2012). "A novel immunohistochemical sequential multi-labelling and erasing technique enables epitope characterization of bone marrow pericytes in primary myelofibrosis". Histopathology. 60 (4): 554–60. doi:10.1111/j.1365-2559.2011.04104.x. PMID 22250648.
  81. ↑ 81.0 81.1 Lundberg LG, Lerner R, Sundelin P, Rogers R, Folkman J, Palmblad J (July 2000). "Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity". Am. J. Pathol. 157 (1): 15–9. doi:10.1016/S0002-9440(10)64511-7. PMC 1850191. PMID 10880370.
  82. ↑ 82.0 82.1 Magyari F, Bedekovics J, Décsy J, Ilonczai P, Illés Á, Simon Z (April 2018). "[Investigation and treatment of prefibrotic/early primary myelofibrosis. A case study]". Orv Hetil (in Hungarian). 159 (15): 603–609. doi:10.1556/650.2018.30995. PMID 29631428.
  83. ↑ 83.0 83.1 Barraco D, Lasho TL, Gangat N, Finke C, Elala YC, Pardanani A, Tefferi A (June 2016). "Leukocytosis and presence of CALR mutation is associated with non-hepatosplenic extramedullary hematopoiesis in primary myelofibrosis". Blood Cancer J. 6: e436. doi:10.1038/bcj.2016.44. PMC 5141359. PMID 27315113.
  84. ↑ 84.0 84.1 Beauverd Y, Alimam S, McLornan DP, Radia DH, Harrison CN (October 2016). "Disease characteristics and outcomes in younger adults with primary and secondary myelofibrosis". Br. J. Haematol. 175 (1): 37–42. doi:10.1111/bjh.14173. PMID 27293069.
  85. ↑ 85.0 85.1 Ota S, Hiramatsu Y, Kondo E, Kasahara A, Takada S, Umena S, Noguchi T, Tanimoto M, Matsumura T (December 2014). "Severe case of peripheral leukocytosis initially diagnosed as myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable, but possibly prefibrotic primary myelofibrosis". Acta Med. Okayama. 68 (6): 363–8. doi:10.18926/AMO/53025. PMID 25519030.
  86. ↑ 86.0 86.1 Scotch AH, Kosiorek H, Scherber R, Dueck AC, Slot S, Zweegman S, Boekhorst P, Commandeur S, Schouten H, Sackmann F, Fuentes AK, Hernández-Maraver D, Pahl HL, Griesshammer M, Stegelmann F, Döhner K, Lehmann T, Bonatz K, Reiter A, Boyer F, Etienne G, Ianotto JC, Ranta D, Roy L, Cahn JY, Harrison CN, Radia D, Muxi P, Maldonado N, Besses C, Cervantes F, Johansson PL, Barbui T, Barosi G, Vannucchi AM, Paoli C, Passamonti F, Andreasson B, Ferrari ML, Rambaldi A, Samuelsson J, Birgegard G, Xiao Z, Xu Z, Zhang Y, Sun X, Xu J, Kiladjian JJ, Zhang P, Gale RP, Mesa RA, Geyer HL (December 2017). "Symptom burden profile in myelofibrosis patients with thrombocytopenia: Lessons and unmet needs". Leuk. Res. 63: 34–40. doi:10.1016/j.leukres.2017.10.002. PMID 29096334. Vancouver style error: initials (help)
  87. ↑ 87.0 87.1 Wassie E, Finke C, Gangat N, Lasho TL, Pardanani A, Hanson CA, Ketterling RP, Tefferi A (April 2015). "A compendium of cytogenetic abnormalities in myelofibrosis: molecular and phenotypic correlates in 826 patients". Br. J. Haematol. 169 (1): 71–6. doi:10.1111/bjh.13260. PMID 25521305.
  88. ↑ 88.0 88.1 Guglielmelli P, Rotunno G, Pacilli A, Rumi E, Rosti V, Delaini F, Maffioli M, Fanelli T, Pancrazzi A, Pieri L, Fjerza R, Pietra D, Cilloni D, Sant'Antonio E, Salmoiraghi S, Passamonti F, Rambaldi A, Barosi G, Barbui T, Cazzola M, Vannucchi AM (September 2016). "Prognostic impact of bone marrow fibrosis in primary myelofibrosis. A study of the AGIMM group on 490 patients". Am. J. Hematol. 91 (9): 918–22. doi:10.1002/ajh.24442. PMID 27264006.
  89. ↑ 89.0 89.1 Xu Z (February 2017). "MDS/MPN with ring sideroblasts and thrombocytosis masquerading as prefibrotic/early primary myelofibrosis". Blood. 129 (5): 657. doi:10.1182/blood-2016-11-749937. PMID 28153839.
  90. ↑ 90.0 90.1 Cheminant M, Delarue R (August 2013). "[Investigation and management of patients presenting with thrombocytosis]". Rev Med Interne (in French). 34 (8): 465–71. doi:10.1016/j.revmed.2013.02.020. PMID 23498669.
  91. ↑ Koumas S, Prokopiou C, Lerni M, Seimeni O, Neokleous N (August 2015). "Isochromosome 17q10 associated with basophilia in primary myelofibrosis while with JAK2 inhibitor". Ann. Hematol. 94 (8): 1421–2. doi:10.1007/s00277-015-2380-5. PMID 25900789.
  92. ↑ Rautenbach Y, Goddard A, Clift SJ (March 2017). "Idiopathic myelofibrosis accompanied by peritoneal extramedullary hematopoiesis presenting as refractory ascites in a dog". Vet Clin Pathol. 46 (1): 46–53. doi:10.1111/vcp.12430. PMID 27874969.
  93. ↑ Takimoto Y, Imanaka F, Hayashi Y, Shindo H (1997). "A patient with basophilic-eosinophilic myeloproliferative disorder showing monosomy 7 and hyperhistaminemia". Acta Haematol. 98 (1): 37–41. doi:10.1159/000203559. PMID 9210912.
  94. ↑ Muth M, Büsche G, Bock O, Hussein K, Kreipe H (November 2010). "Aberrant proplatelet formation in chronic myeloproliferative neoplasms". Leuk. Res. 34 (11): 1424–9. doi:10.1016/j.leukres.2010.03.040. PMID 20430444.
  95. ↑ Kreipe H, Büsche G, Bock O, Hussein K (2012). "Myelofibrosis: molecular and cell biological aspects". Fibrogenesis Tissue Repair. 5 (Suppl 1): S21. doi:10.1186/1755-1536-5-S1-S21. PMC 3368793. PMID 23259436.
  96. ↑ Shimizu S, Onodera Y, Nakamura Y, Ide K, Ayabe T, Isobe H, Nagoshi H, Someya K (December 1989). "[Megakaryocyte proportion versus nucleated cells in the peripheral blood showing leukoerythroblastosis]". Rinsho Ketsueki (in Japanese). 30 (12): 2141–7. PMID 2621794.
  97. ↑ Thiele J, Vykoupil KF, Georgii A (1980). "Ultrastructure of blastic crisis in osteomyelofibrosis. A report of 2 cases with some unusual features". Virchows Arch A Pathol Anat Histol. 389 (3): 287–305. PMID 6935866.
  98. ↑ Hattori A, Koike K, Ito S, Matsuoka M (1975). "Static and functional morphology of the pathological platelets in primary myelofibrosis and myeloproliferative syndrome". Ser Haematol. 8 (1): 126–50. PMID 1129598.
  99. ↑ Tavassoli M, Weiss L (August 1973). "An electron microscopic study of spleen in myelofibrosis with myeloid metaplasia". Blood. 42 (2): 267–79. PMID 4793115.
  100. ↑ By Osaretin - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=36814333
  101. ↑ By Erhabor Osaro (Associate Professor) - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=32131622
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