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At least 19 recordsLinked to original sources

PubMed2005

Anagrelide for control of thrombocytosis due to myeloproliferative disorders.

Myeloproliferative disorders are characterized by overproduction of one or more blood lineages. The clinical course of the Philadelphia-negative myeloproliferative disorders, particularly essential thrombocythemia and polycythemia vera, are characterized by vascular symptoms and in the long-term, transformation to myelofibrosis and leukemia may occur. Control of myeloproliferation has traditionally been achieved using cytotoxic agents but many of these have a documented ability to increase the risk of leukemia. Anagrelide, initially developed as an antiaggregant, is an attractive alternative to these agents as it appears to be relatively selective in reducing the platelet count and is unlikely to be leukemogenic. This article reviews clinical studies in these patients and discusses the future scope for anagrelide.

Animals↗

PubMed2006

Oncogenic mechanisms in myeloproliferative disorders.

Myeloproliferative disorders (MPDs) are clonal haematopoietic malignancies involving the abnormal proliferation of myeloid lineages. The World Health Organisation (WHO) classification of haematopoietic malignancies distinguishes MPDs from myelodysplastic/ myeloproliferative disorders and systemic mastocytosis. These malignancies frequently involve constitutive tyrosine kinase activity, resulting from either oncogenic fusion protein production or from point mutations. Chronic myelogenous leukaemia is the model used for studies of the consequences of such molecular defects. However, the heterogeneity of the clinical course of MPDs should be seen in a more rationale conceptual framework, including the many molecular events associated with these diseases. This review focuses on the various tyrosine kinase-related molecular mechanisms underlying both MPDs and rare diseases with myeloproliferative features. We pay particular attention to the newly identified JAK2 V617F mutation in polycythaemia vera, essential thrombocythaemia and idiopathic myelofibrosis and deal with disease heterogeneity and putative additional molecular mechanisms.

Genes, abl↗

PubMed1993

Life-threatening thrombotic and haemorrhagic problems associated with silent myeloproliferative disorders.

Myeloproliferative disorders are well recognized as being associated with haemorrhage and thrombosis. We describe two cases, one of life-threatening haemorrhage and the other of thrombosis, in patients with normal peripheral blood counts and films, both of whom went on to develop overt manifestations of myeloproliferative disorders (CGL and essential thrombocythaemia) more than a year after their first presentation.

Adult↗

PubMed1995

TGF-beta and megakaryocytes in the pathogenesis of myelofibrosis in myeloproliferative disorders.

Myeloproliferative disorders are clonal disorders of the hematopoietic stem cell and comprise a spectrum of more or less well-defined clinical entities: polycythaemia vera, chronic myeloid leukemia, essential thrombocythaemia, and agnogenic myeloid metaplasia. Myelofibrosis, which contributes substantially to the impaired hematopoiesis, is commonly observed in myeloproliferative disorders but it represents the criterion of agnogenic myeloid metaplasia also termed idiopathic myelofibrosis. Although progress has been made in the elucidation of the pathogenesis of myelofibrosis, it still remains unclear. The aim of this review is to address the new insights that outline the potential role of TGF-beta in the promotion of myelofibrosis, through its release from megakaryocytes/platelets, particularly in agnogenic myeloid metaplasia.

Cell Division↗

PubMed1985

Myeloproliferative disorders.

Myeloproliferative disorders are uncommon in the dog and may be classified as chronic or acute. Excessive proliferation of mature cells leads to an overproduction of terminally differentiated blood cells (chronic MPD). Inability of cells to mature results in the accumulation of poorly differentiated blast cells in the peripheral blood and bone marrow (acute MPD). Because the lesion appears to be at the level of the hematopoietic stem cell, all cell lines in the bone marrow may be affected. Diagnosis depends upon the accurate identification of neoplastic cells and the absence of other diseases associated with bone marrow hyperplasia. The prognosis for chronic MPD is guarded, whereas for acute MPD it is grave. Accurate identification of these disorders in animals is important. Investigation and greater understanding of the pathophysiologic mechanisms may lead to more lasting therapeutic successes in the future.

Animals↗

PubMed1996

Deletions of chromosome 20q and the pathogenesis of myeloproliferative disorders.

Myeloproliferative disorders (MPD) and myelodysplastic syndromes (MDS) represent an overlapping spectrum of clonal preleukaemic conditions in which mutations have resulted in dysregulation of multipotent haemopoietic progenitors. An interstitial deletion of the long arm of chromosome 20 is a recurring abnormality associated with both of these classes of disorders. The association of 20q deletions with 'stem cell' disorders suggests that the deletion may mark the site of one or more genes, loss or inactivation of which perturbs the regulation of haemopoietic progenitors. The identification and study of the target gene(s) on chromosome 20q is therefore likely to illuminate the regulation of normal haemopoietic differentiation as well as the genesis of clonal myeloid disorders. This article provides a review of progress in the search for critical genes harboured within 20q deletions, together with a summary of several insights that these studies have provided into the biology of MPD and MDS.

Chromosome Deletion↗

PubMed1985

Myeloproliferative disorders.

Myeloproliferative disorders result from monoclonal proliferation of the pluripotential hematic precursor cell, with preservation of its capacity to differentiate and mature into functional progeny. Phenotypic expression varies with the degree of involvement of each derivative cell type and the extent to which growth is hyperplastic, dysplastic, or malignant. Hyperplastic bone marrow with increased circulating erythrocytes and platelets, reactivation of hematopoiesis in long bones and extramedullary sites, and the development of secondary marrow fibrosis are responsible for complications of thrombosis, hemorrhage, splenic infarction, hypersplenism, and anemia. A predilection for the geriatric population, chronicity, and great variability in phenotypic expression present a challenge in diagnosis and management. Individualized treatment based on thorough understanding of the pathophysiology of myeloproliferative disease is required to maximize complication-free survival by avoiding both the risk of the disease and its therapy and utilizing all available supportive measures in the prevention and treatment of complications.

Aged↗

PubMed2004

[Myeloproliferative disorders].

Myeloproliferative disorders are caused by abnormalities of hematopoietic stem cells leading to uncontrolled proliferation of one or more cell lines in the blood. Besides sharing common clinical and hematologic features they are characterized by clonal hematopoiesis and genetic instability, resulting in a disease-specific rate of transformation into acute leukemia. This review discusses relevant clinical and prognostic aspects as well as current diagnostic and therapeutic procedures of polycythemia vera, essential thrombocythemia and chronic idiopathic myelofibrosis.

Bone Marrow↗

PubMed2004

Treatment paradigms in the management of myeloproliferative disorders.

Myeloproliferative disorders (MPDs) are chronic conditions that require long-term treatment. MPDs have been considered neoplastic disorders that have a propensity to transform to acute leukemia or myelodysplastic syndrome. One of the MPDs, chronic myeloid leukemia (CML), has the distinct cytogenetic abnormality of the Philadelphia chromosome. In CML, transformation to acute leukemia is a common occurrence, with the timeline measured in years rather than decades. With the other three disorders from this group, polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF), transformation to acute leukemia is less frequently seen and, although variable, can take a longer period of time. The choice of therapy used for MPDs may contribute to leukemic transformation; chlorambucil, busulfan, and radiophosphorus are all examples of therapy that have been shown to be leukemogenic. Several studies have suggested the potential leukemogenicity of hydroxyurea (HU), but this remains controversial because no randomized studies have been conducted. The two newest agents used for MPDs, interferon-alpha and anagrelide, have both been studied for efficacy, but their influence on the potential for leukemic transformation has not been well studied to date.

Antineoplastic Agents, Alkylating↗

PubMed1997

c-kit Point mutation in patients with myeloproliferative disorders.

Myeloproliferative disorders (MPD) constitute a group of hematopoietic neoplasms at the myeloid stem cell level. Myeloid stem cells and/or progenitor cells from MPD have been considered sensitive to hematopoietic growth factors, including erythropoietin, thrombopoietin and stem cell factor (SCF). SCF is a ligand for c-kit receptor with tyrosine kinase. We analysed the gene alteration of the c-kit extracellular domain in MPD patients by PCR-SSCP and subsequent nucleotide sequencing. The point mutation in the N-terminal part of the domain, codon 52 (Asp-->Asn), was found in two patients with primary myelofibrosis and one with chronic myelogenous leukemia. We review the literature regarding the role of SCF/c-kit system in the oncogenesis of leukemia and MPD, and then discuss the significance of our finding in the context of growth advantage of the mutated clones over the normal clones.

Adult↗

PubMed1996

Influence of interferon-alpha on cytokine expression by the bone marrow microenvironment--impact on treatment of myeloproliferative disorders.

Myeloproliferative disorders (MPD) are characterized by several common clinical and biological features, although at the molecular level, each disease entity exhibits distinct abnormalities. IFN-alpha exerts beneficial therapeutic effects in chronic myelogenous leukemia, polycythemia vera and essential thrombocythemia, resulting in control of hematopoietic hyperplasia and, in a minority of patients, in induction of cytogenetic remission. The mechanism of action of IFN-alpha in MPD is poorly defined. Recently published in vitro findings suggest that IFN-alpha interacts with the regulation of hematopoiesis by multiple ways. Its antiproliferative activity is well known for more than a decade, however, substantial growth inhibition is achieved only at relatively high concentrations. Defective adhesion of hematopoietic progenitor cells in CML to bone marrow stromal cells is corrected by IFN-alpha, which might expose CML progenitors to inhibitory cytokines produced by the bone marrow microenvironment. Recent work from our group demonstrated, that IFN-alpha potently interacts with the production of hematopoietic cytokines in bone marrow stromal cells. Expression of stimulatory cytokines, such as GM-CSF, G-CSF, IL-1 and IL-11 is inhibited by IFN-ct, whereas the production of negative regulators, such as IL-1RA and MIP-1 alpha, is stimulated. The combined action of IFN-alpha on paracrine expression of cytokines suggests an indirect antihematopoietic effect, which might contribute to its clinical activity in MPD.

Adipose Tissue↗

PubMed2006

Hematopoietic cell transplantation for chronic myeloproliferative disorders.

Myeloproliferative disorders, including chronic idiopathic myelofibrosis (CIMF), polycythemia vera (PV), essential thrombocythemia (ET), and chronic myelomonocytic leukemia (CMML), are clonal diseases of hematopoietic stem or precursor cells. They often show a protracted or chronic course; however, all have the potential of progressing to severe marrow failure, associated with myelofibrosis, or of transforming into acute leukemia. At that point, hematopoietic cell transplantation (HCT) is the only current treatment strategy with curative potential. If transplantation is being considered and a suitable donor is available, HCT should be carried out before leukemic transformation has occurred, as the success rate of HCT declines steeply in patients who have evolved to leukemia. As many as 75-80% of patients with the original diagnoses of PV or ET, about 65-70% with CIMF, and 45% of patients with CMML are surviving long term after allogeneic HCT using conventional transplant regimens, with follow-up now extending to 15 years. Results with HLA-identical related and unrelated donors are comparable. Major risk factors for the outcome after HCT are the disease stage, the presence of comorbid conditions, and patient age. The development of reduced-intensity conditioning regimens has allowed for successful HCT even for older patients and patients with comorbid conditions. Studies on disease mechanisms, including the recent characterization of an activating mutation in JAK2, may provide additional prognostic guidance and are likely to lead to the development of novel treatment strategies, which will require continuous reassessment as to the optimum timing of HCT.

Age Factors↗

PubMed2001

Diagnosis and treatment of thrombocythemia in myeloproliferative disorders.

Myeloproliferative disorders originate in the clonal expansion of a transformed pluripotential hematopoietic progenitor cell. This results in a group of syndromes that include polycythemia vera, essential thrombocythemia, chronic myelocytic leukemia, and agnogenic myeloid metaplasia. Diagnostic criteria forpolycythemia vera and essential thrombocythemia were codified by the Polycythemia Vera Study Group in 1967 and 1977. Subsequent modifications include criteria for evidence of clonal proliferation by abnormal bone marrow karyotype and demonstration of erythropoietin-independence of erythropoiesis or reduced serum erythropoietin. Phlebotomy is the mainstay of treatment for polycythemia vera. The defining characteristic of essential thrombocythemia is a sustained elevation of the platelet count above 600,000/microL in an untreated patient. Symptoms and risk factors are the main determinants of treatment options for patients with essential thrombocythemia. High-risk patients are candidates for cytoreduction, whereas lower-risk patients receive either no treatment, low-dose aspirin, or another antithrombotic therapy. The availability of newer nonleukemogenic and megakaryocyte-specific agents warrants a reassessment of current treatment options.

Enzyme Inhibitors↗

PubMed1998

Molecular genetics and cytogenetics of myeloproliferative disorders.

The myeloproliferative disorders are believed to represent clonal malignancies resulting from transformation of a pluripotent stem cell. X-inactivation patterns of peripheral blood cells have been proposed as a useful diagnostic tool but this method is limited by the finding of a clonal X-inactivation pattern in a significant proportion of normal elderly women. There is no pathognomonic chromosomal abnormality associated with the myeloproliferative disorders. However, consistent acquired cytogenetic changes include del(20q), del(13q), trisomy 8 and 9 and duplication of segments of 1q, all of which have been observed at diagnosis or before cytoreductive therapy and therefore represent early lesions which contribute to the pathogenesis of these disorders. Although, the acquired molecular defects underlying most myeloproliferative disorders have not yet been elucidated, translocations associated with the rare 8p11 syndrome have permitted identification of a novel fusion protein. The role of a number of candidate genes in the other myeloproliferative disorders has also been studied, but no mutations have been identified so far. It is likely that a number of genes will be involved, given the varied phenotypes of the diseases. Identification of causal genes will be of considerable interest to both clinicians, who currently lack a specific and sensitive diagnostic test, and scientists interested in fundamental issues of stem cell behaviour.

Aged↗

PubMed1994

Recent advances in biological and therapeutic aspects of myeloproliferative disorders.

Chronic myeloproliferative disorders are clonal neoplasias that originate from a clonal pluripotent stem cell and may have a more or less pronounced tendency to acute progression. Except for chronic myelogenous leukemia marked by the Ph chromosome, the BCR/ABL rearrangement, or both, the other chronic myeloproliferative disorder subtypes show less specific, although recurrent, karyotypic and molecular abnormalities. We report here more recent advances in cytogenetics, molecular biology, and treatment of the most common chronic myeloproliferative disorders.

Humans↗

PubMed1982

Deficiency of platelet lipoxygenase activity in myeloproliferative disorders.

The myeloproliferative disorders are characterized by frequent bleeding and thrombotic complications, which have been attributed to abnormal platelet function. In 24 of 60 patients studied, reduced activity of the platelet lipoxygenase pathway for oxygenation of arachidonic acid was revealed by a new direct assay. This assay measured arachidonic acid-induced oxygen consumption in platelets preincubated with aspirin to block cyclooxygenase activity. Patients with secondary polycythemia or thrombocytosis had normal lipoxygenase activity . In the cells of seven of eight patients with lipoxygenase deficiency arachidonic acid induced increased synthesis of thromboxane, the major cyclooxygenase product. Nevertheless, patients with deficient lipoxygenase activity tended to have episodes of hemorrhage rather than thrombosis. Bleeding complications occurred in 67 per cent of patients with lipoxygenase deficiency, but in only 19 per cent of those with normal lipoxygenase activity (P less than 0.001). In contrast, 13 per cent of lipoxygenase-deficient patients, but 31 per cent of patients with other myeloproliferative disorders, had thromboembolic complications. Measurement of platelet lipoxygenase activity may be of diagnostic value in distinguishing myeloproliferative disorders from secondary thrombocytosis or polycythemia. Lipoxygenase deficiency may prove to be a useful natural model for investigating the role of lipoxygenase products in hemostasis.

Blood Platelets↗

PubMed1998

Leukocyte function in chronic myeloproliferative disorders.

The myeloproliferative disorders (MPD) are clonal diseases that originate from a transformed stem cell and involve all myeloid lineage. The affected cells have both proliferative and functional impairment. Therefore, we evaluated and compared neutrophil function in 31 patients with polycythemia vera (PV), idiopathic myelofibrosis (MF), chronic myeloid leukemia (CML), and essential thrombocytosis (ET). Neutrophil chemotaxis, random migration, bactericidal activity and superoxide anion release in these patients were simultaneously compared to those of 31 healthy controls. In this study, chemotactic activity was significantly impaired in patients with PV and CML as compared to controls (M+/-SE: 42 +/- 6 vs. 69+/- 5 cells/field; p<0.005 and 47+/-7 vs. 68+/- 5; p<0.05, respectively). The assessment of the bactericidal activity of neutrophils showed no impairment in most of the patients. In the CML group, the serum had a very strong "lytic" effect on bacteria, possibly due to the high levels of serum lysozyme (22 +/- 2 microgram/ml). The superoxide anion release was found to be normal in most of the patients. Nevertheless, in 25% of PV patients the superoxide production was impaired (less than 60% of the simultaneous controls). In ET most patients had normal neutrophil function. Regarding the effect of treatment, neutrophil chemotactic activity was found to be significantly reduced in the hydrea-treated patients, as compared to the non- treated patients (p<0.001) or healthy controls (<0.0001). We conclude that disturbances in neutrophil function are present in patients with various MPDs, except ET. This probably reflects abnormal maturation of ancessors of the damaged stem cells. Nevertheless, we should keep in mind that therapy itself could affect neutrophil functions. This matter should be studied more extensively. Although infections are not common in MPD disorders, they occasionally occur. It is possible that impairment in the phagocytic function contribute to the development of infections in patients with myeloproliferative disorders.

Adult↗

PubMed1995

Intrauterine diagnosis and management of transient myeloproliferative disorder.

Transient myeloproliferative disorders can be associated with hydrops in Down syndrome fetuses. No cases of prenatal management of such a condition have been reported in the literature. We report a case of myeloproliferative disorder diagnosed by cordocentesis at 31 weeks in a Down syndrome fetus with pericardial effusion. A pericardiocentesis was performed at the first signs of hydrops and successfully improved fetal cardiac function, allowing for continuation of pregnancy.

Adult↗