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PubMed1987

Polycythaemia vera in young people: an analysis of 58 cases diagnosed before 40 years.

Over 20 years, 58 cases of PV in young people (46 meeting the full PVSG criteria, 12 with elevated red cell volume and leucocytosis or thrombocytosis, without splenomegaly) were studied and have been followed for periods of 3-24 years. These cases represent approximately 5% of the cases of PV referred to the Department of Nuclear Medicine of St Louis Hospital during this period. They differ from older patients in the initial clinical severity, the short interval between the first symptoms and the diagnosis, frequent presentation with a life-threatening complication (two cases of hepatic vein thrombosis, six thrombotic or haemorrhagic events, six splenectomies, two abortions) and a very enlarged spleen in half the cases. However, after the initial complications, the overall survival is very long (exceeding 70%, even when including the initial complications, at 15 years). The vascular accidents occur exclusively in the phlebotomized patients, the main risk factor being the poor stability of the haematocrit. Only one acute leukaemia was observed among the 14 cases treated by radioactive phosphorus and/or alkylating chemotherapy. The most frequent late complication was evolution towards myelofibrosis. This spent phase seemed to occur earlier in patients treated by phlebotomy. On the basis of this data, we would advise the following therapeutic strategy: phlebotomies, as soon as the diagnosis is established, and a systematic long-term treatment by hydroxyurea with the hope of reducing the number of vascular complications and of delaying the evolution towards the spent phase and the myelofibrosis.

Adult↗
PubMed1988

High-dose intravenous immunoglobulin and splenectomy for the treatment of HIV-related immune thrombocytopenia in patients with severe haemophilia.

Four patients with severe haemophilia A and one patient with severe Christmas disease developed severe immune thrombocytopenia (platelet count less than 20 x 10(9)/l). All five patients were HIV-antibody positive and one was HIV-antigen positive. Four patients were treated initially with prednisolone, but with only a transient platelet response in three and no response in the fourth. All patients were treated with high dose intravenous immunoglobulin (0.4 g/kg daily for 5 d) resulting in a rise in platelet count in all cases (range 138-300 x 10(9)/l) and then proceeded to splenectomy. Three remain in complete remission after 6-14 months, and one showed a good response with platelet counts ranging from 103 to 187 x 10(9)/l. The fifth patients achieved a normal platelet count for 3 months post-splenectomy, but suffered a relapse with platelet counts ranging from 25 to 108 x 10(9)/l over the next 3 years. However, following a severe Varicella infection 10 months ago, during which he developed a marked transient thrombocytosis, he has also maintained a normal platelet count.

Adolescent↗
PubMed1990

Myelofibrosis with myeloid metaplasia: clinical and haematological parameters predicting survival in a series of 133 patients.

The prognostic value of 12 clinical and haematological parameters, recorded at diagnosis, in myelofibrosis with myeloid metaplasia (MMM) was retrospectively analysed in a consecutive series of 133 patients followed for a minimum of 60 months. Multivariate analysis showed that the following features were associated with a significantly shorter survival: (1) short period of time (less than 13 months) between first symptoms and diagnosis; (2) anaemia (haemoglobin less than 10 g/dl); (3) leucocyte count greater than 12 x 10(9)/l; (4) peripheral blood granulocyte precursors greater than 10%. Age, splenectomy and percentage of peripheral blood metamyelocytes were found significantly to affect survival only from univariate analysis, whereas sex, size of spleen, thrombocytopenia and thrombocytosis were of no prognostic significance. These data suggest that a more intensive chemotherapy might be useful for younger patients with bad prognostic factors at diagnosis.

Adult↗
PubMed1990

Interaction of monocytes and T cells in the regulation of normal human megakaryocytopoiesis in vitro: role of IL-1 and IL-2.

Autologous or allogeneic peripheral blood T cells can stimulate the human megakaryocyte progenitor cell (CFU-Meg)-derived colony formation in a dose-dependent fashion in agar cultures of nonadherent (NA), T cell-depleted (NT) bone marrow (BM) cells. Low concentrations of monocytes and T cells can collaborate in the stimulation of CFU-Meg colony formation or in the production of megakaryocyte colony stimulating factor (Meg-CSF) by T cells in the presence of mitogens or IL-2. Monocytes alone can produce only negligible Meg-CSF under any conditions. When monocyte conditioned medium (CM) was added to T cell-stimulated NA, NT BM cell cultures, CFU-Meg colony growth was appreciably increased compared with that stimulated by T cells alone. Dose-dependent increase in CFU-Meg colony growth was noted when varying concentrations of IL-1 were added to T cell-stimulated NA, NT cell cultures, although IL-1 itself could support no CFU-Meg colony growth in the absence of T cells. These data suggest that a synergistic interaction between T cells and monocytes during the production of Meg-CSF by T cells could be partly mediated by IL-1. IL-2 was found to stimulate Meg-CSF production by T cells in the presence or absence of mitogens. IL-2-stimulated Meg-CSF production by T cells was augmented by the addition of monocytes. Although IL-2 itself had no stimulatory effect on CFU-Meg colony growth, dramatic augmentation in the CFU-Meg colony number was noted when IL-2 was added to T cell-stimulated NA, NT cell cultures. High concentrations of monocytes and prostaglandin E (PGE) inhibited the CFU-Meg colony formation. These results suggest that IL-1 and IL-2 may play a stimulatory role on the normal human in vitro megakaryocytopoiesis, and may be involved in the development of reactive thrombocytosis and bone marrow megakaryocytic hyperplasia in various inflammatory diseases.

Cell Communication↗
PubMed1991

Primary thrombocythaemia: diagnosis and management.

Since PT is more likely than reactive thrombocytosis to be complicated by thromboembolic manifestations, the differential diagnosis is important. A combination of positive clinical and laboratory criteria probably represents the most useful diagnostic method at present, although a molecular biological approach may prove to be of value in females in the future. Treatment to suppress the megakaryocytic proliferation is suggested in all patients, since even young patients are not immune to major complications, and treatment may possibly delay long-term myelofibrotic transition. Acute haemorrhage should be treated by platelet transfusions, with or without platelet apheresis and with rapid control of the count by hydroxyurea. Vascular occlusive lesions should be treated with aspirin, with or without platelet apheresis and with hydroxyurea. Busulphan is suggested as the drug of choice for long-term therapy in patients over 40 years of age while hydroxyurea is proposed below this age. The place of interferon-alpha therapy has not yet been established but may have a particular role in women of child-bearing age.

Female↗
PubMed1991

Interferon in essential thrombocythaemia.

In the present investigation, 20 patients with ET were treated with recombinant interferon alfa-2c (IFN) for up to 4 years. Initially, IFN was administered subcutaneously at a dosage of 6-45 MU/week. The dosage was adjusted according to individual tolerance and response. The median dose during induction was 20 MU/week, 10 MU/week during the remaining first year, 6 MU/week during the second year and 2 MU/week thereafter. 13 patients (65%) achieved complete remission (platelet count less than 440/nl), four patients (20%) had partial remission (greater than 440/nl but a reduction by more than 50% of the initial count). The median platelet count remained steady throughout the 4-year period of treatment, in spite of extreme dose reductions. After withdrawal of IFN, however, platelet counts again increased. The white blood cells showed a marked decrease similar to that of platelet counts, whereas the haemoglobin level remained fairly stable. In the bone marrow, a significant decrease in megakaryocyte density and size could be observed. Concurrently with the improvement of haematological parameters, clinical symptoms improved, but reappeared after withdrawal of IFN. During induction, fever, bone and/or muscle pain, fatigue, lethargy and psychological symptoms were the most prominent side-effects in the majority of patients. In three patients these symptoms led to discontinuation of the treatment. With repeated dose reductions, excellent long-term tolerance was achieved, and during late maintenance treatment the only observed side-effect was an induction of thyroid autoimmunity in three patients. IFN is an effective, well-tolerated alternative in the long-term treatment of symptomatic ET. However, since withdrawal of IFN leads to recurrence of thrombocytosis, continued treatment is to be recommended.

Adult↗
PubMed1994

Characterization of specific functional receptors for HuIFN-alpha on a human megakaryocytic cell line (Dami): expression related to differentiation.

Interferon-alpha (IFN-alpha) treatment has been shown to be highly effective in inhibiting human megakaryocytopoiesis and controlling thrombocytosis in patients with myeloproliferative disorders. These observations suggest that IFN-alpha might play some role in the biological feature of the megakaryocytic lineage and led us to investigate the presence of specific receptors for IFN-alpha on human megakaryocytic cells, i.e. the Dami cell line, and to study the regulation of their expression. Our study demonstrates that [125I]-recombinant human IFN-alpha ([125I]rHu-IFN-alpha) binds to high-affinity specific receptor on these cells. Scatchard analysis of binding data indicates the presence of homogeneous binding sites estimated in the range of 3000-5000, with an apparent equilibrium dissociation constant, Kd, of 1-2 x 10(-9) M. Also, [125I]rHuIFN-alpha binding capacity decreased in Dami cells incubated with unlabelled rHuIFN-alpha. This down-regulation which was dose-dependent appeared to result from a reduction of IFN-alpha cell surface receptors and was observed at doses that elicited antiproliferative effects in Dami cells. Cross-linking of [125I]rHuIFN-alpha to Dami membrane proteins using a bifunctional reagent yielded to a radioactive complex of approximately 150,000 kD on SDS-PAGE. Furthermore, in response to PMA, which induces the differentiation/maturation of the Dami cells as evaluated by surface marker and ploidy analysis, a 3-fold increase of the number of specific membrane receptors for IFN-alpha was observed, without any modification of either the affinity or the M(r) value of the cross-linked complex. Such an increase appeared to be restricted to IFN-alpha receptors; actually it was not observed in [125I]IFN-gamma binding experiments. Transcript analysis indicated that down-regulation and increased expression of the IFN-alpha receptor after PMA treatment are post-transcriptional events.

Antigens, Surface↗
PubMed1995

Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study.

Cytogenetic and clinical details are presented for 66 patients with myeloid malignancy and chromosome abnormalities of 3q21 and/or 3q26 (3qabns). Bone marrow and/or peripheral blood morphology was assessed for 52 cases. 3qabns in Philadelphia negative (Ph-ve) and positive (Ph+ve) cases were inv(3)(q21q26), (21 Ph-ve, 6 Ph+ve); t(3;3)(q21;q26) (nine Ph-ve, four Ph+ve); and t(3;21)(q26;q22) (four Ph-ve, six Ph+ve). Ph-ve cases also had t(1;3)(p36;q21) (three cases), and t(3;5)(q21;q31)/(q21;q35)/(q26;q21) (five cases aged < 40 years). Three cases, aged < 30 years, had t(3;12)(q26;p13) which defines a new 3qabn subgroup. Monosomy 7 and/or 5q- accompanied inv(3) or t(3;3) in 17/30 cases. All cases had a myeloid malignancy (predominantly AML M1, M4 or M7), frequent trilineage myelodysplasia, and markedly abnormal megakaryopoiesis with micromegakaryocytes (< 30 microns). Thrombocytosis occurred in two cases only. Most Ph+ve cases were in myeloid blast crisis and in Ph+ve cases alone, micro-megakaryocytes were uniquely small (10 microns) in 7/11 cases. There were equal numbers of males and females. Seven secondary leukaemias were found in Ph-ve cases with inv(3), t(3;3), t(3;21), t(1;3) or del(3)(q21). Three cases with t(3;21) (one Ph+ve) were de novo AML or had de novo aplastic anaemia. Survival was rarely greater than 12 months from detection of the 3qabn.

Adolescent↗
PubMed2005

Gene expression profiling in polycythaemia vera: overexpression of transcription factor NF-E2.

Summary The molecular aetiology of polycythaemia vera (PV) remains unknown and the differential diagnosis between PV and secondary erythrocytosis (SE) can be challenging. Gene expression profiling can identify candidates involved in the pathophysiology of PV and generate a molecular signature to aid in diagnosis. We thus performed cDNA microarray analysis on 40 PV and 12 SE patients. Two independent data sets were obtained: using a two-step training/validation design, a set of 64 genes (class predictors) was determined, which correctly discriminated PV from SE patients. Separately 253 genes were identified to be upregulated and 391 downregulated more than 1.5-fold in PV compared with healthy controls (P < 0.01). Of the genes overexpressed in PV, 27 contained Sp1 sites: we therefore propose that altered activity of Sp1-like transcription factors may contribute to the molecular aetiology of PV. One Sp1 target, the transcription factor NF-E2 [nuclear factor (erythroid-derived 2)], is overexpressed 2- to 40-fold in PV patients. In PV bone marrow, NF-E2 is overexpressed in megakaryocytes, erythroid and granulocytic precursors. It has been shown that overexpression of NF-E2 leads to the development of erythropoietin-independent erythroid colonies and that ectopic NF-E2 expression can reprogram monocytic cells towards erythroid and megakaryocytic differentiation. Transcription factor concentration may thus control lineage commitment. We therefore propose that elevated concentrations of NF-E2 in PV patients lead to an overproduction of erythroid and, in some patients, megakaryocytic cells/platelets. In this model, the level of NF-E2 overexpression determines both the severity of erythrocytosis and the concurrent presence or absence of thrombocytosis.

Blotting, Northern↗
PubMed1979

A mathematical model of thrombopoiesis in rats.

A mathematical model of thrombopoiesis in rats is presented. This has four compartments; stem cells, megakaryocytes, thrombocytes and thrombopoietin. A high thrombopoietin concentration influences bone marrow proliferation in three ways. Firstly the stem cells are stimulated and a slow increase in megakaryocyte number follows. Secondly there are additional endomitoses in the (early) megakaryocytes resulting in an increase in megakaryocyte volume. Thirdly the megakaryocyte maturation time is shortened. The parameters of the model are determined from experimental values for the normal, maximum and minimum proliferation rates, maturation times and destruction rates. The model is tested by comparing simulated results for acute and chronic thrombocytopenia and thrombocytosis with experimental curves from the literature. The model and data agree within the limits of experimental error. Not all of the thrombopoietic regulatory system is known yet, so some important alternative hypotheses are investigated and compared with the model. Several hypotheses have been excluded in this way.

Animals↗
PubMed2005

Platelets in the paediatric population: the influence of age and the limitations of automation.

Accurate and precise platelet counting is important for the clinical management of children with platelet disorders. Current automated technologies are often unable to discriminate platelets from non-platelet particles particularly in circumstances where platelet anisocytosis is common. This study compares manual methodology and the automated technologies; impedance, optical density and CD61 immunoplatelet method (available on the Cell Dyn 4000) with the reference method of flow cytometric analysis in a paediatric population. A total of 141 samples were analysed and divided into specific age related groups and groups with thrombocytopenia and thrombocytosis. Data analysis showed that the CD61 method compared best with the reference method and this was evident in all the specified groups. The mean platelet count obtained by optical and manual methods were lower, suggesting that these methods are less reliable. The impedance count method was accurate despite its limitations. Strong correlations were observed in the 2-14 year age group but there was greater variation in the <1 month group supporting the theory that there is a greater variation in platelet characteristics in neonates. The CD61 method is the automated method of choice and would be particularly useful in the problem groups (platelet counts <50 x 10(9)/l and neonates <1 month old).

Adolescent↗
PubMed1992

Hemostasis and platelet aggregation in purpuric pigmented angiodermatitis eruptions.

Ten patients with chronic purpuric and pigmented angiodermatitis in the extremities and two patients with acute and disseminated eczematoid-like purpura angiodermatitis were studied with current hemostasis parameters: (1) platelet aggregation, (2) platelet circulating aggregates, (3) clotting factor measurements and high molecular weight kininogen (HMWK) in their coagulation fraction. The results showed: (1) reactional thrombocytosis with morphologic changes; (2) increased levels of platelet circulating aggregates; (3) increased response of platelet aggregation to different agonists, especially at very low doses, and also when we used washed platelets resuspended in normal plasma; (4) delayed activation of the contact system; (5) decrease of the activity of the fibrinolysis activators; and (6) diminished function activity of the HMWK coagulation fraction. As a physiopathogenic hypothesis in these patients, there is a cutaneous pathology that could be entailed to these hematologic alterations of the platelet-HMWK-endothelial cells-kinins-coagulation-fibrinolysis system.

Adult↗
PubMedDate not supplied

Haematological alterations induced by biochemical fractions of Paracoccidioides brasiliensis in mice.

Biochemical fractions of Paracoccidioides brasiliensis were obtained for experimental inoculation in mice followed by haematological analysis. Dead total fungus, total fungus disrupted by ultrasonic waves, lipids of the fungus, supernatant of the lipid purification, and integral and disrupted fungus free of lipids were obtained. The six fractions were obtained from lyophilized yeasts of a recent isolate of P. brasiliensis and from a pool comprising equal amounts of four strains maintained in the laboratory for some time. Different doses of the 12 fractions were intraperitoneally inoculated into mice and haematological analysis was done 30 days later. No significant alterations were detected in the red blood cell series. However, the white blood cell series showed marked alterations, such as leukopenia, with relative neutrophilia and lymphopenia. Thrombocytosis occurred widely. The haematological alterations revealed associations with the injected doses without relation to the biochemical composition of the different fractions. No difference in the capacity for inducing haematological alterations was found between the fractions obtained from the recent isolate and from the older ones.

Animals↗
PubMedDate not supplied

Features of Kawasaki disease at the extremes of age.

AIM: The diagnosis of Kawasaki disease (KD) in those outside the typical age range (6 months-4 years) is often delayed, potentially worsening prognosis. The features of KD in children or=5 years were compared with those presenting within the more typical age distribution. METHODS: Korean children with complete diagnostic criteria for KD were grouped according to their age at presentation: Group A ( or=5 years). The clinical features, laboratory findings and outcome in each group were compared. RESULTS: Of 136 children presenting to a single centre between 1999 and 2003, 10 children were in Group A, 114 in Group B and 12 in Group C. The mean total fever duration was 8 days in Group C and 6.2 days in Group A (P=0.03). All children in Group C had cervical lymphadenopathy, compared with 50% of Group A and 64% of Group B (P=0.01). Coronary artery lesions were commoner in older children (Group C, 42%) compared with Group B (17%, P=0.05). All children had an equivalent leukocytosis, but Group C had significantly higher neutrophil counts (P=0.001). Group A had significantly lower mean haemoglobin (P=0.003) and total protein (P=0.002) at presentation and a more marked thrombocytosis 1 week after intravenous immunoglobulin therapy (P<0.05). CONCLUSION: The clinical and laboratory phenotype of KD varies with age. Older children may have a more marked inflammatory response and worse outcome. Younger children who are treated appropriately may not have a chance to higher risk of coronary artery lesions.

Child↗
PubMedDate not supplied

Unusual haematologic manifestations of Mycoplasma pneumoniae infection.

A 2-year-old male presented with fever, cervical lymphadenopathy, anaemia, neutrophilia and thrombocytosis. There was no evidence of pulmonary disease. Severe cold antibody (IgM) mediated haemolytic anaemia developed during admission. Infection with Mycoplasma pneumoniae was demonstrated, highlighting the extrapulmonary manifestations of the infection, in the absence of pulmonary signs.

Anemia, Hemolytic↗
PubMed1989

Blastic transformation of essential thrombocythemia. A case report.

A case of blastic transformation of essential thrombocythemia (ET) is reported. A 69-year-old male was first admitted to hospital because of fever in February, 1982. He was diagnosed as having ET because of marked thrombocytosis (205.5 x 10(10)/1), absence of erythrocytosis, absence of splenomegaly, normal karyotype and no increment of blasts in the bone marrow, and normal levels of neutrophil alkaline phosphatase, vitamin B12 and folate. He was treated with busulfan, and subsequently his platelet count was well controlled for about five years. At the second admission, blasts were present in the peripheral blood, and later accounted for 49% of the total leukocyte count. Histological examination of a bone biopsy specimen showed homogeneous proliferation of blastic cells and slight reticulin fibrosis. At autopsy, the degree of bone marrow fibrosis had increased. This was considered to be a very rare case of ET with blastic transformation in the terminal phase.

Aged↗
PubMed2005

Advances in the diagnosis, evaluation, and management of malignant pleural mesothelioma.

Malignant mesothelioma is an insidious neoplasm arising from the mesothelial surfaces of the pleural and peritoneal cavities, the pericardium, or the tunica vaginalis. A total of 80% of all cases are pleural in origin. The predominant cause of malignant mesothelioma is inhalational exposure to asbestos, although evidence is increasing to support the hypothesis that simian virus-40 virus plays a role in cocarcinogenesis. Immunohistochemical markers such as calretinin, WT-1, and cytokeratin 5/6 are becoming established diagnostic markers. Preliminary data suggests that a soluble form of mesothelin could serve as a serum marker for established and early cases of mesothelioma. Positron emission tomography with 18-fluorodeoxyglucose in conjunction with computed tomograhy scanning has improved preoperative imaging and staging. Prognostic factors have been identified and verified. Negative indicators include thrombocytosis, high leukocyte counts, poor performance status, and nonepithelial histology. For the first time, there is now evidence that some treatments are increasing the quality and quantity of life for patients with mesothelioma. Chemotherapy, with the new multi-targeted antifolate drug Pemetrexed, combined with cisplatin, has shown superior survival rates in a large phase III trial when compared to cisplatin alone. High-dose intensity-modulated radiotherapy when administered after extrapleural pneumonectomy has resulted in excellent local control. Multimodality treatment programs that combine surgical cytoreduction with novel forms of radiation therapy and more effective chemotherapy combinations may offer significant increases in survival for certain subgroups of mesothelioma patients. Innovative palliative approaches have proved successful in alleviation of the significant symptoms experienced by many mesothelioma patients. Experimental treatments such as immunotherapy and gene therapy present a window of hope for all mesothelioma patients, and in the future, may be combined with 'standard therapy' in multimodality protocols. Patients with adequate performance status should be enrolled into clinical trials where possible. Over the past decade, significant advances have been made on several fronts that have improved the ability to diagnose a stage, define prognosis, and treat malignant pleural mesothelioma.

Combined Modality Therapy↗
PubMed1997

Adverse effects of antibiotics.

The adverse effects caused by antibiotics and the interactions between other drugs based on the results of clinical studies on children recently conducted in Japan, as well as the results of previous studies in the literature were reviewed. Adverse effects of beta-lactam, macrolide and azalide antibiotics commonly observed in children included gastrointestinal symptoms such as diarrhea and loose stool, and hypersensitivity such as rash and fever. The incidences were 1-6% and 0.2-1.6%, respectively. Eosinophilia, thrombocytosis, and elevation of serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase were common abnormal laboratory findings. Although many of the antibiotics used in children are relatively safe, cautions should be given because developing children tend to have adverse effects unique or common in children, in addition to those commonly seen in adults.

Aminoglycosides↗