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Myeloproliferative Disease

Myeloproliferative Disorder

Myeloproliferative diseases are a collective group of disorders characterized by the clonal proliferation of at least one hematopoietic cell lineage. The ensuing conditions are associated with severe complications.

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Presentation

Myeloproliferative diseases have similar clinical pictures and generally feature nonspecific symptoms such as fatigue, weight loss, and anorexia. Once the condition progresses, the patients develop signs and symptoms. Patients with abnormal blood count are prone to bleeding easily, prolonged hemorrhage, and thrombosis. The latter is more common in ET and PV due to the viscosity of the blood, which also increases the risk for cardiovascular events. Leukocytopenia leads to infection of the sinuses, skin, and genitourinary system. Pain and early satiety caused by an enlarged spleen are particularly observed in CML and PMF.

Further signs such as tinnitus, priapism, and stupor are suggestive of leukostasis. Arthralgia and gout occur secondary to hyperuricemia. Note that the Neoplasm Symptom Assessment Form (MPN-SAF) can be administered to patients suffering from myeloproliferative diseases as a method to assess the patient's clinical picture [12].

Physical exam

Remarkable findings on the exam include pallor, petechiae, and ecchymoses. Moreover, patients with these conditions exhibit splenomegaly, and pain the left upper quadrant and left shoulder due to splenic infarction.

Easy Bruising
  • Signs and symptoms Patients may have a history of the following: Easy fatigability Anorexia, weight loss Abdominal discomfort and early satiety secondary to splenomegaly: Most common in chronic myelogenous leukemia and agnogenic myeloid metaplasia Easy[emedicine.medscape.com]
  • Symptoms of aCML may include easy bruising or bleeding and feeling tired or weak. Myelodysplastic/myeloproliferative diseases may progress to acute leukemia.[rarediseases.info.nih.gov]
  • History Presenting complaints in patients with myeloproliferative neoplasms include the following: Easy fatigability Easy bruising, bleeding, and/or symptoms of thrombosis Swollen, painful joint(s) secondary to gouty arthritis secondary to hyperuricemia[emedicine.medscape.com]
  • Bleeding and easy bruising can also occur. This is usually minor and occurs in around one quarter of all patients. Similar to polycythaemia vera many people have no symptoms when they are first diagnosed with ET.[leukaemia.org.au]
Splenomegaly
  • CML: demonstrates increased production of neutrophils and marked splenomegaly.[ncbi.nlm.nih.gov]
  • The unusual case of myeloproliferative disease described here is characterized by the following features: (1) a clinically completely silent course for 11 years without splenomegaly, marrow fibrosis, or cellular morphologic alterations; (2) the presence[ncbi.nlm.nih.gov]
  • Essential thrombocythemia (ET) was suspected by a sustained increase in platelet count ( 400 x 10(9)/l) and slight splenomegaly on echogram.[ncbi.nlm.nih.gov]
  • Our patient in fact did not fulfill the WHO diagnostic criteria for myeloproliferative disease (MPD), while she had splenomegaly and developed features suggestive of latent ET during follow-up.[ncbi.nlm.nih.gov]
  • Both patients were suffering from thrombocytopenia and splenomegaly and underwent splenectomy. The weight of the spleen specimens was more than 2000 g.[ncbi.nlm.nih.gov]
Palpable Spleen
  • spleen and/or liver Occasionally, syndrome of fever accompanied by painful, maculopapular, violaceous lesions on the trunk, arms, legs, and face; this is called acute febrile neutrophilic dermatosis, or Sweet syndrome See Clinical Presentation for more[emedicine.medscape.com]
  • spleen and/or liver Occasionally, a syndrome of fever accompanied by painful maculopapular violaceous lesions on trunk, arms, legs, and face, which is called acute febrile neutrophilic dermatosis or Sweet syndrome Causes As with other malignant disorders[emedicine.medscape.com]
Generalized Lymphadenopathy
  • lymphadenopathy & hepatospleenomegaly -Uncommon in Asians -Dx is made from a sustained ABS lymphocytosis of 5000/ml (N up to 4,000) * Note: There is an expansion of mature appearing lymphocytes involving the lymph nodes and other lymphoid tissues with[quizlet.com]
Massive Splenomegaly
  • When patients are poorly compliant with phlebotomy or issues of massive splenomegaly, leukocytosis, or thrombocytosis supervene, treatment with interferon or pegylated interferon is considered for patients younger than 50 years (who are more likely to[northshore.org]
Dyspnea
  • .  35 y/o previously healthy man  9 month history of tachycardia and dyspnea on exertion  Dec. 2011, dyspnea becomes more severe  Hospitalized in Miami when found to have evidence of acute and chronic P.E.s  Evidence of pulmonary hypertension and[slideshare.net]
  • Myeloproliferative Disorders: -Polycythemia Vera (PV) * Signs/Sxs: -Expanded blood volume & hyperviscosity * lead to: weakness headache light-headedness visual disturbances fatigue dyspnea -Bleeding diathesis (tendency) is common (epistaxis) -Pruritus[quizlet.com]
  • Dyspnea secondary to pulmonary hematopoiesis as presenting symptom of myelofibrosis with myeloid metaplasia Am J Hematol 2006 ; 81 : 124-127 [cross-ref] [18] Kurtman C., Ozbilgin M.K., Andrieu M.N., et al.[em-consulte.com]
  • Patients also may present constitutional symptoms such as dyspnea, fatigue, night sweats, weight loss, fever, and bleeding. Some patients present renal stones and gouty arthritis due to hyperuricemia.[scielo.br]
Hepatomegaly
  • We report that after a long latency period, approximately 33% of mice from two independent transgenic lines and from backcrosses into either the FVB or the C57BL/6 strains succumbed to a similar disease characterized by splenomegaly, hepatomegaly, and[ncbi.nlm.nih.gov]
  • Splenomegaly, hepatomegaly as well as fatigue, malaise or weight loss may appear in advanced stages.[orpha.net]
  • In some cases the liver may also be enlarged: this is called hepatomegaly. Some people experience gout, which usually presents as a painful inflammation of the big toe or foot.[leukaemia.org.au]
  • This is most clearly seen in chronic myelogenous leukemia, where the BCR/ABL gene is involved in enhancement of tyrosine kinase activity.Splenomegaly and hepatomegaly are also fairly common, secondary to extramedullary hematopoiesis.[clinlabnavigator.com]
  • WBC are increased and there is increased thrombocytosis Later phases: increasing and progressive fibrosis in BM, splenomegaly/hepatomegaly, moderate to marked anemia, leukopenia and thrombocytopenia What does the peripheral smear of myelofibrosis show[quizlet.com]
Hepatosplenomegaly
  • Marked myeloid proliferation, anemia, thrombocytopenia and hepatosplenomegaly were present; leukocyte alkaline phosphatase and fetal hemoglobin were moderately elevated. Chromosome analysis of bone marrow cells revealed a mosaicism 47,XX, 21/46,XX.[ncbi.nlm.nih.gov]
  • This story begins in 1892, when Louis Henri Vaquez first described polycythemia vera in a patient with marked erythrocytosis and hepatosplenomegaly that he postulated was the result of hematopoietic cell proliferation. 1 Subsequently, William Osler described[bloodjournal.org]
  • Chronic Neutrophilic Leukemia CNL is diagnosed when the hematologic criteria are met ( Table 1 ) , hepatosplenomegaly is present, no evidence of a physiologic neutrophilia is found, and other MPNs and myelodysplastic disorders are ruled out. 8 A normal[questdiagnostics.com]
Headache
  • Symptoms resulting from hypervolemia and hyperviscosity, such as headache, dizziness, visual disturbances and paresthesias, are sometimes present.[medindia.net]
  • It does not promote leukemia but can cause dizziness, headaches, fluid retention, rapid heartbeats, diarrhea , and rare cases of heart failure.[encyclopedia.com]
  • May treat headache and burning pain in the skin. Hydroxyurea (Droxia, Hydrea) or anagrelide (Agrylin) reduces number of blood cells. Aminocaproic acid. Reduces bleeding. This treatment may be used before surgery to prevent bleeding as well.[pennstatehershey.adam.com]
  • Mean age of diagnosis: 60 Most symptoms are related to increased RBC mass and abnormal blood flow: -Venous stasis, thrombosis and hemorrhage -Hypertension -Headache, weakness, sweating -Intense puritis -Increased incidence of peptic ulcer disease The[quizlet.com]
Stroke
  • Many people with these conditions have few, if any, symptoms, but complications can occur, including stroke in patients with poorly controlled disease.[ucsfhealth.org]
  • This can cause serious health problems such as a stroke, heart attack or pulmonary embolism Is one of a related group of blood cancers known as “myeloproliferative neoplasms” (MPNs) in w...[lls.org]
  • This may cause heart disease, stroke, or gangrene (tissue death) of the arms and legs.[pennstatehershey.adam.com]
  • Less frequently, patients with polycythemia veradevelop myocardial infarction, stroke, venous thrombosis and congestive heart failure. Overall survival is long (10 to 20 years).[medindia.net]
  • They increase your risk of stroke and heart attack, and may cause an enlarged spleen. Our doctors make an accurate diagnosis to ensure your condition is managed effectively.[dukehealth.org]
Dizziness
  • Symptoms resulting from hypervolemia and hyperviscosity, such as headache, dizziness, visual disturbances and paresthesias, are sometimes present.[medindia.net]
  • It does not promote leukemia but can cause dizziness, headaches, fluid retention, rapid heartbeats, diarrhea , and rare cases of heart failure.[encyclopedia.com]
  • Insiduous onset with mean age range 50-60 Most present with a thrombotic event (MI or stroke) Other symptoms include HA and dizziness and can see splenomegaly in 50% of patients Describe the course and prognosis of thrombocythemia: Indolent disorder characterized[quizlet.com]
  • After progressing, it may cause headaches, shortness of breath, bleeding, dizziness, itchiness, or an enlarged spleen. The disease can also increase the likelihood of developing blood clots and the risk of stroke.[mskcc.org]
Tingling
  • […] the ears pain in the chest (angina) weakness or cramping pains in the legs that disappear during rest redness of the face a blue tinge to the skin and other body surfaces (cyanosis) high blood pressure itching , especially after a warm bath or shower tingling[encyclopedia.com]
  • They include: Headache Dizziness or lightheadedness Chest pain Fainting Temporary vision changes Numbness or tingling of the hands and feet Redness, throbbing and burning pain in the hands and feet (erythromelalgia) Less commonly, essential thrombocythemia[mayoclinic.org]
  • This can cause symptoms such as headaches, dizziness, visual distortion, itching, and numbness or tingling ( paresthesia ).[labtestsonline.org]
Stupor
  • […] splenomegaly: Most common in chronic myelogenous leukemia and agnogenic myeloid metaplasia Easy bruising, bleeding, and/or symptoms of thrombosis Swollen, painful joint(s) secondary to gouty arthritis that is secondary to hyperuricemia Priapism, tinnitus, or stupor[emedicine.medscape.com]
  • ), splenic infarction (left upper-(tinnitus, stupor), splenic infarction (left upper-quadrant and left shoulder pain), urticaria (resultquadrant and left shoulder pain), urticaria (resultof histamine release)of histamine release) Physical signsPhysical[slideshare.net]
  • […] pressure Blockage of blood vessels, potentially leading to heart disease, stroke , or gangrene (tissue death) of the arms and legs Painful swollen joints, caused by gouty arthritis , which is in turn caused by hyperuricemia Bone pain Priapism Tinnitus Stupor[diagnose-me.com]
Anemia
  • Here is reported the case of an elderly woman that, after surgical intervention, showed an important anemia, leucocytosis and thrombocytopenia. The leucocytosis was accompanied with clean increase of the monocytes.[ncbi.nlm.nih.gov]
  • Marked myeloid proliferation, anemia, thrombocytopenia and hepatosplenomegaly were present; leukocyte alkaline phosphatase and fetal hemoglobin were moderately elevated. Chromosome analysis of bone marrow cells revealed a mosaicism 47,XX, 21/46,XX.[ncbi.nlm.nih.gov]
  • .- ) Type 1 Excludes acute myelofibrosis ( C94.4- ) idiopathic myelofibrosis ( D47.1 ) leukoerythroblastic anemia ( D61.82 ) myelofibrosis with myeloid metaplasia ( D47.4 ) myelophthisic anemia ( D61.82 ) myelophthisis ( D61.82 ) primary myelofibrosis[icd10data.com]
  • The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by anemia of varying severity and the presence of ringed sideroblasts in the bone marrow. 11 Ringed sideroblasts are erythroblasts with iron-loaded mitochondria[haematologica.org]
Pain
  • Antiplatelet therapy resulted in prompt relief of pain and the disappearance of platelet aggregates.[ncbi.nlm.nih.gov]
  • Patients with painful, massively enlarged spleens refractory to myelosuppressive therapy are occasionally treated with radiation therapy, but they may ultimately require splenectomy.[emedicine.medscape.com]
  • Left upper quadrant and left shoulder pain as a consequence of splenic infarction and perisplenitis In many patients, abnormal blood counts are noted on a blood test performed for other reasons.[emedicine.medscape.com]
  • : weakness dizziness headaches prickling or tingling in the skin erythromelalgia (warmth, redness, and pain in the extremities) Other symptoms of polycythemia vera can include: headaches dizziness ringing in the ears pain in the chest (angina) weakness[encyclopedia.com]
Fatigue
  • We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: December 1, 2018[patientslikeme.com]
  • Splenomegaly, hepatomegaly as well as fatigue, malaise or weight loss may appear in advanced stages.[orpha.net]
  • The resulting fibrous scar tissue formation leads to severe anemia, weakness, fatigue and an enlarged spleen and liver. Is a type of chronic leukemia and can occur on its own (p...[llscanada.org]
  • Signs and Symptoms Patients of myeloproliferative diseases can often experience non-specific symptoms such as fatigue and loss of appetite.[knowcancer.com]
Weight Loss
  • Splenomegaly, hepatomegaly as well as fatigue, malaise or weight loss may appear in advanced stages.[orpha.net]
  • Symptomatic patients have fatigue, shortness of breath, weight loss, bleeding or abdominal discomfort related to splenomegaly. Acute leukemia can develop over time and, when it occurs, progresses rapidly.[medindia.net]
  • Its side effects include flu-like symptoms (fever, chills, postnasal drip and poor appetite), fatigue, weight loss, depression , insomnia, memory loss, and nausea.[encyclopedia.com]
  • Signs and symptoms Patients may have a history of the following: Easy fatigability Anorexia, weight loss Abdominal discomfort and early satiety secondary to splenomegaly: Most common in chronic myelogenous leukemia and agnogenic myeloid metaplasia Easy[emedicine.medscape.com]
Weakness
  • The resulting fibrous scar tissue formation leads to severe anemia, weakness, fatigue and an enlarged spleen and liver. Is a type of chronic leukemia and can occur on its own (p...[llscanada.org]
  • Blood cell numbers drop, causing fatigue and weakness from anemia . Many of the cells found in the blood are also immature or oddly shaped.[encyclopedia.com]
  • -May have indications of: * "HYPERVISCOSITY SYNDROME" * fatigue * bleeding from skin and mucous membranes * weakness * visual disturbances * headaches.[quizlet.com]
  • Mean age of diagnosis: 60 Most symptoms are related to increased RBC mass and abnormal blood flow: -Venous stasis, thrombosis and hemorrhage -Hypertension -Headache, weakness, sweating -Intense puritis -Increased incidence of peptic ulcer disease The[quizlet.com]
Abdominal Pain
  • When anemia develops, it can cause fatigue, weakness, and abdominal pain from an enlarged spleen. Myelofibrosis can occur by itself or with other blood disorders. Myelofibrosis Treatment There are a variety of treatments for myelofibrosis.[mskcc.org]
  • Symptoms Signs  Fatigue  Malaise  Early satiety  Weight loss  Fever  Abdominal pain  Bone pain  Pruritis  Splenomegaly  Abnormal blood counts  Abnormal peripheral blood smears  Hyperuricemia and gout  Thrombosis or bleeding 8.[slideshare.net]
  • An enlarged spleen can cause abdominal pain and a feeling of fullness.[pennstatehershey.adam.com]
  • Symptoms that can be seen in any of these diseases include: fatigue poor appetite ( anorexia ) weight loss night sweats fullness in the stomach after eating only a small amount abdominal pain or discomfort, especially in the upper left side nosebleeds[encyclopedia.com]
Early Satiety
  • Signs and symptoms Patients may have a history of the following: Easy fatigability Anorexia, weight loss Abdominal discomfort and early satiety secondary to splenomegaly: Most common in chronic myelogenous leukemia and agnogenic myeloid metaplasia Easy[emedicine.medscape.com]
  • Symptoms Signs  Fatigue  Malaise  Early satiety  Weight loss  Fever  Abdominal pain  Bone pain  Pruritis  Splenomegaly  Abnormal blood counts  Abnormal peripheral blood smears  Hyperuricemia and gout  Thrombosis or bleeding 8.[slideshare.net]
  • Approximately 25-50% of patients will have symptoms from an enlarged spleen at diagnosis, including pain with deep breaths, loss of appetite and feeling full after eating a small amount (called early satiety).[oncolink.org]
  • They complain about feeling early satiety, increased abdominal volume, left hypochondriac pain or bowel constipation. Epistaxis and ecchymosis are common.[scielo.br]
Nausea
  • Its side effects include flu-like symptoms (fever, chills, postnasal drip and poor appetite), fatigue, weight loss, depression , insomnia, memory loss, and nausea.[encyclopedia.com]
Bleeding Gums
  • This may appear as nosebleeds, bleeding gums or bruising. Rarely, essential thrombocythemia may progress to these potentially life-threatening diseases: Acute myelogenous leukemia.[mayoclinic.org]
  • gums Gastrointestinal bleeding Blood in the urine High blood pressure Blockage of blood vessels, potentially leading to heart disease, stroke , or gangrene (tissue death) of the arms and legs Painful swollen joints, caused by gouty arthritis , which[diagnose-me.com]
Thrombosis
  • We investigated whether thrombosis involving the inferior vena cava (IVC) is also related to the JAK2V617F mutation or CMD. Blood samples were obtained from 40 IVC thrombosis patients.[ncbi.nlm.nih.gov]
  • Splanchnic vein thrombosis (SVT) is a severe complication of essential thrombocythemia (ET).[ncbi.nlm.nih.gov]
  • The JAK2 V617F point mutation was found in 3 patients with extrahepatic portal vein thrombosis who had multiple thrombotic events but did not fulfill the traditional diagnostic criteria for MPDs.[ncbi.nlm.nih.gov]
  • The present study describes portal vein thrombosis (PVT) in two women as the first and single presenting symptom of latent or masked myeloproliferative disease (MPD).[ncbi.nlm.nih.gov]
  • In addition, there were no significant correlations between bone marrow CD34 levels and the JAK-2 V617F mutation, thrombosis, WBC, LDH, TS, ferritin, or bone marrow cellularity (P   0.05).[ncbi.nlm.nih.gov]
Chest Pain
  • .  Vasomotor symptoms: Headache, Lightheadedness, Syncope, Atypical chest pain Acral paresthesia, Livedo reticularis  Erythromelalgia - burning pain of the hands or feet associated with erythema and warmth.  Transient visual disturbances (eg, amaurosis[slideshare.net]
  • They include: Headache Dizziness or lightheadedness Chest pain Fainting Temporary vision changes Numbness or tingling of the hands and feet Redness, throbbing and burning pain in the hands and feet (erythromelalgia) Less commonly, essential thrombocythemia[mayoclinic.org]
  • Patients may experience headaches, dizziness, fatigue , chest pains, or weakness and cramping in the calves while walking. The abnormal blood flow can also result in bleeding tendencies or blood clotting inside the veins.[encyclopedia.com]
  • They also may have tingling in the hands and feet, headaches, chest pain or discomfort, bloating in the upper left abdominal area, weakness, dizziness, nosebleeds, and easy bruising.[labtestsonline.org]
Cyanosis
  • Other symptoms of polycythemia vera can include: headaches dizziness ringing in the ears pain in the chest (angina) weakness or cramping pains in the legs that disappear during rest redness of the face a blue tinge to the skin and other body surfaces (cyanosis[encyclopedia.com]
  • Thrombosis in small blood vessels can lead to cyanosis, erythromelalgia (painful vessel dilation in the extremities), ulceration, or gangrene in the fingers or toes.[clevelandclinicmeded.com]
  • Chronic cyanosis with polycythemia and enlarged spleen: a new clinical entity. Am J Med Sci. 2008;335(6):411-7. [ Links ] Comment in: Am J Med Sci. 2008;335(6):418-9. [ Links ] 46. Berlin NI. Diagnosis and classification of the polycythemias.[scielo.br]
Tachycardia
  • .  35 y/o previously healthy man  9 month history of tachycardia and dyspnea on exertion  Dec. 2011, dyspnea becomes more severe  Hospitalized in Miami when found to have evidence of acute and chronic P.E.s  Evidence of pulmonary hypertension and[slideshare.net]
Blurred Vision
  • Common symptoms include: headaches blurred vision fatigue weakness dizziness itchiness (pruritus) night sweats raised blood pressure (hypertension). Other symptoms experienced in MPN are a result of the affected cell involved with the MPN.[leukaemia.org.au]
  • As the disease progresses, the following symptoms may appear: Blood clot Headache Excessive sweating Blurred vision or blind spots Dizziness Itchiness, especially after a warm shower or bath Redness or a purplish appearance of skin Peptic ulcers Bloat[cancersupportcommunity.org]
Tinnitus
  • […] to splenomegaly: Most common in chronic myelogenous leukemia and agnogenic myeloid metaplasia Easy bruising, bleeding, and/or symptoms of thrombosis Swollen, painful joint(s) secondary to gouty arthritis that is secondary to hyperuricemia Priapism, tinnitus[emedicine.medscape.com]
  • […] sweatingweight loss, excessive sweating Less frequent symptomsLess frequent symptoms::Night sweats, heat intolerance- mimickingNight sweats, heat intolerance- mimickinghyperthyroidism, symptoms of leukostasishyperthyroidism, symptoms of leukostasis(tinnitus[slideshare.net]
  • Clinical description Symptoms are often insidious at onset and may include headache, dizziness, vertigo, tinnitus, visual disturbances, and pruritus after bathing, a ruddy complexion that manifests in the face, palms, nailbeds, mucosa and conjunctiva.[orpha.net]
  • […] blood pressure Blockage of blood vessels, potentially leading to heart disease, stroke , or gangrene (tissue death) of the arms and legs Painful swollen joints, caused by gouty arthritis , which is in turn caused by hyperuricemia Bone pain Priapism Tinnitus[diagnose-me.com]
Bone Pain
  • Symptoms Signs  Fatigue  Malaise  Early satiety  Weight loss  Fever  Abdominal pain  Bone pain  Pruritis  Splenomegaly  Abnormal blood counts  Abnormal peripheral blood smears  Hyperuricemia and gout  Thrombosis or bleeding 8.[slideshare.net]
  • Waldenstrom's Macroglobulinemia Plasma Cell Dyscrasias (PCDs) -Multiple Myeloma * Symptoms -Unexplained: * bone pain (back, thorax) * renal failure * recurrent bacterial infections most common (b/c the ABN plasma cells are using all of the resources to[quizlet.com]
  • pain Diagnosis The diagnosis of a myeloproliferative disease relies mainly on a physical examination, examination of a blood sample, and sometimes a bone marrow biopsy .[encyclopedia.com]
  • Blood in the urine High blood pressure Blockage of blood vessels, potentially leading to heart disease, stroke , or gangrene (tissue death) of the arms and legs Painful swollen joints, caused by gouty arthritis , which is in turn caused by hyperuricemia Bone[diagnose-me.com]
Shoulder Pain
  • pain as a consequence of splenic infarction and perisplenitis Clinical symptoms can include the following: Pallor (except in patients with polycythemia vera) Plethora secondary to polycythemia Petechiae and/or ecchymosis Palpable spleen and/or liver[emedicine.medscape.com]
  • pain as a consequence of splenic infarction and perisplenitis In many patients, abnormal blood counts are noted on a blood test performed for other reasons.[emedicine.medscape.com]
  • pain), urticaria (resultquadrant and left shoulder pain), urticaria (resultof histamine release)of histamine release) Physical signsPhysical signs::Pallor, splenomegaly, sternal painPallor, splenomegaly, sternal pain 15.[slideshare.net]
  • pain (due to spleen tissue death and inflammation of the surface of the spleen) Enlarged spleen and/or liver Occasionally, a syndrome of fever with painful, maculopapular, violet-colored sores across the body; this is known as acute febrile neutrophilic[diagnose-me.com]
Arthralgia
  • Treatment revolves around measures to maintain hydration, to relieve arthralgias, to prevent thrombotic episodes, and to prevent infections.[ncbi.nlm.nih.gov]
  • […] be grouped into 1) constitutional symptoms; 2) skin conditions such as pruritus and urticaria; 3) mast cell mediator-related features including abdominal pain, flushing, headache, and respiratory symptoms; and 4) musculoskeletal complaints including arthralgia[questdiagnostics.com]
Leg Pain
  • Painful swollen joints, caused by gouty arthritis , which is in turn caused by hyperuricemia Bone pain Priapism Tinnitus Stupor due to leukostasis Left upper quadrant and left shoulder pain (due to spleen tissue death and inflammation of the surface[diagnose-me.com]
Night Sweats
  • Common symptoms include: headaches blurred vision fatigue weakness dizziness itchiness (pruritus) night sweats raised blood pressure (hypertension). Other symptoms experienced in MPN are a result of the affected cell involved with the MPN.[leukaemia.org.au]
  • sweats Abnormal bleeding Chronic myelogenous leukemia (CML) Fatigue, general malaise Weight loss or loss of appetite Fever and night sweats Bone or joint pain Heart attack or stroke Trouble breathing Gastrointestinal bleeding Infection All myeloproliferative[pennstatehershey.adam.com]
  • Symptoms that can be seen in any of these diseases include: fatigue poor appetite ( anorexia ) weight loss night sweats fullness in the stomach after eating only a small amount abdominal pain or discomfort, especially in the upper left side nosebleeds[encyclopedia.com]
Petechiae
  • […] stupor from leukostasis Left upper quadrant and left shoulder pain as a consequence of splenic infarction and perisplenitis Clinical symptoms can include the following: Pallor (except in patients with polycythemia vera) Plethora secondary to polycythemia Petechiae[emedicine.medscape.com]
  • […] carry oxygen) Shortness of breath Pale skin Weakness and fatigue Lack of appetite Bleeding in excess (even when you get a minor cut) Sinus infections Skin infections Urinary tract infections ( UTIs ) Headaches Fatigue Bruising easily Night sweats Fevers Petechiae[webmd.com]
  • […] blinded opinion of patient symptoms. [17] Physical Examination Physical examination findings in patients with myeloproliferative disease may include the following: Pallor, except in patients with polycythemia vera Plethora secondary to polycythemia Petechiae[emedicine.medscape.com]
  • Symptoms of MDS While MDS rarely has symptoms at first, overtime, it may cause: Fatigue Shortness of breath Unusual paleness (pallor) due to anemia Easy or unusual bruising or bleeding Pinpoint-sized red spots just beneath your skin caused by bleeding (petechiae[mountsinai.org]
Pruritus
  • Common symptoms include: headaches blurred vision fatigue weakness dizziness itchiness (pruritus) night sweats raised blood pressure (hypertension). Other symptoms experienced in MPN are a result of the affected cell involved with the MPN.[leukaemia.org.au]
  • […] with intractable pruritus.[clevelandclinicmeded.com]
  • Clinical description Symptoms are often insidious at onset and may include headache, dizziness, vertigo, tinnitus, visual disturbances, and pruritus after bathing, a ruddy complexion that manifests in the face, palms, nailbeds, mucosa and conjunctiva.[orpha.net]
  • Myeloproliferative Disorders: -Polycythemia Vera (PV) * Signs/Sxs: -Expanded blood volume & hyperviscosity * lead to: weakness headache light-headedness visual disturbances fatigue dyspnea -Bleeding diathesis (tendency) is common (epistaxis) -Pruritus[quizlet.com]
Urticaria
  • Urticaria pigmentosaUrticaria pigmentosa 52. Mast cell leukemiaMast cell leukemia[slideshare.net]
  • Systemic Mastocytosis Clinical symptoms of SM can be grouped into 1) constitutional symptoms; 2) skin conditions such as pruritus and urticaria; 3) mast cell mediator-related features including abdominal pain, flushing, headache, and respiratory symptoms[questdiagnostics.com]
Purpura
  • Thrombotic thrombocytopenic purpura – This results in the reduction of platelet production and bleeding tendencies. Unexplained cytopenia – This results in decrease in production of all cell types.[news-medical.net]
Epistaxis
  • Myeloproliferative Disorders: -Polycythemia Vera (PV) * Signs/Sxs: -Expanded blood volume & hyperviscosity * lead to: weakness headache light-headedness visual disturbances fatigue dyspnea -Bleeding diathesis (tendency) is common (epistaxis) -Pruritus[quizlet.com]
  • Abnormalities in platelet function lead to bleeding complications that include epistaxis, bruising, and gastrointestinal and gingival bleeding in 5% to 10% of patients. 15 Severe bleeding episodes are unusual.[clevelandclinicmeded.com]
  • Epistaxis and ecchymosis are common. Ischemic manifestations of the central nervous system (CNS) are potentially debilitating and should be feared.[scielo.br]

Workup

When in early stages, MPNs may be discovered incidentally on routine tests. In others, the clinical picture will warrant further investigation. Asymptomatic patients with abnormal tests and symptomatic patients should all undergo a clinical assessment that consists of a thorough history, a complete physical exam, and appropriate studies. A CBC with differential, blood smear, bone marrow/aspiration, and genetic analyses are key studies that provide information about the disease and its degree of severity.

In CML, cytogenic testing will demonstrate the presence of the Philadelphia chromosome. Polymerase chain reaction (PCR) and fluorescent in-situ hybridization (FISH) are other diagnostic techniques that can be used as well.

The index of suspicion for PV is high for men with a hemoglobin above 18.5 g/dL and women with a hemoglobin greater than 16.5 g/dL. In addition to the abnormal hemoglobin values, the WHO proposes that the presence of JAK2 mutation on PCR analysis is another major criterion for the diagnosis of PV. Note that the clinician should exclude secondary etiologies of polycythemia.

The workup for ET is comprised of PCR detection of JAK2 V617F mutation or another clonal marker. According to the WHO [13], the following are the criteria for the diagnosis of ET: 1) a platelet count above or equal to 450 x 109/L, 2) evidence of megakaryocyte proliferation, 3) presence of above mutation, and 4) failure to meet criteria for other myeloid neoplasms. Note that reactive thrombocytosis must be ruled out.

Histologic studies on peripheral blood smear reflect a picture of leukoerythroblastosis im PMF. Moreover, bone marrow biopsy studies reveal increased fibrosis. The WHO [2] outlines the following diagnostic criteria 1) proliferation of megakaryocytes on bone marrow analysis, 2) presence of JAK2 V617F mutation or other clonal marker, and 3) exclusion of other causes. Also, about half of all patients have cytogenic defects such as various deletions and trisomies [14].

In CEL, thorough anamnesis and physical examination should be conducted to identify possible triggers of secondary eosinophilia. The latter may be induced by hypersensitivity reactions, infestation with parasites, autoimmune disorders, psoriasis and other skin diseases, among others. These are not necessarily associated with severe clinical symptoms, and if patients are unaware of their condition and don't seek medical attention, they may develop chronic eosinophilia. In case of confirmed primary eosinophilia, blood smears should be prepared because they may reveal important morphological features of distinct cell populations. Results may or may not hint at a malignancy, and they may allow for the distinction of myeloid and lymphoid neoplasms and myelodysplastic syndromes. FIP1L1-PDGFRA fusion has been reported to be the most common chromosomal rearrangement causing CEL. Consequently, patients suspicious of CEL should first be tested to this effect. Nested reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization may be applied to demonstrate the absence of loci physiologically located between those genes encoding for FIP1L1 and PDGFRA. A combined approach may significantly increase the sensitivity of tests. Blood and bone marrow specimens that test negative for FIP1L1-PDGFRA should subsequently be subjected to analysis for PDGFRB or FGFR1 rearrangements. According to the diagnostic guidelines given by the World Health Organization, identification of any of the aforementioned cytogenetic anomalies warrants the diagnosis of an eosinophilic myeloproliferative disorder due to rearrangements of PDGFRA, PDGFRB or FGFR1. However, CEL-NOS is not associated with any of those abnormalities, and other myeloid malignancies should be ruled by the following measures:

  • Demonstration of clonality of eosinophils.
  • Screens for chromosomal and genetic anomalies known to be involved in the pathogenesis of chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, e.g., Philadelphia chromosome, somatic mutations of the gene encoding cytoplasmic Janus kinase 2 or the thrombopoietin receptor.
  • Ascertainment of blast cell ratios in blood and bone marrow. In case of CEL-NOS, they do exceed 2% and 5%, respectively, but are lower than 20%. Even higher blast counts may indicate acute myeloid leukemia.

If these criteria are not met by a patient presenting with chronic eosinophilia, they are usually diagnosed with IHS.

Thrombocytosis
  • The clonal origin of myeloproliferative disorders has been clearly demonstrated and it is known that reactive thrombocytosis occurs as a non specific response to various inflammatory or neoplastic conditions.[ncbi.nlm.nih.gov]
  • One patient clearly represents a case of RARS with reactive thrombocytosis. Two cases have features suggestive of the coincidental occurrence of essential thrombocythemia and RARS.[ncbi.nlm.nih.gov]
  • JAK2V617F mutations are present in almost all patients with polycythemia vera, and in approximately half of those with essential thrombocytosis and myelofibrosis.[ncbi.nlm.nih.gov]
  • The diagnosis of an essential thrombocytosis is demonstrated in this presentation of a well-looking 53 year old man who had a five-year history of increasing facial asymmetry as evidenced by deviation of his mandible to the right and malocclusion.[ncbi.nlm.nih.gov]
  • Children with Down syndrome (DS) display macrocytosis, thrombocytosis, and a 500-fold increased risk of developing megakaryocytic leukemia; however, the specific effects of trisomy 21 on hematopoiesis remain poorly defined.[ncbi.nlm.nih.gov]
Erythrocytosis
  • These data suggest that erythrocytosis and granulocytosis in JAK2(V617F) mice are the net result of a complex interplay between cell intrinsic and extrinsic factors.[ncbi.nlm.nih.gov]
  • Our data seem to indicate that both thrombocytosis and erythrocytosis resembled primary forms in these subjects; however, none of them suffered serious thrombotic and/or hemorrhagic symptoms.[ncbi.nlm.nih.gov]
  • There have been no prospective national studies to estimate the incidence or outcomes of myeloproliferative disorders, persistent thrombocytosis or erythrocytosis in pregnancy.[npeu.ox.ac.uk]
  • Philadelphia-negative chronic myeloproliferative disorders (polycythemia vera, essential thrombocythemia, primary myelofibrosis) are characterized by various combinations of erythrocytosis, leukocytosis and thrombocytosis, i.e., the opposite of cytopenia[haematologica.org]
  • Although JAK2V617F is observed in PV, ET, and PMF, exon 12 mutations to date have only been identified in patients with JAK2V617F erythrocytosis, and in most cases are observed in patients with idiopathic erythrocytosis (IE) without associated thrombocytosis[bloodjournal.org]
Karyotype Abnormal
  • abnormalities, and the number of cytopenias.[em-consulte.com]
  • In the remaining patients, clonal karyotypic abnormalities may include 8, 9, del (20q) and del (11q).[ 1 , 3 , 4 , 5 ] There is no Philadelphia chromosome or BCR/ABL fusion gene.[northshore.org]
Hemoglobin Increased
  • Erythroid-specific expression of heterozygous or homozygous Jak2V617F resulted in a polycythemia-like phenotype characterized by increase in hematocrit and hemoglobin, increased red blood cells, erythropoietin-independent erythroid colonies and splenomegaly[ncbi.nlm.nih.gov]
Platelet Aggregation Abnormal
  • Although platelet aggregation abnormalities exist in most patients, these abnormalities do not appear to correlate with the risk of bleeding or thrombosis.[clevelandclinicmeded.com]
Hypercellular Bone Marrow
  • The chronic myeloproliferative diseases are characterized by relatively effective hematopoiesis, which results in a hypercellular bone marrow and elevation of one or more of the cell lines in the peripheral blood.[clinlabnavigator.com]
  • bone marrow although BM may be NORMAL.[quizlet.com]

Treatment

The main class of drugs used in the treatment of CML targets the tyrosine kinase. Hence, the tyrosine kinase inhibitors (TKIs) such as imatinib, and other new ones are used as first-line agents. Chemotherapy, allogenic stem cell transplantation, and interferon have all been used in the past but are associated with adverse effects.

Patients developing CEL due to rearrangements involving those genes encoding for PDGFRA or PDGFRB generally respond well to treatment with imatinib. Allogeneic stem cell transplantation should be considered in cases of advanced CEL and poor response to drug therapy.

The goals for patients with PV are to reduce the red blood cell count and to decrease the risk of thrombosis. Hence, phlebotomy is the mainstay therapy, as it decreases the hemoglobin level and viscosity of the blood. Furthermore, aspirin 81mg is used for prevention of thrombotic events unless the patient has contraindications. Myelosuppressive drugs such as hydroxyurea, interferon, and JAK inhibitors may be helpful.

Treatment of ET is approached differently for low and high-risk groups. The low risk refers to patients who 1) are younger than the age of 60, 2) possess risk factors for thrombosis or cardiovascular events, and 3) exhibit platelet count of ≤1,500 x 109/L. These individuals can be observed or treated with low dose aspirin. High-risk patients are older than 60 years of age and/or positive for a history of a thrombotic episode. These patients should be treated with cytoreductive therapy.

While allogeneic hematopoietic cell transplantation can reverse the process of this disease, the advanced age of these individuals renders them as poor candidates. The only drug approved for PMF is a selective JAK1/JAK2 inhibitor called ruxolitinib. Other similar agents are currently undergoing clinical trials [15]. Supportive transfusions are very beneficial for these patients.

Prognosis

Many cases of myeloproliferative disorders develop gradually and slowly. With prompt and appropriate management, the outcomes are promising. The prognosis is reflective of numerous factors such as the type of disease, the clinical presentation, percentage of blasts present in the peripheral blood and blood marrow, and existing chromosomal defects.

Patients with PV have a close to normal life expectancy with at least 10 years after diagnosis. Those with ET have a normal lifespan. Furthermore, individuals with PMF have a poor prognosis with a median survival of 3.5 to 5.5 years [11]. The common causes of death in the latter are attributed to infection, cardiovascular events, hemorrhage, and thrombosis.

It is estimated that 1070 patients with CML will die in 2016 [7]. Furthermore, the later stages of CML are difficult to control and associated with increased risk of fatality. Advanced CML is more aggressive that the other proliferative disorders.

Complications

There are serious sequelae that can arise from myeloproliferative diseases such as myocardial infarction, stroke, infection, liver failure, renal failure, anemia, hemorrhage, and hepatomegaly/splenomegaly. Additionally, CML has the potential to transform into acute leukemia.

Etiology

Myeloproliferative disease encompasses a group of neoplasms affecting then proliferation of hematopoietic cell lineages in the bone marrow, and possibly the spleen and liver [3]. The etiology may be multifactorial in which there is genetic and environmental interplay.

More than 90% of all cases of CML occur secondary to the presence of the Philadelphia chromosome, which results from a balanced reciprocal translocation between chromosomes 9 and 22. The new chromosome includes the BCR-ABL fusion oncogene which codes for a constitutively active tyrosine kinase. The latter leads to the overproduction of the progenitor hematopoietic cells.

Certain subtypes of CEL are associated with genetic anomalies provoking constitutive activity of tyrosine kinases. The respective rearrangements of PDGFRA, PDGFRB or FGFR1 have not only been detected in eosinophils, but also in non-eosinophilic granulocytes, monocytes and mast cells, and this observation implies that chromosomal alterations originate from common precursor cells, i.e., from myeloblasts or earlier developmental stages of myeloid cells.

More than 90% of PV cases exhibit a mutation in the Jak2 gene [4]. There are familial cases that have been linked to a mutated erythropoietin (EPO) receptor.

ET emerges due to the hypersensitivity of megakaryocyte progenitor cells to cytokines such as interleukin-3 (IL-3) and IL-6 [5]. Furthermore, about 50% to 65% of individuals with ET have a mutation in the JAK2 kinase, which leads to its overactivity and contribution to the disease.

The underlying mechanism responsible for PMF is the clonal proliferation of hematopoietic stem cells. Approximately half of all cases have a JAK2 mutation. This causes the myeloid cells to increase their response to cytokines. Risk factors for PMF include exposure to radiation and petrochemicals such as toluene and benzene.

Epidemiology

The incidence of CML in 2016 is 1.8 per population of 100,000 [6]. Furthermore, the median age at diagnosis is 64 years [7]. There is a gender preference for males. The overall annual incidence of CEL and idiopathic hypereosinophilic syndrome has been estimated to be 0.036 per 100,000 inhabitants.

The prevalence of PV in the United States is approximately 44 to 57 individuals per population of 100,000 [8]. This affects both genders of all ethnicities but is more common in East European Jewish background. It typically presents in the 6th or the 7th decade of life, with a possible predilection for men [9] [10].

The prevalence of ET is about 30 to 57 per population of 100,000. [8]. The median age at diagnosis is 60 years old. Furthermore, it is more commonly found in younger women.

The estimated incidence of PMF between 2008 and 2010 was 1 per population of 100,000 [8]. The median age at diagnosis is 67 years. It affects men and women equally and occurs more in Caucasians. This disease may develop in progressive cases of PV and other myeloproliferative neoplasms.

Sex distribution
Age distribution

Pathophysiology

The pathophysiology of CML is explained by the underlying tyrosine kinase that exhibits a gain of function characteristic, which leads to the excessive production of granulocytes as well as red blood cells, megakaryocytes, monocytes, etc. The clinical course of CML evolves over three stages which are the chronic, accelerated, and blast phases. The chronic phase is insidious and may last months to years. The accelerated phase is aggressive and eventually progresses to the blast crisis. It is thought that genetic instability and additional chromosomal defects play a role in the evolution of the disease.

In PV, the pathogenesis emerges from the abnormal proliferation of pluripotent stem cells and their differentiation into granulocytes, red blood cells, and platelets. This occurs as a consequence of progenitor cells projecting a high response to erythropoietin, IL-3, and granulocyte-macrophage-colony-stimulating factor. The majority of cases have a constantly active JAK-STAT pathway. Thrombosis and bleeding are serious sequelae [10], which manifest as a result of the viscosity caused by the overproduction of red blood cells and platelets.

In ET, megakaryocyte precursors have an increased response to cytokines and maybe even thrombopoietin. The mutations associated with ET are found in JAK2, thrombopoietin receptor (MPL) and/or calreticulin (CALR). Clinical complications include thrombosis and bleeding although the mechanisms are not fully understood.

PMF is characterized by excessive marrow fibrosis as well as extramedullary hematopoiesis. Originating from clonal stem cells, the myeloid cells secrete platelet-derived growth factor (PDGF), transforming growth factor-B (TGF-B), epidermal growth factor (EGF), and basic fibroblastic growth factor (FGF). The resultant bone marrow fibrosis ultimately leads to pancytopenia and extramedullary hematopoiesis.

Prevention

There is no prevention for myeloproliferative diseases.

Summary

The myeloproliferative disorders, currently known as myeloproliferative neoplasms (MPNs), describe a group of conditions caused by the proliferation of clonal hematopoietic stem cells in the bone marrow and occasionally in the spleen and liver [1]. The World Health Organization (WHO) classified chronic myelogenous leukemia (CML), polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL), not otherwise specified and mastocytosis among the MPNs [2].

While these disorders have overlapping features, they also vary. CML is the only neoplasm with the characteristic BCR-ABL fusion oncogene that leads to excessive production of blast cells. PV occurs secondary to a Janus kinase 2 (JAK2) mutation that results in an overproduction of red blood cells. Furthermore, ET is defined as the proliferation of megakaryocytes and the ensuing thrombocytosis. PMF is characterized by the marrow fibrosis and extramedullary hematopoiesis.

Myeloproliferative disorders are often slow developing and do not initially present with symptoms. Moreover, the majority of patients are diagnosed incidentally while undergoing routine testing. The clinical picture in early stages is often nonspecific with symptoms including fatigue, weight loss and anorexia. As the disease evolves with the involvement of the bone marrow, more ominous findings and signs manifest. Serious complications such thrombosis and hemorrhage arise.

The diagnosis is achieved through a thorough assessment of the patient's history, physical examination, and pertinent studies. The latter includes the complete blood count (CBC), analysis of peripheral blood smear, bone marrow biopsy and aspiration, and chromosomal studies.

The therapeutic approach depends on the present disorder. The goals aim to prolong survival and improve the quality of life. The treatment ranges from specific target drugs to plasmapheresis.

Patient Information

What are myeloproliferative disorders?

This group of diseases occurs largely due to mutations in the stem cells of the bone marrow causing an overproduction of various types of blood cells. The following are the main myeloproliferative disorders:

What are the signs and symptoms?

These diseases take months to years to progress. In the early stages, there may be no symptoms. As the disease progresses, patients will mostly likely experience the following:

Complications include:

How are they diagnosed?

Most patients with these diseases are diagnosed while undergoing routine blood work. They are usually without symptoms in the early stages. When a patient has an abnormal laboratory finding or symptoms like the above, the clinician should obtain the full history, perform a complete physical exam, and order the appropriate tests such as:

  • Complete blood count
  • Blood smear
  • Bone marrow biopsy
  • Bone marrow aspiration
  • Chromosomal analysis through various diagnostic techniques

The World Health Organization has set forth guidelines to aid the clinicians in diagnosing the patients accurately.

How are they treated?

The treatment goals aim to prolong survival and improve the quality of life. CML is treated with medications such as imatinib that target the chromosomal defect as well as other options such as chemotherapy. PV is treated with plasmapheresis. ET can be observed in a group of patients. PMF is treated with blood transfusions, stem cell transplantation, and/or other drugs.

What is the prognosis of these diseases?

Many cases of myeloproliferative disorders develop gradually and slowly. With early diagnosis and appropriate management, the prognosis is promising. The prognosis is reflective of numerous factors such as the type of disease, the clinical presentation, percentage of blood cells present in the peripheral blood and blood marrow, existing chromosomal defects.

References

Article

  1. Assamonti F, Mora B, Maffioli M. New molecular genetics in the diagnosis and treatment of myeloproliferative neoplasms. Current Opinion in Hematology. 2016; 23(2):137–143.
  2. Vardiman JW, Thiele J, Arber DA, et al. The 2008 Revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009; 114(5):937–951.
  3. Passamonti F, Mora B, Maffioli M. New molecular genetics in the diagnosis and treatment of myeloproliferative neoplasms. Current Opinion in Hematology. 2016; 23(2):137–143.
  4. Nangalia J, Green TR. The evolving genomic landscape of myeloproliferative neoplasms. Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. 2014; 2014 (1):287–296.
  5. Tefferi A, Solberg LA, Silverstein MN. A clinical update on polycythemia vera and essential thrombocythemia. American Journal of Medicine. 2000; 109(2):141–149.
  6. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Chronic Myeloid Leukemia (CML). http://seer.cancer.gov/statfacts/html/cmyl.html. Accessed: August 19, 2016.
  7. American Cancer Society. Leukemia--Chronic Myeloid (Myelogenous). http://www.cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-statistics. Accessed: August 19, 2016.
  8. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leukemia and Lymphoma. 2014; 55(3):595–600.
  9. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. New England Journal of Medicine. 2007; 356(5):459–468.
  10. Vannucchi AM. How I treat polycythemia vera. Blood. 2014; 124(22):3212–3220.
  11. Tefferi A. Myelofibrosis with myeloid metaplasia. New England Journal of Medicine. 2000; 342(17):1255–1265.
  12. Scherber R, Dueck AC, Johansson P, et al. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international prospective validation and reliability trial in 402 patients. Blood. 2011;118(2):401-408.
  13. Tefferi A, Thiele J, Vannucchi AM, Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia. 2014; 28(7):1407–1413.
  14. Hussein K, Pardanani A, Van Dyke DL, Hanson CA, Tefferi A. International Prognostic Scoring System-independent cytogenetic risk categorization in primary myelofibrosis. Blood. 2010; 115(3):496–499.
  15. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. New England Journal of Medicine. 2012; 366(9):799–807.

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Last updated: 2018-06-21 21:16