Abstract:
:The primary physiologic regulator of platelet production, Mpl ligand, has recently been cloned and characterized. To define the regulatory role of Mpl ligand on platelet production and function we measured the effects of a recombinant truncated human Mpl ligand, megakaryocyte growth and development factor (rHu-MGDF) on megakaryocytopoiesis, platelet function, and thrombogenesis in nonhuman primates. rHu-MGDF was administered to 10 baboons for 28 days while performing pharmacokinetics and repeated measurements of the following: (1) platelet count, volume, turnover, and function ex vivo and in vitro; (2) marrow megakaryocyte number, volume, and ploidy; and (3) platelet deposition and fibrin accumulation on segments of vascular graft and endarterectomized aorta in vivo. Daily subcutaneous injections of rHu-MGDF (5 microgram/kg/d) attained plasma concentrations averaging 1,300 +/- 300 pg/mL 2 hours after injection with trough levels of 300 +/- 65 pg/mL before the next dose. These levels of rHu-MGDF incrementally increased the peripheral platelet concentration threefold by day 7 and fivefold by day 28 (P < 10(-4)) associated with a reciprocal decrease of 25% in mean platelet volumes (P < 10(-3)). Platelet mass turnover, a steady-state measure of platelet production, increased fivefold (P < 10(-4)). Platelet morphology, life span, and recovery were normal. No significant change occurred in peripheral leukocyte, neutrophil, or erythrocyte counts (P > .1 in all cases). The platelet count gradually returned to baseline within 2 weeks after discontinuing rHu-MGDF infections. Marrow megakaryocyte volume doubled (P < 10(-3)) three days after initiating rHu-MGDF therapy and the modal ploidy shifted from 16N to 64N (P < 10(-4)). Marrow megakaryocyte number increased twofold by day 7, and nearly fourfold by day 28 (P < 10(-4)), resulting in a 6.5-fold increase in marrow megakaryocyte mass (P < 10(-3)). The effects of rHu-MGDF on thrombosis were determined by comparing baseline, day 5, and day 28 rHu-MGDF-treatment measurements of 111In-platelet deposition and 125I-fibrin accumulation on segments of homologous endarterectomized aorta (EA) and vascular graft (VG) interposed in arteriovenous femoral shunts. rHu-MGDF increased 111In-platelet deposition in direct proportion to the circulating concentration of platelets for both EA and VG (r=.98 in both cases), without significant changes in fibrin accumulation (P > .5 in both cases). During the first week of rHu-MGDF treatment ex vivo platelet aggregatory responsiveness was enhanced to physiologic agonists (adenosine diphosphate, collagen, and thrombin receptor agonist peptide, TRAP1-6) (P < .05 in all cases). Although in vitro platelet aggregation was not induced by any concentration of rHu-MGDF tested (P > .5), rHu-MGDF enhanced aggregatory responses to low doses of physiologic agonists, effects that were maximal at 10 ng/mL for baboon platelets and 100 ng/mL for human platelets, and were blocked by excess soluble c-Mpl receptor. Flow cytometric expression of platelet activation epitopes was not increased on resting platelets (ligand-induced binding sites, P-selectin, or Annexin V binding sites; P > .1 in all cases). Megakaryocyte growth and development factor regulates platelet production and function by stimulating endoreduplication and megakaryocyte formation from marrow progenitor cells, and transiently enhancing platelet functional responses ex vivo. rHu-MGDF has the potential for achieving platelet hemostatic protection with minimal thrombo-occlusive risk.
journal_name
Bloodjournal_title
Bloodauthors
Harker LA,Hunt P,Marzec UM,Kelly AB,Tomer A,Hanson SR,Stead RBsubject
Has Abstractpub_date
1996-03-01 00:00:00pages
1833-44issue
5eissn
0006-4971issn
1528-0020journal_volume
87pub_type
杂志文章相关文献
BLOOD文献大全abstract::Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of ALL in children. There are conflicting data on the incidence and prognosis of Ph-like ALL in adults. Patients with newly diagnosed B-cell ALL (B-ALL) who received frontline chemotherapy at MD Anderson Cancer Center underwent...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2016-07-726588
更新日期:2017-02-02 00:00:00
abstract::Using data from ARISTOTLE, we describe the periprocedural management of anticoagulation and rates of subsequent clinical outcomes among patients chronically anticoagulated with warfarin or apixaban. We recorded whether (and for how long) anticoagulant therapy was interrupted preprocedure, whether bridging therapy was ...
journal_title:Blood
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1182/blood-2014-08-595496
更新日期:2014-12-11 00:00:00
abstract::Azacitidine treatment of myelodysplastic syndromes (MDSs) generally exacerbates thrombocytopenia during the first treatment cycles. A Study of Eltrombopag in Myelodysplastic Syndromes Receiving Azacitidine (SUPPORT), a phase 3, randomized, double-blind, placebo-controlled study, investigated the platelet supportive ef...
journal_title:Blood
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1182/blood-2018-06-855221
更新日期:2018-12-20 00:00:00
abstract::The plasminogen activator inhibitor PAI-1 is markedly elevated in vivo and in vitro upon exposure to the inflammatory mediators tumor necrosis factor alpha (TNF alpha), interleukin-1 (IL-1), and bacterial lipopolysaccharide. Here we report that the isoflavone compound genistein prevents the increase in synthesis of PA...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1994-11-01 00:00:00
abstract::High-dose cyclophosphamide, without stem cell rescue, has been used successfully to treat aplastic anemia and other autoimmune disorders. To determine the safety and efficacy of high-dose cyclophosphamide among patients with severe refractory autoimmune hemolytic anemia, we treated 9 patients with cyclophosphamide (50...
journal_title:Blood
pub_type: 临床试验,杂志文章
doi:10.1182/blood-2002-01-0087
更新日期:2002-07-15 00:00:00
abstract::BCL3 encodes a protein with close homology to IkappaB proteins and interacts with p50 NF-kappaB homodimers. However, the regulation and transcriptional activity of BCL3 remain ill-defined. We observed here that interleukin-9 (IL-9) and IL-4, but not IL-2 or IL-3, transcriptionally upregulated BCL3 expression in T cell...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1999-06-15 00:00:00
abstract::Despite major therapeutic advances, most mature B-cell malignancies remain incurable. Compelling evidence suggests that crosstalk with accessory stromal cells in specialized tissue microenvironments, such as the bone marrow and secondary lymphoid organs, favors disease progression by promoting malignant B-cell growth ...
journal_title:Blood
pub_type: 杂志文章,评审
doi:10.1182/blood-2009-06-225326
更新日期:2009-10-15 00:00:00
abstract::T-cell function directly influences several B-cell functions. The effect of T-cell subgroups on B-cell function (DNA synthesis) was evaluated for controls and patients with B-cell type of CLL. Control and CLL intact T cells, T cells with receptors for IgG (T gamma), and T cells without Fc receptors at isolation (T non...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1981-03-01 00:00:00
abstract::A number of studies have recently demonstrated that super-enhancers, which are large cluster of enhancers typically marked by a high level of acetylation of histone H3 lysine 27 and mediator bindings, are frequently associated with genes that control and define cell identity during normal development. Super-enhancers ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2017-06-792184
更新日期:2017-11-23 00:00:00
abstract::Congenital deficiency in coagulation factor XIII is a rare autosomal recessive bleeding disorder. Although the defect was characterized over 30 years ago, little is known about the molecular basis of the disorder. Here, we show two novel point mutations in the gene of the A-subunit of factor XIII in the genetically is...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1994-07-15 00:00:00
abstract::In this issue of Blood, Poli et al demonstrate that heparin analogs engineered to minimize their anticoagulant properties can potently downregulate hepcidin production in vitro and in vivo, and may potentially be used to treat the anemia of inflammation. ...
journal_title:Blood
pub_type: 评论,杂志文章
doi:10.1182/blood-2014-01-549519
更新日期:2014-03-06 00:00:00
abstract::Because the causes of most lymphoid neoplasms remain unknown, comparison of incidence patterns by disease subtype may provide critical clues for future etiologic investigations. We therefore conducted a comprehensive assessment of 114,548 lymphoid neoplasms diagnosed during 1992-2001 in 12 Surveillance, Epidemiology, ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2005-06-2508
更新日期:2006-01-01 00:00:00
abstract::Insights into immune-mediated thrombotic thrombocytopenic purpura (iTTP) pathophysiology have led to novel targeted therapies. Immunomodulatory strategies target anti-ADAMTS13 antibodies: rituximab is effective in inducing responses in refractory/relapsed TTP and increasing relapse-free survival; caplacizumab targets ...
journal_title:Blood
pub_type: 杂志文章,评审
doi:10.1182/blood.2019000954
更新日期:2019-08-01 00:00:00
abstract::Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARalpha fusion protein and responsiveness to treatment with all-trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocati...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1998-04-15 00:00:00
abstract::Serotonin (5-hydroxytryptamine, or 5-HT), released from activated platelets, not only accelerates aggregation of platelets but also is known to promote mitosis, migration, and contraction of vascular smooth muscle cells (VSMCs). These effects are considered to contribute to thrombus formation and atherosclerosis. The ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.v97.6.1697
更新日期:2001-03-15 00:00:00
abstract::Interleukin-11 (IL-11), a pleiotropic cytokine originally isolated from a primate bone marrow stromal cell line, has been shown to stimulate T-cell-dependent B-cell maturation, megakaryopoiesis, and various stages of myeloid differentiation, but to inhibit adipogenesis. Because stromal cells are essential for the main...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1992-09-01 00:00:00
abstract::We evaluated the efficacy of umbilical cord blood (UCB) in the setting of a nonmyeloablative regimen consisting of fludarabine (200 mg/m2), cyclophosphamide (50 mg/kg), and a single fraction of total body irradiation (200 cGy) with cyclosporine and mycophenolate mofetil for posttransplantation immunoprophylaxis. The t...
journal_title:Blood
pub_type: 临床试验,杂志文章
doi:10.1182/blood-2007-04-067215
更新日期:2007-10-15 00:00:00
abstract::Human megakaryocyte differentiation and maturation were studied in fresh marrow aspirates by using multiparameter flow cytometric correlative analysis. The expression of glycoprotein (GP)IIb/IIIa, GPIIIa, GPIb, and CD36 correlated directly with cell size and ploidy (r > 0.97); however, GPIb acquisition was relatively ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2004-02-0769
更新日期:2004-11-01 00:00:00
abstract::To determine whether the sensitivity of the human long-term culture-initiating cell (LTC-IC) assay could be increased, we have evaluated a spectrum of different fibroblast cell lines for their abilities to influence the number of cells detectable as LTC-IC, to influence LTC-IC maintenance, and/or to influence LTC-IC d...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1996-11-15 00:00:00
abstract::The beta-globin locus control region (LCR) is a large DNA element that is required for high-level expression of beta-like globin genes from the endogenous mouse locus or in transgenic mice carrying the human beta-globin locus. The LCR encompasses 6 DNaseI hypersensitive sites (HSs) that bind transcription factors. The...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2005-06-2308
更新日期:2006-01-15 00:00:00
abstract::Cytogenetic and histopathologic data were correlated with clinical parameters from 423 patients with non-Hodgkin's lymphoma (NHL). Clinical correlations were performed on subgroups of 149 patients with low-grade lymphoma (LG) and 205 patients with diffuse lymphoma with a large cell component (DLLC). Correlations were ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1991-04-01 00:00:00
abstract::We prepared a heterohybrid cell line that secretes a human IgM monoclonal autoantibody that recognizes an antigen found on thrombin-activated or stored platelets. The surface expression of the epitope recognized by this autoantibody, 5E5, increases with time as platelets age in vitro, suggesting that it may represent ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1987-07-01 00:00:00
abstract::Human cord blood (CB) offers an attractive source of cells for clinical transplants because of its rich content of cells with sustained repopulating ability in spite of an apparent deficiency of cells with rapid reconstituting ability. Nevertheless, the clonal dynamics of nonlimiting CB transplants remain poorly under...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2013-06-508432
更新日期:2013-10-31 00:00:00
abstract::Gene delivery via the hematopoietic stem cell (HSC) offers an attractive means to introduce antiviral genes into both T cells and macrophages for acquired immunodeficiency syndrome (AIDS) gene therapy. An amphotropic retroviral vector encoding a bicistronic gene coexpressing RevM10 and the murine CD8alpha' chain (lyt2...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1997-04-01 00:00:00
abstract::In this issue of Blood, Kasirer-Friede and colleagues show that the adhesion and degranulation promoter protein (ADAP) promotes αIIbβ3 activation by presenting the cytoplasmic proteins talin and kindlin to the β3 cytoplasmic tail. ...
journal_title:Blood
pub_type: 评论,杂志文章
doi:10.1182/blood-2014-02-557355
更新日期:2014-05-15 00:00:00
abstract::Immunizing bone marrow donors prior to bone marrow transplant (BMT) has the potential for adoptively transferring specific immunity against opportunistic pathogens. Studies have shown that long-term antibody production occurs in the bone marrow and that specific humoral immunity may be transferred from donor to recipi...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1997-09-01 00:00:00
abstract::Epidemiologic studies have correlated elevated plasma fibrinogen (hyperfibrinogenemia) with risk of cardiovascular disease and arterial and venous thrombosis. However, it is unknown whether hyperfibrinogenemia is merely a biomarker of the proinflammatory disease state or is a causative mechanism in the etiology. We ra...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2010-11-316885
更新日期:2011-05-05 00:00:00
abstract::The role of hematopoietic growth factors in lineage commitment and differentiation is unclear. We present evidence that heterologous expression of an erythroid specific receptor allows granulocytic differentiation of a myeloid cell line. We have previously characterized a truncation mutant of the erythropoietin recept...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1998-08-15 00:00:00
abstract::Using flow cytometric techniques, we determined the pretreatment distribution of DNA content in propidium iodide-stained leukemic blasts from 205 children with "standard-risk" acute lymphoblastic leukemia (ALL). Risk assignment was based on an initial WBC count less than 100 X 10(9)/L, no thymic mass, no meningeal leu...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1985-05-01 00:00:00
abstract::The blockade of platelet integrin glycoprotein (GP) IIb/IIIa is a promising new antiplatelet strategy. The binding of ligands or of the ligand-mimetic peptide RGD causes a conformational change of GP IIb/IIIa from the nonactivated to the activated state. Because several blocking agents/inhibitors are ligand-mimetics, ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1998-11-01 00:00:00