Myelofibrosis

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Myelofibrosis , also known as osteomyelofibrosis , is a relatively rare bone marrow cancer. Currently classified as a myeloproliferative neoplasm, in which abnormal clonal proliferation of hematopoietic stem cells in the bone marrow and other sites produces fibrosis, or replacement of the marrow with scar tissue.

The term myelofibrosis alone usually refers to primary mielofibrosis ( PMF ), also known as chronic idiopathic myelofibrosis ( cIMF ); the term idiopathic and primary means that in this case the disease is unknown or spontaneous. This is different from myelofibrosis that develops secondary to polycythemia vera or essential thrombocythaemia. Myelofibrosis is a form of myeloid metaplasia, which refers to the change of cell type in the blood-forming tissue of the bone marrow, and often the two terms are used synonymously. The terms agnogenic myeloid metaplasia and myelofibrosis with myeloid metaplasia ( MMM ) are also used to refer to primary myelofibrosis.

Video Myelofibrosis

Signs and symptoms

The main sign of myelofibrosis is reactive bone marrow fibrosis, but it is often accompanied by:

• Full stomach is associated with an enlarged spleen (splenomegaly).
• Bone pain
• Bruising and bleeding are easy due to inadequate platelet count
• Cachexia (loss of appetite, weight, and fatigue)
• Enlarged liver and spleen
• Fatigue
• Uric acid and high uric acid levels
• Increased susceptibility to infections, such as pneumonia
• Pale and shortness of breath due to anemia
• In more rare cases, the volume of red blood cells is high
• Cutaneous myelofibrosis is a rare skin condition characterized by dermal and subcutaneous nodules.

Maps Myelofibrosis

Cause

There is a relationship between mutations with JAK2, CALR, or MPL and myelofibrosis genes. About 90% of those with myelofibrosis have one of these mutations and 10% do not carry any of these mutations. These mutations are not specific to myelofibrosis, and are associated with other myeloproliferative neoplasms, particularly polycythemia vera and essential thrombocythemia.

V617F mutations into JAK2 protein are found in about half of individuals with primary myelofibrosis. The V617F mutation is a change of valine to phenylalanine at position 617. Janus kinases (JAKs) are non-receptor tyrosine kinase important for the activation of signaling mediated by cytokine receptors that have no catalytic activity. These include receptors for erythropoietin, thrombopoietin, most interleukins and interferon. JAK2 mutations are important because JAK2 plays a role in controlling the production of blood cells from hematopoietic stem cells. V617F mutations seem to make hematopoietic cells more sensitive to growth factors requiring JAK2 for signal transduction, which includes erythropoietin and thrombopoietin.

Code of the MPL gene for proteins that act as receptors for thrombopoietin. A mutation in the gene, known as the W515 mutation, leads to the production of abnormal thrombopoietin receptor proteins, resulting in an abundance of abnormal megakaryocytes production. Megakaryocytes abnormally stimulate other cells, fibroblasts, to produce collagen in the bone marrow.

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Mechanism

Myelofibrosis is a clonal neoplastic disorder of hematopoiesis, the formation of a component of blood cells. This is one myeloproliferative disorder, a disease in the bone marrow where excess cells are produced at a certain stage. The production of cytokines such as fibroblast growth factor by abnormal hematopoietic cell clones (mainly by megakaryocytes) causes replacement of hematopoietic tissue from bone marrow by connective tissue through collagen fibrosis. Decreased hematopoietic tissue interferes with the patient's ability to produce new blood cells, resulting in progressive pancytopenia, deficiency of all types of blood cells. However, the proliferation of fibroblasts and the deposition of collagen is a secondary phenomenon, and fibroblasts themselves are not part of abnormal cell clones.

In primary mielofibrosis, progressive scarring, or fibrosis, of the bone marrow occurs, for the reasons described above. The result is extramedular hematopoiesis, which is the formation of blood cells that occur in places other than the bone marrow, since haemopoetic cells are forced to migrate to other areas, especially the liver and spleen. This causes enlargement of these organs. At heart, the abnormal size is called hepatomegaly. Splenic enlargement is called splenomegaly, which also causes pancytopenia, especially thrombocytopenia and anemia. Another complication of extramedular hematopoiesis is poikilocytosis, or the presence of abnormally shaped red blood cells.

Myelofibrosis can be a late complication of other myeloproliferative disorders, such as polycythemia vera, and, more rarely, essential thrombocythemia. In this case, myelofibrosis occurs as a result of somatic evolution of an abnormal hematopoietic stem cell clone that causes the original disorder. In some cases, the development of myelofibrosis after this disorder can be accelerated by oral hydroxyurea chemotherapy drugs.

The cause and risk factors for primary myelofibrosis are unknown.

Site hematopoiesis

The main site of extramedular hematopoiesis in myelofibrosis is the spleen, which is usually marked enlarged, sometimes weighing as much as 4000 g. As a result of large enlargement of the spleen, multiple subcapular infarction is common in the spleen, meaning that oxygen supply is impaired to partial or complete tissue death of the spleen. At the cellular level, the spleen contains precursors of red blood cells, granulocyte precursors and megakaryocytes, with megakaryocytes prominent in their numbers and in their peculiar form. Megakaryocytes are believed to be involved in causing secondary fibrosis seen in this condition, as discussed under "Mechanisms" above. Sometimes the unusual activity of red blood cells, white blood cells, or platelets is seen.

The liver is often enlarged moderately, with the focus of extramedular hematopoiesis. Microscopically, the lymph nodes also contain the focus of hematopoiesis, but this is not enough to cause enlargement.

There are also reports of hematopoiesis occurring in the lungs. These cases are associated with hypertension in the pulmonary artery.

Bone marrow in typical cases is hypercellular and diffuse fibrotic. Both early and advanced disease, megakaryocytes are often prominent and usually dysplastic.

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Diagnosis

Epidemiology, disorder usually develops slowly and is primarily observed in people over the age of 50. It may also develop as a treatment side effect with some drugs targeting haematological disorders, such as polycythemia vera or chronic myelogenous leukemia. The diagnosis of myelofibrosis is made on the basis of bone marrow biopsy. Abdominal examination may show enlargement of the spleen, liver, or both.

Blood tests are also used in diagnosis. Primary myelofibrosis can begin with a blood image similar to that found in polycythemia vera or chronic myelogenous leukemia. Most people with myelofibrosis have moderate to severe anemia. Finally thrombocytopenia, decreased blood platelets develop. When viewed through a microscope, the smear of blood will appear very abnormal, with a presentation of pancytopenia, which is a reduction in the number of all types of blood cells: red blood cells, white blood cells, and platelets. Red blood cells may exhibit abnormalities including strange forms, such as teardrop-shaped cells, and precursors of red coronated blood cells may appear in blood smears. (Normally, mature red blood cells in adults do not have a cell nucleus, and the presence of red blood cells indicates that immature cells are released into the bloodstream in response to the very high demand for bone marrow to produce new red blood. Cells.) The immature white cells are also seen in the blood sample, and the basophil count increases.

When late in the progression of the disease, attempts made to take bone marrow samples with aspiration can produce a dry tap, meaning that where the needle can usually suck the sample from the semi-liquid bone marrow, it does not produce the sample because the marrow has been replaced with collagen fibers. Bone marrow biopsy will reveal collagen fibrosis, replacing the marrow that usually occupies the space.

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Treatment

The known curative treatment is an allogeneic stem cell transplant, but this approach involves significant risks. Other treatment options mostly support, and do not change the course of the disorder (with the possible exception of ruxolitinib, as discussed below). These options may include regular folic acid, allopurinol or blood transfusions. Dexamethasone, alpha-interferon and hydroxyurea (also known as hydroxycarbamide) can play a role.

Lenalidomide and thalidomide can be used in its treatment, although peripheral neuropathy is a troublesome side-effect.

Frequent blood transfusions may also be needed. If the patient has diabetes and takes sulfonylurea, this should be stopped periodically to exclude drug-induced thrombocytopenia.

Splenectomy is sometimes considered a treatment option for patients with myelofibrosis in which large splenomegaly contribute to anemia due to hypersplenism, especially if they have severe requirements for blood transfusion. However, splenectomy in the presence of large splenomegaly is a high-risk procedure, with a risk of death as high as 3% in some studies.

In November 2011, the FDA approved ruxolitinib (Jakafi) as a treatment for medium or high risk mielofibrosis. Ruxolitinib serves as an inhibitor of JAK 1 and 2. The New England Journal of Medicine (NEJM) publishes the results of two ruxolitinib III phase studies. These data suggest that treatment significantly reduces the volume of the spleen, improves myelofibrosis symptoms, and is associated with a much better overall survival rate compared with placebo.

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History

Myelofibrosis was first described in 1879 by Gustav Heuck.

Older terms include "myelofibrosis with myeloid metaplasia" and "agnogenic myeloid metaplasia". The World Health Organization uses the name "chronic idiopathic myelofibrosis", while the International Working Group on Research and Treatment Myelofibrosis calls "primary myelofibrosis" disease. In 2008 WHO has adopted the name "primary myelofibrosis." The eponym for this disease is Heuck-Assmann's disease or Assmann's Disease, for Herbert Assmann, who published the description under the term "osteosclerosis" in 1907.

It is characterized as a myeloproliferative condition in 1951 by William Dameshek. Leukemia and Lymphoma Society describe myelofibrosis as a rare type of blood cancer, which manifests as a type of chronic leukemia.

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References

src: www.bloodjournal.org

External links

Source of the article : Wikipedia