During initial stages of the disease, thrombocytosis accounts for symptoms like thrombosis and thromboembolism. Poikilocytosis with teardrop-shaped erythrocytes may also be detected.

As the disease progresses, blood cell depletions and consequences of anemia, immune deficiency and coagulation disorders manifest, and this still happens before considerable bone marrow fibrosis becomes evident. Thus, patients may present with symptoms associated with either of those conditions. The following list may provide some guidance to this end:

• Patients suffering from mild to moderate anemia may report fatigue and weakness, problems with concentration and reduced performance as well as headaches. Dyspnea, tachycardia and dizziness are experienced in case of severe anemia.
• Disturbances in leukopoiesis render the patient prone to infections, e.g., to upper respiratory infection and urinary tract infection. Consequently, they may present with fever, night sweats and chills.
• PMF patients may claim a tendency to bleed. Gastrointestinal hemorrhages, hematochezia and melena, are commonly reported.

Hepatosplenomegaly may cause upper abdominal pain, portal hypertension and ascites. In some cases, gastrointestinal symptoms like feelings of fullness in the epigastric region and early satiety may prompt the patient to seek medical attention.

Hyperuricemia, gout and nephrolithiasis have been observed in PMF patients and may be considered consequences of increased extramedullary hematopoiesis or symptoms of tumor lysis syndrome [9].

• Splenomegaly

  Abstract Although splenomegaly is major characteristic of primary myelofibrosis (PMF), splenomegaly has been devalued due to a less reliable method based on physical examination (PEx). [ncbi.nlm.nih.gov]

  Splenomegaly [ 1 ] First-line: hydroxycarbamide (in the absence of cytopenias). [patient.info]

  Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped RBCs. [merck.com]

• Massive Splenomegaly

  She also underwent splenectomy when she was 13 years old, due to massive splenomegaly, anemia and various infection disease episodes. [ncbi.nlm.nih.gov]

  Treatment may include hydroxyurea for thrombocytosis and massive splenomegaly, androgens, erythropoietin, or red cell transfusions for severe anemia, local irradiation of fibrohematopoietic tumors or of the spleen, and splenectomy. [accessmedicine.mhmedical.com]

  [citation needed] Splenectomy is sometimes considered as a treatment option for patients with myelofibrosis in whom massive splenomegaly is contributing to anaemia because of hypersplenism, particularly if they have a heavy requirement for blood transfusions [en.wikipedia.org]

  Splenectomy is a potential treatment modality of choice for patients with massive splenomegaly unresponsive or intolerant to medical treatments, or in patients with severe life-threatening thrombocytopenia and anemia. [cancertherapyadvisor.com]

• Palpable Spleen

  He has hepatosplenomegaly with a palpable spleen of 6 cm below the left costal margin and a liver size of 2.5 cm below the right costal margin. [ncbi.nlm.nih.gov]

  COMFORT-II was a multi-centre, randomised open-label, controlled phase III study that included adults with either PMF, post-PV-MF or post ET-MF, who had a palpable spleen of at least 5cm below the costal margin and no previous treatment with a JAK inhibitor [eviq.org.au]

  (A 35% decrease in spleen volume equates to a roughly 50% reduction in palpable spleen length.) Other endpoints included symptom control, survival, and toxicity. [hematologyandoncology.net]

  Panel D shows the mean percentage change from baseline in palpable spleen length over time. I bars represent standard errors. BAT denotes best available therapy. [doi.org]

• Easy Bruising

  Easy bruising or bleeding. Petechiae (flat, red, pinpoint spots under the skin that are caused by bleeding). Fever. Night sweats. Weight loss. Certain factors affect prognosis (chance of recovery) and treatment options for primary myelofibrosis. [navigatingcare.com]

  As disruption of normal blood cell production increases, signs and symptoms may include: Feeling tired, weak or short of breath, usually because of anemia Pain or fullness below your ribs on the left side, due to an enlarged spleen Easy bruising Easy [mayoclinic.org]

  Indicators for Primary Myelofibrosis include: Abdominal pain and fullness, especially just below the left side of the rib cage Shortness of breath, fatigue Susceptibility to infection Easy bruising Persistent bleeding Presence of kidney stones Fever Night [dovemed.com]

  This can result in: Easy bruising, even after a minor bump Easy bleeding Bleeding gums Sudden nosebleeds Symptoms in Your Body As your disease gets worse, you spleen can become enlarged. [webmd.com]

• Anemia

  The main clinical manifestations of PMF are anemia, bleeding, hepatosplenomegaly, fatigue, and fever. Here we report a rare case of PMF with anemia, small bowel obstruction and ascites due to extramedullary hematopoiesis and portal hypertension. [ncbi.nlm.nih.gov]

  The main adverse effects of ruxolitinib are anemia and thrombocytopenia. [merck.com]

• Fever

  Although ruxolitinib rapidly induced relief, he developed a high-grade fever. A comprehensive fever work-up found no apparent cause of the fever, except for PMF. [ncbi.nlm.nih.gov]

• Fatigue

  The main clinical manifestations of PMF are anemia, bleeding, hepatosplenomegaly, fatigue, and fever. Here we report a rare case of PMF with anemia, small bowel obstruction and ascites due to extramedullary hematopoiesis and portal hypertension. [ncbi.nlm.nih.gov]

  March 2017 A 67-year old woman presents to her primary care physician with complaints of fatigue, abdominal fullness, night sweats, and 17-lb weight loss over the past 6 months. [targetedonc.com]

  Common signs of MF during physical examinations may include: An enlarged spleen (splenomegaly) Pale mucous membranes (pallor), if anemia is present Loss of muscle mass Cachexia (wasting syndrome characterized by weight loss, muscle atrophy, weakness and fatigue [mpnresearchfoundation.org]

  Common symptoms include: Abdominal fullness, pain or feeling full before finishing a meal (because of an enlarged spleen) Bone pain Fatigue Itching Night sweats Bruising Easy bleeding Increased likelihood of getting an infection Pale skin Shortness of [aamds.org]

• Weight Loss

  Constitutional symptoms, such as night sweats, pruritus, weight loss and fever may be treated with Jakafi. [mpnresearchfoundation.org]

  Weight loss. Certain factors affect prognosis (chance of recovery) and treatment options for primary myelofibrosis. Prognosis (chance of recovery) depends on the following: The age of the patient. [navigatingcare.com]

  A 53-year-old woman complains of increasing abdominal discomfort, early satiety, and 15-lb weight loss over the past 5 months Abdominal examination reveals splenomegaly, palpable 8 cm. below the costal margin without hepatomegaly CT scans of the chest [targetedonc.com]

  loss Diagnostic Exams Cytogenetic studies Peripheral blood smear Progression and Transformation None Epidemiology and Mortality Age: 60-70's years median age Incidence: 0.5-1.5 per 100,000 persons per year Sex: no male or female predominance Survival [seer.cancer.gov]

• Weakness

  CASE REPORT A 51-year-old Korean man was admitted to our hospital with general weakness and left-side abdominal pain. The patient was diagnosed with acute urate nephropathy with hyperphosphatemia, hyperkalemia, hypocalcemia, and metabolic acidosis. [ncbi.nlm.nih.gov]

  Myelofibrosis causes extensive scarring in your bone marrow, leading to severe anemia that can cause weakness and fatigue. It can also cause a low number of blood-clotting cells called platelets, which increases the risk of bleeding. [mayoclinic.org]

  But as the normal cells are pushed out, primary myelofibrosis may manifest itself in the following ways: Anemia Fatigue Shortness of breath Weakness Lightheadedness Pale skin Headaches Irritability Fever Night sweats Frequent bacterial/fungal infections [patientworthy.com]

  Fatigue, weakness, or shortness of breath Anemia Unexplained weight loss Night sweats Bruising or easy bleeding Enlarged liver Frequent infections Discomfort in upper left side of abdomen, caused by an enlarged spleen and an abnormally quick feeling of [texasoncology.com]

• Pneumonia

  The patient died of pneumonia eight months after developing the axillary tumor. At autopsy, multiple MyS masses were detected in his soft tissue, but his bone marrow only contained fibrosis. [ncbi.nlm.nih.gov]

  다운로드 (기관인증 필요) 초록보기 Background: Ventilator-associated pneumonia caused by multi-drug resistant Acinetobacter baumannii has been increasing and growing as a threat in intensive care units. [kiss.kstudy.com]

  The causes of death in the best-available-therapy group were pneumonia, septic shock, multisystem organ failure, and acute myeloid leukemia (in 1 patient); post-splenectomy Klebsiella pneumoniae sepsis (1); splenectomy, peritoneal hemorrhage, and respiratory [doi.org]

  Infections, commonly pneumonia, may occur as a result of immune deficiency. Leukaemic transformation to acute myeloid leukaemia may occur. [patient.info]

  Infections, commonly pneumonia, may occur as a result of immune deficiency. Physical Examination Splenomegaly is the most common finding in patients with primary myelofibrosis, and it is present in approximately 90% of patients. [emedicine.medscape.com]

• Pleural Effusion

  Symtomatic portal hypertension and non hepatoslenic extramedullary hematopoiesis may lead to variceal bleeding, ascites, pleural effusion and/or pulmonary hypertension. Leukemic transformation is observed in approximately 20% of patients. [orpha.net]

  The condition may result in spinal cord compression, focal seizures, symptoms related to brain tumours, ascites, haematuria, pericardial effusion, pleural effusion, haemoptysis and respiratory failure. Signs Splenomegaly (may be massive). [patient.info]

  The condition may result in GI tract hemorrhage, spinal cord compression, focal seizures, symptoms related to brain tumors, ascites, hematuria, pericardial effusion, pleural effusion, hemoptysis, and respiratory failure. [emedicine.medscape.com]

• Dyspnea

  Dyspnea, tachycardia and dizziness are experienced in case of severe anemia. Disturbances in leukopoiesis render the patient prone to infections, e.g., to upper respiratory infection and urinary tract infection. [symptoma.com]

  Case 3 This 69 year old male presented with dyspnea and loss of appetite of 2/52 duration. On examination he had pallor but no organomegaly or lymphadenopathy or bleeding manifestations. [omicsonline.org]

  Anemia may cause easy fatigability, weakness, dyspnea, and palpitations. Splenomegaly may result in early satiety and left upper quadrant discomfort. [emedicine.medscape.com]

  Splenomegaly (90%): often considered a hallmark Hepatomegaly (50%): portal hypertension can develop as a complication of hepatomegaly and may precede the onset of the disease (Gastroenterology 1988;94:1063) Constitutional symptoms such as fatigue, dyspnea [pathologyoutlines.com]

  At week 48, patients receiving ruxolitinib had marked reductions in myelofibrosis-associated symptoms, including appetite loss, dyspnea, fatigue, insomnia, and pain, whereas patients receiving the best available therapy had worsening symptoms ( Figure [doi.org]

• Hemoptysis

  • No rash, bleeding gums, swelling of joints, bone pain, fever, night sweats, cough with expectoration, hemoptysis, chest pain, orthopnoea, PND • No h/o jaundice, abdominal distension, hematemesis, melena • No h/o easy bruisability or uncontrolled bleeding [slideshare.net]

  The condition may result in GI tract hemorrhage, spinal cord compression, focal seizures, symptoms related to brain tumors, ascites, hematuria, pericardial effusion, pleural effusion, hemoptysis, and respiratory failure. [emedicine.medscape.com]

• Early Satiety

  A 53-year-old woman complains of increasing abdominal discomfort, early satiety, and 15-lb weight loss over the past 5 months Abdominal examination reveals splenomegaly, palpable 8 cm. below the costal margin without hepatomegaly CT scans of the chest [targetedonc.com]

  The spleen continues to enlarge, which leads to early satiety. Painful episodes of splenic infarction may occur. The patient becomes cachectic and may experience severe bone pain, especially in the upper legs. [accessmedicine.mhmedical.com]

  The diagnostic criteria for prefibrotic/early PMF (pre-PMF) are: Major criteria 1. [seer.cancer.gov]

  During clinical trials, it was shown to reduce spleen size, abdominal discomfort, early satiety, bone pain, night sweats and itching in MF patients as well as the level of “pro-inflammatory cytokines” in the blood, which may cause some symptoms such as [mpnresearchfoundation.org]

  Patients with advanced disease experience severe constitutional symptoms (general malaise, weight loss, night sweats and low-grade fever), massive splenomegaly (pain, early satiety, splenic infarction, portal hypertension and dyspnoea), progressive marrow [patient.info]

• Abdominal Pain

  CASE REPORT A 51-year-old Korean man was admitted to our hospital with general weakness and left-side abdominal pain. The patient was diagnosed with acute urate nephropathy with hyperphosphatemia, hyperkalemia, hypocalcemia, and metabolic acidosis. [ncbi.nlm.nih.gov]

  Liver, spleen and other organs may swell and cause local mass effects, e.g., upper abdominal pain and ascites. [symptoma.com]

  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]

  Pain. A severely enlarged spleen can cause abdominal pain and back pain. Growths in other areas of your body. [mayoclinic.org]

  Indicators for Primary Myelofibrosis include: Abdominal pain and fullness, especially just below the left side of the rib cage Shortness of breath, fatigue Susceptibility to infection Easy bruising Persistent bleeding Presence of kidney stones Fever Night [dovemed.com]

• Diarrhea

  Besides abdominal swelling, other symptoms such as digestive disorders (diarrhea and constipation) heartburn, and indigestion triggered by fatty foods may also appear. [aoporphan.com]

  The most frequently reported nonhematologic adverse event of any grade in the ruxolitinib group was diarrhea (with diarrhea of any grade occurring in 23% of the patients and grade 3 or 4 diarrhea occurring in 1%); diarrhea was also the only adverse event [doi.org]

  Occasionally, patients may have diarrhea related to pressure on the colon. A hypermetabolic state occurs and can result in weight loss, night sweats, and low-grade fever. Gout and urate kidney stones may develop. [emedicine.medscape.com]

  If significant, splenomegaly can result in left upper quadrant abdominal discomfort, left shoulder pain, early satiety, and diarrhea, which are often found to be the presenting complaints. [cancertherapyadvisor.com]

  Patients have difficulty walking, and the enlarged spleen stretches out the stomach, resulting in constipation, diarrhea or other gastrointestinal problems. [healio.com]

• Loss of Appetite

  Case 2 This 67 year old female presented with loss of appetite and weight loss of six months duration. At presentation she was mildly pale and had hepatosplenomegaly, no lymphadenopathy or bleeding manifestations. [omicsonline.org]

  […] of appetite and weight loss fever and night sweats Tests to diagnose myelofibrosis You have a blood test to check your blood cell count. [cancerresearchuk.org]

  An enlarged spleen may also cause pressure on your stomach causing a feeling of fullness, indigestion and a loss of appetite. Abdominal discomfort can also result from an enlarged liver (hepatomegaly), which occurs in around two-thirds of cases. [leukaemia.org.au]

  Bone pain Bruising and easy bleeding due to inadequate numbers of platelets Cachexia (loss of appetite, weight loss, and fatigue) Enlargement of both the liver and spleen Fatigue Gout and high uric acid levels Increased susceptibility to infection, such [en.wikipedia.org]

• Abdominal Distension

  A 53-year-old man with a long history of primary myelofibrosis, presented with abdominal distension and inguinal mass. [ncbi.nlm.nih.gov]

  distension/fluid retention (if portal hypertension or increased blood pressure within the portal vein is present) Compromised liver function Abnormal growth of blood forming cells outside of the bone marrow Routine medical examinations including complete [mpnresearchfoundation.org]

  • No rash, bleeding gums, swelling of joints, bone pain, fever, night sweats, cough with expectoration, hemoptysis, chest pain, orthopnoea, PND • No h/o jaundice, abdominal distension, hematemesis, melena • No h/o easy bruisability or uncontrolled bleeding [slideshare.net]

• Thrombosis

  (Mann–Whitney test, 0.60 without thrombosis vs 1.10 with thrombosis, p < 0.05). [diagnosticpathology.biomedcentral.com]

  However, multivariate analysis showed that only CD18 methylation and age >65 years were independent prognostic factors of thrombosis (p = 0.02 and p = 0.04, respectively). [ncbi.nlm.nih.gov]

  Main symptoms and co-morbidities for PMF include: Portal hypertension Thrombosis Anaemia Gout Extramedullary haematopoiesis Leukocytosis Splenomegaly Acute myeloid leukaemia This report is built using data and information sourced from the proprietary [giikorea.co.kr]

• Palpitations

  Symptoms of anaemia are common and include unexplained tiredness, weakness, shortness of breath and palpitations. [leukaemia.org.au]

  Symptoms of myelofibrosis include: fatigue weight loss paleness fever sweating weakness heart palpitations shortness of breath itchiness feeling full after eating a small amount of food stomach pain or discomfort pain in the left shoulder or upper left [medical-dictionary.thefreedictionary.com]

  Anemia may cause easy fatigability, weakness, dyspnea, and palpitations. Splenomegaly may result in early satiety and left upper quadrant discomfort. [emedicine.medscape.com]

  Only 20% of patients initially presented with symptoms such as fatigue, weight loss, palpitations, shortness of breath, dizziness, abdominal fullness, fever, or abdominal pain. [kjim.org]

• Tachycardia

  Dyspnea, tachycardia and dizziness are experienced in case of severe anemia. Disturbances in leukopoiesis render the patient prone to infections, e.g., to upper respiratory infection and urinary tract infection. [symptoma.com]

  • Hb: 3.3 g% • TC:2600 • DC: P80l18E2 • ESR: 70/95 mm • PCV: 11% • Platelet: 33,000 • Sugar: 84 • Urea: 22 • Creatinine: 0.8 • Na: 132 • K: 3.6 • Bleeding Time: 2 min 30s • Clotting time: 4 min 30s • CXR: mild cardiomegaly, ↑BVM • ECG: Sinus rhythm, tachycardia [slideshare.net]

• Hepatomegaly

  The patient, a 62-year-old female, having had primary myelofibrosis for 13 years and a splenectomy 4 years before, was admitted because of high fever, hepatomegaly, thrombocythemia and leukocytosis. [ncbi.nlm.nih.gov]

  Clinical manifestations depend on the type of blood cell affected and may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. [orpha.net]

  General lymphadenopathy Musculoskeletal osteosclerosis diffuse pattern no bony architectural distortion typical distribution: axial skeleton ribs proximal humerus and femur bone scan may give " superscan " appearance Abdominal hepatomegaly splenomegaly [radiopaedia.org]

  A 53-year-old woman complains of increasing abdominal discomfort, early satiety, and 15-lb weight loss over the past 5 months Abdominal examination reveals splenomegaly, palpable 8 cm. below the costal margin without hepatomegaly CT scans of the chest [targetedonc.com]

• Hepatosplenomegaly

  It is characterized by bone marrow fibrosis, extramedullary hematopoiesis with hepatosplenomegaly and leukoerythroblastosis in the peripheral blood. [ncbi.nlm.nih.gov]

  In case those organs are affected, the patient presents with hepatosplenomegaly. [symptoma.com]

  Renee Webb, Dolores lopez-Terrada and Lakshmi Venkateswaran Blood 2010 116:3079; Abstract Abstract 3079 Primary myelofibrosis is a chronic myeloproliferative disorder characterized by cytopenias, leukoerythroblastosis, extramedullary hematopoiesis, hepatosplenomegaly [bloodjournal.org]

• Night Sweats

  […] fatigue, fever, night sweats and weight loss. [mpnresearchfoundation.org]

  March 2017 A 67-year old woman presents to her primary care physician with complaints of fatigue, abdominal fullness, night sweats, and 17-lb weight loss over the past 6 months. [targetedonc.com]

  No new therapeutic intervention was initially required; however, 2 years later, the patient reported symptomatic splenomegaly and drenching night sweats, so ruxolitinib therapy was started. [ncbi.nlm.nih.gov]

  Night sweats. Weight loss. Certain factors affect prognosis (chance of recovery) and treatment options for primary myelofibrosis. Prognosis (chance of recovery) depends on the following: The age of the patient. [navigatingcare.com]

  Bone/muscle pain Itching Night sweats. Weight loss. These symptoms can have a profound impact on quality of life. Diagnosis of Myelofibrosis Individuals diagnosed with myelofibrosis often have no symptoms. [hoafredericksburg.com]

• Pruritus

  Abstract Primary myelofibrosis (PMF)-associated pruritus is often severe and requires treatment. [ncbi.nlm.nih.gov]

  Constitutional symptoms, such as night sweats, pruritus, weight loss and fever may be treated with Jakafi. [mpnresearchfoundation.org]

  Myeloids Panmyelosis, ± erythroid hyperplasia, atypical megas Panmyelosis, atypical megas ↑↑Megas Marrow fibrosis Varies ↑In spent phase ↑↑In fibrotic phase Minimal Splenomegaly ++ ++ +++ ± Clinical Presentation /Other B symptoms Hypertension, thrombosis, pruritus [surgpathcriteria.stanford.edu]

  Clinical manifestations depend on the type of blood cell(s) affected and may include severe anemia, pallor, petechiae, ecchymosis, bleeding, thrombosis, pancytopenia, pruritus, hypermetabolic state, marked hepato/splenomegaly, and/or constitutional symptoms [orpha.net]

• Petechiae

  Clinical manifestations depend on the type of blood cell affected and may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. [orpha.net]

  Petechiae (flat, red, pinpoint spots under the skin that are caused by bleeding). Fever. Night sweats. Weight loss. Certain factors affect prognosis (chance of recovery) and treatment options for primary myelofibrosis. [navigatingcare.com]

  Spontaneous bleeding may occur and vary from insignificant cutaneous petechiae to severe, life-threatening gastrointestinal tract bleeding. [patient.info]

• Bone Pain

  Painful episodes of splenic infarction may occur. The patient becomes cachectic and may experience severe bone pain, especially in the upper legs. [accessmedicine.mhmedical.com]

  […] common locomotor manifestation in Lymphoma: * Clinical; bone pain in rate of 60% * Radiological: meylofibrosis in rate of 20% The most common locomotor manifestation in Multiple Meyloma: * Clinical; bone pain in rate of 90% * Radiological: dactalytic [tishreen.edu.sy]

  Involved field radiotherapy is most useful for post-splenectomy hepatomegaly, non-hepatosplenic EMH, PMF-associated pulmonary hypertension, and extremity bone pain. [ncbi.nlm.nih.gov]

  B5: constitutional symptoms: drenching night sweats, weight loss >10% over six months, unexplained fever (>37.5°C ) or diffuse bone pains. B6: histological evidence of extramedullary haematopoiesis. [patient.info]

• Shoulder Pain

  Splenic infarcts, perisplenitis, or subcapsular haematoma may cause severe left upper quadrant or left shoulder pain. [patient.info]

  Splenic infarcts, perisplenitis, or subcapsular hematoma may occur, causing severe left upper quadrant or left shoulder pain. Occasionally, patients may have diarrhea related to pressure on the colon. [emedicine.medscape.com]

  If significant, splenomegaly can result in left upper quadrant abdominal discomfort, left shoulder pain, early satiety, and diarrhea, which are often found to be the presenting complaints. [cancertherapyadvisor.com]

• Hematuria

  The condition may result in GI tract hemorrhage, spinal cord compression, focal seizures, symptoms related to brain tumors, ascites, hematuria, pericardial effusion, pleural effusion, hemoptysis, and respiratory failure. [emedicine.medscape.com]

• Headache

  Side effects can include: Bleeding Infection Bruising Dizziness Headaches The only treatment that could potentially cure the disease is a stem cell transplant. [webmd.com]

  But as the normal cells are pushed out, primary myelofibrosis may manifest itself in the following ways: Anemia Fatigue Shortness of breath Weakness Lightheadedness Pale skin Headaches Irritability Fever Night sweats Frequent bacterial/fungal infections [patientworthy.com]

  References:[4][5][6] Essential thrombocythemia Genetics: JAK2 mutation in 50% of cases Clinical features: 50% asymptomatic Thromboembolic events Increased risk of fetal loss Vasomotor symptoms (headache, visual disturbances, acral paresthesias) Acute [amboss.com]

  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]

• Dizziness

  Side effects can include: Bleeding Infection Bruising Dizziness Headaches The only treatment that could potentially cure the disease is a stem cell transplant. [webmd.com]

  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]

  Some of the most common treatment side effects include: nausea dizziness pain or tingling in the hands and feet fatigue shortness of breath fever temporary hair loss Side effects usually go away after your treatment is completed. [healthline.com]

  Patients are observed for low blood counts, headache, dizziness, bruising or infection. For more about Jakafi, click here (will be directed to the manufacturer’s website). [mpnresearchfoundation.org]

  Dyspnea, tachycardia and dizziness are experienced in case of severe anemia. Disturbances in leukopoiesis render the patient prone to infections, e.g., to upper respiratory infection and urinary tract infection. [symptoma.com]

• Seizure

  Extramedullary hematopoiesis may involve any organ and may result in gastrointestinal bleeding, spinal cord compression, seizures, haemoptysis, and/or effusions. These can be controlled with low-dose radiation. [patient.info]

  These tumors may cause problems such as bleeding in your gastrointestinal system, coughing or spitting up of blood, compression of your spinal cord, or seizures. Bleeding complications. [mayoclinic.org]

  Over time you might notice: Major weight loss Itching Coughing up blood Seizures Pressure on your spinal cord Bone and joint pain Easy bleeding that could make surgery risky Pain and swelling in your joints, called gout Some people can also get acute [webmd.com]

In general, laboratory analyses of blood samples are carried out in order to clarify the causes of persistent fatigue, recurrent infections, thrombosis or bleeding diathesis, hepatosplenomegaly or any other of the aforementioned symptoms. During early stages of the disease, increased blood cell counts may be observed, and they correspond to the hypercellulary stage of the disease [9]. In contrast, pancytopenia is a common result in patients suffering from advanced PMF. Serum concentrations of lactate dehydrogenase are usually elevated. CD34+ cell counts are highly diagnostic, but they are not generally realized. Thus, although the aforementioned findings may be highly suspicious of PMF, it is often difficult to rule out differential diagnoses like other chronic myeloproliferative disorders. Histopathological analysis of a tissue sample obtained by bone marrow biopsy are required to support the tentative diagnosis of myelofibrosis. Such examinations may also be helpful to distinguish primary from secondary myelofibrosis.

Further diagnostic measures may be applied to reinforce the diagnosis of PMF. Plain radiography, for instance, typically reveals osteosclerotic lesions. Increased bone density may not be observed evenly in all parts of the skeleton or over whole bones. More complex imaging techniques, especially magnetic resonance imaging, allow for the depiction of bone marrow fibrosis. However, and as has been indicated above, myelofibrosis only develops during late stages of the disease. The degree of fibrosis observed in the proximal femur is generally considered a good measure of disease severity.

Molecular diagnostic techniques may allow for the detection of the underlying gene defect, but genes may be similarly affected in different chronic myeloproliferative diseases.

• Pericardial Effusion

  The condition may result in spinal cord compression, focal seizures, symptoms related to brain tumours, ascites, haematuria, pericardial effusion, pleural effusion, haemoptysis and respiratory failure. Signs Splenomegaly (may be massive). [patient.info]

  The condition may result in GI tract hemorrhage, spinal cord compression, focal seizures, symptoms related to brain tumors, ascites, hematuria, pericardial effusion, pleural effusion, hemoptysis, and respiratory failure. [emedicine.medscape.com]

• Nephrolithiasis

  Hyperuricemia, gout and nephrolithiasis have been observed in PMF patients and may be considered consequences of increased extramedullary hematopoiesis or symptoms of tumor lysis syndrome. [symptoma.com]

• Thrombocytosis

  BM Gomori silver impregnation (400×) Primary myelofibrosis, overt fibrosis. 72-year old man, leucocytosis 16×109/L, thrombocytosis 767×109/L, JAK2 unmutated. Intense reticulin fibrosis (MF-2 according to the EUMNET classification). [leukemia-cell.org]

  Myelofibrosis can also occur as a secondary process following the other myeloproliferative disorders (eg, polycythemia vera, essential thrombocytosis). [accessmedicine.mhmedical.com]

  Objectives: To compare the mutational profiles of patients with primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET). [ncbi.nlm.nih.gov]

  Hydroxyurea has traditionally been the preferred and most commonly used agent - moderately effective at improving splenomegaly, leukocytosis and thrombocytosis [ 5 ]. [patient.info]

• Poikilocytosis

  The peripheral blood smear is dramatic, with significant poikilocytosis and numerous teardrop forms in the red cell line (eFigure 13–21). [accessmedicine.mhmedical.com]

  Primary melofibrosis (Agnogenic myeloid metaplasia-AMM) is a chronic myeloproliferative disease characterized by splenomegaly, a leukoerythroblastic blood picture, teardrop poikilocytosis and varying degrees of marrow fibrosis. [ncbi.nlm.nih.gov]

  In case 3, compared to previous cases, patient had no organomegaly, leukoerythroblastic blood film or tear drop poikilocytosis but had pancytopenia. [omicsonline.org]

  Myelofibrosis – leukoerythroblastic blood film There is anemia with anisocytosis and poikilocytosis and ‘tear drop‘ red cells (dacrocytes). Immature red and white cells in the blood ‘leukoerythroblastic blood film‘. [askhematologist.com]

  Normocytic–normochromic anemia is present in most, but not all, patients (see Table 91–2). 7–15,262–265 Mean hemoglobin concentration in a series of patients at diagnosis is approximately 9.0 to 12.0 g/dL (range: 4–20 g/dL). 7–15,264,265 Anisocytosis and poikilocytosis [patient-help.com]

• Erythroblast

  PB MGG (1000×) Peripheral blood smear with a left shift: a myelocyte (yellow arrow), a monocyte (red arrow) and an erythroblast (blue arrow). BM MGG (200×) Hypocellular marrow aspirate smear with clumps of thrombocytes. [leukemia-cell.org]

  Primary myelofibrosis is a chronic clonal myeloid disorder characterized by (1) anemia; (2) splenomegaly; (3) immature granulocytes, increased CD34+ cells, erythroblasts, and teardrop-shaped red cells in the blood; (4) marrow fibrosis; and (5) osteosclerosis [accessmedicine.mhmedical.com]

  The laboratory findings show a leuko-erythroblastic blood film, tear drop poikilocytosis, reticulin fibrosis in bone marrow and elevated levels of various inflammatory and pro-angiogenic cytokines [ 1 ]. [omicsonline.org]

  The disease is a chronic clonal myeloid disorder characterized by (a) anemia, (b) splenomegaly, (c) immature granulocytes, erythroblasts, teardrop-shaped red cells and an increase in CD34+ cells in the blood, (d) marrow fibrosis, (e) osteosclerosis, and [doi.org]

• Lactate Dehydrogenase Increased

  dehydrogenase Prefibrotic: normal or borderline increased lactate dehydrogenase Overt: increased lactate dehydrogenase Alkaline phosphatase, uric acid, leukocyte alkaline phosphatase and vitamin B12 are increased (Leuk Lymphoma 1996;22:303) Bone marrow [pathologyoutlines.com]

  […] serum lactate dehydrogenase Increased serum lactate dehydrogenase A leukoerythroblastic blood smear These changes are often accompanied by increased cellularity, granulocytic proliferation and decreased erythropoiesis. a Megakaryocyte proliferation and [onlinelibrary.wiley.com]

• Decreased Platelet Count

  Decreasing platelet counts in ET to below 600 x 10 9 /L can decrease thrombotic complications. 46 High platelet counts (>1,000 x 10 9 /L) are associated with acquired von Willebrand disease resulting from the adsorption of von Willebrand multimers onto [clevelandclinicmeded.com]

• Pleural Effusion

  Symtomatic portal hypertension and non hepatoslenic extramedullary hematopoiesis may lead to variceal bleeding, ascites, pleural effusion and/or pulmonary hypertension. Leukemic transformation is observed in approximately 20% of patients. [orpha.net]

  The condition may result in spinal cord compression, focal seizures, symptoms related to brain tumours, ascites, haematuria, pericardial effusion, pleural effusion, haemoptysis and respiratory failure. Signs Splenomegaly (may be massive). [patient.info]

  The condition may result in GI tract hemorrhage, spinal cord compression, focal seizures, symptoms related to brain tumors, ascites, hematuria, pericardial effusion, pleural effusion, hemoptysis, and respiratory failure. [emedicine.medscape.com]

Advances with regards to the disease' etiology have allowed for the development of therapeutic agents for PMF patients. Since the majority of affected individuals shows a mutation of the gene encoding for JAK2, they may benefit from inhibitors of the corresponding pathway. Ruxolitinib, a Janus kinase inhibitor, has been approved to this end. But although ruxolitinib treatment may slow down disease progression and improve life quality by relieve of symptoms [10], myelofibrosis cannot be reversed by means of drug therapy. According to current knowledge, this can only be achieved by realizing hematopoietic stem cell transplantation. Non-myeloablative stem cell transplantation may be considered for patients aged 55 years and older.

In case the latter a stem cell transplantation not feasible, supportive therapy can be provided:

• Low-dose corticosteroid therapy or application of immunomodulators like lenalidomide may ease symptoms associated with PMF.
• If patients claim pain, analgesics should be prescribed.
• Infections may be treated with antimicrobial compounds.
• Transfusion of blood products should be considered in case of anemia or thrombocytopenia.
• Splenectomy may be indicated in case of portal hypertension or splenic infarction. Of note, intractable anemia may also result from splenomegaly and thus, splenectomy may be the therapeutic approach of choice in these cases.
• In general, extramedullary hematopoiesis may be reduced by means of radiation therapy.

Of note, watchful waiting is often recommended for asymptomatic patients.

PMF is associated with a reduced life expectancy. About 50% of PMF patients are expected to live beyond five years after diagnosis, only about 20% beyond a decade. However, the mean age of PMF patients - the disease is typically diagnosed in the elderly - has to be taken into account when interpreting this data. Common causes of death are infections and cardiovascular failure that do, in turn, result from bone marrow failure. Leukemic transformation, i.e. progression to acute myeloid leukemia, has also been reported.

The prognosis may vary depending on the underlying genetic defect. For instance, the above mentioned insertion of about 50 base pairs into the CALR gene is presumably related to longer survival times than a deletion of 5 base pairs in that same gene. In general, an abnormal karyotype, evidence of neoangiogenesis, severe anemia, leukopenia or leukocytosis as well as thrombocytopenia are considered poor prognostic factors. Patients who present with more than one of those conditions may live for less than one year; those who present neither may live for more than ten years.

High incidence rates among survivors of the atomic bombings hint at radiation as a possible etiologic factor [2], but the precise trigger of hematopoietic stem cell transformation is still unknown. However, genome analyses revealed certain anomalies that are frequently shown by PMF patients.

A determined somatic mutation of the gene encoding for cytoplasmic Janus kinase 2 (JAK2) may be encountered in about two-thirds of PMF patients. This gene is located on the short arm of chromosome 9, and the aforementioned mutation causes the substitution of valine for phenylalanine at position 617. This change in the amino acid sequence of JAK2 alters its susceptibility to regulatory mediators, which eventually leads to an uncontrolled proliferation of the affected stem cell and its clones. Of note, other, less frequent mutations of that gene have been described in PMF patients.

Furthermore, considerable shares of PMF patients present somatic mutations of the gene encoding for the thrombopoietin receptor. This proto-oncogene is generally referred to as myeloproliferative leukemia protein (MPL), and the respective mutation provokes constitutive activation of the receptor and subsequent formation of increased quantities of megakaryocytes. These cells may release growth factors that contribute to the pathogenesis of PMF [1].

Those patients that do neither present mutations of JAK2 nor MPL are likely to show a defect concerning the gene encoding for calreticulin (CALR) [3] [4]. In general, mutations are located in exon 9 of this gene, and they may consist in either deletions or insertions of several base pairs. Distinct mutations have been described, whereby an insertion of about 50 base pairs seems to be the most common one. Calreticulin interacts with thrombopoietin receptors and thus has pathophysiological consequences similar to those described in the previous paragraph.

Besides, mutations of JAK2, MPL and CALR have also been observed in patients suffering from other myeloproliferative disorders, e.g., essential thrombocytosis and polycythemia vera.

Other mutations have been related to PMF, too. They are listed elsewhere [5].

The annual incidence of PMF has been reported to be less than 1 per 100,000 inhabitants [6]. The disease is most commonly diagnosed in Caucasians, males and the elderly. Few PMF patients are younger than 50 years and if pediatric patients are affected, symptom onset usually occurs in infancy. Interestingly, gender predilection seems to reverse in the younger population.

Particularly high incidence rates have been reported for survivors of the atomic bombings in Japan; Ashkenazi Jews are generally prone to develop myeloproliferative malignancies [5].

Release of cytokines by clones of the degenerated stem cell, particularly by megakaryocytes, is a central pathophysiological process underlying bone marrow fibrosis. Besides bFGF and PDGF, transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) are produced by these cells and alter gene expression and signaling pathways in fibroblasts and endothelial cells, among other cell types.

• Stimulation of fibroblast proliferation, synthesis of extracellular matrix components and inhibition of collagenase lead to myelofibrosis. This process is further aggravated by a reduction of matrix metalloproteinase activity and by increase of concentrations of tissue inhibitors of metalloproteinases [7].
• TGF-β does not only contribute to the aforementioned events, but also induces an increased production of osteoprotegerin and hinders osteoclast proliferation and this eventually causes osteosclerosis.
• Neoangiogenesis can also be observed and primarily results from VEGF release. Although neoangiogenesis is not considered the main feature of PMF, it is generally detectable before fibrosis sets in.

In the long term, symptoms of bone marrow failure manifest, i.e., patients become susceptible to infections, develop anemia and tend to show hemorrhages. This broad range of complications is the result of disturbances in erythropoiesis, leukopoiesis and thrombopoiesis.

Abnormal hematopoietic stem cell trafficking, homing to peripheral organs and proliferation in these organs are intermediate steps leading to extramedullary hematopoiesis, which can be observed in advanced stages of PMF [8]. This behavior is only shown by degenerated stem cells, by clones of that cell that presents with gene defects. Thus, extramedullary hematopoiesis does by no means compensate for bone marrow deficits. It typically occurs in sites of fetal hematopoiesis, e.g., in liver and spleen. In case those organs are affected, the patient presents with hepatosplenomegaly. However, local mass effects due to excess proliferation of degenerated cells may also occur elsewhere in the body, and may provoke compression of nervous tissue, blood or lymphatic vessels. Symptoms vary depending on the affected organ and may range from portal or pulmonary hypertension and effusion to neurological deficits.

No specific measures can be recommended to prevent PMF.

Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder and thus pertains to the same group of diseases as chronic myeloid leukemia, essential thrombocytosis and polycythemia vera, among others [1]. These disorders are characterized by transformation and subsequent proliferation of a hematopoietic stem cell that shows an altered susceptibility to regulatory growth factors. Accordingly, they are classified as clonal hematopoietic malignancies. PMF is the most severe, but fortunately also the rarest chronic myeloproliferative disease.

Transformed stem cell clones release a variety of growth factors, e.g., basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). This is the pathophysiological basis of PMF symptoms like myelofibrosis and thrombocytosis. As a consequence of the altered microenvironment in the bone marrow, stem cells are mobilized, reach the circulation and peripheral organs. They subsequently colonize these organs, mainly liver and spleen, which results in extramedullary hematopoiesis and hepatosplenomegaly.

Knowledge about the disease's etiology acquired during recent years has allowed for the development of drugs that permit a causative therapy. The respective compounds inhibit those enzymes that are overexpressed owing to gain-of-function mutations. Such treatment relieves symptoms and decelerates disease progression. Nevertheless, stem cell transplantation is often required in later stages of PMF and is the only treatment option with a potential for cure. Still, the disease significantly reduces the patient's life expectancy and mean survival times are about five years.

Primary myelofibrosis (PMF) is a chronic disease characterized by excess proliferation of hematopoietic stem cells, extramedullary hematopoiesis, progressive fibrosis of the bone marrow and possible failure of peripheral organs. PMF is a hematopoietic malignancy that shows certain similarities to diseases like chronic myeloid leukemia and polycythemia vera.

The aforementioned events occur in distinct stages of the disease:

• Malignant degeneration of a hematopoietic stem cell is the initial event. Owing to mutations, this cell loses its susceptibility to regulatory mediators and starts to divide in an uncontrolled manner.
• Hugh quantities of stem cell clones release cytokines like basic fibroblast growth factor and platelet-derived growth factor, and these substances mediate stem cell mobilization (and subsequent colonization of peripheral organs like liver and spleen) and fibroblast proliferation (which leads to bone marrow fibrosis).
• Hematopoiesis in the bone marrow becomes increasingly insufficient and patients develop anemia, recurrent infections and coagulation disorders.
• Liver, spleen and other organs may swell and cause local mass effects, e.g., upper abdominal pain and ascites.

Transplantation of hematopoietic stem cells is often required to reverse bone marrow fibrosis, and is indeed the only treatment option with a potential for cure. It may, however, not be feasible in the elderly. Here, drug therapy and symptomatic treatment of PMF-associated symptoms are indicated. These may comprise administration of ruxolitinib and immunomodulatory compounds, transfusion of blood products, surgical removal of the spleen and radiation therapy.

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