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Results for “recombinant human thrombopoietin”

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PubMed2026

Recombinant Human Thrombopoietin Reduces the Need for Platelet Transfusion in Patients With Chronic Liver Disease and Thrombocytopenia.

Chronic liver disease (CLD)-related thrombocytopenia can limit the feasibility of invasive procedures. Recombinant human thrombopoietin (rhTPO) has demonstrated a favorable safety profile without hepatotoxicity. We evaluated the efficacy and safety of rhTPO in patients with CLD-related thrombocytopenia who were undergoing elective invasive procedures. In this multicenter, randomized (2:1), double-blind, placebo-controlled phase III trial, 120 adult Chinese patients with CLD-related thrombocytopenia (platelet count < 50 × 109/L) received rhTPO (n = 80) or placebo (n = 40) once daily for up to 5 or 7 days. The primary endpoint was the proportion of patients with sustained platelet counts ≥ 50 × 109/L from 24 h before invasive procedure to 7 days post-procedure, without requiring emergency bleeding management. The primary endpoint was achieved by 85.0% of patients in the rhTPO group versus 12.5% in the placebo group (p < 0.0001). Preoperatively, platelet counts ≥ 50 × 109/L were achieved in 92.5% and 20.0% of patients in the rhTPO and placebo groups, respectively (p < 0.0001). Platelet transfusion was avoided in 92.5% of rhTPO-treated patients versus 25.0% of placebo-treated patients (p < 0.0001). The median duration of platelet counts ≥ 50 × 109/L was significantly longer with rhTPO than with placebo (21.0 vs. 3.0 days, p = 0.0007). Treatment-related treatment-emergent adverse events (TEAEs) occurred in 12.5% of patients in both the rhTPO and placebo groups. No treatment-related serious adverse events were reported. Overall, rhTPO was effective and well tolerated in patients with CLD-related thrombocytopenia and may represent a viable therapeutic option for those undergoing elective invasive procedures. Trial Registration: www.chinadrugtrials.org.cn: number CTR20230919.

Humans↗

PubMed1987

[Recombinant blood hormones in clinical practice].

Explore the source record for details and available documents.

Colony-Stimulating Factors↗

PubMed1990

Stimulation of thrombopoiesis in mice by human recombinant interleukin 6.

To date, testing of various cytokines for the stimulation of blood cell production has not demonstrated a consistent effect on peripheral platelet levels. In this report, we provide evidence that human recombinant IL-6 increased platelet production in mice, as measured by both peripheral platelet levels and [75Se]selenomethionine (75SeM) incorporation into newly forming platelets. Peripheral white blood cell counts also were increased, but only to a modest extent, and hematocrit values were unchanged. A dose-response relationship between the amount of IL-6 administered and platelet count, 75SeM incorporation, and white blood cell count was demonstrated. Detectable megakaryocyte and granulocyte-macrophage colony-forming cells in mice that had received IL-6 also were increased in both bone marrow and spleen. These results demonstrate the ability of a purified, recombinant protein to stimulate platelet production in vivo.

Animals↗

PubMed1988

Effect of recombinant and purified hematopoietic growth factors on human megakaryocyte colony formation.

The effect of a number of purified or recombinant hematopoietic growth factors, including recombinant erythropoietin (rEpo), thrombocytopoiesis stimulating factor (TSF), recombinant interleukin 1 alpha (rIL-1 alpha), recombinant granulocyte colony-stimulating factor (rG-CSF), macrophage colony-stimulating factor (CSF-1), recombinant interleukin 3 (rIL-3), and recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), on megakaryocyte (MK) colony formation by normal human marrow cells in a serum-depleted assay system was determined. Neither rEpo, TSF, CSF-1, rIL-1 alpha, nor rG-CSF alone augmented MK colony formation. Both rGM-CSF and rIL-3 at optimal doses increased MK colony formation eightfold and tenfold, respectively, above baseline values. Addition of increasing amounts of either rGM-CSF or rIL-3 led to progressively greater numbers of MK colonies formed until plateau levels were reached. Both rGM-CSF and rIL-3 also led to a dose-related increase in the number of cells per MK colony formed in culture. These molecules were equivalent stimulators of MK colony formation when their effects at optimal concentrations were compared. The effects of rGM-CSF and rIL-3 were additive at suboptimal concentrations of rIL-3 in that colony formation by a combination of the two growth factors approximated the sum of colony formation by each growth factor alone. These data suggest that rGM-CSF and rIL-3 alone and in combination are important regulators of in vitro megakaryocytopoiesis at the progenitor cell level.

Cell Division↗

PubMed1990

Thrombopoietic activity of human interleukin-6.

Thrombopoietin (TPO), a regulatory factor in platelet production, was purified from the conditioned medium of TNK-01 cells cultured in the presence of human interleukin-1. The N-terminal sequence of purified TPO was determined to be VPPGEDSKDVAAPHRQPLT, identical to that of the N-terminal region of human interleukin-6 (IL-6). Two forms of TPO with molecular masses of 24 and 27 kDa were identified as IL-6 by Western analysis using an anti-IL-6 antibody. Commercial recombinant human IL-6 produced in Escherichia coli, stimulated megakaryocyte colony formation in the presence of mouse interleukin-3 and increased the number of peripheral platelets in mice in a dose-dependent manner. From these results, it is concluded that human IL-6 has thrombopoietic activity.

Amino Acid Sequence↗

PubMed1992

Is interleukin 6 the physiological regulator of thrombopoiesis?

Interleukin 6 (IL-6) is a multifunctional cytokine that also influences megakaryocyte (MK) development. To delineate the relationship between IL-6 and thrombopoietin (TPO), the putative physiological regulator of MK maturation, serum IL-6 levels and platelet counts were correlated in various clinical disorders. IL-6 was measured by a [3H] thymidine incorporation assay using the IL-6-dependent B9 cell line; 1 U is approximately equal to 1 pg/ml of a recombinant (r)IL-6 standard. Specificity of the assay was confirmed by neutralizing rIL-6 and selected sera containing IL-6 activity with anti-IL-6 antibody. Samples (n = 120) were obtained from normal individuals and patients with leukemia, myeloproliferative and rheumatologic disorders, solid tumors, and after bone marrow transplantation and chemotherapy. Patients were also grouped as to whether they had an ongoing inflammatory process, that is, an active infection, solid tumor malignancy, or rheumatological disorder. Serum IL-6 levels were 4.6 +/- 1.4 U/ml for normal individuals and ranged up to 14.8 x baseline; moderate increases (greater than 2 x normal) were found in 21.5% of all patients. Whereas only 39% of thrombocytopenic sera (less than 150,000 platelets) had elevated IL-6 levels, 91% of these sera were from patients with an ongoing inflammatory process. Only 29% of the thrombocytotic sera (greater than 400,000) had elevated IL-6 levels, but 86% of these sera were from patients suffering from concurrent inflammation. Overall, 80% of all patients with elevated serum IL-6 had definitive ongoing inflammatory processes. There was no inverse relationship between platelet numbers and IL-6 levels. Thus, the idea that IL-6 is TPO appears doubtful. However, production of IL-6 during inflammation may result in increased platelet numbers and account for the secondary thrombocytosis observed in some patients.

Blood Platelets↗

PubMed1989

The regulation of megakaryocyte and platelet production.

Thrombopoietin, a hormone that regulates blood platelet production, is now recognized to be an important in vivo hematopoietic stimulator. In this concise review, the background on thrombopoietin, development of assays, and identification of sources of the hormone are summarized, along with brief descriptions of other controlling factors, sites of thrombopoietin production, results of producing antibodies against the factor, sites of action of thrombopoietin both in vitro and in vivo, and its effect on blood platelet production. Suitable assays and stable sources of thrombopoietin have now been identified and their development will permit production of recombinant material. Once the gene is cloned, it is expected that recombinant thrombopoietin will be invaluable for treating patients with several platelet production problems.

Animals↗

PubMed1992

Thrombopoietin. Its biology, clinical aspects, and possibilities.

Thrombopoietin or thrombocytopoiesis-stimulating factor (TSF) is known to be the natural stimulator of megakaryocytopoiesis and, thus, stimulates thrombocytopoiesis. In the past 15 years, new assay technology and sources of the hormone have made possible partial characterization of the molecule and clarification of the biologic role of thrombopoietin. Experiments describing the biology and characterization of TSF are reviewed. In addition, a brief history of the molecule, its biology, and the effects of thrombopoietin on both thrombocytopoiesis and megakaryocytopoiesis are discussed, including the effects of thrombopoietin on platelet counts, platelet sizes, and incorporation of isotopes. In the discussion of thrombopoietin's control of megakaryocytopoiesis there is specific information showing that thrombopoietin stimulates an increase in megakaryocyte size and number, DNA content, endomitosis, and maturation. Thrombopoietin also increases the number of early precursor cells of the megakaryocytic series, that is, small acetyl-cholinesterase-positive cells. New information is given on the chemistry of thrombopoietin, along with present assays and the relationship of thrombopoietin to interleukin-6. The clinical aspects of thrombopoietin, with detailed descriptions of several disease states in which decreases and excesses of the hormone have been found, are presented. The potential uses of thrombopoietin in clinical medicine are reviewed. In the near future, it appears that successful gene cloning of the hormone will be achieved, which will allow production of large amounts of recombinant thrombopoietin. The pure material will be helpful in clarifying the hormone's mode of action. Thrombopoietin will no doubt prove to be useful in treating patients with various hematologic disorders, such as patients undergoing bone marrow transplantation, chemotherapy, or radiotherapy, and other patients with various types of marrow hypoplasia.

Blood Platelets↗

PubMed1988

Synergistic regulation of human megakaryocyte development.

Little information exists concerning differing levels of regulation occurring during human megakaryocyte development. We hypothesize that megakaryocytic proliferation and maturation is controlled by two, synergistic regulatory factors. One, megakaryocyte colony-stimulating activity, is an obligate requirement for colony formation and drives the development of relatively immature cells. Megakaryocyte colony-stimulating activity is a functional component of the human recombinant proteins, interleukin 3 or GM-CSF. Human recombinant growth factors, interleukin 1, interleukin 6, or crythropoietin, do not effect megakaryocyte development either alone or in combination with interleukin 3. Full maturation requires a second synergistic activity which increases megakaryocyte number, size, and cytoplasmic and antigenic content. In culture, this synergistic regulator augments maturation by increasing the number of colonies, colony cellularity, and size. In suspension cultures, this cofactor increases megakaryocyte cytoplasmic and antigenic content, and shifts the morphological distribution from immature to mature megakaryocytes. Finally, this activity also increases the number of antigen positive megakaryocytes, either by stimulating proliferation or conversion of antigen-negative to antigen-positive cells. Comparative studies of megakaryocytic regulation suggests that this in vitro regulator mimicks some of the known effects of thrombopoietin in vivo.

Adolescent↗

PubMed1992

In vivo effects of interleukin-6 on thrombopoiesis in healthy and irradiated primates.

We have studied the in vivo effects of recombinant human interleukin-6 (rhIL-6) on hematopoiesis in eight healthy and nine irradiated cynomolgus monkeys. Of the healthy animals, three received rhIL-6 alone (10 micrograms/kg/d, subcutaneously [SC]), one received rhIL-6 in combination with rhIL-3 (10 micrograms/kg/d, SC), one received rhIL-6 in combination with recombinant cynomolgus granulocyte-macrophage colony-stimulating factor (rcGM-CSF; 10 micrograms/kg/d, SC), two received rhIL-6 in combination with recombinant human granulocyte-CSF (rhG-CSF; 10 micrograms/kg/d, SC), and one received rhIL-6 in combination with recombinant human leukemia inhibitory factor (rhLIF; 10 micrograms/kg/d, SC). All animals were treated for at least 2 weeks with rhIL-6 or the above mentioned combinations. rhIL-6 alone significantly increased the peripheral blood platelet counts (2- to 3.5-fold). The platelets reached a plateau between days 10 and 15 of treatment. No synergistic effects on platelet numbers were observed when rhIL-6 was combined with rhIL-3, rcGM-CSF, rhG-CSF, or rhLIF. In addition to rhIL-6, only rhLIF increased the platelet numbers when administered alone. To test whether rhIL-6 might also protect the animal from thrombocytopenia or shorten the time of thrombocytopenia after irradiation, we treated nine animals with total body irradiation (3.8 Gy). Six of the animals were additional treated with rhIL-6 (4 with 10 micrograms/kg/d; and 2 with 100 micrograms/kg/d) from day -1 or +1 to day 28 post irradiation. In these animals, rhIL-6 at the same dose effective in healthy animals (10 micrograms/kg/d) was not capable of protecting the animals from platelet nadir. However, when pegylated rhIL-6 was used at a dosage of 100 micrograms/kg/d post irradiation, the mean of the nadirs was 71,000/microL as compared with 39,000/microL in control animals and the time of thrombocytopenia was shorter (3 v 5 days). In all animals (healthy and irradiated), rhIL-6 did not increase the number of bone marrow megakaryocytes but induced a right shift of DNA ploidy in megakaryocytes. These data suggest that IL-6 acts as "thrombopoietin"-like activity, but not as "megakaryocyte-CSF"-like activity.

Animals↗

PubMed1990

Haemopoietic growth factors.

The availability of recombinant haemopoietic growth factors has permitted more precise in vitro experiments and human in vivo studies to be performed. In general, the results have been in accord with expectations from previous in vitro studies. The clinical exploitation of the haemopoietic growth factors offers great promise but careful studies are required to define their value. The effects of some growth factors are multiple and complex, and it cannot be assumed that improvements in blood cell counts are per se beneficial to the patient under all circumstances. Randomized controlled trials with clinical end-points are now essential. In the situation of chemotherapy-induced neutropenia, large studies would be required to show an improvement in mortality although lesser morbidity would be easier to demonstrate. In the field of cancer therapy the major benefit of the haemopoietic growth factors will be if they permit dosage escalation and there is a consequent improvement in response rate and long-term survival. This will require careful patient selection and large, probably multicentre, trials. It is also likely that such studies will be limited by the development of severe thrombocytopenia and an effective means to ameliorate this (perhaps the elusive thrombopoietin) will be required. The possibility of using haemopoietic growth factors as an adjunct to the treatment of severe infections is enticing, but designing a trial to evaluate this possibility is fraught with difficulties. Finally, it must be noted that all the studies reported to date use single factors. This is just the beginning and the use of other factors and synergistic combinations may give greater efficacy without increased toxicity.

Bone Marrow Diseases↗

PubMed1991

[Hematopoietic growth factors].

In the paper the role of interleukin-3, granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF) and macrophage colony stimulating factor (M-CSF), in the proliferation and differentiation of haemopoietic cells and pathogenesis of leukaemia are reviewed. Role of erythropoietin, thrombopoietin and other thrombopoiesis-stimulating factors in the development of hematopoietic is presented. Potential applications of recombinant haemopoietic growth factors in the treatment of myelodysplastic syndromes. AIDS and other haematologic, infections and neoplastic disorders are also discussed.

Acquired Immunodeficiency Syndrome↗

PubMed1987

Regulation of megakaryocytopoiesis by thrombopoietin.

It is clear that thrombopoietin is a major hormonal regulator of megakaryocytopoiesis both in vitro and in vivo, and, thus, blood platelet production. Existing data show that the action, chemical nature, and immunologic properties of thrombopoietin from HEK cell culture medium and either endogenously produced or exogenously administered thrombopoietin from animal sources are similar, if not identical. Absolute identity, however, will require comparisons of amino acid sequences of the two preparations. Recent studies have shown that not only does TSF potentiate the action of meg-CSF, but it also has a direct effect on precursor cells to increase the number of megakaryocytic colonies. Other in vitro work showed that TSF stimulates directly the SAChE+ precursor cells to become mature megakaryocytes and causes FMLC to differentiate into megakaryocytic colonies. In vivo, TSF increases megakaryocyte size and number, it causes an elevation in the number of the SAChE+ precursor cells in mouse marrow and increases the maturation of megakaryocytes. Moreover, TSF increases the endomitosis of megakaryocytes in the marrow of mice, along with elevating the number of megakaryocytic colonies in spleens of lethally irradiated bone marrow reconstituted mice. Platelet production is also stimulated in mice by TSF as evidenced by elevated isotopic incorporation into platelets; it increases platelet sizes, and when administered in high doses TSF elevates platelet counts. Full development of colonies of megakaryocytes may depend on two growth factors. It has been hypothesized that one factor, meg-CSF, is effective in clonal expansion whereas a second factor is predominately involved in the endomitotic phase of megakaryocyte development. Multifactoral regulation has been observed for the other cell lineages, and a general proposal for hematopoietic development has been outlined by Iscove. In this scheme, specificity of erythropoietin to erythroid cell lineage is indicated. Previous work, however, shows that recombinant erythropoietin can act as a meg-CSF stimulus, indicating that much is yet to be learned about the action of hematopoietic regulatory factors. Although the present study showed that TSF may in some circumstances stimulate an early cell in the megakaryocytic series, its major effect is probably on the more differentiated population, leading to maturation of megakaryocytes and platelet production.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholinesterase↗

PubMed1989

Interleukin-1 potentiates granulopoiesis and thrombopoiesis by producing hematopoietic factors in vivo.

In vivo administration of recombinant human interleukin-1 beta (rHu IL-1 beta) selectively enhanced the recovery from granulocytopenia and thrombocytopenia caused by whole body irradiation, in a dose dependent manner. Since IL-1 itself in vitro had no colony-stimulating activity (CSA), we studied whether IL-1 can produce hematopoietic factors in vivo, which in turn will promote granulopoiesis and thrombopoiesis. Serum from IL-1 injected mice showed marked granulocyte/macrophage CSA (GM-CSA), but little megakaryocyte CSA (Meg-CSA). Interestingly, strong megakaryocyte potentiator (Meg-POT) activity was detected in the serum. Further analysis of the serum by gel filtration chromatography showed that Meg-POT activity could be eluted in different fractions from GM-CSA. Since erythropoietin which is known to stimulate erythropoiesis also exhibited remarkable Meg-POT activity, serum from IL-1 injected mice were assayed for erythroid CSA. We found that unlike erythropoietin the serum showed no erythroid CSA. Taken together, these results suggest that IL-1 may potentiate granulopoiesis and thrombopoiesis by producing at least two distinct types of hematopoietic growth factors in vivo, namely granulocyte/macrophage colony-stimulating factor and a thrombopoietin-like factor.

Agranulocytosis↗

PubMed1990

Simultaneous assay for megakaryocyte colony-stimulating factor and megakaryocyte potentiator and its application.

We have devised a simultaneous assay system for megakaryocyte colony-stimulating factor (Meg-CSF) and megakaryocyte potentiator (Meg-Pot) by modifying a quantitative measuring technique for acetylcholinesterase activity (Ach-E) of megakaryocytes by automatic colorimetry using microplates. We cultured murine bone marrow cells treated with diisopropyl fluorophosphate in a serum-free system with serum-free pokeweek mitogen-stimulated spleen cell conditioned medium (PWM-SCM) and an unknown factor, preparing two microplates with the identical culture system. In the first plate, the total number of Ach-E-positive cells induced solely by the factor tested was indicative of Meg-CSF activity and additive increases in this parameter on simultaneous addition of PWM-SCM and the factor tested were indicative of early Meg-Pot activity. Total Ach-E activity (total change at optical density of 414 nm) per well was measured in the second plate to calculate total change at optical density of 414 nm per megakaryocyte, an indicator of late Meg-Pot activity. With this system, recombinant human erythropoietin showed both Meg-CSF and early and late Meg-Pot activities in in vitro megakaryopoiesis. Recombinant murine granulocyte-macrophage colony-stimulating factor possessed weak Meg-CSF and early Meg-Pot activity, whereas recombinant human granulocyte colony-stimulating factor exhibited late Meg-Pot activity and thrombocytopenic serum exhibited early and late Meg-Pot activities. This assay system is useful in screening Meg-CSF or Meg-Pot activities in unknown factors.

Acetylcholinesterase↗

PubMed1991

Thrombopoietic factor enhances murine megakaryopoiesis induced by recombinant erythropoietin.

Partially purified thrombopoietic factor (TPF) potentiated in vitro murine megakaryopoiesis induced by recombinant human erythropoietin (rh-Epo). High doses (2.5-10 units) of rh-Epo generated a considerable number of megakaryocytes in a dose-dependent manner in a serum-free liquid culture, whereas low doses of rh-Epo (0.5-1 units) failed to generate megakaryocytes. The addition of high doses of rh-Epo and TPF caused a significant increase of megakaryocytes in comparison with high doses of rh-Epo alone. Furthermore, low doses of rh-Epo with TPF caused generation of a small number of megakaryocytes, although TPF alone did not generate megakaryocytes. In addition, TPF enhanced the acetylcholinesterase (Ach-E) activity of megakaryocytes induced by rh-Epo. The potentiating effects of both factors, rh-Epo and thrombopoietic factor, may play an important role in thrombocytopenic states in vivo as well as in in vitro megakaryopoiesis.

Acetylcholinesterase↗

PubMed1989

Recombinant human erythropoietin has little influence on megakaryocytopoiesis in mice.

The availability of a preparation of recombinant human erythropoietin (rEp) prompted us to investigate the role of Ep in the regulation of megakaryocytopoiesis in mice, using experimental procedures by which the effects on the mitotic and post-mitotic compartment of megakaryocytes could be evaluated separately. In agar cultures of murine bone marrow cells, either serum-depleted or serum-supplemented, rEp (0.1-2 U/ml) did not stimulate megakaryocyte colony formation and when it was added to suboptimal amount of spleen cell-conditioned medium (SCM), it failed to show a significant synergistic activity. On the contrary, rEp increased the number of megakaryocytic colonies developed from splenic precursors in the presence of suboptimal amounts of SCM, although it was unable per se to stimulate colony formation. The effects of rEps on megakaryocyte maturation and platelet production were studied in vivo evaluating the incorporation of 75Se-selenomethionine into platelets, the platelet count and platelet size, and the number of megakaryocyte precursors (small acetylcholinesterase positive cells, sAchE) in the bone marrow of mice injected with 1-8 U of rEp. No modification of these parameters was found in comparison with control mice. On the other hand, rEp increased the number of recognizable splenic megakaryocytes in a dose-dependent fashion. These data suggest that rEp has little influence on megakaryocytopoiesis, at least at the doses we used and which are known to elicit a maximal response of erythropoiesis. However, a subset of megakaryocytes with particular kinetic properties, such as those in the spleen of mice, may be responsive to relatively high doses of rEp. The significance of this observation in the overall regulation of megakaryocytopoiesis remains to be determined.

Animals↗