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.

• Splenomegaly

  CML: demonstrates increased production of neutrophils and marked splenomegaly. [ncbi.nlm.nih.gov]

  Slow onset with presentation related to splenomegaly or anemia. [quizlet.com]

  Patients with chronic myelogenous leukemia and polycythemia vera might develop splenomegaly, hence an abdominal examination is essential to exclude this common finding. [lecturio.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]

• Palpable Spleen

  Patients with painful, massively enlarged spleens refractory to myelosuppressive therapy are occasionally treated with radiation therapy, but they may ultimately require splenectomy. [emedicine.com]

  Among all evaluable patients, 44% experienced ≥ 50% decrease in palpable spleen size. [doi.org]

• Massive Splenomegaly

  Patients with massive splenomegaly benefit from splenectomy. The only possible curative treatment for these patients is allogeneic hematopoietic stem cell transplantation. [lecturio.com]

  Splenomegaly, sometimes massive, is a characteristic finding. Symptoms include the following: Splenic pain. Early satiety. Anemia. Bone pain. Fatigue. Fever. Night sweats. Weight loss. [northshore.org]

• 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.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]

  Patients can develop easy bruising or thrombosis, especially in essential thrombocythemia. Due to the overload of uric acid from the breakdown of large numbers of peripheral blood cells, patients are at risk of developing gouty arthritis. [lecturio.com]

  Bleeding and easy bruising can also occur. This is usually minor and occurs in around one quarter of all patients. [leukaemia.org.au]

• Anemia

  ) 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]

  Abstract 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]

  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]

  Slow onset with presentation related to splenomegaly or anemia. [quizlet.com]

• Pain

  Patients with painful, massively enlarged spleens refractory to myelosuppressive therapy are occasionally treated with radiation therapy, but they may ultimately require splenectomy. [emedicine.com]

  Antiplatelet therapy resulted in prompt relief of pain and the disappearance of platelet aggregates. [ncbi.nlm.nih.gov]

  This procedure is known to cause some pain. [docdoc.com.sg]

  An enlarged spleen can cause abdominal pain and a feeling of fullness. [mountsinai.org]

• Fatigue

  Patients usually present with fatigue, weight loss, anemia, night sweats, and splenomegaly. [icd9data.com]

  Symptoms of polycythemia vera include red and itchy skin—especially after a hot bath or shower—fatigue, fevers, weight loss, and night sweats. [nyulangone.org]

  Splenomegaly, hepatomegaly as well as fatigue, malaise or weight loss may appear in advanced stages. [orpha.net]

  Other signs and symptoms may include: Shortness of breath during exertion Weakness and fatigue Pale skin Loss of appetite Prolonged bleeding from minor cuts due to low platelet counts Purpura, a condition in which the skin bleeds, causing black and blue [ucsfhealth.org]

• Weight Loss

  Patients usually present with fatigue, weight loss, anemia, night sweats, and splenomegaly. [icd9data.com]

  They may also experience shortness of breath, feeling full faster when eating, easily bleeding or bruising, fever, night sweats, and weight loss. [docdoc.com.sg]

  Splenomegaly, hepatomegaly as well as fatigue, malaise or weight loss may appear in advanced stages. [orpha.net]

  Some of the more common symptoms include: Fatigue and tiredness Shortness of breath during exertion Pale skin Loss of appetite Weight loss Bone pain Night sweats Itching Infections and fever Pain or a feeling of fullness below the ribs from an enlarged [aamds.org]

• Weakness

  High levels of abnormal stem cells can cause anemia, a condition in which there are too few healthy red blood cells, leading to weakness and fatigue. People with myeloproliferative disorders do not always have symptoms. [nyulangone.org]

  Other signs and symptoms may include: Shortness of breath during exertion Weakness and fatigue Pale skin Loss of appetite Prolonged bleeding from minor cuts due to low platelet counts Purpura, a condition in which the skin bleeds, causing black and blue [ucsfhealth.org]

  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]

  Check with your doctor if you are experiencing: Fatigue, weakness, or shortness of breath. [cancersupportcommunity.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]

• 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]

  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

  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 (hepatomegaly). [leukaemia.org.au]

  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]

  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]

• 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]

  These cells then can infiltrate your organs and cause enlargement of the liver and spleen (hepatosplenomegaly). [verywellhealth.com]

  Patients with isolated splenomegaly or hepatosplenomegaly might need ultrasonography and other imaging studies to evaluate the size of these two organs and plan possible surgical intervention if needed. [lecturio.com]

  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]

• Stroke

  Lower levels can cause increased infections; higher levels can cause the blood to become more viscous, meaning sticky and thick, which can lead to stroke or abnormal bleeding. [nyulangone.org]

  Many people with these conditions have few, if any, symptoms, but complications can occur, including stroke in patients with poorly controlled disease. [ucsfhealth.org]

  hospitalization for unstable angina or coronary revascularization) and the key secondary composite endpoint (cardiovascular death, non-fatal MI or non-fatal stroke). [worldpharmanews.com]

  This may cause heart disease, stroke, or gangrene (tissue death) of the arms and legs. [mountsinai.org]

• Headache

  The only symptoms that may be experienced include headaches, redness, burning or tingling sensation in the hands or feet and vision and hearing problems. [docdoc.com.sg]

  Symptoms can include: Anemia Bruising or bleeding easily Fatigue Fever Headache Loss of appetite Night sweats Pale skin Petechiae (pinpoint red dots under the skin) Shortness of breath Sinus infections Skin infections Unexplained weight loss Urinary tract [templehealth.org]

  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]

• 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]

  This can cause symptoms such as headaches, dizziness, visual distortion, itching, and numbness or tingling ( paresthesia ). [labtestsonline.org]

• Tingling

  The only symptoms that may be experienced include headaches, redness, burning or tingling sensation in the hands or feet and vision and hearing problems. [docdoc.com.sg]

  This can cause symptoms such as headaches, dizziness, visual distortion, itching, and numbness or tingling ( paresthesia ). [labtestsonline.org]

  […] 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]

• 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.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]

  Leukostasis may lead to priapism, tinnitus, and stupors. However, most of the patients are asymptomatic, and the diagnosis is usually incidental due to an abnormal blood count or peripheral blood smear. [lecturio.com]

  […] 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]

• Abdominal Pain

  Expansion of mutated mast cell population causes spleen and liver enlargement, bone marrow failure, skin lesions, marrow fibrosis, osteoporosis, abdominal pain, peptic ulcer and diarrhea, flushing of the skin and itching. [hopkinsmedicine.org]

  Epidemiology: peak incidence between age 60–70 years Etiology: unknown Genetics: JAK2 mutation in 50% of cases Clinical features Weakness, fatigue, weight loss Splenomegaly: left upper quadrant abdominal pain Hyperproliferative phase (early phase): thrombocytosis [amboss.com]

  As myelofibrosis progresses, scar tissue can form in the bone marrow, causing bone pain. As abnormal blood cells circulate in the bloodstream and collect and grow in the spleen, it enlarges. This can cause abdominal pain and swelling. [nyulangone.org]

  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]

• 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.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]

  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. [symptoma.com]

• Nausea

  Related to Cancer Treatments, Mar 2, 2020 Taking Your Treatment on Schedule: Its Importance in Managing Cancer, Feb 26, 2020 Care for Your Bones During & After Cancer Treatment: Tips to Improve Bone Health, Nov 18, 2019 Preventing Chemotherapy Induced Nausea [cancercare.org]

  […] vs 32%, respectively) with a significantly longer median survival (58 months vs 45 months, P =.008, respectively). 3,6 Hydroxyurea is generally better tolerated than busulfan; the side-effects associated with hydroxyurea are rare and mild and include nausea [es.slideshare.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]

  Adverse events were all reversible and dose dependent and included nausea/vomiting, diarrhea, thrombocytopenia, and anemia. [doi.org]

• Vomiting

  Cancer Treatments, Mar 2, 2020 Taking Your Treatment on Schedule: Its Importance in Managing Cancer, Feb 26, 2020 Care for Your Bones During & After Cancer Treatment: Tips to Improve Bone Health, Nov 18, 2019 Preventing Chemotherapy Induced Nausea and Vomiting [cancercare.org]

  […] respectively) with a significantly longer median survival (58 months vs 45 months, P =.008, respectively). 3,6 Hydroxyurea is generally better tolerated than busulfan; the side-effects associated with hydroxyurea are rare and mild and include nausea, vomiting [es.slideshare.net]

  Adverse events were all reversible and dose dependent and included nausea/vomiting, diarrhea, thrombocytopenia, and anemia. [doi.org]

• Abdominal Distension

  Fibrosis contributes to morbidity and mortality in patients with MPNs together with additional risk factors. (5), (6) Patients usually suffer from fatigue, malaise, weight loss, bone pain, and abdominal distension. [go.gale.com]

• Bleeding Gums

  and/or symptoms of thrombosis Nosebleeds Headache Vision problems Bleeding 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 [diagnose-me.com]

  gums Bleeding and bruising – due to lack of platelets There are some symptoms that are only seen in certain patients or forms of leukaemia. [leukaemiacare.org.uk]

• Thrombosis

  We investigated whether thrombosis involving the inferior vena cava (IVC) is also related to the JAK2V617F mutation or CMD. METHODS: Blood samples were obtained from 40 IVC thrombosis patients. [ncbi.nlm.nih.gov]

• Chest Pain

  In general, you may see some of the following symptoms: bleeding problems repeated headaches anemia shortness of breath chest pain infections fatigue enlarged spleen, an organ in the upper left of the abdomen enlarged liver night sweats bone pain weight [massgeneral.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]

  In symptomatic patients, vasomotor symptoms can be seen in 30% to 40% of patients and often manifest as headache, lightheadedness, syncope, erythromelalgia, acral paresthesia, livedo reticularis, atypical chest pain, and transient visual disturbance. [cancernetwork.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]

  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]

  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]

• 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 Fatigue Headache Excessive sweating Blurred vision or blind spots Weakness Dizziness Itchiness, especially after a warm shower or bath Redness or a purplish appearance of skin Peptic [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.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]

  […] 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]

  Leukostasis may lead to priapism, tinnitus, and stupors. However, most of the patients are asymptomatic, and the diagnosis is usually incidental due to an abnormal blood count or peripheral blood smear. [lecturio.com]

• Night Sweats

  Patients usually present with fatigue, weight loss, anemia, night sweats, and splenomegaly. [icd9data.com]

  Symptoms of polycythemia vera include red and itchy skin—especially after a hot bath or shower—fatigue, fevers, weight loss, and night sweats. [nyulangone.org]

  Symptoms can include: Anemia Bruising or bleeding easily Fatigue Fever Headache Loss of appetite Night sweats Pale skin Petechiae (pinpoint red dots under the skin) Shortness of breath Sinus infections Skin infections Unexplained weight loss Urinary tract [templehealth.org]

  Some of the more common symptoms include: Fatigue and tiredness Shortness of breath during exertion Pale skin Loss of appetite Weight loss Bone pain Night sweats Itching Infections and fever Pain or a feeling of fullness below the ribs from an enlarged [aamds.org]

• Petechiae

  Symptoms can include: Anemia Bruising or bleeding easily Fatigue Fever Headache Loss of appetite Night sweats Pale skin Petechiae (pinpoint red dots under the skin) Shortness of breath Sinus infections Skin infections Unexplained weight loss Urinary tract [templehealth.org]

  […] 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.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]

  They may also develop petechiae, which are flat, red spots that form under the skin and are caused by bleeding. [docdoc.com.sg]

• Pruritus

  […] progressive increase over time in all blood cell types, its complications include arterial or venous thrombosis due to red blood cell-induced hyperviscosity; transient ischemic attacks, ocular migraine or erythromelalgia due to activated platelets; aquagenic pruritus [hopkinsmedicine.org]

  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]

  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]

  Interferon-a (IFN-a) is effective in suppressing erythrocytosis, reducing spleen size and alleviating pruritus in 80% to 90% of patients with PV. [cancernetwork.com]

• Purpura

  Other signs and symptoms may include: Shortness of breath during exertion Weakness and fatigue Pale skin Loss of appetite Prolonged bleeding from minor cuts due to low platelet counts Purpura, a condition in which the skin bleeds, causing black and blue [ucsfhealth.org]

  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]

  Weakness, tiredness, shortness of breath, light-headedness, palpitations Infections – due to lack of normal white blood cells Infections are more frequent, more severe and last longer Fever, malaise (general feeling of illness) and sweats Purpura (small [leukaemiacare.org.uk]

• Skin Bleeding

  Other signs and symptoms may include: Shortness of breath during exertion Weakness and fatigue Pale skin Loss of appetite Prolonged bleeding from minor cuts due to low platelet counts Purpura, a condition in which the skin bleeds, causing black and blue [ucsfhealth.org]

• Bone Pain

  Some of the more common symptoms include: Fatigue and tiredness Shortness of breath during exertion Pale skin Loss of appetite Weight loss Bone pain Night sweats Itching Infections and fever Pain or a feeling of fullness below the ribs from an enlarged [aamds.org]

  General symptoms of increased blood cell production in myeloproliferative disorders are fatigue, fevers, weight loss, bone pain, and night sweats. Abnormal blood cell levels may also cause infections. [nyulangone.org]

  Fibrosis contributes to morbidity and mortality in patients with MPNs together with additional risk factors. (5), (6) Patients usually suffer from fatigue, malaise, weight loss, bone pain, and abdominal distension. [go.gale.com]

  Signs that you have one of these disorders include: Fatigue Itchy skin Night sweats Bone pain Fever Weight loss Major complications of these disorders include: Excessive bleeding, which can happen with a minor cut, bruising or when capillaries break under [webmd.com]

• Shoulder Pain

  […] joint(s) secondary to gouty arthritis that is secondary to hyperuricemia Priapism, tinnitus, or stupor from leukostasis Left upper quadrant and left shoulder pain as a consequence of splenic infarction and perisplenitis Clinical symptoms can include [emedicine.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]

  […] 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 of the spleen [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]

  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. [symptoma.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 of [diagnose-me.com]

• Epistaxis

  Epistaxis and ecchymosis are common. Ischemic manifestations of the central nervous system (CNS) are potentially debilitating and should be feared. [scielo.br]

  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]

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]

  Essential Thrombocytosis This is most indolent myeloproliferative disorder and is characterized by increased platelet production (thrombocytosis) alone. [hopkinsmedicine.org]

• 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]

  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]

  The central and shared feature in MPNs is effective clonal myeloproliferation with resultant peripheral blood granulocytosis, thrombocytosis, or erythrocytosis that is devoid of dyserythropoiesis, or granulocytic dysplasia. [accessmedicine.mhmedical.com]

• Neutrophilia

  Five months after CBT, gradual neutrophilia of unknown origin developed following the myeloid reconstitution after CBT. [ncbi.nlm.nih.gov]

  जीर्ण translocation (9, 22) टी BCR-ABL translocation जो तीन breakpoints है: ए परिभाषित करने के साथ myelogenous लेकिमिया (CML) u-BCR-ABL (p230): leads to CML with usual neutrophilia and basophilia. [helpebookhindi.wikifoundry.com]

  They include hereditary thrombocytosis ( THPO, MPL, JAK2 genes), hereditary erythrocytosis ( EPOR, VHL, EGLN1 and EPAS1 genes) and hereditary neutrophilia ( gene). [atlasgeneticsoncology.org]

  Extracutaneous manifestations are possible with fever, peripheral neutrophilia, kidney, liver, joint, muscle, eye, and pulmonary involvement. [em-consulte.com]

• Karyotype Abnormal

  The International Prognostic Scoring System (IPSS) refines the prognosis of these diseases into four categories: low risk, intermediate 1 risk, intermediate 2 risk, and high risk, depending on the percentage of marrow blasts, the karyotype abnormalities [em-consulte.com]

  Cytogenetic and Molecular Findings Chromosomal abnormalities Karyotypic abnormalities in ET are uncommon (< 5% to 10% of cases). Trisomy 8 or 9, del(13q), and del(20q) are most common abnormalities. [cancernetwork.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]

• Bone Marrow with Hyperplasia

  […] glucocorticoids In myelofibrosis, RBCs shed tears (teardrop cells), because they have been forced out of the fibrosed bone marrow (extramedullary hematopoiesis). [amboss.com]

  […] of bone marrow Mild bone marrow hyperplasia Moderate bone marrow hyperplasia Myeloid hyperplasia of bone marrow Myelosuppression Neuropathy in blood dyscrasias Neutrophilic hyperplasia of bone marrow On examination - bone marrow- myeloid cells Osteoporotic [icd9data.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]

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.

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.

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.

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.

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.

There is no prevention for myeloproliferative diseases.

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.

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:

• Chronic myeloid leukemia (CML)
• Polycythemia vera (PV)
• Essential thrombocythemia (ET)
• Primary myelofibrosis (PMF)
• Chronic neutrophilic leukemia
• Chronic eosinophilic leukemia, not otherwise specified
• Mastocytosis

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:

• Fatigue
• Decreased appetite
• Weight loss
• Abdominal discomfort due to enlarged spleen
• Bruising easily
• Bleeding easily
• Pain and swelling of the joints
• Ringing in the ears
• Prolonged penile erection

Complications include:

• Heart attack
• Stroke
• Infection
• Hemorrhage
• Anemia
• Kidney failure
• Liver failure

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.

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.