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PubMed1992

Myelofibrosis and systemic lupus erythematosus: reversal of fibrosis with high-dose corticosteroid therapy.

A case of myelofibrosis in association with systemic lupus erythematosus (SLE) is reported. Acute thrombocytopenia and a bleeding tendency developed in a 24-year-old woman with SLE. Bone marrow aspiration was unsuccessful due to myelofibrosis. Pulse therapy with methylprednisolone reversed both thrombocytopenia and myelofibrosis. A review of the literature revealed that the coexistence of SLE and myelofibrosis is a rare occurrence. Only 7 cases, to our knowledge, have ever been reported in detail. The present case is the 3rd in which myelofibrosis was reversed by corticosteroids.

Adult↗

PubMed2005

A pathobiologic pathway linking thrombopoietin, GATA-1, and TGF-beta1 in the development of myelofibrosis.

Idiopathic myelofibrosis (IM) is a disease characterized by marrow fibrosis, abnormal stem/progenitor cell trafficking, and extramedullary hematopoiesis frequently associated with alterations in megakaryocytes (Mks). Mice harboring genetic alterations in either the extrinsic (ectopic thrombopoietin expression, TPO(high) mice) or intrinsic (hypomorphic GATA-1 mutation, GATA-1(low) mice) control of Mk differentiation develop myelofibrosis, a syndrome similar to IM. The relationship, if any, between the pathobiologic mechanism leading to the development of myelofibrosis in the 2 animal models is not understood. Here we show that plasma from GATA-1(low) mice contained normal levels of TPO. On the other hand, Mks from TPO-treated wild-type animals (TPO(high) mice), as those from GATA-1(low) animals, had similar morphologic abnormalities and contained low GATA-1. In both animal models, development of myelofibrosis was associated with high transforming growth factor beta1 (TGF-beta1) content in extracellular fluids of marrow and spleen. Surprisingly, TPO treatment of GATA-1(low) mice restored the GATA-1 content in Mks and halted both defective thrombocytopoiesis and fibrosis. These data indicate that the TPO(high) and GATA-1(low) alterations are linked in an upstream-downstream relationship along a pathobiologic pathway leading to development of myelofibrosis in mice and, possibly, of IM in humans.

Animals↗

PubMed2006

Monocyte/macrophage dysfunctions do not impair the promotion of myelofibrosis by high levels of thrombopoietin.

Several lines of evidence indicate that the megakaryocyte/platelet lineage is crucial in myelofibrosis induction. The demonstration that NOD/SCID mice with functionally deficient monocytes do not develop fibrotic changes when exposed to thrombopoietin (TPO) also suggests an important role for monocyte/macrophages. However, in this animal model, the development of myelofibrosis is dependent on the level of TPO. This study was conducted to investigate whether NOD/SCID mice exposed to high TPO levels mediated by a retroviral vector would be refractory to the development of bone marrow fibrosis. We show that TPO and TGF-beta1 in plasma from NOD/SCID and SCID mice engrafted with TPO-overexpressing hemopoietic cells reach levels similar to the ones reached in immunocompetent mice, and all animals develop a myeloproliferative disease associated with a dense myelofibrosis at 8 wk posttransplantation. Monocytes in NOD/SCID mice are functionally deficient to secrete cytokines such as IL-1alpha in response to stimuli, even under TPO expression. Surprisingly, the plasma of these mice displays high levels of IL-alpha, which was demonstrated to originate from platelets. Together, these data suggest that completely functional monocytes are not required to develop myelofibrosis and that platelets are able, under TPO stimulation, to synthesize inflammatory cytokines, which may be involved in the pathogenesis of myelofibrosis and osteosclerosis.

Animals↗

PubMed2000

Idiopathic myelofibrosis associated with renal extramedullary hematopoiesis and nephrotic syndrome: case report.

Idiopathic myelofibrosis is characterized by bone marrow fibrosis, anemia, leukoerythroblastosis, and extramedullary hematopoiesis in many organs. Renal abnormalities in idiopathic myelofibrosis have been rarely described in the literature and include extramedullary hematopoiesis in the pararenal or retroperitoneal areas resulting in obstructive uropathy and hemtopoietic cell infiltration in tubulointerstitial area and urolithiasis. These lead to azotemia or acute renal failure, which may respond well to radiotherapy and adjuvant chemotherapy. To our knowledge, there has been only one case report of nephrotic syndrome associated with glomerulonephritis in a myelofibrosis patient; however, no effective treatment was described. Herein, we report the case of a patient with idiopathic myelofibrosis who initially presented with hepatomegaly, anemia, and leukoerythroblastosis. A nephrotic syndrome developed 7 years after initial diagnosis. Renal biopsy disclosed the unique pathological finding of simultaneous mesangial proliferative glomerulonephritis, renal extramedullary hematopoiesis, and gouty nephropathy. Despite treatment with busulfan, proteinuria persisted that implied irreversible glomerular injury and a terminal prognosis. We focus on the unusual pathological finding and the association between nephrotic syndrome and idiopathic myelofibrosis.

Aged↗

PubMed1979

[Bone marrow lymphoid follicles in myelofibrosis compared with chronic myelogenous leukaemia (author's transl)].

The trephine bone marrow biopsies of 51 patients with myeloproliferative syndromes were revised searching for lymphoid follicles and lymphoplasmocytosis: 18 of these had idiopathic myelofibrosis and 33 chronic myelogenous leukaemia. Six of the 18 biopsies on patients with myelofibrosis showed lymphoid follicles but only one of the 33 with chronic meylogenous leukaemia did (P = 0.01, Fisher exact test). In addition, four of the six myelofibrosis having follicles had two or more of them. When the pathological pattern of myelofibrosis was considered according to the Lennert and al. classification we found significantly more follicles in the cellular phase of the disease than in the advanced phases (P = 00.4, Fisher exact test). These findings can be considered as a morphological argument supporting the idea of an immunological mechanism in the development of myelofibrosis.

Biopsy↗

PubMed1979

[Clinical characteristics of primary myelofibrosis].

The authors followed-up five patients with primary myelofibrosis in the course of 4 years. The diagnosis, in all cases, was confirmed via histologic investigation of trepenation biopsy material of bone marrow and bone. The clinical and hematologic variety, observed by the authors, provided grounds for the formation of the following variants of the primary myelofibrosis: myelemic-anemic form, form with leucosis transformation, form with sarcomatization, myelofibrosis with immune hemolytic anemia and myelofibrosis in aplastic state. The establishment of transitory forms between the myeloproliferation and dysanaplastic blast processes allows the presumption that the pathogenesis essence of primary myelofibrosis is manifested in clonal lesion of the stem bone-marrow cells.

Aged↗

PubMed1984

Properties of myelofibrosis-derived fibroblasts.

Fibroblasts derived from bone marrow of patients with primary myelofibrosis and of patients with other well-differentiated myeloproliferative disorders without myelofibrosis (MPD), exhibit in vitro the same properties as fibroblasts derived from normal bone marrow. The cell density distribution, cell sedimentation rate distribution and time-dependent adherence of bone marrow fibroblast colony-forming cells (CFU-F) of MPD patients are similar to those of normals. The in vitro growth parameters, namely anchorage, serum dependence, and contact inhibition are analogous in fibroblasts derived from fibrotic and normal bone marrow. The intra- and extra-cellular distribution of fibronectin, type I, type III and type V collagens is similar in cultured marrow fibroblasts from normals, and from MPD patients with and without myelofibrosis. The plasminogen-dependent fibrinolytic activity elicited from normal and myelofibrotic marrow fibroblasts are equivalent. Moreover, marrow fibroblasts from patients with myelofibrosis do not exhibit the chromosomal abnormalities present in hematopoietic cells. These observations provide strong evidence for the absence of changes associated with neoplastic states in fibroblasts derived from fibrotic bone marrow, and support the hypothesis that myelofibrosis associated with MPD results from the abnormal interaction between hematopoietic cells and marrow collagen-producing cells, rather than from a primary disorder affecting the latter cells.

Animals↗

PubMed1981

Agnogenic myelofibrosis in children--a case report and review of the literature.

The case presented here is an 18-month-old female infant with agnogenic myelofibrosis. Clinically, this case was characterized by pancytopenia, hepatosplenomegaly, and rapidly fatal course, without response to steroids or other chemotherapy. Bone marrow biopsy and postmortem examination, revealed myeloid metaplasia of the liver, spleen, and lymph nodes, and conspicuous proliferation of immature cells, presumably of reticulum cells or precursors of hematopoietic cell lines, associated with prominent proliferation of reticular fibrous tissue. These morphologic features corresponded with those of agnogenic myelofibrosis, classified as a form of myeloproliferative disorder. A review of 15 cases of myelofibrosis in children collected from the literature showed a mean age of 2 years and 9 months with most cases being less than 2 years of age. There was a distinct female preponderance, while male infants with myelofibrosis were associated with Down's syndrome or C monosomy. The mean survival was 6.7 months. Approximately 25 cases of myelofibrosis have been reported in the English literature, while only 5 cases have been described in Japan.

Bone Marrow↗

PubMed1995

[Aplastic anemia with giant splenomegaly and myelofibrosis successfully treated with antilymphocyte globulin].

Severe aplastic anemia was diagnosed in a 58-year-old female because of pancytopenia with leukocyte count 700/microliters, hemoglobin 3.4 g/dl, platelet count 4.2 x 10(4)/microliters and fatty hypoplastic bone marrow in August 1992. In January 1993, she was admitted with an abdominal skin infection caused by pseudomonas aeruginosa. After treatment of the infection, antilymphocyte globulin was given at a dose of 2,000 mg/day for four consecutive days in July 1993. This resulted in a gradual but steady improvement in her hematological data. In February 1995, her leukocyte count increased to 2,000/microliters, hemoglobin to 15.2 g/dl and platelet count to 11.0 x 10(4)/microliters. Although no splenomegaly or myelofibrosis was found previously, from April 1993, the spleen enlarged and was palpable 10 cm below the costal margin. Her bone marrow biopsy in June 1993 revealed prominent myelofibrosis. Thereafter no changes were found in these features. Splenomegaly and myelofibrosis are characteristic of primary myelofibrosis and although the relationship is uncertain, there is no previous report on aplastic anemia with splenomegaly and myelofibrosis.

Anemia, Aplastic↗

PubMedDate not supplied

Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia.

BACKGROUND: Essential thrombocythemia (ET) is a clonal myeloproliferative disease associated with thrombohemorrhagic complications and myeloid transformation to diseases such as myelofibrosis and acute myeloid leukemia. METHODS: A multicenter study was conducted among 231 consecutive Chinese patients with ET. The literature about leukemogenic risk associated with the use of hydroxyurea therapy was reviewed. RESULTS: The median patient age was 65 years. Thrombosis rates at and after diagnosis of ET were comparable to those of white patients, but bleeding rates at and after diagnosis were much lower. The projected 10-year thrombosis-free, bleeding-free, and overall survival rates were 66%, 83%, and 80%, respectively. There were no deaths among patients 60 years or younger during a maximum follow-up of 15 years, and splenomegaly at diagnosis of ET appeared to protect against thrombosis. In multivariate analysis, advanced age predicted inferior 10-year thrombosis-free and overall survival, and male sex predicted inferior bleeding-free survival. Half the deaths were related to ET. The probability of myelofibrosis transformation was 9.7% at 10 years. Prior myelofibrosis (P = .008) and the use of melphalan treatment (P = .002) were risk factors for acute myeloid leukemia evolution. CONCLUSIONS: Essential thrombocythemia is a benign disease of older persons. Chinese patients have a low risk of bleeding, and prior myelofibrosis is a major risk factor for evolution to acute myeloid leukemia. Leukemic transformation with hydroxyurea therapy alone is rare and warrants further prospective studies.

Acute Disease↗

PubMed1999

Pulmonary hypertension in patients with myelofibrosis secondary to myeloproliferative diseases.

We examined the clinical characteristics of six patients with myelofibrosis secondary to myeloproliferative diseases whose clinical courses were complicated by pulmonary hypertension to determine possible causal links between the two disorders. Six patients (four male, two female), with diagnoses of myeloproliferative disease, myelofibrosis (one with polycythemia vera, three with agnogenic myeloid metaplasia, one with unclassified myeloproliferative syndrome, one with essential thrombocytosis), and pulmonary hypertension are presented. Measurement of the pulmonary artery pressure was performed by Doppler echocardiography in all patients and by right sided heart catheterization in four patients. The range of resting pulmonary artery systolic pressure was 35 to 47 mmHg above the mean right atrium by echocardiography. One patient had autopsy evidence of pulmonary myeloid metaplasia and interstitial fibrosis; another had acute leukemic infiltration of the lung parenchyma. All patients had thrombocytosis; symptomatology in one patient with marked thrombocytosis improved with plateletpheresis. Two patients suffered systemic thrombosis. All patients had severe hepatomegaly. Two patients had evidence of left ventricular dysfunction. The interval between the development of dyspnea and death was less than seven months in five of the patients. A causal link between pulmonary hypertension and myelofibrosis secondary to myeloproliferative diseases is suggested for each patient. Hematopoietic infiltration of the pulmonary parenchyma, portal hypertension, thrombocytosis, hypercoagulability, and left ventricular failure may account in part for the development of pulmonary hypertension in these patients. Patients with myelofibrosis and dyspnea should have Doppler echocardiography to evaluate pulmonary artery pressures.

Adult↗

PubMed2003

Primary autoimmune myelofibrosis: definition of a distinct clinicopathologic syndrome.

Myelofibrosis is characterized by reticulin fibrosis of the bone marrow with resulting features of myelophthisis. Besides hematopoietic malignancies and other neoplasms involving the bone marrow, myelofibrosis has been described in association with autoimmune disorders, especially systemic lupus erythematosus. We describe the clinicopathologic features of a primary form of autoimmune myelofibrosis (AIMF) in patients who do not have systemic lupus erythematosus or another well-defined autoimmune syndrome. Absence of marked splenomegaly, peripheral blood cytopenias with mild teardrop poikilocytosis and leukoerythroblastosis, bone marrow lymphoid aggregates, and presence of autoantibodies are some of the salient features of primary AIMF. AIMF should especially be differentiated from chronic idiopathic myelofibrosis, a neoplastic myeloproliferative disease. Primary AIMF appears to have an excellent prognosis, with all patients reported in this series responding to a short course of corticosteroid therapy.

Adrenal Cortex Hormones↗

PubMed1988

Myelopoietic effect of bone marrow fibroblasts cultured from patients with myelofibrosis.

Bone marrow fibroblasts (BMF) have been shown to be able to support granulopoiesis. The present studies were designed to see whether BMF in patients with agnogenic myeloid metaplasia (AMM) are also able to support granulopoiesis. Myeloid colony-stimulating activity (CSA) was assayed in BMF derived from the three groups of patients. 1) Group I: Patients with hip fracture but without underlying hematological disease; patients with solid tumor but without bone marrow metastasis; and patients with iron deficiency anemia. 2) Group II: Patients with myeloproliferative disorders other than AMM. 3) Group III: Patients with AMM or myelofibrosis with prior history of polycythemia vera. CSA was determined in a bilayer agar culture system in which BMF served as a feeder layer and either mouse or human marrow cells were employed as target cells. There was no difference of CSA production by BMF among these three patient groups. These studies suggest that BMF cultured from patients with myelofibrosis exhibit similar myeloid stimulating activity as do BMF from other patients. A significant correlation was also found between CSA production by BMF and white blood cell counts in patients with myelofibrosis (group III). This suggests that BMF may have a role in either supporting or producing CSA for granulopoiesis in myelofibrosis.

Aged↗

PubMed1990

Procollagen type III aminoterminal peptide in serum in idiopathic myelofibrosis and allied conditions: relation to disease activity and effect of chemotherapy.

The serum concentration of the aminoterminal propeptide of type III procollagen (PIIINP) was measured serially in patients with idiopathic myelofibrosis and other myeloproliferative syndromes. Two different assays were applied, the RIA-gnost assay (Hoechst, Frankfurt, FRG) and a new equilibrium RIA for the N-terminal propeptide of human type III procollagen (Farmos Diagnostica, Oulu, Finland). A positive correlation was found between the results obtained by the two RIA's (rho = 0.90, P less than 0.001). The highest propeptide levels were recorded in patients with idiopathic myelofibrosis, particularly in those with active disease. Elevated serum PIIINP levels decreased during treatment with various cytotoxic drugs, including intensive chemotherapy. By contrast, serum PIIINP was unchanged or increased in patients undergoing interferon alpha-2b therapy. Gel filtration of sera on Sephacryl S-300 column (Pharmacia, Sweden) showed that smaller PIIINP related peptides dominated in healthy subjects and in osteomyelosclerosis with stable disease. Conversely, the relative proportion of intact propeptide increased in accelerating disease stages and acute myelofibrosis. In conclusion, the present study implicates serum PIIINP as a useful indicator of disease activity in idiopathic myelofibrosis. The propeptide also appears to be a sensitive sero-marker of chemotherapy effect on fibrogenesis related to clonal myeloproliferation. Finally, the propeptide is suggested as an early predictor of relapse during cytotoxic therapy.

Acute Disease↗

PubMed1991

Morphometric analysis of myelofibrosis in agnogenic myeloid metaplasia and chronic myelogenous leukemia.

A morphometric analysis of bone marrow biopsy specimens from patients with myelofibrosis was made to determine the amount of lattice fiber and the number of megakaryocytes, to compare the degree of myelofibrosis in primary and secondary myelofibrosis, and to assess the relationship between the morphometric findings and other parameters. Eight patients with agnogenic myeloid metaplasia (AMM) and six with chronic myelogenous leukemia associated with frank myelofibrosis (CML-MF) were studied. When the main clinical, hematological, and laboratory features of both groups of patients were compared, the only significant difference was in the neutrophil alkaline phosphatase score. Morphometric study showed that the amount of lattice fiber and the number of megakaryocytes in AMM were not statistically different from those in CML-MF, and that neither the number of megakaryocytes nor the platelet count correlated with the amount of lattice fiber.

Aged↗

PubMed1999

Dual implication of fibrogenic cytokines in the pathogenesis of fibrosis and myeloproliferation in myeloid metaplasia with myelofibrosis.

Though the diagnostic criteria of myeloid metaplasia with myelofibrosis (MMM) are now well established, the origin and pathophysiological mechanisms of this myeloproliferative disorder remain unclear. Concerning its pathophysiology, myeloproliferation and myelofibrosis are the intrinsic characteristics of the disease. Whereas the myeloproliferation was shown to result from a clonal amplification of primitive progenitor cells, fibroblast proliferation appeared to be polyclonal, thus suggesting that myelofibrosis was a reactive process. The myeloproliferation observed in MMM patients is characterized by an increased number of circulating CD34(+) hematopoietic progenitors. When cultured at high concentration without added exogenous growth factors, unpurified progenitors from MMM patients gave rise to spontaneous colonies of all myeloid lineages. Such an autonomous growth disappeared when purified CD34(+) progenitors were plated. These results suggested that growth factors are involved in the dysregulation of proliferation and/or differentiation of MMM hematopoietic progenitors. Cytokines such as PDGF, TGF-beta, and bFGF, produced mainly by megakaryocytes, have been proposed to be involved in the abnormal activation of fibroblasts, resulting in fibrosis. Recently the role of the fibrogenic cytokines, TGF-beta and bFGF, in the regulation of primitive hematopoiesis has been reported. The aim of this review is to address the question of the potential dual implication of TGF-beta and bFGF in the pathogenesis of both myelofibrosis and myeloproliferation in MMM patients.

Cytokines↗

PubMed1999

Imaging findings in patients with myelofibrosis.

The purpose of this review is to illustrate the wide range of radiological abnormalities in myelofibrosis. Myelofibrosis, also called myeloid metaplasia, is a myeloproliferative disorder of unknown etiology. The common imaging findings in patients with myelofibrosis are osteosclerosis, hepatosplenomegaly, and lymphadenopathies. In addition, extramedullary hematopoiesis may develop in multiple sites such as chest, abdomen, pelvis, and central nervous system, simulating malignant disease. Selected plain-film, CT, and MR images in patients with myelofibrosis are shown as pictorial essay to allow ready recognition of the most common imaging abnormalities of the disease.

Bone and Bones↗

PubMed1982

Myelofibrosis and acute megakaryoblastic leukemia in a child: topographic relationship between fibroblasts and megakaryocytes with an alpha-granule defect.

In a child with acute megakaryoblastic leukemia--severe thrombocytopenia and myelofibrosis, EM studies on bone marrow showed a strict topographic relationship between the presence of clusters of abnormal megakaryocytes and the increased number of fibroblasts and extracellular fibers. Megakaryocytes and platelets lacked alpha-granules while the plasma thromboglobulin level was three times the normal level. This suggested that the alpha-granular proteins were synthesized but not retained in alpha-granules. If this occurs, the increased marrow levels of platelet-derived growth factor and factor 4 would favor the proliferation of fibroblasts and the synthesis of collagen, and thereby promote myelofibrosis. After therapy-induced remission, the number of marrow megakaryocytes decreased, the alpha-granules were normally produced, the plasma beta-thromboglobulin level was normal and the myelofibrosis disappeared. These observations suggest that during acute megakaryoblastic leukemia, an acquired gray-platelet syndrome occurs and that the local excretion of alpha-granule proteins triggers the myelofibrosis.

Blood Platelets↗