Edit concept Question Editor Create issue ticket

Primary Myelofibrosis

Bone Marrow Fibrosis

Primary myelofibrosis is a myeloproliferative disorder induced by somatic mutations in hematopoietic stem cells. Uncontrolled proliferation of stem cells that release a variety of growth factors leads to bone marrow fibrosis and extramedullary hematopoiesis.

Primary Myelofibrosis - Symptom Checker

Ad Check possible symptoms of Primary Myelofibrosis now!

Presentation

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:

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].

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]
  • bruising unusually heavy or prolonged bleeding bleeding for no apparent reason severe headache or visual changes stiff neck joint pain petechiae, or tiny areas of pinpoint bleeding on the skin of the arms or legs Follow-up care and prognosis MF requires[uihc.org]
  • These symptoms are associated with a decrease in the red blood cells (anemia) Pain or fullness below the ribs on the left side, as a result of an enlarged spleen Poor appetite Enlarged liver Pale skin Easy bruising or bleeding Flat, red, pinpoint spots[cancersupportcommunity.org]
  • Severe anemia, easy bruising or bleeding, and multiple infections can result because of the lack of healthy blood cells. An enlarged spleen (splenomegaly) and/or liver (hepatomegaly) may also occur.[oncolink.org]
Splenomegaly
  • Abstract We report a patient with very advanced myelofibrosis and huge splenomegaly who showed a complete hematological response to low dose thalidomide with reversal of splenomegaly and bone narrow fibrosis after 30 months of the treatment.[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]
  • We present a case of a 76-year-old man diagnosed with primary myelofibrosis who presented with constitutional symptoms and symptomatic splenomegaly. Ruxolitinib was started (15 mg twice daily) and his disease-related symptoms disappeared.[ncbi.nlm.nih.gov]
  • 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]
Massive Splenomegaly
  • Abstract Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by progressive anemia, massive splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis and in about 50% of cases the presence of JAK2V617F mutation.[ncbi.nlm.nih.gov]
  • 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]
  • 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]
  • First two patients have massive splenomegaly, leukoerythroblastic blood picture with tear drop poikilocytosis but no cytopenias. In addition to bone marrow fibrosis, megakaryocytic dysplasia was present with clustering of megakaryocytes.[omicsonline.org]
Anemia
  • The diagnosis was made based on anemia, leukoerythroblastic change and presence of giant platelets in the peripheral blood, and a bone marrow biopsy showing myelofibrosis. Most of them had anemia, fever, and hepatosplenomegaly on admission.[ncbi.nlm.nih.gov]
  • 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]
  • Anemia and thrombocytopenia are the main secondary effects. However, there are case reports of rare but serious adverse events following drug withdrawal.[ncbi.nlm.nih.gov]
  • There are also some drugs currently in clinical trial that aim to improve anemia for people with myelofibrosis.[mpnresearchfoundation.org]
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]
  • 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 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]
  • Constitutional symptoms, such as night sweats, pruritus, weight loss and fever may be treated with Jakafi.[mpnresearchfoundation.org]
  • Most of them had anemia, fever, and hepatosplenomegaly on admission. The anemia was severe and refractory to repeated transfusions and steroid therapy in 3 out of the 4 cases. Splenectomy was performed in 1 case, but without satisfactory results.[ncbi.nlm.nih.gov]
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 10%, night sweats), gout, infections, thrombotic episodes, bleeding Rarely, extramedullary hematopoiesis forms masses (exclude myeloid sarcoma with CD34 immunostain) in breast ( Am J Surg Pathol 1980;4:281 ), lung ( Arch Pathol Lab Med 2008;132:[pathologyoutlines.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]
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]
  • In this paper we present a case of a 47-year-old male patient who was admitted to the hospital with symptoms of fatigue and small amount of urine, and clinical signs of plethora and enlarged spleen.[ncbi.nlm.nih.gov]
  • 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]
  • 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]
Weakness
  • 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[mpnresearchfoundation.org]
  • 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]
  • 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]
  • Signs that you have one of these disorders include: Anemia (you don’t have enough red blood cells to carry oxygen) Shortness of breath Pale skin Weakness and fatigue Lack of appetite Bleeding in excess (even when you get a minor cut) Sinus infections[webmd.com]
  • Symptoms of anaemia are common and include unexplained tiredness, weakness, shortness of breath and palpitations.[leukaemia.org.au]
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]
  • 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]
  • 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]
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]
  • Anemia may cause easy fatigability, weakness, dyspnea, and palpitations. Splenomegaly may result in early satiety and left upper quadrant discomfort.[emedicine.medscape.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]
  • […] hematologic or solid neoplasms in patients with CLL. 13 Primary myelofibrosis PMF is a myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and progressive anemia. 14, 15 Patients are compromised by symptoms such as fatigue, dyspnea[dovepress.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]
Pleural 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]
Hemoptysis
  • 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]
  • satiety Fatigue Fever Night sweats Splenomegaly Thrombocytosis Weight 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[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]
  • In some cases, gastrointestinal symptoms like feelings of fullness in the epigastric region and early satiety may prompt the patient to seek medical attention.[symptoma.com]
  • 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
  • Liver, spleen and other organs may swell and cause local mass effects, e.g., upper abdominal pain and ascites.[symptoma.com]
  • A severely enlarged spleen can cause abdominal pain and back pain. Growths in other areas of your body.[mayoclinic.org]
  • pain, and constitutional symptoms.[dovepress.com]
  • The most common grade 3 or 4 nonhematologic adverse events (abdominal pain, fatigue, and dyspnea) occurred more frequently in the placebo group.[doi.org]
  • We previously used splenic radiation in some of these cases, but we use it less often now because it is minimally efficacious, the effects are transient, and it can lead to abdominal pain, nausea, and vomiting.[hematologyandoncology.net]
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]
  • 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]
  • 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]
  • Patients have difficulty walking, and the enlarged spleen stretches out the stomach, resulting in constipation, diarrhea or other gastrointestinal problems.[healio.com]
  • Gastrointestinal complications The most common gastrointestinal side effects associated with long-term hydroxycarbamide therapy are oral mucosal ulcerations (4.5%); less common are nausea and vomiting, epigastric pain, and diarrhea [18,31] Harrison CN[doi.org]
Loss of Appetite
  • 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]
  • 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]
  • Approximately 25-50% of patients will have symptoms from an enlarged spleen at diagnosis, including pain with deep breaths, loss of appetite and feeling full after eating a small amount (called early satiety).[oncolink.org]
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]
Thrombosis
  • 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]
  • Abstract We report a case of a regenerative nodular hyperplasia with a portal vein cavernomatosis with a subsequent progression to symptomatic, occlusive thrombosis of the superior mesenteric vein.[ncbi.nlm.nih.gov]
  • Abstract Cavernous transformation in the liver was examined histologically by serial section observations, in an autopsy case of portal venous thrombosis and primary myelofibrosis.[ncbi.nlm.nih.gov]
  • OUTCOMES: After 30 months of the progression (at the recent follow-up), this patient had no obvious symptoms or thrombosis. LESSONS: PMF rarely progresses to PV, however, the progression will significantly improve the quality of life and prognosis.[ncbi.nlm.nih.gov]
  • However, the third case of IMF that met diagnostic criteria for essential thrombocythemia with a JAK2V617F mutation had central venous thrombosis that resulted in blindness.[ncbi.nlm.nih.gov]
Palpitations
  • Symptoms of anaemia are common and include unexplained tiredness, weakness, shortness of breath and palpitations.[leukaemia.org.au]
  • Anemia may cause easy fatigability, weakness, dyspnea, and palpitations. Splenomegaly may result in early satiety and left upper quadrant discomfort.[emedicine.medscape.com]
  • 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]
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]
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]
  • 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]
  • 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]
  • Involved field radiotherapy is most useful for post-splenectomy hepatomegaly, non-hepatosplenic EMH, PMF-associated pulmonary hypertension and extremity bone pain. Am. J.[ncbi.nlm.nih.gov]
Hepatosplenomegaly
  • It is characterized by bone marrow fibrosis, extramedullary hematopoiesis with hepatosplenomegaly and leukoerythroblastosis in the peripheral blood.[ncbi.nlm.nih.gov]
  • Most of them had anemia, fever, and hepatosplenomegaly on admission. The anemia was severe and refractory to repeated transfusions and steroid therapy in 3 out of the 4 cases. Splenectomy was performed in 1 case, but without satisfactory results.[ncbi.nlm.nih.gov]
  • 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]
  • 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]
Bone Pain
  • 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]
  • Involved field radiotherapy is most useful for post-splenectomy hepatomegaly, non-hepatosplenic EMH, PMF-associated pulmonary hypertension and extremity bone pain. Am. J.[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]
  • Common MF symptoms and signs may include: Tiredness, weakness, or shortness of breath with mild exertion Fullness, discomfort or pain in the left upper area of the abdomen Fever Night sweats Weight loss or malnutrition Bone pain Itching (pruritus) Easy[mpnresearchfoundation.org]
  • JAK2 CML, Fibrotic Phase History of CML / BCR-ABL1 MDS with Fibrosis Dysplastic features in marrow Acute Megakaryoblastic Leukemia Blasts, acute onset Osteosclerotic Myeloma Plasma cells. light chain restricted Acute Pan-myelosis with Myelofibrosis Bone[surgpathcriteria.stanford.edu]
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]
Night Sweats
  • […] fatigue, fever, night sweats and weight loss.[mpnresearchfoundation.org]
  • 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]
  • sweats), gout, infections, thrombotic episodes, bleeding Rarely, extramedullary hematopoiesis forms masses (exclude myeloid sarcoma with CD34 immunostain) in breast ( Am J Surg Pathol 1980;4:281 ), lung ( Arch Pathol Lab Med 2008;132:99 ), prostate ([pathologyoutlines.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]
  • 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]
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]
  • Bleeding is observed in one fourth of patients with primary myelofibrosis and varies in severity from insignificant cutaneous petechiae to severe, life-threatening GI tract bleeding.[emedicine.medscape.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
  • 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]
  • Anemia (you don’t have enough red blood cells to carry oxygen) Shortness of breath Pale skin Weakness and fatigue Lack of appetite Bleeding in excess (even when you get a minor cut) Sinus infections Skin infections Urinary tract infections ( UTIs ) Headaches[webmd.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]
  • 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.[symptoma.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
  • 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]
  • 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]
  • 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]
  • The most common adverse drug reactions, observed in at least 1 percent of the patients treated with ruxolitinib, included low platelets, anemia, bruising, dizziness, and headache.[verywell.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]
  • 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]
  • 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]

Workup

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
  • Objectives: To compare the mutational profiles of patients with primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET).[ncbi.nlm.nih.gov]
  • Haematological investigations revealed thrombocytosis, leucocytosis and peripheral blood smear showed a leucoerythroblastic picture. JAK 2 mutation was positive.[ncbi.nlm.nih.gov]
  • Because of severe thrombocytosis, administration of aspirin 150 mg/day was recommended. OUTCOMES: The pregnancy was uneventful.[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]
  • During initial stages of the disease, thrombocytosis accounts for symptoms like thrombosis and thromboembolism. Poikilocytosis with teardrop-shaped erythrocytes may also be detected.[symptoma.com]
Poikilocytosis
  • 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]
  • 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]
  • Poikilocytosis with teardrop-shaped erythrocytes may also be detected.[symptoma.com]
  • Investigations Peripheral blood film: leuko-erythroblastosis with teardrop poikilocytosis. Large platelets and megakaryocyte fragments may also be seen. May be anaemia and leukopenia. Thrombocytosis is more common than thrombocytopenia.[patient.info]
Erythroblast
  • 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]
Pleural 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]

Treatment

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.

Prognosis

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.

Etiology

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].

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

No specific measures can be recommended to prevent PMF.

Summary

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.

Patient Information

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.

References

Article

  1. Lataillade JJ, Pierre-Louis O, Hasselbalch HC, et al. Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence. Blood. 2008; 112(8):3026-3035.
  2. Anderson RE, Hoshino T, Yamamoto T. Myelofibrosis with Myeloid Metaplasia in Survivors of the Atomic Bomb in Hiroshima. Annals of internal medicine. 1964; 60:1-18.
  3. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. The New England journal of medicine. 2013; 369(25):2379-2390.
  4. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. The New England journal of medicine. 2013; 369(25):2391-2405.
  5. Jones AV, Cross NC. Inherited predisposition to myeloproliferative neoplasms. Therapeutic advances in hematology. 2013; 4(4):237-253.
  6. Kutti J, Ridell B. Epidemiology of the myeloproliferative disorders: essential thrombocythaemia, polycythaemia vera and idiopathic myelofibrosis. Pathologie-biologie. 2001; 49(2):164-166.
  7. Agarwal A, Morrone K, Bartenstein M, Zhao ZJ, Verma A, Goel S. Bone marrow fibrosis in primary myelofibrosis: pathogenic mechanisms and the role of TGF-beta. Stem cell investigation. 2016; 3:5.
  8. Prakash S, Hoffman R, Barouk S, Wang YL, Knowles DM, Orazi A. Splenic extramedullary hematopoietic proliferation in Philadelphia chromosome-negative myeloproliferative neoplasms: heterogeneous morphology and cytological composition. Mod Pathol. 2012; 25(6):815-827.
  9. Cvetković ZP, Cvetković BR, Celeketić D, Milenković D, Perunicić-Peković G. Bilateral ureteral obstruction due to primary myelofibrosis caused hyperuricaemia. Acta chirurgica Iugoslavica. 2010; 57(2):79-83.
  10. Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015; 100(4):479-488.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2018-06-22 01:25