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| myelofibrosis 1 |
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| myelofibrosis 2 |
DEFINITION
Mielofibrosis is a disease in the bone marrow in which collagen form a fibrosis tissue in cavum marrow. This happens because the uncontrolled growth of blood cell precursors, which eventually led to the accumulation of connective tissue in the bone marrow. Connective tissue that forms blood cells which ultimately lead to dysfunctional form. Our bodies are aware of this, and tries to compensate by sending a signal to hematopoietic extramedulare organs, namely liver and spleen to produce new blood cells. But the blood cells that eventually produced by these organs is still not functioning properly and the body finally experiencing anemia.
ETIOLOGY
Mielofibrosis idiopathic or primary mielofibrosis usually associated with genetic factors. The cause is idiopathic. There were no trigger factor, a epidemiologist who is expected to have some substance as causes, such as: Toluene, benzene, ionizing radiation. The highest incidence in patients due to radiographic contrast material administration with the basic ingredients of thorium, which is Torotras. Victims of the Hiroshima atomic bomb also has a 18 times greater risk than other populations, syndrome first appeared 6 years after exposure.
INCEDENCE
Mielofibrosis idiopathic about 2 from 1 million people. Approximately 10-15% of cases of idiopathic mielofibrosis appears at first as polistemia vera or essential thrombosis. MMM attack the middle and older age group, usually found at the age above 50 years, mean age 60 or 65 years, men and women have the same ability. MMM less frequently attack young age and rarely in children. 2 times boys than girls. In some reported cases of familial factors.
The occurrence of several conditions that Allows Mielofibrosis
A. Neoplastic conditions
1. Acute leukemia
2. Chronic myelogenous leukemia
3. Hairy cell leukemia
4. Hodgkin's disease
5. Lymphoma
6. Multiple myeloma
7. Myelodysplasia
8. Metastatic carcinoma
9. Polycythemia vera
10. Systemic mastocytosis
B. Non-neoplastic Conditions1. HIV infection
2. Hyperparathyroidism
3. Renal osteodystrophy
4. SLE
5. Tuberculosis
6. Vitamin D deficiency
7. Thorium dioxide exposure
8. Gray platelet syndrome.
PATHOGENESIS
Signs of mielofibrosis is an increase in staining reticuline. Fibrotic tissue was found on mielofibrosis tissue containing collagen and fibronectin, where reticuline staining (silver or Gomori) react with proteins contained in type III collagen and is usually estimated as a form of procollagen.
Idiopathic Mielofibrosis affects production of blood cells, erythrocytes very little is produced, too many leukocytes and platelets are produced.
Fibrosis in bone marrow may be able to describe the excess production of matrix. As already mentioned, this can be linked to many diseases. Matrix homeostasis resulting from the balance of formation and expenditure. Formation is influenced by growth factors, the most influential are the platelet derived growth factor (platelet-derived growth factor / PDGF), and expenditures described collagenase activity towards monocytes, macrophages and granulocytes. Therefore, diseases associated with mielofibrosis can be classified either according to the basic defect matrix production, decreased reabsorbs or both. If included in the category of both, can be characterized by deficiency of vitamin D because 1,25 (OH) 2D3 which is the active form of vitamin D3 inhibits megakarioycte and trigger the proliferation of monocyte differentiation / macrophages.
Some researchers believe that abnormal stroma of bone marrow is directly trigger the systemic circulation and dissemination of hematopoietic precursors by yet unknown mechanisms. This led to the hematopoietic ekstramedulare in the liver, spleen, limphonody or (usually) the kidneys, which causes metaplasie mieloid in these organs, which eventually become enlarged. Usually, hypersplenism also can contribute to the occurrence of cytopenia.
Among the adults whose mielofibrosis idiophatik, Cytogenetics of bone marrow analysis showed abnormal clone at roughly one-third of patients. By using comparative genomic hybridization technique, Al-Assar et al studied bone marrow mielofibrosis idiophatic and found chromosomal imbalances in 21 of 25 cases. Mutations of the gene 9p, 13q, 2q, 3p and 12q are common chromosomal abnormalities found. Hematopoietic origin of cell proliferation is more evenly with effected spleen and liver. There are secondary in the bone marrow fibrosis. Presumably precursor megakariocyt abnormal release of growth factors that stimulate fibroblasts.
The existence of mutagen is estimated as a factor that triggers produce clonal hemopatia on mielofibrosis. Cytogenetics abnormalities were not consistent as it changes its gene bcr / abl in CML, which was presented as a candidate gene important in pathogenesis. Changes in the molecular level of mielofibrosis remained unclear, until now still in the research.
Panel of candidate gene expression differences were observed between cytokine-independent progenitor cells from patients mielofibrosis with cytokine-progenitor progenitor (predicted normal). Immunophilin excessive FKBP51 expression in all patients studied and this function especially in cytokine-independence. Gata-1 transcription factor active on normal megakariocyte differentiation. In the rat study there were failures Gata-1 expression produces a syndrome resembling mielofibrosis. So the changes directly on the Gata-1 is important for the occurrence of mielofibrosis. Several genes associated with other growth have been investigated, for example: retino-blastoma gene that may have deletions or changes in calcitonin gene expression and methylation are experiencing. Mielofibrosis development may be related to abnormalities in the p53 gene or genes of race.
Mielofibrosis in MMM is a secondary reaction to the clonal hemopathy. Fibroblast cell secreting collagen that will be accumulated, these cells are normal and polyclonal. They are stimulated by cytokines released from megakariocyte and of clonal neoplastic cells developed hematopoitic other. Destruction and collagen synthesis occurs so that the concentration procollagen (results of collagen solution) is a marker of new collagen synthesis associated with disease activity. Collagen deposited in the extracellular space and vascular elements in the bone marrow. Four of the five types of collagen found here. Collagen type 1 and 3 is the main component of fibrosis in MMM, and increased collagen deposits equivalent to the duration of the disease.
At this early stage of MMM is the highest percentage of collagen type 3, whereas at the final stage of type 1 collagen (collagen polimetrik) the highest. In MMM there is a small portion of matrix molecules that contain more heksosamin than normal. Vascularization also increased, the extent of neovascularization is associated with the extent of disease and perhaps this is essential to the occurrence of fibrosis. Transforming growth factor (TGF) - β as the major mediator of collagen accumulation in the MMM. Cytokines are synthesized by endothelial cells such as megakariocyte and his case in the system monocytes - macrophages. TGF - β is more potent in secreting collagen than platelet derivate growth factor or epidermal growth factor and may regulate both these cytokines. TGF - β is also a potent stimulus to angiogenesis.
The increase in TGF - β can be detected by increasing the circulation of platelets and which is a fragment megakariocyte MMM. Several other growth factors are also expected to stimulate fibroblasts in MMM, among others: Platelet derived growth factor contained in megakariocyte MMM, epidermal growth factor, endothelial cell growth factor, interleukin -1, basic fibroblast growth factor, and kalmoudulin. Several independent mechanisms to increase levels of cytokines in the bone marrow environment, among others: a simple secretion of granule - α megakariocyte, megakariocyte dysplastic bone marrow damage and destruction in the cytoplasm of megakariocyte by PMN leukocytes.
Distribution of hematopoietic ekstramedulare on MMM involving fetal liver and spleen. Model mielofibrosis by damaging blood vessels, the ultrastructure examination showed an increase beyond marrow hematopoietic which solidified, and began releasing hematopoietic precursors. Non ekstramedulare overgrown hematopoietic cell transfer. The liberation from marrow precursors similar to the damage results hematopoietic ekstramedulare sinusoids in cancer metastasis and may be a common mechanism.
CLINICAL FEATURES
In 25% of cases are asymptomatic looking mielofibrosis, diagnosis dissugestion in the presence of abnormal blood tests or splenomegaly inseidensil there. Clinical symptoms in general muscle fatigue and weight loss (7-39%), hipermetabolik syndrome (fever, night sweats present in 50-20% of patients), bleeding and bruised, sometimes there are times in the stomach, gout and renal colic, there are 4 - 6%, tophi are rarely obtained, diarrhea with no clear cause and pain Substernal sometimes found.
It can also be found pale in patients, palpitations, shortness of breath, itching, abdominal pain or discomfort in the abdomen, pain in the left shoulder or upper body left, spontaneous bleeding, bone pain , especially in the legs.
Clinical disorders for diagnosis of patients Mielofibrosis
Very frequently found (> 50% of cases)
• Splenomegaly
• hepatomegaly
• Fatigue
• Anemia
• leukocytosis
• thrombocytosis
Often found (10-50% of cases)
• Asymptomatic
• Weight loss
• Sweat night
• Bleeding
• Leukocytopenia
• Thrombocytopenia
Less common (<10% of cases)
• Peripheral edema
• Portal Hypertension
• Lymphadenopathy
• Yellow
• Gout
Substantial splenomegaly is a major physical discovery. Hepatomegaly was found in half of patients, 2-6% have portal hypertension, may be followed by complications: ascites, esophageal varices, gastrointestinal bleeding and hepatic encephalopathy. Also found petechiae, ekhimosis, and limfadenopatia. Some patients show a similar dermatosis neutrofilik sweet-syndrome and suffered hematopoietic ekstramedulare dermal, who partially followed osteosclerosis periostitis with bone pain and deafness. When the surface of the serous was involved in hematopoietic may have pleural effusion or ascites and perikard. Sometimes followed by neurological complications such as: elevation of intracranial pressure, delirium, coma, subdural hemorrhage, damage to motor, sensory and paralysis.
Mielofibrosis is a disease in the bone marrow in which collagen form a fibrosis tissue in cavum marrow. This happens because the uncontrolled growth of blood cell precursors, which eventually led to the accumulation of connective tissue in the bone marrow. Connective tissue that forms blood cells which ultimately lead to dysfunctional form. Our bodies are aware of this, and tries to compensate by sending a signal to hematopoietic extramedulare organs, namely liver and spleen to produce new blood cells. But the blood cells that eventually produced by these organs is still not functioning properly and the body finally experiencing anemia.
ETIOLOGY
Mielofibrosis idiopathic or primary mielofibrosis usually associated with genetic factors. The cause is idiopathic. There were no trigger factor, a epidemiologist who is expected to have some substance as causes, such as: Toluene, benzene, ionizing radiation. The highest incidence in patients due to radiographic contrast material administration with the basic ingredients of thorium, which is Torotras. Victims of the Hiroshima atomic bomb also has a 18 times greater risk than other populations, syndrome first appeared 6 years after exposure.
INCEDENCE
Mielofibrosis idiopathic about 2 from 1 million people. Approximately 10-15% of cases of idiopathic mielofibrosis appears at first as polistemia vera or essential thrombosis. MMM attack the middle and older age group, usually found at the age above 50 years, mean age 60 or 65 years, men and women have the same ability. MMM less frequently attack young age and rarely in children. 2 times boys than girls. In some reported cases of familial factors.
The occurrence of several conditions that Allows Mielofibrosis
A. Neoplastic conditions
1. Acute leukemia
2. Chronic myelogenous leukemia
3. Hairy cell leukemia
4. Hodgkin's disease
5. Lymphoma
6. Multiple myeloma
7. Myelodysplasia
8. Metastatic carcinoma
9. Polycythemia vera
10. Systemic mastocytosis
B. Non-neoplastic Conditions1. HIV infection
2. Hyperparathyroidism
3. Renal osteodystrophy
4. SLE
5. Tuberculosis
6. Vitamin D deficiency
7. Thorium dioxide exposure
8. Gray platelet syndrome.
PATHOGENESIS
Signs of mielofibrosis is an increase in staining reticuline. Fibrotic tissue was found on mielofibrosis tissue containing collagen and fibronectin, where reticuline staining (silver or Gomori) react with proteins contained in type III collagen and is usually estimated as a form of procollagen.
Idiopathic Mielofibrosis affects production of blood cells, erythrocytes very little is produced, too many leukocytes and platelets are produced.
Fibrosis in bone marrow may be able to describe the excess production of matrix. As already mentioned, this can be linked to many diseases. Matrix homeostasis resulting from the balance of formation and expenditure. Formation is influenced by growth factors, the most influential are the platelet derived growth factor (platelet-derived growth factor / PDGF), and expenditures described collagenase activity towards monocytes, macrophages and granulocytes. Therefore, diseases associated with mielofibrosis can be classified either according to the basic defect matrix production, decreased reabsorbs or both. If included in the category of both, can be characterized by deficiency of vitamin D because 1,25 (OH) 2D3 which is the active form of vitamin D3 inhibits megakarioycte and trigger the proliferation of monocyte differentiation / macrophages.
Some researchers believe that abnormal stroma of bone marrow is directly trigger the systemic circulation and dissemination of hematopoietic precursors by yet unknown mechanisms. This led to the hematopoietic ekstramedulare in the liver, spleen, limphonody or (usually) the kidneys, which causes metaplasie mieloid in these organs, which eventually become enlarged. Usually, hypersplenism also can contribute to the occurrence of cytopenia.
Among the adults whose mielofibrosis idiophatik, Cytogenetics of bone marrow analysis showed abnormal clone at roughly one-third of patients. By using comparative genomic hybridization technique, Al-Assar et al studied bone marrow mielofibrosis idiophatic and found chromosomal imbalances in 21 of 25 cases. Mutations of the gene 9p, 13q, 2q, 3p and 12q are common chromosomal abnormalities found. Hematopoietic origin of cell proliferation is more evenly with effected spleen and liver. There are secondary in the bone marrow fibrosis. Presumably precursor megakariocyt abnormal release of growth factors that stimulate fibroblasts.
The existence of mutagen is estimated as a factor that triggers produce clonal hemopatia on mielofibrosis. Cytogenetics abnormalities were not consistent as it changes its gene bcr / abl in CML, which was presented as a candidate gene important in pathogenesis. Changes in the molecular level of mielofibrosis remained unclear, until now still in the research.
Panel of candidate gene expression differences were observed between cytokine-independent progenitor cells from patients mielofibrosis with cytokine-progenitor progenitor (predicted normal). Immunophilin excessive FKBP51 expression in all patients studied and this function especially in cytokine-independence. Gata-1 transcription factor active on normal megakariocyte differentiation. In the rat study there were failures Gata-1 expression produces a syndrome resembling mielofibrosis. So the changes directly on the Gata-1 is important for the occurrence of mielofibrosis. Several genes associated with other growth have been investigated, for example: retino-blastoma gene that may have deletions or changes in calcitonin gene expression and methylation are experiencing. Mielofibrosis development may be related to abnormalities in the p53 gene or genes of race.
Mielofibrosis in MMM is a secondary reaction to the clonal hemopathy. Fibroblast cell secreting collagen that will be accumulated, these cells are normal and polyclonal. They are stimulated by cytokines released from megakariocyte and of clonal neoplastic cells developed hematopoitic other. Destruction and collagen synthesis occurs so that the concentration procollagen (results of collagen solution) is a marker of new collagen synthesis associated with disease activity. Collagen deposited in the extracellular space and vascular elements in the bone marrow. Four of the five types of collagen found here. Collagen type 1 and 3 is the main component of fibrosis in MMM, and increased collagen deposits equivalent to the duration of the disease.
At this early stage of MMM is the highest percentage of collagen type 3, whereas at the final stage of type 1 collagen (collagen polimetrik) the highest. In MMM there is a small portion of matrix molecules that contain more heksosamin than normal. Vascularization also increased, the extent of neovascularization is associated with the extent of disease and perhaps this is essential to the occurrence of fibrosis. Transforming growth factor (TGF) - β as the major mediator of collagen accumulation in the MMM. Cytokines are synthesized by endothelial cells such as megakariocyte and his case in the system monocytes - macrophages. TGF - β is more potent in secreting collagen than platelet derivate growth factor or epidermal growth factor and may regulate both these cytokines. TGF - β is also a potent stimulus to angiogenesis.
The increase in TGF - β can be detected by increasing the circulation of platelets and which is a fragment megakariocyte MMM. Several other growth factors are also expected to stimulate fibroblasts in MMM, among others: Platelet derived growth factor contained in megakariocyte MMM, epidermal growth factor, endothelial cell growth factor, interleukin -1, basic fibroblast growth factor, and kalmoudulin. Several independent mechanisms to increase levels of cytokines in the bone marrow environment, among others: a simple secretion of granule - α megakariocyte, megakariocyte dysplastic bone marrow damage and destruction in the cytoplasm of megakariocyte by PMN leukocytes.
Distribution of hematopoietic ekstramedulare on MMM involving fetal liver and spleen. Model mielofibrosis by damaging blood vessels, the ultrastructure examination showed an increase beyond marrow hematopoietic which solidified, and began releasing hematopoietic precursors. Non ekstramedulare overgrown hematopoietic cell transfer. The liberation from marrow precursors similar to the damage results hematopoietic ekstramedulare sinusoids in cancer metastasis and may be a common mechanism.
CLINICAL FEATURES
In 25% of cases are asymptomatic looking mielofibrosis, diagnosis dissugestion in the presence of abnormal blood tests or splenomegaly inseidensil there. Clinical symptoms in general muscle fatigue and weight loss (7-39%), hipermetabolik syndrome (fever, night sweats present in 50-20% of patients), bleeding and bruised, sometimes there are times in the stomach, gout and renal colic, there are 4 - 6%, tophi are rarely obtained, diarrhea with no clear cause and pain Substernal sometimes found.
It can also be found pale in patients, palpitations, shortness of breath, itching, abdominal pain or discomfort in the abdomen, pain in the left shoulder or upper body left, spontaneous bleeding, bone pain , especially in the legs.
Clinical disorders for diagnosis of patients Mielofibrosis
Very frequently found (> 50% of cases)
• Splenomegaly
• hepatomegaly
• Fatigue
• Anemia
• leukocytosis
• thrombocytosis
Often found (10-50% of cases)
• Asymptomatic
• Weight loss
• Sweat night
• Bleeding
• Leukocytopenia
• Thrombocytopenia
Less common (<10% of cases)
• Peripheral edema
• Portal Hypertension
• Lymphadenopathy
• Yellow
• Gout
Substantial splenomegaly is a major physical discovery. Hepatomegaly was found in half of patients, 2-6% have portal hypertension, may be followed by complications: ascites, esophageal varices, gastrointestinal bleeding and hepatic encephalopathy. Also found petechiae, ekhimosis, and limfadenopatia. Some patients show a similar dermatosis neutrofilik sweet-syndrome and suffered hematopoietic ekstramedulare dermal, who partially followed osteosclerosis periostitis with bone pain and deafness. When the surface of the serous was involved in hematopoietic may have pleural effusion or ascites and perikard. Sometimes followed by neurological complications such as: elevation of intracranial pressure, delirium, coma, subdural hemorrhage, damage to motor, sensory and paralysis.
The following grouping of symptoms according to the cause
• hepatosplenomegaly:
o Enlarged abdomen
o Abdominal pain
o Weight loss
• Symptoms of Anemia:
o Fatigue \
o Shortness of breath
o Weakness
o Looks pale
o Palpitations
• Symptoms of Infection:
o Fever reach or over 38 ° C
o Chills
o Sweat night
o Coughing
o Sore throat
o Blisters on the lips or mouth
o The heat or pain during urination
o Swelling that does not get better, remove secretions, redness and warm to the touch
o Stiff neck
• Symptoms of Bleeding:
o Easy bleeding
o Bleeding massive and elongated
o spontaneous bleeding
o severe head pain or impaired vision
o Stiff neck
o Joint pain
o Petechiae
Examination Support
a. Blood
On examination of peripheral blood cells obtained tear drop-shaped erythrocytes which are connected the core in circulating erythrocytes, leukocytes and neutrophils immatur abnormally large platelets. Reticulocyte increases; erythrocyte policromasia, fragmentation and target cells are also frequently found. These morphological abnormalities caused by changes hematopoietic, free cell earlier than bone marrow and hematopoietic ekstramedulare. How did these changes occur remains unclear.
Anemia with hemoglobin less than 10 g / dl were found in 60% of cases, which can occur due to hemodilution from increased plasma volume, impaired bone marrow production and hemolysis. Patient's peripheral blood smear mielofibrosis: aniso-poikilositosis, oval of erythrocyte, leukomoid reaction (granulocytes side there is one metamielosit, one promielosit and one normoblast). While the cause of hemolysis is estimated: hypersplenism, autoantibodies erythrocytes, hemoglobin H are obtained and the sensitivity of the complement membrane similar PNH (Paroxysmal nocturnal hemoglobinuria).
The morphology of anemia is not generally normositik normokromik KHS, makrositik if folic acid deficiency and microcytic hipokromik when Fe deficiency or gastrointestinal bleeding. The number of leukocytes increased at 50% of cases, followed by eosinophilia and basofilia, while the number of normal lymphocytes. Some meiloblas found in the peripheral circulation and may not have considered the conversion towards acute leukemia, but mieloblas concentration> 1% memeberikan poor prognosis. Also found hipersegmen neutrophils, increases neutrophil enzymes, platelets increased in early MMM, on the progression of the disease can occur thrombocytopenia.
Platelets are usually large, in the circulation megakariocyte found intact or undergo fragmentation. Often abnormal platelet function, bleeding time disruption and retraction jendalan and decline: levels of platelet factor 3, platelet adhesiveness and lipogenesis activity. Changes in soluble factor that can terajdi pemebekuan the disease. Disseminated intravascular coagulation (DIC) subclinical can be found in 15% of MMM patients with advanced form and acquired factor V deficiency can occur in patients tersebnut above. Uric acid levels and lactate dehydrogenase enzyme is almost always increased, describing the existence of an excessive period of hematopoietic cells or the hematopoietic an ineffective or both. It can also increase serum levels of enzymes alkalinefosfatase which is bone involvement, a decline in levels of albumin, cholesterol and lipoproteins. Can increase levels of vitamin B12 in patients with leukocytosis, which is a reflection of the increase in the neutrophil.
b. Bone marrow
Aspiration of bone marrow may not be successful (drytap) and requires a bone marrow biopsy to diagnose MMM. A consensus has been made by the Italian Society of Hematology.
Morphology and clinical data were combined to diagnose appeal MMM from other CMPD disease, and from mielodisplasi syndrome with bone marrow fibrosis. The criteria were: bone marrow fibrosis and bone marrow hyperplasia morphology disorder and hematopoietic ekstramedulare. The three elements above must be contained to the criteria MMM.
Fibrosis have occurred in all cases of MMM, and usually in the patient information. In the early stages of fibrosis were minimal and bone marrow hyperplasia may be more clear. The above situation is called cellular phase MMM. When bone marrow fibrosis patients suspected not proven MMM, have taken material from other places, because the spread is uneven.
Fibrosis may need to be graded by a system that has been publicated and proven. When the massive fibrosis, cellularity whole will go down, but there remain megakariocyte hyperplasia. Bone marrow sinusoids will be widespread, there has been hematopoietic intravascular.
The increase in the number of mast cells can be observed in patients with a fibrosis at the time of biopsy. In the preparation of bone marrow smears, not a cursory look kelaianan, but often found hyperplasia neutrofilik and megakariocyte. The presence mikromegakariocyte and makromegakariocyte can be found, giving rise to nuclear-cytoplasmic asynchrony.
Granulocytes can be hypo or hiperlobulasi so memeperlihatkan Pelger-Huet anomaly obtained or the presence of nuclear-cytoplasmic asynchrony. Precursor erythroid normal or increased, which can be checked by scanning isotope sulfur colloid bone marrow for cell retikuloendoteliel and with colloidal iron for cell erythroid indicating an expansion in the bone marrow to the long bones of normal inactive.
c. Chromosome abnormalities
Half of MMM patients contained clonal karyotype abnormality. Only a few patients showed abnormalities in metaphase, which proves the MMM patients hematopoietic leaving normal cells. Often found deletion of chromosome segments linked to the retinoblastoma gene, del 13 (q13q21) and del 20q. Chromosomes are often disrupted are: 1,5,7,8,9,13,20 and 21. Form of trisomy and monosomy, partial deletions and translocations are also frequently found. Fibroblasts do not contribute to chromosomal abnormalities in MMM.
d. Damage to the immune system
Clinically immune system abnormality common in MMM, this contrasts with other CMPD. T and B lymphocyte cells directly affected by stem cell defect in MMM and functional defects of B cells and T may be shown. Variations humoral immune system abnormalities have been found. The reduced levels of C3 may occur and cause a rise in the possibility of bacterial infection. Pathological autoantibodies may be found among others: Erythrocyte autoantibodies, platelet antibodies, antinuclear antibody, antiimunoglobulin and antibody antiphosfolipid. In MMM filtered lymphoid bone marrow. Monoclonal Gamopati to arise 10% of MMM patients, in some cases the simultaneous occurrence of MMM and plasma cell dyscrasias have been reported.
d. Pathological examination
Typical picture of the MMM is the presence of bone marrow fibrosis and hematopoietic ekstramedulare. Bone marrow fibrosis followed the osteosclerosis 30-70% of cases, especially regarding the axial skeleton and the proximal long bones. Cortical bone is thickened and the normal pattern of trabeculae disappeared. Hematopoietic mainly occurs in the spleen in the presence of splenomegaly, liver and some other organs can also be involved, for example: lymph node, kidney, adrenal, periosteum, intestines, pleura, lung, fat tissue, skin, mammary, dura, ovarian and thimus. Hematopoietic cluster may contain a mixture of derivatives and possible precursor mieloid seen as microscopic or tumor infiltrates makroskopis. The proportion of erythroid ekstramedulare higher on the side rather than in bone marrow and hematopoietic ekstramedulare, there is a tendency of low mitotic index, immature cells and megaloblastic higher than hematopoietic medulare . Damage target organ may occur due to physical pressure around normal tissue, but normal architecture can still be maintained.
Italian Consensus Conference for the Diagnosis Mielofibrosis
A. Major Criteria
1. Diffuse bone marrow fibrosis
2. The loss of T9: 22 chromosome or bcr / abl Rearrangement in peripheral blood cells
3. Splenomegaly
B. Minor Criteria
1. Anisopoikilocytosis with tear drop red cells
2. Clustred marrow megakaryoblast and anomalous megakariocytes
3. Metaplasia mieloid
Management
The goal of treatment is to reduce symptoms and reduce the risk of complications. MMM may be cured with hematopoetic stem cells Transplantation (HSCT), but usually successful HSCT for younger patients and represents a significant risk of death. No other form of therapy to prolong survival or prevent the progression mielofibrosis.
Supportive therapy is directed directly to the complications that occur. Some patients are asymptomatic and require observation. Allopurinol is given to maintain blood uric acid levels remain normal, to inhibit: nefropathy vein, renal calculi and gout. Anemia and thrombocytopenia may arise, and will continue until symptoms develop. When some failed to improve hematopoietic therapy, transfusion is required to maintain blood count. Folic acid supplementation is necessary because of frequent occurrence of hemolysis. Blood transfusions can be given to overcome the anemia that occurs in patients.
a. Antirachitis
Mielofibrosis has been described that can occur in patients and lead to deficiency of vitamin D. In addition, patients mielofibrosis associated with trombositemia esencial or mielomonositik leukemia, as acute (idiopathik) mielofibrosis, has given good response to vitamin D. Vitamin D and its analogues can suppress proliferation and repair mielofibrosis megakariocyte associated with rickets. Direct inhibitory effects on thrombosis has been demonstrated. However, some studies do not show the same response on paien with idiopathic mielofibrosis.
Commonly used are calcitriol, which is the primary active metabolite of vitamin D3. it can increase calcium levels by triggering the absorption of calcium from the digestive tract and in urine retention. The dose given to patients mielofibrosis higher than 5 to 10 times the physiological dose. In adults is usually 2.5 mcg / day, orally. Contraindications hypersensitive patients, hypercalcaemia or the presence of malabsorption syndrome.
b. Corticosteroid
These drugs have immunosuppressive and cytotoxic effects. Cytotoxic mechanism of corticosteroids is still not yet known (but apparently through the glucocorticoid receptor). Preparations are usually used is prednisone which act as immunosuppressants in autoimmune disorders. Prednisone can reduce the effects of inflammation by increasing capillary permeabilizas and suppressing PMN activity. Prednisone also can mensstabilkan lysosome membrane and also suppress the production of lymphocytes and antibodies. Efficiency in some cases may reflect an underlying autoimmune defect and / or pressing clones proliferated.
The usual dose is 50-60 mg / day orally. Contraindicated in patients with hypersensitivity, viral infection, peptic ulcers, insufiensi liver, connective tissue infections, fungal infections or tuberculosis of the skin, gastrointestinal bleeding or ulceration of the gastrointestinal tract.
Moreover, it can also be used methylprednison which can suppress the inflammatory process by pressing the spread of PMN leukocytes and also increase capillary permeability.
c. Immunomodulator
Immunomodulator can suppress the autoimmune process, triggered imunoregulasi of abnormal clones. Preparations commonly used are interferon alpha 2a. treatment with these preparations has shown efficient results in the long term for adult patients. Interferon considered because it can suppress the activity of TGF - β and its effectiveness in CML. Interferon - α might be beneficial relieve bone pain, thrombocytopenia and splenectomy, but the effectiveness is decreased by a flulike syndrome and memberatnya severe anemia. The dose commonly used 1-6 million units / day, subcutaneous. It can also be used thalidomide preparations. Thalidomide is statu immunomodulatory agent that can suppress excessive production of tumor necrosis factor alpha (TNF-α) and can decrease adhesion regulation of cell membrane associated with the migration of leukocytes. Because some peretimbangan, including teratogeniknya effects, thalidomide is not freely sold and only given by doctors who are responsible for their patients and only sold by pharmacies who have been enrolled in the program and Safety Education Thalidomide Perscribe (STEPS). Patients must follow a survey that will be executed while getting therapy, and thalidomid only be granted for a period of 28 days.
These preparations are widely used to improve anemia and reduce transfusion of blood or thrombosis associated with mielofibrosis. Patients with severe MMM antiangiogenic preparations can be given thalidomide, 20% of cases occur constitutional symptoms improved with the decrease, the size of the spleen and improvement of blood counts. Serious side effects reported include: severe leukocytosis and thrombocytosis hematopoietic ekstramedulare pericardial, and can occur at very low initial dose of 50 mg / day.
Some researchers provide a combination of thalidomide 50 mg / day with prednisone 0.5 mg / kg / day, 95% complete response within 3 months of treatment. A single dose of 200 mg / day, per oral, then dose titration to achieve the target dose of 800 mg / day, orally. In combination with the provision of prednisone, used 50mg/hari per oral dose.
d. Allogenic hematopoietic stem cell Transplantion
Almost all patients with CMPD may be cured with Allogenic hematopoietic stem cell Transplantation (AHSCT). Limitation of this approach because the factor of age and condition of the patient, using a suitable donor match and morbidity and mortality associated with the procedure. The presence of bone marrow fibrosis and splenomegaly apparently not a barrier to HSCT.
Reported by Guardiola et al (1999) and Jurado et al (2001) Internacional cooperative group trial with 55 patients, almost all young age, mean age 42 years, with HLA-identical related donor. MMM with age> 45 years 5-year survival by 14%. The more it becomes clear, that in younger patients with 2 risk factors, with a predicted low survival, with no curative treatment, HSCT performed immediately considered the diagnosis Estela upright. For older patients with HSCT may provide a low-end result and a bad risk factor is not found, then you should first reach difunda risk factors emerged, although data on this subject has not been widely reported.
e. Androgens and Corticosteroid Therapy
The hormone androgen can be administered in anemia due to MMM. With a response rate of 29-57%. Munngkin spontaneous improvement can occur in MMM, so that the response to therapy should be carefully analyzed. Women with minimal splenomegaly and patients with normal karyotype provide better prognosis. Before therapy with androgens, men need prostate gland screened both physically and with prostate-specific antigen, in women to consider the effects of virilization. During androgen therapy should be monitored with liver function.
Some dosage schedules have given quite good results, including an oral synthetic androgen: fluoksimesteron, dose: 2 - 3 times 10 mg daily. If no improvement Estela 3-6 months of therapy, the androgen should be discontinued. Some patients who do not respond to androgens, the possibility of a response other preparations, due to shortened erythrocyte survival in MMM, the possibility of adrenal corticosteroids improve the vitality of erythrocytes and fix anemia. Oral prednisone, with the dose: 1 mg / kg per day, giving a response in 25-50% of patients. The best responses have been reported in female patients. Patients with hemolysis should be given folic acid supplements. Androgens and corticosteroids can sometimes be combined. Dose started with prednisone 30 mg / day, with a combination fluoksimesteron 10 mg twice a day, if there is a response after one month of therapy, reduced dose prednisone tappering off while fluoksimeteron resumed.
f. Chemotherapy
Chemotherapy rarely give haematological remission, and does not provide general changes in MMM, but may be very dramatic change in symptoms. Chemotherapy can reduce the hepatomegaly and splenomegaly and improve weight loss, fever and night sweats to 70% of patients, and reduce leukocytosis, thrombocytosis, and anemia. Chemotherapy has also been used: busulfan, melfalan, 6-tioguanin and hydroxyurea. In MMM chemotherapy should be more careful because there tends to be toxic to bone marrow than other CMPD. For example, busulfan administration 2-4 mg / day had a maximum dose that can be provided with a degree of safety in the MMM. Patients should be monitored by frequent and continuous, especially when emerging cytopenia.
Hydroxyurea can be given reduced doses of 500-1000 mg daily intervals, with dose adjustments depending on clinical response and blood counts. Hydroxyurea (Hydrea) has effect:
• Lowering the platelet counts are too high
• Reduce the size of splenomegaly and complications
• Reduce or eliminate night sweats and weight loss
• Increasing the hemoglobin concentration
• Sometimes it can reduce the degree of bone marrow fibrosis
g. Irradiation
Patients with hypersplenism may be able to respond with irradiation splenik, especially bial there is a contraindication to splenectomy. Almost all patients had improvement of pain complaints and> 50% reduction in spleen size. Irradiation splenik will provide improvements cytopenia, given by a small faction with close monitoring. Dose fractions of 15-100 cGy, 2 -3 times per week. Total dose of 700 - 2400 cGy to provide results that comfortable with the tolerance of toxicity. Preliminary results can only be seen after several months. Tumor hematopoietic ekstramedulare also symptomatic response to irradiation therapy, especially suitable in bone pain from a tumor or on deposit periostitis and central nervous system.
h. Splenectomy
Splenectomy be considered in patients refractory to therapy: cytopenia, portal hypertension, or symptoms due to hypersplenism. With splenectomy deliver improved: symptoms hypersplenism, portal hypertension, anemia and thrombocytopenia, although these improvements are not always able to be maintained after one year of action. Splenectomy in MMM must be careful, because organomegaly large enough so that it may happen adhesions, increase blood flow and compromised status of patients. The existence of DIC (KID) light which marked an increase of D-dimer levels are often found in MMM, with the risk of bleeding that is not easily corrected preoperative. Acute surgery mortality can reach 38%, at an early stage of disease, whereas mortality in hospital care that is more modern down <10% and 25% within 3 months. Splenectomy sometimes cause Aplastic crisis as a place hematopoietic ekstramedulare lien on severe bone marrow fibrosis. Splenectomy reported any significant complications: intraabdominal infection, severe thrombocytosis and hepatomegaly with rapid thrombosis enlarged. Last two cycles of chemotherapy may require pascaoperatif.
Splenectomy be considered for patients with: a. Transfusion needs that can not be accepted; b. Massive splenomegaly causes unpleasant symptoms that can not be controlled by radiotherapy or chemotherapy and c. Severe thrombocytopenia accompanied by recurrent bleeding.
In advanced disease with severe splenomegaly, the risk is very big surgery, patients in poor general condition and high death rates due to post operative bleeding and infection. Post-splenectomy thrombocytosis has a high risk of thromboembolism.
i. Other Treatment
Anagrelid can lower platelets but does not improve other clinical abnormalities. Some patients may be given eritropoetin even better when combined with interferon. Suramin and imatinib reportedly been given to the MMM, with unclear results.
Mechanical curettage of the iliac bone marrow fibrotic tissue, is expected to increase fixing hematopoietic and anemia, although this complex procedure and not always successful in all patients.
Analog HSCT after high-dose busulfan, ever done on a number of advanced MMM is refractory to other therapies, although with relatively high mortality (6 of 12 patients), almost all patients with symptoms of hypersplenism and improvement occurred half of patients been improved anemia and thrombocytopenia.
Diagnosis
Diagnosis is based on the triad MMM: bone marrow fibrosis, hematopoietic ekstramedulare and hematopoietic clonal with no discovery of the underlying disease. Found no sign - a sign of clonal hematopoietic pathognomonic and evidence are not directly when not found an abnormal karyotype. Bone marrow biopsy is necessary to determine the presence of fibrosis and prove the existence of clonal hematopoietic in the form panhiperplasia and to get rid of the infiltration process. For diagnosis using concensus Italian conference even though they may not apply to the early phase of MMM.
MMM need to be distinguished from CML, ET and PV. When bone marrow fibrosis as the main picture then the diagnosis becomes difficult. PV ended with MMM like syndrome is 15-20%. Mielofibrosis in PV is more common after several years of travel sickness. Because patients with PV postpolisitemik, become symptomatic due to the expansion of the red blood cells and into the early attention, and its diagnosis is usually made prior to bone marrow fibrosis arise. Patients with PV, first discovered the existence of phase mielofibrosis postpolisitemik more progressive way than the MMM Patients. Mielofibrosis can also occur in CML, but with a MMM deferensial diagnosis based on genetic analysis.
Mielofibrosis also can be caused by a reaction to: malignancy, infection and some other. It can be connected with change of hematopoietic peripheral blood and looking like MMM.
Mielofibrosis secondary diagnosis based on the underlying disease. Secondary Mielofibrosis a regular description of certain conditions including postpolisitemik PV and a rare complication of systemic lupus erithematosus and rickets. When mielofibrosis because infection is usually chronic form, spread widely and is usually easy to detect. Almost all secondary mielofibrosis due process of malignancy. Examination of urine hidroksiprolin a metabolite of collagen can distinguish between secondary mielofibrosis with MMM. In MMM normal excretion, in the process of malignancy and secondary mielofibrosis excretion increases.
Treatment of secondary mielofibrosis especially treatment of the underlying primary disease. Improved treatment of fibrosis, is reported after successful treatment of PV, Hodgkin's disease, metastasis of prostate and mammary carcinoma.
2.8 Prevention
In addition to the above treatment can be given, there are also several steps can be taken of patients who can mnegurangi mielofibrosis or prevent the occurrence of symptoms, namely:
• Avoid exposure of people or a crowd that brought flux or other infectious diseases if the patient leukocyte levels low.
• Making good hygiene, including washing hands in frequency.
• Brushing your teeth regularly, clean themselves (bath) regularly and notice the areas that are hard to clean like the folds of skin around the rectal area.
• Avoid activities that can cause bruising.
• Use an electric shaver, and be careful when cutting the nails, use a knife, etc..
• Use shoes with hard soles, gloves and long pants while doing outdoor activities such as gardening.
• Use a soft toothbrush if you have had bleeding gums.
• Avoid the use of aspirin or other medications that are similar to aspirin (eg Motrin, Ibuprofenther medications that are similar to aspirin (eg Motrin, Ibuprofen, anti-inflammatory or other) unless it is absolutely necessary. These medications can affect blood clotting.
• A balanced diet, because it can help the body produce new red blood cells.
• Sleep and rest enough to save energy.
• Come with a mild exercise, like brisk walking, which is intended to stimulate circulation and increase energy levels.
• Tell the dentist's other patients and medical staff who may be involved with the patient that the patient had the disease, because there is a high bleeding risk from infection and bleeding while undergoing multiple procedures.
Prognosis
As leukemia, mielofibrosis develop progressive and often requires therapy to control disease. Mielofibrosis can develop into acute lymphocytic leukemia or lymphoma. Although a number of factors to predict survival time has been spent, but usually the survival rate or developments anemia usually have poor prognosis. Survival rate in patients mielofibrosis usually 5 years.
On average MMM can survive 3-7 years and approximately 20% over 10 years to life. Median life extension - about 3-4 years but many patients live 10 years or more. Less than 10% of patients experienced late transformáis become acute leukemia. Prognosis was estimated according to the mid-emergence time blast crisis in CML and possibly worse in ET and PV. Patients with evidence of more disease provide more short survival. Jira better prognosis: there are no constitutional symptoms, Hb> 10gr/dl, platelets> 100 x 10 9 / L and no hepatomegaly. Younger patients have better survival skills, like its low concentration in the circulation mieloblas. Cytogenetics abnormalities including single clone with a translocation of chromosome 1, 5q-, Trisomy 8, 13q-, or 20q-, perhaps with a worse prognosis than a normal karyotype. Similarly, patients with increased plasma volume or increased levels of soluble IL-2 receptor and have poorer survival. 3
Reily, Snowden and Spearing et al (1997) makes several score prognosis include: age, Hb level, symptoms of the constitution and karyotype. Mayo can also be used Prognostic Scoring System (MPSS), which includes:
• Hemoglobin greater than 10 mg / dl
• Calculate the leukocytes of less than 4 or more than 30 x 109 / L.
• Platelet count less than 100 x 109 / L
• Calculate the absolute monocyte type equal to or greater than 1 x 109 / L. 2
Patients were categorized according to risk group with the shortest survival of 16 months and the longest 180 months. As time goes by symptoms and become heavy despite cytopenia be happening spontaneously repair. Some of the problems that arise such as: weight loss, edema extremitas down, infections especially pneumonia. Almost all patients with splenomegaly occurs increasingly become heavy, causing pain and bone pain.
Most patients with portal hypertension with esophageal varices, a result of: increased blood flow splenoportal, hepatica vein thrombosis, portal vein thrombosis, post-transfusion and hematopoietic haemochromatosis intrasinusoid.
Bleeding can be caused by thrombocytopenia, platelet defect, disseminated intravascular coagulation (DIC) or deficiency of factor pemebekuan. MMM patient deaths caused by variated among others: infection, bleeding, heart failure, cerebrovascular accidents, renal failure, liver failure and thrombosis. Conversion towards leukemia reported 50-20% of cases. This shift toward leukemia not clear, some cases without exposure sitostatica therapy, the incidence of acute lymphocytic leukemia direction similar to acute Mieloid Leukemia.