Overview of Myeloproliferative Disease
Myeloproliferative disorders in which the hematopoietic tissue of the bone marrow is replaced by fibrous tissue may be asymptomatic or manifest only as weakness, weight loss, and abdominal distension; in severe cases, there may be bone pain, fever, etc. The primary cause of the disease is unknown; the secondary cause is usually caused by exposure to chemical solvents, ionizing radiation, and tumors; the primary cause has no definitive cure except for hematopoietic stem cell transplants; and the secondary cause is treated primarily for the disease.
Definition
Myelofibrosis is a proliferative disease in which the collagen in the hematopoietic tissues of the bone marrow proliferates due to various reasons, forming a large amount of fibrous tissue and replacing the original hematopoietic tissues of the bone marrow.
Myelofibrosis seriously affects hematopoiesis. Primary myelofibrosis is a type of myeloproliferative tumor.
Epidemiology
Prevalence
The prevalence of primary myelofibrosis is estimated to be (0.3-1.5)/100,000, with secondary forms more common than primary.
Gender distribution
Men are slightly more likely to develop myelofibrosis than women, but there is no overall difference.
Age distribution
Myelofibrosis is most common in middle-aged and older adults between the ages of 50 and 70.
Types of Myelofibrosis
Myelofibrosis can be divided into primary and secondary according to whether the causative factor is clear or not.
Primary myelofibrosis: It is a chronic proliferative tumor of the bone marrow caused by clonal proliferation of hematopoietic stem cells.
Secondary myelofibrosis: most of the causative factors are clear, such as exposure to chemical solvents ionizing radiation or tumors.
Causes
Causes
Primary myelofibrosis
The cause of the disease is currently unknown.
It may be related to genetic mutations affecting cellular pathways.
Secondary Myelofibrosis
Clinical studies have found that secondary myelofibrosis may be related to long-term exposure to organic solvents such as benzene and carbon tetrachloride.
Ionizing radiation can also cause myelofibrosis.
It may be associated with infections especially Mycobacterium tuberculosis infection.
Hematopoietic malignancies such as leukemia and bone metastases from other malignancies can also lead to myelofibrosis.
Autoimmune diseases such as systemic lupus erythematosus are also associated with myelofibrosis.
Metabolic disorders such as parathyroid dysfunction and vitamin D metabolism disorders may also lead to myelofibrosis.
Pathogenesis
Primary myelofibrosis
The mechanism is unclear and may be related to the following factors.
50% to 60% of patients with primary myelofibrosis have a mutation in the JAK2V617F gene, 3% to 5% have a mutation in the MPL gene, and 15% to 25% have a mutation in the CALR gene, which in turn leads to dysregulation of the JAK-STAT signaling pathway.
Fibrous tissue proliferation is associated with the appearance of heterogeneous megakaryocytes and increased release of fibroblast growth factors from megakaryocyte alpha granules (e.g., platelet-derived growth factor, fibroblast growth factor, epidermal growth factor, transforming growth factor-β, and other cytokines).
Abnormal production of cytokines is inferred to be causally related to the somatic symptoms and cachexia associated with primary myelofibrosis.
Secondary Myelofibrosis
The mechanisms by which some of the causative factors cause secondary myelofibrosis are unknown.
The causative factors of secondary myelofibrosis are often more clearly defined, with pathologic changes from the primary disease.
Symptoms
Myelofibrosis has an insidious onset and progresses slowly, with no obvious symptoms in the early stages of the disease.
As the disease progresses, symptoms associated with giant spleen and anemia may appear.
Typical symptoms
Megasplenism: This is usually a symptom caused by compression of the surrounding organs, such as pain in the left upper abdomen. However, there is usually no pain when the spleen is touched.
Anemia: mild anemia has no obvious symptoms, but only causes dizziness, fatigue, accelerated and deepened respiration, increased heart rate and palpitations after activity; in severe anemia, shortness of breath and dizziness may occur even in a calm state.
Accompanying symptoms
Metabolic abnormalities: fever, usually low; palpitations; increased sweating.
Bone pain: some patients with myelofibrosis have bone pain.
Decreased appetite: caused by the spleen pressing on the stomach.
Fatigue, weakness and weight loss.
Complications.
Complications of myelofibrosis are cirrhosis of the liver.
It is caused by obstruction of blood vessels around the hepatic blood sinusoids and increased portal blood flow due to extramedullary hematopoiesis of the hepatic sinusoids, which can lead to portal hypertension or Budd-Chiari syndrome due to thrombosis within the hepatic vein or portal vein, which can be complicated by cirrhosis, with the following symptoms:
Weakness and lethargy.
Decreased appetite.
Edema of both lower extremities.
Fluid accumulation in the abdominal and thoracic cavities.
Abdominal distension and abdominal pain.
Yellowing of the skin all over the body (jaundice) and darkening of the facial skin.
Bleeding from the gums and nasal passages. Skin petechiae, ecchymosis.
Menstrual disorders, infertility and even amenorrhea in females; males may have breast development, etc.
Pain in the liver area.
Varicose veins of the abdominal wall (hydrocele).
Seek medical attention
Conditions requiring medical attention
If the following symptoms occur for a prolonged period of time, it is advisable to seek medical attention to prevent delays.
Fatigue and weakness.
Palpitations, i.e. self-consciousness.
Spleen enlargement and abdominal discomfort.
Decreased appetite.
Bone pain.
Increased perspiration.
Fever, especially low grade.
Recommended Department
A visit to the hematology department is recommended.
Preparation for Consultation
If there are no special circumstances, you need to register through the hospital’s official website, official app, 114 and other regular channels, prepare your social security card (medical insurance card) and other medical documents, bring your previous medical documents, and apply for record-keeping procedures for patients who seek medical treatment in other places.
What questions the doctor may ask
What kind of discomfort do you have? Is there any fatigue, weakness, palpitations, abdominal discomfort, increased sweating, etc.?
How long have the above symptoms been present? Is there any relief in the middle of the day?
How has your appetite been recently compared to the past?
Has there been any recent change in weight?
Have you taken your temperature regularly? If so, is there any abnormality?
Is there any change in the character of the feces from normal?
What kind of work do you do? Have you been exposed to chemical solvents, physical radiation, etc.?
What is your past medical history? Have you had tuberculosis, malignant tumors, systemic lupus erythematosus, etc.? Have they been treated?
Have you ever consumed alcohol? If so, how much per day and for how many years?
Has there been any relevant examination after the current discomfort?
Have you had any treatment since the present illness? What was the treatment? How effective was the treatment?
Is there any history of drug and food allergies?
Questions you can ask your doctor
What is the cause of these symptoms?
Do you need to do any tests?
Do you need treatment? What treatments are available? What are the differences between the various treatments?
How much does the treatment cost?
Can it be cured? How long does it take?
Can it be cured on its own without treatment?
What should I pay attention to in my daily life?
Will there be any after-effects?
Diagnosis
Disease Diagnosis
The diagnosis of primary myelofibrosis should be in accordance with the World Health Organization (WHO) 2016 revised criteria: including pre-fibrotic/early primary myelofibrosis and primary myelofibrosis in the stage of marked fibrosis.
Diagnostic criteria for pre-fibrotic/early primary myelofibrosis (WHO 2016)
Confirmation of the diagnosis requires fulfillment of 3 primary criteria, and at least 1 secondary criterion.
Primary criteria
Presence of megakaryocytic hyperplasia and heterogeneous megakaryocytes without significant reticulofibrillar proliferation (≤ MF-1), age-adjusted degree of myeloproliferative hyperplasia, and proliferation of granulocytes while erythrocytes are often reduced.
Failure to meet WHO diagnostic criteria for true erythrocytosis, chronic myeloid leukemia (BCR-ABL fusion gene negative), myelodysplastic syndromes (absence of granulocytic and erythroid pathologic hematopoiesis), or other myeloid neoplasms.
Presence of mutations in the JAK2, CALR or MPL genes, or absence of these mutations but other clonal markers, or evidence of secondary myelofibrosis.
Secondary criteria
Anemia not due to co-morbidities.
White blood cell count ≥ 11 x 109/L.
Palpable enlarged spleen.
Increased serum lactate dehydrogenase level.
Diagnostic criteria for primary myelofibrosis in the apparent fibrotic phase (WHO 2016)
Confirmation of the diagnosis requires fulfillment of 3 primary criteria, and at least 1 secondary criterion.
Primary criteria
Megakaryocytic hyperplasia and heterogeneous megakaryocytes, often with reticular or collagenous fibers (MF-2 or MF-3).
Failure to meet WHO diagnostic criteria for true erythrocytosis, chronic myeloid leukemia (BCR-ABL fusion gene negative), myelodysplastic syndromes (absence of granulomatous and erythropoietic hematopoiesis), or other myeloid tumors.
Presence of mutations in the JAK2, CALR or MPL genes, or absence of these mutations but other clonal markers, or evidence of secondary myelofibrosis.
Secondary criteria
Anemia not due to co-morbidities.
White blood cell count ≥ 11 x 109/L.
Splenomegaly, palpable.
Increased serum lactate dehydrogenase level.
Presence of young granulocytes and young erythrocytes in the peripheral blood.
Medical History.
History of occupational exposure: frequent exposure to organic solvents such as benzene and carbon tetrachloride; prolonged high-dose exposure to ionizing radiation.
History of tuberculosis.
History of hematopoietic malignancy (leukemia), and/or bone metastases from malignancies in other organs.
History of autoimmune disease such as systemic lupus erythematosus.
History of parathyroid disease, such as hypoparathyroidism or hyperparathyroidism.
Clinical manifestations
Symptoms
Symptoms such as fatigue, palpitations, abdominal pain, decreased appetite, bone pain, increased sweating and low-grade fever.
Physical signs
Splenomegaly: 90% of myelofibrosis cases may present with splenomegaly. Normally the spleen is essentially inaccessible under the rib margins. If the doctor is able to palpate it, splenomegaly is present.
Liver enlargement: 50% to 80% of myelofibrosis cases may have an enlarged liver. Doctors can determine if hepatomegaly is present by palpating the edges of the liver and percussing to understand the turbid border of the liver.
Laboratory Tests
Bone marrow aspiration
Bone Marrow Smear: Myelofibrosis may present with a characteristic “dry spot”. Bone marrow aspiration is the inability to aspirate bone marrow fluid due to non-medical factors.
Bone marrow pathology: One of the most accurate tests for diagnosing myelofibrosis. The degree of reticular fibers and collagen fibers can be clearly determined with the help of silver staining and trichrome staining, thus determining whether or not the disease is present.
Peripheral blood smear
A peripheral blood smear is used to determine the status of the disease by looking at the morphology of the blood cells.
Red blood cells: Myelofibrosis affects the hematopoiesis of the bone marrow, therefore, red blood cells of different sizes can be seen in the peripheral blood smear. Abnormal red blood cells such as malformed, tear-drop shaped, and target shaped red blood cells can also be observed.
Platelets: Aberrant platelets may be found in the peripheral blood smear due to the bone marrow hematopoietic abnormality.
Leukocytes: primitive granulocytes are seen in the peripheral blood smear.
Blood biochemistry
Patients with myelofibrosis may have many abnormalities in blood biochemistry tests, such as abnormally high levels of lactate dehydrogenase and alkaline phosphatase.
Before the blood biochemistry test, you should follow the doctor’s instructions to fasting, no water. Please inform your doctor in advance if you need to take any medication.
Interpretation of the results should be made by a clinical physician in conjunction with medical history, symptoms, signs and other auxiliary test results.
Chromosomal examination
About half of the patients with primary myelofibrosis will have chromosomal abnormalities in hematopoietic cells. Therefore, chromosomal examination of hematopoietic cells is helpful in the diagnosis of this disease.
Genetic testing
50% to 60% of patients with primary thrombocythemia have mutations in the JAK2V617F gene, 3% to 5% have mutations in the MPL gene, and 15% to 25% have mutations in the CALR gene. Therefore, genetic testing is one of the necessary tests for the diagnosis of this disease.
Imaging
Imaging findings of hepatomegaly, splenomegaly, unexplained neurologic signs or other unexplained signs should be considered for myeloid tumors.
Magnetic resonance imaging: it cannot distinguish primary myelofibrosis from secondary myelofibrosis, but it can detect osteosclerosis and spinal changes (“sandwich” spine), which are valuable in the diagnosis of the disease.
Differential diagnosis
Chronic granulocytic leukemia
Similarities: Both may present with splenomegaly, anemia symptoms such as dizziness, fatigue and palpitations, accompanied by bone pain and fever.
Differences: the bone marrow picture of chronic granulocytic leukemia is dominated by granulocyte hyperplasia, while myelofibrosis is dominated by fibrosis; Philadelphia chromosome can be seen in chronic granulocytic leukemia. It can be differentiated by bone marrow aspiration and chromosomal examination.
True erythrocytosis
Similarity: Both are subtypes of myeloproliferative neoplasms, and both may present with hemocytosis and splenomegaly.
Differences: peripheral erythrocytosis in true erythrocytosis is characterized by increased peripheral red blood cells, symptoms of embolism, and myeloproliferative hyperplasia of the bone marrow. Myelofibrosis does not have these characteristics. It can be differentiated with the help of bone marrow aspiration and bone marrow pathology.
Primary thrombocythemia
Similarity: Both are myeloproliferative tumors, and both may present with thrombocytosis or splenomegaly.
Difference: The bone marrow pathology of primary myelofibrosis can show different degrees of reticulocyte fibrosis with abnormal morphology and distribution of megakaryocytes, whereas the bone marrow pathology of most patients with primary thrombocythemia does not have obvious fibroplasia, which can be differentiated with the help of bone marrow pathology.
Myelodysplastic syndrome
Similarity: Primary myelofibrosis with hematopoiesis and myelodysplastic syndromes are associated with anemia and bleeding.
Differences: Unlike primary myelofibrosis, myelodysplastic syndromes are often characterized by a decrease in the number of whole blood cells, with fewer anomalous and fragmented red blood cells. The bone marrow often shows significant trilineage developmental abnormalities, and collagenous fibrosis is very rare, and there is often no hepatosplenomegaly.
Treatment
Primary myelofibrosis has no definitive cure except for allogeneic hematopoietic stem cell transplantation, which can be treated with JAK inhibitors and symptomatic therapy, while secondary myelofibrosis is mainly treated for the primary disease.
General treatment
Correcting anemia: when the anemia is severe, component blood transfusion treatment can be carried out, such as transfusion of red blood cells.
Quit smoking and drinking during treatment.
Avoid overeating and eat a balanced diet rich in protein and trace elements.
Avoid staying up late and ensure the sleep time and quality.
Medication
Drugs for anemia
Commonly used drugs: glucocorticoids, androgens (stanozolol or danazol), thalidomide and erythropoietin.
Androgens can speed up the production of red blood cells by the bone marrow, thus relieving the symptoms of anemia; and erythropoietin can promote the synthesis of ALA synthase, a key enzyme in the process of hemoglobin production, and promote the production of red blood cells.
The exact type of medication used should be prescribed by a doctor and should not be purchased and used on one’s own.
Drugs for splenomegaly
Rucotinib can be used as first-line treatment for primary myelofibrosis patients with splenomegaly.
Hydroxyurea: Spleen reduction is about 40% effective. Patients who fail hydroxyurea therapy may be replaced with other myelosuppressive agents. The specific therapy to be used should be as prescribed by the physician.
Treatment of somatic symptoms
Abnormal cytokine production is currently hypothesized to be causally related to the somatic symptoms and cachexia associated with primary myelofibrosis. Rucotinib significantly improves the somatic symptoms of primary myelofibrosis.
Specific use of the drug should be as prescribed by the physician.
Surgery
PURPOSE: Surgery is aimed at removing the enlarged spleen and relieving the compressive symptoms associated with ineffective drug therapy.
Indications: The spleen is a common extramedullary hematopoietic tissue in primary myelofibrosis; therefore, removal of the spleen is not generally recommended in this disease. However, surgical treatment may be considered once the following indications are present.
Symptomatic portal hypertension (e.g., variceal bleeding, ascites).
Medication-refractory significant splenomegaly with pain or in combination with severe malignancy.
Transfusion-dependent anemia.
Hazards: The perioperative mortality rate for splenectomy for primary myelofibrosis is 5% to 10%, and the postoperative complication rate is approximately 50%. Complications include bleeding at the surgical site, thrombosis, subdiaphragmatic abscesses, accelerated liver enlargement, extremely high platelet counts, and leukocytosis with excess of primitive cells.
The specific suitability of this treatment is determined by the doctor.
Hematopoietic stem cell transplantation
Hematopoietic stem cell transplantation is currently the only promising cure for primary myelofibrosis, but there is a high rate of treatment-related mortality and complications.
Hematopoietic stem cell transplantation involves the intravenous infusion of normal hematopoietic stem cells into the patient’s body to re-establish normal hematopoietic and immune functions.
The suitability of this treatment is determined by the doctor.
Prognosis
Cure
Primary myelofibrosis is difficult to cure, but symptoms can be improved with treatment.
Secondary myelofibrosis can improve when the primary disease is controlled, but it is still difficult to cure.
Hazards
Myelofibrosis not only affects normal life, but also has complications and even affects normal life expectancy.
Impact on normal life
Myelofibrosis can cause abdominal pain that interferes with eating.
Myelofibrosis can cause dizziness, fatigue, accelerated and deepened breathing, and anemia symptoms such as accelerated heart rate and palpitations, which can affect normal working life and study.
Causes complications
Myelofibrosis can cause complications such as portal hypertension, which can seriously affect the quality of life.
Impact on life expectancy
As the disease progresses, myelofibrosis can lead to severe anemia, infections, and bleeding due to a serious impairment of hematopoietic function, resulting in the inability to synthesize the red blood cells, white blood cells, and platelets needed by the body, which can be life-threatening.
Myelofibrosis complicates portal hypertension and can also affect health due to gastrointestinal bleeding.
Daily life
Daily life
Myelofibrosis patients need to avoid infections in their daily lives, as well as pay attention to lifestyle modifications.
Keep indoor air circulating, and open windows when the air quality is good.
When opening windows for ventilation, pay attention to keeping warm and preventing from getting cold.
Avoid crowded places such as shopping malls and hospitals.
Wear a mask when you go out.
Live a regular life and combine work and rest.
Eat and drink properly, do not be too hungry or too full.
Keep your mood relaxed.
Follow the doctor’s instructions for regular follow-up.
During treatment, if the symptoms are not relieved, or even worsened, or new symptoms appear, you need to go to the hospital in time.
Prevention
Avoid contact with chemical solvents such as benzene and carbon tetrachloride.
Avoid ionizing radiation, good occupational protection, wear good lead clothing, lead cap, etc.
Avoid pathogenic infections, you can improve your immunity through appropriate exercise.
Actively treat primary diseases, such as tuberculosis, systemic lupus erythematosus, parathyroid disease, leukemia and bone metastases.