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E M Mazur

Publications and source records attributed to E M Mazur.

34 records · Page 2Linked to original sources
PubMed1987

Megakaryocytopoiesis and platelet production: a review.

During the past 10-15 years, there has been a rapid expansion in our knowledge about the hematopoietic system which maintains homeostasis of the peripheral blood platelet concentration. This interpretive review attempts to consolidate recent in vitro and in vivo observations into a unified framework. Evidence for a two-level regulatory model of megakaryocytopoiesis is presented and interactions among developmental levels are proposed.

Blood Platelets↗
PubMed1987

In vitro megakaryocytopoiesis in children with acute idiopathic thrombocytopenic purpura.

Idiopathic thrombocytopenic purpura (ITP) of childhood is a disorder characterized by a history of previous viral illness followed by acute onset of low circulating platelet count with present or increased megakaryocytes in the bone marrow. The majority of children recover a normal platelet count within 6 months to 1 year after onset of the disease. To better understand the regulation of megakaryocytopoiesis in this disorder, we studied nine patients with childhood ITP with the plasma clot colony assay in vitro for megakaryocyte colony forming units (CFU-Mk). Mononuclear bone marrow cells from some of the patients with ITP contained greater numbers of CFU-Mk and greater numbers of cells per colony than mononuclear bone marrow cells from healthy adult volunteers (p less than 0.026) when the cultures contained no added megakaryocyte colony-stimulating activity (Mk-CSA). The serum from patients with ITP did not stimulate in vitro megakaryocytopoiesis from healthy adult volunteers' bone marrow mononuclear cells above baseline values. These findings are consistent with the hypothesis that a decrease in bone marrow megakaryocytes is needed for Mk-CSA production. Alternatively, Mk-CSA is consumed by active megakaryocytopoiesis in the bone marrow.

Adolescent↗
PubMed1986

Hand mirror cell lymphoid leukemia in adults. A distinct clinicopathologic syndrome. Case report and literature review.

Hand mirror cell (HMC) lymphoid leukemia is an unusual variant of acute lymphocytic leukemia (ALL) in which the bone marrow lymphoblasts manifest distinctive hand mirror morphologic features. Reported here is a 66-year-old woman with HMC lymphoid leukemia whose clinical course was characterized by 12 months of initial disease stability while she was receiving no chemotherapy; a prompt response to cyclophosphamide, vincristine, and prednisone therapy once instituted; and a hyperleukocytic episode (leukocyte count 607,000/mm3), which resulted in her death after 22 months of disease. This patient and 13 other reported adults (15 years and older) with HMC lymphoid leukemia (greater than 40% bone marrow HMC) are reviewed. HMC lymphoid leukemia appears to differ from typical adult ALL in that it has a female predominance, a relatively indolent early clinical course that lasts 1 year or longer, and it manifests the possibility of survival for 1 or 2 years despite the failure to achieve a complete remission with chemotherapy. Phenotypically, the HMC leukemic cells from all adults evaluated were null cells, Ia-positive, TdT-positive, and stained positively with acid phosphates, which suggests that HMC lymphoid leukemia is a variant of non-T, non-B-ALL. HMC lymphoid leukemia in adults appears to be a distinctive clinicopathologic entity.

Aged↗
PubMed1986

Alpha-interferon: differential suppression of colony growth from human erythroid, myeloid, and megakaryocytic hematopoietic progenitor cells.

The effect of varying concentrations of interferon-alpha (IFN-alpha) on the in vitro colony growth from all single-lineage human hematopoietic colony-forming progenitor cells was evaluated. IFN-alpha was tested at concentrations of 0, 2, 20, and 200 U/ml in optimally stimulated bone marrow cultures from each of 4 volunteer donors. Substantial donor-to-donor variability and distinct, lineage-specific patterns of stem cell sensitivity to IFN-alpha were observed. In the erythroid series, the more primitive progenitor or burst-forming unit (BFU-E) was substantially more resistant to growth inhibition at low IFN-alpha concentrations than the mature colony-forming unit (CFU-E). Colony growth by the megakaryocyte progenitor cell (CFU-Meg) was decreased by all concentrations of IFN-alpha which produced a biphasic, inhibitory dose response. The response of the colony-forming unit granulocyte/macrophage (CFU-GM) was heterogeneous among the donors tested. CFU-GM growth from 2 donors was insensitive to IFN-alpha at all concentrations. Conversely, CFU-GM from the other 2 donors manifested a steep dose-response curve that was similar to that of the CFU-E. These data demonstrate a heterogeneity of progenitor cell sensitivity to growth suppression by IFN-alpha which appears to be influenced by (i) hematopoietic lineage, (ii) degree of differentiation of the progenitor cell, and (iii) individual variability.

Colony-Forming Units Assay↗
PubMed1985

Human megakaryocyte colony-stimulating factor in sera from aplastic dogs: partial purification, characterization, and determination of hematopoietic cell lineage specificity.

We have previously shown that human megakaryocyte colony-stimulating activity (Meg-CSA) is present in sera from patients with bone marrow megakaryocyte aplasia. In this report, we demonstrate that Meg-CSA is also present in sera from dogs rendered aplastic by 1000 rad total body irradiation. Canine serum Meg-CSA has activity comparable to human when assayed in plasma clot cultures containing human bone marrow mononuclear cells. Because of the uniform high potency and ready availability of aplastic canine sera, it was utilized initially for Meg-CSA purification. Sequential ammonium sulfate precipitation to approximately 80% saturation resulted in recovery of 59%-69% of the serum protein and of 75%-103% of the original serum Meg-CSA. The fraction precipitable between ammonium sulfate saturations of 0% and 44%-50% (fraction I) contained 53%-76% of the initial serum Meg-CSA and 25%-32% of the initial serum protein. This represents an enrichment of Meg-CSA specific activity by over 100%. The Meg-CSA eluted from Sephacryl S-300 in a single peak corresponding to a molecular weight of 175,000. This Meg-CSA peak also contained IgG, but the Meg-CSA did not bind to protein A-agarose. Meg-CSA was 90% inactivated by trypsin digestion for 4 h at 37 degrees C and by exposure to 5mM dithiothreitol for 2 h at room temperature. Exposure to either 6 M guanidine for 1 h at room temperature or 8 M urea for 1 h at 4 degrees C resulted in a 70% loss of Meg-CSA. At culture concentrations capable of stimulating maximal megakaryocyte colony formation, fraction I supported no colony growth by myeloid (CFU-GM) or late erythroid (CFU-E) human hematopoietic progenitor cells. Erythroid burst-promoting activity (BPA) was not detected in fraction I from two of three different aplastic canine sera tested. Therefore, Meg-CSA is functionally distinct from granulocyte-monocyte colony-stimulating factor (GM-CSF), erythropoietin, and BPA. The data indicate that serum Meg-CSA is a 175,000-dalton protein (megakaryocyte colony-stimulating factor, Meg-CSF) in which higher order structure and disulfide bonding are necessary for biologic activity. Partially purified Meg-CSF manifests functional specificity for the CFU-Meg hematopoietic progenitor cell.

Anemia, Aplastic↗
PubMed1984

Human serum megakaryocyte colony-stimulating activity increases in response to intensive cytotoxic chemotherapy.

Sera from patients with aplastic anemia and amegakaryocytic thrombocytopenia contain an activity that stimulates megakaryocyte colony formation in vitro. We have assayed this megakaryocyte colony-stimulating activity (Meg-CSA) in sera of four patients receiving intensive antileukemic chemotherapy to determine whether the appearance of Meg-CSA is a physiologic response to the suppression of megakaryocytopoiesis. Three of the four patients were receiving consolidation or late intensification therapy for acute myoblastic leukemia (AML) in remission. The fourth was receiving induction therapy for de novo AML. During all or part of four chemotherapeutic cycles, serial Meg-CSA levels were assessed and correlated with the corresponding peripheral platelet counts. All courses of cytotoxic chemotherapy resulted in increases in serum Meg-CSA comparable to activity levels present in sera from patients with aplastic anemia. Two of the three patients studied during the early postchemotherapy interval manifested initial serum Meg-CSA elevations seven days before their thrombocytopenic nadirs when platelet counts were still between 100,000/mm3 and 140,000/mm3. Bone marrow recovery from chemotherapy was characterized by a decrease in serum Meg-CSA to pretherapy levels that occurred concurrently with the rise in platelet count to normal. These observations support the hypothesis that Meg-CSA is a physiologic humoral regulator of megakaryocytopoiesis elaborated in response to the depletion of either bone marrow megakaryocytes or megakaryocyte progenitor cells.

Acute Disease↗
PubMed1982

Myeloblastoma and acute myelogenous leukemia: presentation with a cervical neuropathy and complete response to chemotherapy.

Myeloblastoma is an uncommon complication of acute and chronic myelogenous leukemia. This is report of a 25-year-old man who was seen with simultaneous acute myelogenous leukemia (AML) and a myeloblastoma involving right-sided C7 and C8 nerve roots. The myeloblastoma, visible as a left apical mass on chest radiogram, resolved completely after six days of intensive AML induction chemotherapy. The patient subsequently had a complete remission with total resolution of all neurologic deficits. He remains in remission now 2 1/2 years after initial diagnosis. An abnormal karyotype was present initially which became normal following chemotherapy. This case is an unusual example of myeloblastoma with peripheral nerve involvement. It illustrates that complete and durable resolution of these myeloblastic tumors can be achieved by intensive chemotherapy alone.

Adult↗
PubMed1982

Eosinophilic fasciitis.

Eosinophilic fasciitis (EF, a diffuse fasciitis with eosinophilia) is a recently recognized connective tissue disorder. It consists of deeply indurated, bound-down plaques of skin and subcutaneous tissue, most commonly present on the extremities. It is associated with peripheral eosinophilia, hypergammaglobulinaemia and an elevated sedimentation rate. There is usually no evidence of Raynaud's phenomenon, acral sclerosis or visceral involvement. Antinuclear antibodies are usually absent. The abnormal histopathology primarily involves the lower subcutis and the fascia. The clinical and laboratory features usually improve following the administration of systemic corticosteroids. Serious haematological abnormalities have been associated with eosinophilic fasciitis (EF) and have been discussed in detail. The similarities and distinctions between eosinophilic fasciitis and scleroderma have been discussed.

Adrenal Cortex Hormones↗
PubMed1982

Differing responses of globin and glycophorin gene expression to hemin in the human leukemia cell line K562.

The human leukemia cell line, K562, produces embryonic and fetal hemoglobins and glycophorin A, proteins normally associated only with erythroid cells. Hemoglobin accumulation is enhanced by exposure of the cells to 0.05 mM hemin. We have examined K562 cells before and after exposure to hemin to determine whether expression of these erythroid proteins was shared by all cells or confined to specific subpopulations. Globin gene expression was examined by quantitation of globin mRNA sequences, using a 3H-globin cDNA molecular hybridization probe. Constitutive cells produced globin mRNA, the content of which was increased 3-4-fold by hemin. Cell-to-cell distribution of globin mRNA was determined by in situ hybridization of 3H-globin cDNA to constitutive and hemin-treated K562 cells. Virtually all cells in the culture exhibited grain counts above background, indicating globin gene expression by all cells, rather than a confined subpopulation. Virtually all hemin-treated cells had 3-5-fold higher grain counts, indicating uniformly increased globin gene expression. The glycophorin content of K562 cells was estimated by fluorescence-activated cell sorting (FACS) of cells labeled with fluorescein-labeled antiglycophorin antiserum. The vast majority of constitutive cells contained glycophorin, but exhibited to apparent increase in glycophorin accumulation after hemin exposure. Thus, glycophorin and globin genes exhibited differential responses to hemin. These differences could reflect normal differences in the patterns of specialized gene expression in stem cells. Alternatively, different aberrations of gene expression could be occurring in response to the determinants of the neoplastic properties of K562.

Amino Acid Sequence↗
PubMed1981

Regulation of human megakaryocytopoiesis. An in vito analysis.

We have recently described an assay system for human peripheral blood megakaryocyte colony-forming unit cells (CFU-M) using an anti-platelet glycoprotein antiserum probe to define megakaryocyte colonies grown in vitro. This system was applied to study the nature and regulation of human bone marrow CFU-M. In the absence of a specific megakaryocyte growth-promoting factor, 12.4 +/- 3.0 (means +/- SEM) megakaryocyte colonies were cloned per 5 X 10(5) cells cultured. Colonies were present after 6 d of incubation reaching peak numbers between days 10 and 14 and slowly decreasing thereafter. Erythropoietin in concentrations of up to 4 U/ml failed to augment colony numbers. Also failing to enhance megakaryocyte colony plating efficiency were media containing burst-promoting activity and colony-stimulating activity. A medium conditioned by human embryonic kidney cells, which has been previously demonstrated to contain thrombopoietin, also had no effect on megakaryocyte colony numbers. In contrast, sera from three patients with severe aplastic anemia produced significant enhancement of CFU-M-derived colony formation in vitro. Both the number of megakaryocyte colonies present and the number of megakaryocytes per colony were increased in proportion to the final concentration of aplastic anemia serum. In the presence of 10% aplastic anemia serum, cultured megakaryocyte colony numbers were linear with respect to the number of bone marrow mononuclear cells plated suggesting a clonal origin of each of the colonies. This in vitro assay for bone marrow CFU-M is a reliable means by which to study the regulation of human megakaryocytopoiesis. Initial data suggest that megakaryocyte production is stimulated by a factor detectable in aplastic anemia serum that may be distinct from other known hematopoietic stem cell regulators.

Anemia, Aplastic↗
PubMed1981

Immunofluorescent identification of human megakaryocyte colonies using an antiplatelet glycoprotein antiserum.

The development of a satisfactory in vitro assay system for human megakaryocyte colony forming progenitor cells has been delayed by the lack of a suitable marker for cells of human megakaryocyte lineage. For this purpose we raised an antiserum directed against a purified human platelet glycoprotein preparation. In conjunction with indirect immunofluorescent staining of human bone marrow, this antiserum labeled only platelets, megakaryocytes, and an infrequent population of small mononuclear cells. These small mononuclear cells, not otherwise identifiable as members of the megakaryocyte series, constituted 22.9% of the total fluorescein positive nucleated bone marrow cells. This antiserum was also used to label colonies cultured from human peripheral blood mononuclear cells using a modified plasma clot technique. A mean of 123 fluorescein-labeled colonies were cloned per 10(6) mononuclear cells cultured. Granulocyte-macrophage and erythroid burst colonies did not label using this method. No augmentation of colony numbers was found with varying concentrations of erythropoietin, human embryonic kidney cell conditioned media (a source of thrombopoietin), or media conditioned by a human T lymphoblast cell line (a source of both colony stimulating and burst promoting activities). Immunofluorescent labeling for platelet glycoproteins is a convenient phenotypic marker for cells of human megakaryocyte lineage useful in the study of in vitro human megakaryocytopoiesis.

Antibody Specificity↗
PubMed1980

Embryonic-fetal erythroid characteristics of a human leukemic cell line.

We have studied a number of cell surface, enzyme, and protein markers in the human leukemic K562 cell line. We have confirmed previous observations that these cells accumulate human embryonic hemoglobins after exposure to hemin. In addition, our results demonstrated that these cells possess in the "ininduced" state i surface antigen, lactate dehydrogenase isoenzymes characteristic of embryonic or fetal erythroid cells, fetal and embryonic globin chains, and globin mRNAs. The levels if i antigen, embryonic globin chains, and embryonic globin mRNA increased substantially after exposure of the cells to hemin in suspension culture. In contrast, K562 cells lacked several surface, enzymatic, and functional properties typical of granulocytes, lymphocytes, monocytes, or adult erythroblasts, including HLA surface antigens, surface immunoglobulins, sheep erythrocyte rosetting, phagocytosis, terminal deoxynucleotidyl transferase, carbonic anhydrase, ABO and Rh blood groups, and adult hemoglobins. The K562 cell line therefore exhibits phenotypic properties of embryonic erythroid progenitor cells and a quantitative increase in the expression of some of these properties can be achieved by exposure of the cells to hemin.

Antigens, Surface↗
PubMed1978

Idiopathic thrombocytopenic purpura occurring in a subject previously splenectomized for traumatic splenic rupture. Role of splenosis in the pathogenesis of thrombocytopenia.

A 25 year old woman presented with idiopathic thrombocytopenic purpura. She had undergon splenectomy 12 years previously for traumatic splenic rupture. Thrombocytopenia was ultimately resistant to steroid therapy. Howell-Jolly bodies were absent from the peripheral smear and 99mTC-spleen scan demonstrated foci of increased uptake thought consistent with accessory spleens. However, splenosis alone was demonstrated at laparotomy, and all visible splenotic tissue was surgically removed. The patient responded and adequate platelet counts were maintained after discontinuation of steroid therapy. The functional capacity of splenic implants has been previously demonstrated both in animal and man. However, reports linking splenosis to hematologic disease are rare. In the present case, characteristic splenic function was demonstrated by both the the -9mTc-spleen scan and the absence of the typical peripheral blood findings of asplenia. The hematologic response to the removal of the splenotic tissue attests to its importance in maintaining the thrombocytopenic state. In the setting of prior splenectomy for splenic trauma, splenosis may contribute to hematologic disease. Removal of this splenotic tissue may result in hematologic remission.

Adult↗