Original Article
AMG 531, a Thrombopoiesis-Stimulating Protein, for Chronic ITP
N Engl J Med 2006; 355:1672-1681October 19, 2006
- Abstract
Background
Most current treatments for chronic immune thrombocytopenic purpura (ITP) act by decreasing platelet destruction. In a phase 1–2 study, we administered a thrombopoiesis-stimulating protein, AMG 531, to patients with ITP.
Methods
In phase 1, 24 patients who had received at least one treatment for ITP were assigned to escalating-dose cohorts of 4 patients each and given two identical doses of AMG 531 (0.2 to 10 μg per kilogram of body weight). In phase 2, 21 patients were randomly assigned to receive six weekly subcutaneous injections of AMG 531 (1, 3, or 6 μg per kilogram) or placebo. The primary objective was to assess the safety of AMG 531; the secondary objective was to evaluate platelet counts during and after treatment.
Results
No major adverse events that could be attributed directly to AMG 531 occurred during the treatment period; 4 of 41 patients had transient post-treatment worsening of thrombocytopenia. In phase 1, a platelet count that was within the targeted range (50,000 to 450,000 per cubic millimeter) and at least twice the baseline count was achieved in 4 of 12 patients given 3, 6, or 10 μg of AMG 531 per kilogram. Overall, a platelet count of at least 50,000 per cubic millimeter was achieved in 7 of 12 patients, including 3 with counts exceeding 450,000 per cubic millimeter. Increases in the platelet count were dose-dependent; mean peak counts were 163,000, 309,000, and 746,000 per cubic millimeter with 3, 6, and 10 μg of AMG 531 per kilogram, respectively. In phase 2, the targeted platelet range was achieved in 10 of 16 patients treated with 1 or 3 μg of AMG 531 per kilogram per week for 6 weeks. Mean peak counts were 135,000, 241,000, and 81,000 per cubic millimeter in the groups that received the 1-μg dose, the 3-μg dose, and placebo, respectively.
Conclusions
AMG 531 caused no major adverse events and increased platelet counts in patients with ITP. (ClinicalTrials.gov number, NCT00111475.)
Media in This Article
Figure 1
Structure of AMG 531.Figure 2
Study Designs for Phase 1 and Phase 2.Article Activity
- Article
Immune thrombocytopenic purpura (ITP) is an autoimmune disorder in which antiplatelet autoantibodies cause platelet destruction.1-6 The annual incidence of ITP in the United States is estimated to be approximately 16,000 cases.1,4
The initial treatment for ITP, usually corticosteroids, intravenous immune globulin, or Rh0(D) immune globulin acts primarily by interfering with platelet destruction.7 Other immunomodulatory agents suppress the production of antiplatelet antibodies, but relapse is common when these agents are discontinued. Splenectomy, by contrast, can have lasting effects and even cures the disease in some patients.
There is evidence that platelet production is suboptimal in a substantial proportion of patients with ITP,8-21 suggesting that a strategy of increasing platelet production may be effective in managing the disorder. In previous studies, polyethylene glycol–conjugated recombinant human megakaryocyte growth and development factor (PEG-MGDF), a recombinant thrombopoietin, increased platelet counts in four of five patients with ITP.22,23 However, antibodies against PEG-MGDF developed in healthy volunteers and in patients with cancer, and the antibodies cross-reacted with endogenous thrombopoietin in the patients, causing severe, persistent thrombocytopenia.24,25 As a result, clinical development of PEG-MGDF was stopped.
A novel thrombopoiesis-stimulating protein, AMG 531 (Amgen), has recently been developed. It has no sequence homology with endogenous thrombopoietin,26,27 a feature that should preclude the development of cross-reacting antibodies. We conducted a study to evaluate the safety and efficacy of treatment with AMG 531 in patients with ITP.
Methods
AMG 531
AMG 531 is a protein that stimulates thrombopoiesis26 (Figure 1Figure 1
Structure of AMG 531.). It consists of disulfide-bonded human IgG1 heavy-chain and kappa light-chain constant regions (an Fc fragment) with two identical peptide sequences linked covalently at residue 228 of the heavy chain with the use of a polyglycine. The Fc component extends the half-life of the molecule in the circulation. The peptide portion was selected by screening libraries of peptides that have no sequence homology with human thrombopoietin to find one with a tertiary structure that would allow it to bind to and activate the human thrombopoietin receptor, called Mpl. In healthy volunteers, AMG 531, a clear, colorless liquid administered by subcutaneous injection, increased platelet production and platelet counts and did not induce neutralizing or cross-reacting antibodies against thrombopoietin.28 Patients
Nine U.S. centers enrolled patients with chronic ITP in two sequential trials. The institutional review boards at the participating centers approved the protocols, and all patients gave written informed consent before undergoing eligibility screening. Inclusion criteria were an age of 18 to 65 years, a history of ITP (according to the American Society of Hematology guidelines5) for at least 3 months; one or more prior treatments for ITP; a mean platelet count (the mean value of two counts) of less than 30,000 per cubic millimeter (with no count >35,000 per cubic millimeter) for patients not receiving corticosteroids or a mean count of less than 50,000 per cubic millimeter (with no count >55,000 per cubic millimeter) for patients receiving corticosteroids. Patients were eligible for enrollment regardless of whether they had undergone splenectomy or whether they were receiving corticosteroid therapy, as long as there had been no changes in the corticosteroid dose or schedule of administration for at least 4 weeks. The following intervals since the last administration of therapy for ITP were required: 2 weeks for intravenous immune globulin, 8 weeks for alkylating agents, 16 weeks for rituximab, and 4 weeks for all other treatments. Exclusion criteria were any known risk factor for thromboembolic events, a history of cardiovascular disease, active cancer, and a history of a bone marrow disorder.
Study Design
This study was a multicenter, dose- and schedule-finding trial consisting of two phases (Figure 2Figure 2
Study Designs for Phase 1 and Phase 2.), with no overlap between patients in phase 1 and those in phase 2.Phase 1 (conducted from July 1, 2002, to October 13, 2003) was an open-label, dose-escalation trial with sequential cohorts of patients. The primary objective was to assess the safety and tolerability of two injections of AMG 531 in patients with ITP. Secondary objectives were to determine the dose that would result in a platelet count that was within the targeted range (50,000 to 450,000 per cubic millimeter) and that was at least twice the baseline count and to determine the adequacy of two AMG 531 injections given within 2 to 3 weeks for achieving this range.
AMG 531 was administered to cohorts of four patients each at doses of 0.2, 0.5, 1, 3, 6, and 10 μg per kilogram of body weight. The drug was administered by subcutaneous injection on day 1, followed by 14 days of observation. Health status, complete blood counts, and blood chemical values were monitored throughout the study. Assays to detect anti–AMG 531 antibodies were performed before treatment, at the end of treatment, and at the end of the study. If the platelet count was less than 50,000 per cubic millimeter on day 15, a second identical dose was administered. If the platelet count was 50,000 per cubic millimeter or more on day 15, the second dose was delayed until day 22; if at that time the platelet count remained 50,000 per cubic millimeter or more, the second dose was not given. A data review committee, composed of investigators and Amgen staff members who were not directly involved in the execution of the study, reviewed antibody and other safety data from the current and previous cohorts before treating the next sequential cohort. The protocol required termination of the study if antibodies that cross-reacted with thrombopoietin were detected. After the treatment was completed, patients were followed for an additional 8 weeks.
Phase 2 (conducted from October 6, 2003, to June 17, 2004) was a double-blind, placebo-controlled evaluation of AMG 531 in patients with ITP. The placebo consisted of the excipients of the AMG 531 formulation. The objectives were to evaluate the safety of AMG 531 and to determine a weekly dose that would result in a platelet count that was within the targeted range used in phase 1 (50,000 to 450,000 per cubic millimeter) and that was at least twice the baseline count. Patients were randomly assigned to receive AMG 531 at one of three doses (1, 3, or 6 μg per kilogram) or placebo once a week for 6 weeks, with a ratio of AMG 531 assignments to placebo assignments of 4:1. A protocol amendment later eliminated the 6-μg cohort; only one patient was randomly assigned to this dose. No dose adjustments were allowed, although doses were withheld in the event of a platelet count greater than 350,000 per cubic millimeter. Patients were followed for 6 weeks after the last dose of study drug.
In collaboration with the investigators, Amgen designed the study, conducted the statistical analyses, and interpreted the data, which Amgen held. The investigators had unrestricted access to the primary data. The academic authors wrote this article, with editing assistance from Amgen; no limitations were imposed by Amgen in the writing of the article. The authors vouch for the completeness and accuracy of the results.
Assays for Thrombopoietin and for Antibodies against AMG 531 and Thrombopoietin
Blood samples were drawn at baseline and at specified points under standard conditions. The serum was separated, frozen, and shipped to Amgen for testing. Thrombopoietin levels were measured with the use of a modified, commercially available enzyme-linked immunosorbent assay kit (R&D Systems).27 The presence of antibodies that neutralized AMG 531 or thrombopoietin was determined with the use of a cell-based bioassay.27,28 The threshold of detection was approximately 400 ng per milliliter for a control rabbit antihuman AMG 531 antibody and 200 ng per milliliter for a control rabbit antihuman thrombopoietin antibody.
Statistical Analysis
Demographic characteristics, baseline clinical characteristics, and hematologic and other laboratory values were summarized with the use of descriptive statistics. Enrolled patients were included in all analyses, except that the single patient randomly assigned to the 6-μg dose of AMG 531 in phase 2 was excluded from the platelet-related analyses. The study did not have the statistical power to detect a significant difference between dose groups, and no statistical hypothesis testing was performed.
A general linear model was used to investigate the relationship between the peak platelet count and the baseline thrombopoietin level, adjusted for the AMG 531 dose received. Logistic-regression models, adjusted for the AMG 531 dose, were used to determine whether the platelet response was associated with any of the following variables: the baseline serum thrombopoietin level, the baseline platelet count, splenectomy status, and the presence or absence of concurrent corticosteroid therapy.
Platelet counts obtained after the administration of rescue medications were excluded from the efficacy analyses. A rescue medication was defined as any medication, not administered at baseline, that was given to increase platelet counts, or corticosteroids given at a higher dose or frequency than that at baseline.
Results
Study Populations
Phase 1
A total of 24 patients with ITP were enrolled in six dose cohorts (4 patients each at AMG 531 dose levels of 0.2, 0.5, 1, 3, 6, and 10 μg per kilogram). Table 1Table 1
Baseline Characteristics of the Patients. summarizes the demographic and clinical characteristics of the patients at baseline. The majority of the patients were women (17 of 24) and were white (22 of 24); the median age was 45 years. The median platelet count at baseline was 11,000 per cubic millimeter, and the median time since the diagnosis of ITP was 6.2 years. Seven patients (29%) were receiving corticosteroids, and 19 (79%) had undergone a splenectomy.Phase 2
A total of 21 patients were enrolled in phase 2; 4 were assigned to the placebo group, and 17 to one of the AMG 531 groups (8 each to the 1-μg and 3-μg groups and 1 to the 6-μg group). The placebo and AMG 531 groups were similar with respect to demographic characteristics (Table 1). Fifteen patients were women, and 14 were white; the median age was 49 years. The median platelet count at baseline was 16,000 per cubic millimeter, and the median time since the diagnosis of ITP was 5.2 years. Seven patients (33%) were receiving corticosteroids, and 14 (67%) had undergone a splenectomy.
Safety
Table 2Table 2
Adverse Events in 10% or More of Patients. summarizes adverse events that occurred in 10% or more of the patients. Adverse events with an incidence of less than 10% are provided in the Supplementary Appendix, available with the full text of this article at www.nejm.org.Phase 1
Since single doses of AMG 531 that were less than 3 μg per kilogram did not affect the platelet count in phase 1, data on adverse events were considered for two combined dose groups: 0.2 to 1 μg per kilogram and 3 to 10 μg per kilogram. The most frequently reported adverse events were contusions, ecchymosis, or both, which occurred in 67% of the 24 patients (6 of 12 patients receiving 0.2 to 1 μg per kilogram and 10 of 12 receiving 3 to 10 μg per kilogram), and mild-to-moderate headache, which occurred in 46% of the patients (6 of 12 receiving 0.2 to 1 μg per kilogram and 5 of 12 receiving 3 to 10 μg per kilogram).
Serious adverse events were reported in three patients. One patient receiving the 0.2-μg dose had grade 3 vertigo, thought by the investigator to be unrelated to AMG 531, and was briefly hospitalized. The second patient, also receiving the 0.2-μg dose, had a life-threatening subdural hemorrhage 21 days after the second injection, which was also thought by the investigator to be unrelated to AMG 531. In the third patient, who received the 10-μg dose, the platelet count transiently decreased below the baseline value after the discontinuation of treatment; this event was thought by the investigator to be related to the withdrawal of AMG 531.
Phase 2
The most frequently reported adverse events in phase 2 were contusions, ecchymosis, or both (occurring in 59% of the patients in the AMG 531 groups and 75% of those in the placebo group); epistaxis (41% and 50%, respectively); mild-to-moderate headache (29% and 0%, respectively), and oral mucosal blistering (also 29% and 0%, respectively) (Table 2). All patients with oral mucosal blistering had a history of oral bleeding and had bleeding at the time of enrollment. Most bleeding events occurred during the post-treatment period or in patients who did not have a response to the study drug.
Three patients (two who received placebo and one who received AMG 531) had serious adverse events. The two patients in the placebo group had a total of three serious adverse events: one had asthma, and the other had an intracranial hemorrhage and, after splenectomy, popliteal deep-vein thrombosis. The patient treated with AMG 531 (3 μg per kilogram) had vaginal bleeding with severe but transient worsening of thrombocytopenia 19 days after the discontinuation of AMG 531.
None of the patients had a positive test for antibodies against AMG 531 or thrombopoietin. With the exception of platelet counts, no clinically significant changes were observed in vital signs or in hematologic or serum chemical values.
Efficacy
Phase 1
The targeted platelet response was not achieved in the patients who received 0.2, 0.5, or 1 μg of AMG 531 per kilogram, with the exception of one patient in the 0.2-μg group, who had received rituximab 4 weeks before enrollment. Of the 12 patients who received AMG 531 at a dose of 3, 6, or 10 μg per kilogram, however, 4 had platelet counts that reached the targeted range, and 3 additional patients had counts that exceeded 450,000 per cubic millimeter, for a total of 7 patients with peak platelet counts that were 50,000 per cubic millimeter or higher (Figure 3Figure 3
Peak Individual Platelet Counts in Phase 1.). The median time to the targeted response ranged from 5 to 8 days. The increase in platelet counts appeared to be dose-dependent. Mean peak platelet counts after the first AMG 531 injection were 163,000 per cubic millimeter for 3 μg per kilogram, 309,000 per cubic millimeter for 6 μg per kilogram, and 746,000 per cubic millimeter for 10 μg per kilogram. Median times to peak counts were 11, 10, and 14 days, respectively. Individual peak platelet counts were highly variable at each dose level.Phase 2
In one patient, the platelet count increased to 520,000 per cubic millimeter on day 21. The data review committee closed the highest-dose cohort because of concern that the patient had received the 6-μg dose and that the platelet count exceeded the upper limit of the targeted range. When the study was unblinded, it was confirmed that the patient had received the 6-μg dose.
Weekly doses of AMG 531 at 1 and 3 μg per kilogram increased the platelet count in most patients (Figure 4Figure 4
Peak Platelet Counts in Phase 2.). The median time from the first dose to the peak count was 18 days (range, 8 to 43) for 1 μg per kilogram, 19 days (range, 8 to 36) for 3 μg per kilogram, and 63 days (range, 7 to 78) for placebo. The targeted platelet range was reached in seven of eight patients receiving 1 μg per kilogram and in three of eight patients receiving 3 μg per kilogram; the targeted range was exceeded in an additional two patients receiving the 3-μg dose. Overall, in 12 of 16 patients treated with AMG 531 at a weekly dose of 1 or 3 μg per kilogram, the targeted range was reached (in 10 patients) or exceeded (in 2 patients), and in 9 of these patients, the platelet response had occurred by the first assessment on day 8.In five patients at each dose (1 and 3 μg per kilogram), the peak platelet count exceeded 100,000 per cubic millimeter. A total of 14 patients treated with AMG 531 had increases in platelet counts of at least 20,000 per cubic millimeter over the baseline count. Individual platelet responses varied in the AMG 531 and placebo groups (Figure 1 of the Supplementary Appendix). The mean peak platelet counts were 135,000 and 241,000 per cubic millimeter in the groups that received 1 and 3 μg per kilogram, respectively, and 81,000 per cubic millimeter in the placebo group; these counts were 8.5, 17, and 2.7 times as high as the baseline counts, respectively. One of four patients in the placebo group had a spontaneous remission; this patient had undergone a splenectomy 3.5 months before entering the study.
No significant relationship was observed between the peak platelet count and the baseline thrombopoietin level. Only the baseline platelet count in phase 1 was predictive of the platelet response (the higher the baseline count, the greater the likelihood of a platelet response; P=0.049).
Discussion
Thrombocytopenia occurs in patients with ITP when the rate of platelet destruction exceeds the ability of the bone marrow to increase platelet production. Autoantibodies from patients with ITP inhibit the production of megakaryocytes in vitro.19,20 In addition, apoptotic megakaryocytes have been detected in such patients by means of electron microscopy.19-21 Moreover, kinetic data show that platelet production, as measured by platelet turnover, is reduced or normal in approximately two thirds of patients with ITP.16-18 Plasma levels of endogenous thrombopoietin are not elevated in patients with ITP, as they are in patients with thrombocytopenia due to chemotherapy or aplastic anemia8-15; the mechanism underlying this phenomenon is thought to be related to clearance of endogenous thrombopoietin by the megakaryocyte and platelet pools.29,30 All these findings, which suggest that platelet production in ITP is often impaired, led to the hypothesis that stimulation of platelet production can alleviate the thrombocytopenia.
We evaluated AMG 531 in 41 patients with severe, refractory ITP; 32 of the patients had had no response to conventional treatments, including splenectomy. None of the patients had neutralizing antibodies to AMG 531 or thrombopoietin after as many as six weekly doses of AMG 531. Except for headache and transient post-treatment worsening of thrombocytopenia, all adverse events appeared to be related to the underlying disease. Thirty-nine percent of patients reported mild-to-moderate headache, occurring within 24 hours after the administration of AMG 531 and persisting for several hours, which was controlled with acetaminophen and did not require the discontinuation of treatment.
AMG 531 does not appear to affect the ongoing rate of platelet destruction; in all patients receiving the drug, the platelet count returned to the baseline value after the discontinuation of short-term treatment. In four patients with a platelet response, at least one post-treatment count was less than 10,000 per cubic millimeter and was at least 10,000 per cubic millimeter lower than the baseline value within 4 weeks after the last dose; these low counts persisted for 3 to 17 days. In two of the four patients, rescue treatment with intravenous immune globulin or corticosteroids was administered and was successful. This transient post-treatment worsening of thrombocytopenia had no relationship to the peak platelet count or any other clinical variable that we could evaluate. The phenomenon may be due to increased clearance of endogenous thrombopoietin by the pharmacologically expanded megakaryocyte mass, as demonstrated in studies of animals and humans.29,31
Patients completing this and other AMG 531 studies were eligible to enroll in an ongoing, open-label extension with weekly administration of AMG 531 and dose adjustment based on the platelet count. Preliminary data32 indicate that 21 of 26 patients treated for up to 24 weeks had a protocol-defined platelet response to AMG 531 and 12 had a durable response. Two patients who participated in the present study and subsequently entered the extension study were found to have a mild-to-moderate increase in bone marrow reticulin but without collagen fibrosis and with normal cytogenetic findings.33 Both patients were asplenic and were receiving relatively high doses of AMG 531 (>10 μg per kilogram), with a minimal response or none. A bone marrow biopsy performed in one of the patients 14 weeks after discontinuation of the treatment showed decreased reticulin deposition. A follow-up biopsy specimen has not yet been obtained for the other patient. In animal models, the increase in reticulin with the administration of PEG-MGDF resolved after discontinuation of the drug,34,35 and in patients with leukemia who were treated with thrombopoietin, the increase resolved within 6 weeks after the discontinuation of treatment.36
In our study, with the results combined for doses higher than 1 μg per kilogram in phase 1 and for the 1-μg and 3-μg doses in phase 2, 19 of 28 patients had platelet counts that reached or exceeded the targeted range. No complications, including thrombotic events, were reported for patients with platelet counts that exceeded 450,000 per cubic millimeter. In phase 2, considerable week-to-week fluctuation in platelet counts was observed, even though the administered dose of AMG 531 was not changed. The role of individual dose adjustment will need to be explored in future studies. The mechanism by which AMG 531 increases platelet counts in ITP may involve the prevention of premature megakaryocyte apoptosis, as well as stimulation of megakaryocyte progenitors and megakaryocyte maturation and endomitosis, as has been demonstrated with other thrombopoietic growth factors.37
In this dose-finding study, not all patients received the optimal dose of AMG 531 or the optimal schedule of administration. For this reason and because of the short duration of treatment in a relatively small number of patients, the results must be considered preliminary.
Supported by Amgen.
All investigators report having received clinical research support from Amgen for study expenses. Mr. Kelly, Dr. Chen, and Ms. Nichol report being employed by Amgen. Dr. Bussel reports having served on advisory boards for Amgen, GlaxoSmithKline, Baxter, and Talecris; having an equity interest in Amgen and GlaxoSmithKline; and having received lecture fees from Baxter and GlaxoSmithKline. Dr. Kuter reports having served as a consultant to Amgen, GlaxoSmithKline, Pfizer, and Ligand. Dr. George reports having served as a consultant to and having received grant support from Amgen. Dr. McMillan reports having served as a consultant to Amgen, Genzyme, Ligand, and GlaxoSmithKline and having an equity interest in GlaxoSmithKline. Dr. Aledort reports having received lecture fees from Baxter. Dr. Lichtin reports having served on an advisory board for Amgen. Dr. Lyons reports having served as a consultant to and having received grant support from Amgen and Pharmion. Dr. Wiznitzer reports having an equity interest in Amgen. No other potential conflict of interest relevant to this article was reported.
We are indebted to the study coordinators and nurses involved in phases 1 and 2 of the study; to Matthew Guo, Ph.D. (Amgen), for biostatistical support; and to Michele Vivirito (Amgen) for editorial assistance.
Source Information
From the New York Presbyterian Hospital, New York (J.B.B.); Massachusetts General Hospital, Boston (D.J.K.); University of Oklahoma Medical Center, Oklahoma City (J.N.G.); Scripps Cancer Center, La Jolla, CA (R.M., J.N.); Mount Sinai Medical Center, New York (L.M.A.); Diagnostic Clinic of Houston, Houston (G.T.C.); Cleveland Clinic Foundation, Cleveland (A.E.L.); Hematology–Oncology Associates of South Texas, San Antonio, TX (R.M.L.); DeQuattro Community Cancer Center, Manchester, CT (J.S.W.); Broward General Medical Center, Fort Lauderdale, FL (I.W.); and Amgen, Thousand Oaks, CA (R.K., C.-F.C., J.L.N.).
Address reprint requests to Dr. Bussel at Weill Cornell University, Division of Pediatric Hematology, Payson 609, 525 E. 68th St., New York, NY 10021, or at jbussel@med.cornell.edu.
- References
References
1
Bottiger LE ,Westerholm B . Thrombocytopenia. I. Incidence and aetiology. Acta Med Scand 1972;191:535-540
Web of Science | Medline2
McMillan R . Chronic idiopathic thrombocytopenic purpura. N Engl J Med 1981;304:1135-1147
Full Text | Web of Science | Medline3
Kelton JG ,Gibbons S . Autoimmune platelet destruction: idiopathic thrombocytopenic purpura. Semin Thromb Hemost 1982;8:83-104
CrossRef | Web of Science | Medline4
George J, Harake M, Aster R. Thrombocytopenia due to enhanced platelet destruction by immunologic mechanisms. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams hematology. 5th ed. New York: McGraw-Hill, 1995:1315-55.
5
George JN ,Woolf SH ,Raskob GE , et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88:3-40
Web of Science | Medline6
British Committee for Standards in Haematology General Haematology Task Force
CrossRef | Web of Science | Medline7
Cines DB ,Bussel JB . How I treat idiopathic thrombocytopenic purpura (ITP). Blood 2005;106:2244-2251
CrossRef | Web of Science | Medline8
Nichol JL . Thrombopoietin levels after chemotherapy and in naturally occurring human diseases. Curr Opin Hematol 1998;5:203-208
CrossRef | Medline9
Usuki K ,Tahara T ,Iki S , et al. Serum thrombopoietin level in various hematological diseases. Stem Cells 1996;14:558-565
CrossRef | Web of Science | Medline10
Kosugi S ,Kurata Y ,Tomiyama Y , et al. Circulating thrombopoietin level in chronic immune thrombocytopenic purpura. Br J Haematol 1996;93:704-706
CrossRef | Web of Science | Medline11
Chang M ,Suen Y ,Meng G , et al. Differential mechanisms in the regulation of endogenous levels of thrombopoietin and interleukin-11 during thrombocytopenia: insight into the regulation of platelet production. Blood 1996;88:3354-3362
Web of Science | Medline12
Nichol JL ,Hokom MM ,Hornkohl A , et al. Megakaryocyte growth and development factor: analyses of in vitro effects on human megakaryopoiesis and endogenous serum levels during chemotherapy-induced thrombocytopenia. J Clin Invest 1995;95:2973-2978
CrossRef | Web of Science | Medline13
Marsh JC ,Gibson FM ,Prue RL , et al. Serum thrombopoietin levels in patients with aplastic anaemia. Br J Haematol 1996;95:605-610
CrossRef | Web of Science | Medline14
Emmons RV ,Reid DM ,Cohen RL , et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood 1996;87:4068-4071
Web of Science | Medline15
Ichikawa N ,Ishida F ,Shimodaira S ,Tahara T ,Kato T ,Kitano K . Regulation of serum thrombopoietin levels by platelets and megakaryocytes in patients with aplastic anaemia and idiopathic thrombocytopenic purpura. Thromb Haemost 1996;76:156-160
Web of Science | Medline16
Heyns AD ,Lotter MG ,Badenhorst PN , et al. Kinetics and sites of destruction of 111Indium-oxine-labeled platelets in idiopathic thrombocytopenic purpura: a quantitative study. Am J Hematol 1982;12:167-177
CrossRef | Web of Science | Medline17
Heyns Adu P ,Badenhorst PN ,Lotter MG ,Pieters H ,Wessels P ,Kotze HF . Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Cr-labeled platelets differ. Blood 1986;67:86-92
Web of Science | Medline18
Ballem PJ ,Segal GM ,Stratton JR ,Gernsheimer T ,Adamson JW ,Slichter SJ . Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura: evidence of both impaired platelet production and increased platelet clearance. J Clin Invest 1987;80:33-40
CrossRef | Web of Science | Medline19
McMillan R ,Wang L ,Tomer A ,Nichol J ,Pistillo J . Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 2004;103:1364-1369
CrossRef | Web of Science | Medline20
Chang M ,Nakagawa PA ,Williams SA , et al. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood 2003;102:887-895
CrossRef | Web of Science | Medline21
Houwerzijl EJ ,Blom NR ,van der Want JJ , et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 2004;103:500-506
CrossRef | Web of Science | Medline22
Nomura S ,Dan K ,Hotta T ,Fujimura K ,Ikeda Y . Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with idiopathic thrombocytopenic purpura. Blood 2002;100:728-730
CrossRef | Web of Science | Medline23
Rice L ,Nichol JL ,McMillan R ,Roskos LK ,Bacile M . Cyclic immune thrombocytopenia responsive to thrombopoietic growth factor therapy. Am J Hematol 2001;68:210-214
CrossRef | Web of Science | Medline24
Li J ,Yang C ,Xia Y , et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 2001;98:3241-3248
CrossRef | Web of Science | Medline25
Basser RL ,O'Flaherty E ,Green M , et al. Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. Blood 2002;99:2599-2602
CrossRef | Web of Science | Medline26
Broudy VC ,Lin NL . AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine 2004;25:52-60
CrossRef | Web of Science | Medline27
Aledort LM ,Hayward CPM ,Chen M-G ,Nichol JL ,Bussel JB . Prospective screening of 205 patients with ITP, including diagnosis, serological markers, and the relationship between platelet counts, endogenous thrombopoietin, and circulating antithrombopoietin antibodies. Am J Hematol 2004;76:205-213
CrossRef | Web of Science | Medline28
Wang B ,Nichol JL ,Sullivan JT . Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther 2004;76:628-638
CrossRef | Web of Science | Medline29
Kuter DJ ,Beeler DL ,Rosenberg RD . The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci U S A 1994;91:11104-11108
CrossRef | Web of Science | Medline30
Scheding S ,Bergmann M ,Shimosaka A , et al. Human plasma thrombopoietin levels are regulated by binding to platelet thrombopoietin receptors in vivo. Transfusion 2002;42:321-327
CrossRef | Web of Science | Medline31
Stoffel R ,Wiestner A ,Skoda RC . Thrombopoietin in thrombocytopenic mice: evidence against regulation at the mRNA level and for a direct regulatory role of platelets. Blood 1996;87:567-573
Web of Science | Medline32
Bussel JB ,Kuter DJ ,George JN , et al. Long-term dosing of AMG 531 is effective and well tolerated in thrombocytopenic patients with immune thrombocytopenic purpura. Blood 2005;106:68a-68a
Web of Science33
Stepan DE ,Sergis-Deavenport E ,Kelly R , et al. Safety profile of AMG 531 in healthy volunteers and in thrombocytopenic patients with immune thrombocytopenic purpura. Blood 2005;106:361a-361a
Web of Science34
Ulich TR ,del Castillo J ,Senaldi G , et al. Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice. Blood 1996;87:5006-5015
Web of Science | Medline35
Yanagida M ,Ide Y ,Imai A , et al. The role of transforming growth factor-beta in PEG-rHuMGDF-induced reversible myelofibrosis in rats. Br J Haematol 1997;99:739-745
CrossRef | Web of Science | Medline36
Douglas VK ,Tallman MS ,Cripe LD ,Peterson LC . Thrombopoietin administered during induction chemotherapy to patients with acute myeloid leukemia induces transient morphologic changes that may resemble chronic myeloproliferative disorders. Am J Clin Pathol 2002;117:844-850
CrossRef | Web of Science | Medline37
Harker LA ,Carter RA ,Marzec UM , et al. Correction of thrombocytopenia and ineffective platelet production in patients infected with human immunodeficiency virus (HIV) by PEG-rHuMGDF therapy. Blood 1998;92:707a-707a
Web of Science
- Citing Articles (153)
Citing Articles
1
Hannes Sallmon, Martha Sola-Visner. (2012) Clinical and research issues in neonatal anemia and thrombocytopenia. Current Opinion in Pediatrics 24:1, 16-22
CrossRef2
Gillian M. Keating. (2012) Romiplostim. Drugs 72:3, 415-435
CrossRef3
M. Iskedjian, A. T. Tinmouth, D. M. Arnold, R. Deuson, J. J. Isitt, J. Mikhael. (2012) Elicitation of utility scores in Canada for immune thrombocytopenia treated with romiplostim or watch and rescue. Journal of Medical Economics1-19
CrossRef4
Leonardo Boiocchi, Attilio Orazi, Waleed Ghanima, Melissa Arabadjief, James B Bussel, Julia Turbiner Geyer. (2012) Thrombopoietin receptor agonist therapy in primary immune thrombocytopenia is associated with bone marrow hypercellularity and mild reticulin fibrosis but not other stromal abnormalities. Modern Pathology 25:1, 65
CrossRef5
Reid K. Nakamura, Emily Tompkins, Domenico Bianco. (2012) Therapeutic options for immune-mediated thrombocytopenia. Journal of Veterinary Emergency and Critical Caren/a-n/a
CrossRef6
Ferrán Catalá-López, Inmaculada Corrales, Gloria Martín-Serrano, Aurelio Tobías, Gonzalo Calvo. (2012) Risk of thromboembolism treated with thrombopoietin receptor agonists in adult patients with thrombocytopenia: systematic review and meta-analysis of randomized controlled trials. Medicina Clínica
CrossRef7
2011. Hematopoietic Growth Factors in Transfusion Medicine. , 474-491.
CrossRef8
C Calmettes, S Vigouroux, R Tabrizi, N Milpied. (2011) Romiplostim (AMG531, Nplate) for secondary failure of platelet recovery after allo-SCT. Bone Marrow Transplantation 46:12, 1587-1589
CrossRef9
H. A. Liebman, V. Pullarkat. (2011) Diagnosis and Management of Immune Thrombocytopenia in the Era of Thrombopoietin Mimetics. Hematology 2011:1, 384-390
CrossRef10
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CrossRef11
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CrossRef12
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CrossRef13
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CrossRef14
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CrossRef15
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CrossRef16
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CrossRef17
E. Monteagudo, R. Fernández-Delgado, A. Sastre, T. Toll, A. Llort, J. Molina, I. Astigarraga, M.A. Dasí, A. Cervera. (2011) Protocolo de estudio y tratamiento de la trombocitopenia inmune primaria (PTI-2010). Anales de Pediatría 74:6, 414.e1-414.e8
CrossRef18
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CrossRef19
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CrossRef20
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CrossRef21
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CrossRef22
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CrossRef23
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CrossRef24
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CrossRef25
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CrossRef26
Lisa J. Toltl, Donald M. Arnold. (2011) Pathophysiology and management of chronic immune thrombocytopenia: focusing on what matters. British Journal of Haematology 152:1, 52-60
CrossRef27
A. Pecci, P. Gresele, C. Klersy, A. Savoia, P. Noris, T. Fierro, V. Bozzi, A. M. Mezzasoma, F. Melazzini, C. L. Balduini. (2010) Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. Blood 116:26, 5832-5837
CrossRef28
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CrossRef29
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CrossRef30
H Sallmon, R K Gutti, F Ferrer-Marin, Z-J Liu, M C Sola-Visner. (2010) Increasing platelets without transfusion: is it time to introduce novel thrombopoietic agents in neonatal care?. Journal of Perinatology 30:12, 765-769
CrossRef31
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CrossRef32
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CrossRef33
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CrossRef34
Shaul Yaari, Benjamin Koslowsky, Dana Wolf, Tova Chajek-Shaul, Tiberiu Hershcovici. (2010) CMV-related thrombocytopenia treated with foscarnet: A case series and review of the literature. Platelets 21:6, 490-495
CrossRef35
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CrossRef36
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CrossRef37
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CrossRef38
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CrossRef39
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CrossRef40
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CrossRef41
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CrossRef42
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CrossRef43
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CrossRef44
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CrossRef45
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CrossRef46
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CrossRef47
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CrossRef48
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CrossRef49
Sean Deane, Suzanne S. Teuber, M. Eric Gershwin. (2010) The geoepidemiology of immune thrombocytopenic purpura. Autoimmunity Reviews 9:5, A342-A349
CrossRef50
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CrossRef51
D. Provan, R. Stasi, A. C. Newland, V. S. Blanchette, P. Bolton-Maggs, J. B. Bussel, B. H. Chong, D. B. Cines, T. B. Gernsheimer, B. Godeau, J. Grainger, I. Greer, B. J. Hunt, P. A. Imbach, G. Lyons, R. McMillan, F. Rodeghiero, M. A. Sanz, M. Tarantino, S. Watson, J. Young, D. J. Kuter. (2010) International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 115:2, 168-186
CrossRef52
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CrossRef53
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CrossRef54
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CrossRef55
James B. Bussel. (2009) Traditional and New Approaches to the Management of Immune Thrombocytopenia: Issues of When and Who to Treat. Hematology/Oncology Clinics of North America 23:6, 1329-1341
CrossRef56
David J. Kuter, Terry B. Gernsheimer. (2009) Thrombopoietin and Platelet Production in Chronic Immune Thrombocytopenia. Hematology/Oncology Clinics of North America 23:6, 1193-1211
CrossRef57
B. Psaila, A. Petrovic, L. K. Page, J. Menell, M. Schonholz, J. B. Bussel. (2009) Intracranial hemorrhage (ICH) in children with immune thrombocytopenia (ITP): study of 40 cases. Blood 114:23, 4777-4783
CrossRef58
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Full Text59
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CrossRef60
M. P. Lambert. (2009) TPO-mimetics and myelofibrosis? A reticulin question!. Blood 114:18, 3722-3723
CrossRef61
D. J. Kuter, G. J. Mufti, B. J. Bain, R. P. Hasserjian, W. Davis, M. Rutstein. (2009) Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim. Blood 114:18, 3748-3756
CrossRef62
Jagdish Chandra, V. P. Choudhry. (2009) Stimulating platelet production to raise platelet count in immune thrombocytopenic purpura: A novel approach. The Indian Journal of Pediatrics 76:10, 1065-1066
CrossRef63
Mark D. Danese, Karla Lindquist, Michelle Gleeson, Robert Deuson, Joseph Mikhael. (2009) Cost and mortality associated with hospitalizations in patients with immune thrombocytopenic purpura. American Journal of Hematology 84:10, 631-635
CrossRef64
Diane Nugent, Robert McMillan, Janet L. Nichol, Sherrill J. Slichter. (2009) Pathogenesis of chronic immune thrombocytopenia: increased platelet destruction and/or decreased platelet production. British Journal of Haematology 146:6, 585-596
CrossRef65
Robert J. Cersosimo. (2009) Romiplostim in chronic immune thrombocytopenic purpura. Clinical Therapeutics 31:9, 1887-1907
CrossRef66
Adrian Newland. (2009) Thrombopoietin receptor agonists in the treatment of thrombocytopenia. Current Opinion in Hematology 16:5, 357-364
CrossRef67
Yukari Shirasugi, Kiyoshi Ando, Satoshi Hashino, Toshiro Nagasawa, Yoshiyuki Kurata, Yuji Kishimoto, Koji Iwato, Tomoko Ohtsu, Dietmar P. Berger. (2009) A phase II, open-label, sequential-cohort, dose-escalation study of romiplostim in Japanese patients with chronic immune thrombocytopenic purpura. International Journal of Hematology 90:2, 157-165
CrossRef68
David J. Kuter. (2009) New Thrombopoietic Growth Factors. Clinical Lymphoma, Myeloma & Leukemia 9:0, S347-S356
CrossRef69
Kotoe Iesato, Naoki Hatakeyama, Masaki Yamamoto, Tsukasa Hori, Natsuko Inazawa, Hiroyuki Tsutsumi, Nobuhiro Suzuki. (2009) Treatment of an infant with severe acute refractory immune thrombocytopenic purpura using combination therapy including rituximab. Pediatric Blood & Cancer 53:2, 203-205
CrossRef70
N. Kluger, D. Bessis, P. Quittet, V. Rigau, B. Guillot, C. Girard. (2009) Romiplostim-induced erythromelalgia in a patient with idiopathic thrombocytopenic purpura. British Journal of Dermatology 161:2, 482-484
CrossRef71
T. Robak, A. Salama, L. Kovaleva, Y. Vyhovska, S. V. Davies, M. G. Mazzucconi, O. Zenker, P. Kiessling, . (2009) Efficacy and safety of Privigen<SUP>®</SUP>, a novel liquid intravenous immunoglobulin formulation, in adolescent and adult patients with chronic immune thrombocytopenic purpura. Hematology 14:4, 227-236
CrossRef72
Dina DiMaggio, Alan Anderson, James B. Bussel. (2009) Cytomegalovirus can make immune thrombocytopenic purpura refractory. British Journal of Haematology 146:1, 104-112
CrossRef73
Mo Yang, Godfrey C.F. Chan, Ruixia Deng, Margaret H. Ng, Sau Wan Cheng, Ching Po Lau, Jie Yu Ye, Liangjie Wang, Chang Liu. (2009) An herbal decoction of Radix astragali and Radix angelicae sinensis promotes hematopoiesis and thrombopoiesis. Journal of Ethnopharmacology 124:1, 87-97
CrossRef74
Y. IKEDA, Y. MIYAKAWA. (2009) Development of thrombopoietin receptor agonists for clinical use. Journal of Thrombosis and Haemostasis 7, 239-244
CrossRef75
Alan T Nurden, Jean-François Viallard, Paquita Nurden. (2009) New-generation drugs that stimulate platelet production in chronic immune thrombocytopenic purpura. The Lancet 373:9674, 1562-1569
CrossRef76
Shailendra Kapoor. (2009) Romiplostim: an alternative treatment option besides rituximab for the management of steroid refractory idiopathic thrombocytopenic purpura. Journal of Thrombosis and Thrombolysis 27:4, 453-453
CrossRef77
A. Podolanczuk, A. H. Lazarus, A. R. Crow, E. Grossbard, J. B. Bussel. (2009) Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood 113:14, 3154-3160
CrossRef78
Daniel Thomas, Angel F Lopez. 2009. Haematopoietic Growth Factors. .
CrossRef79
F. Rodeghiero, R. Stasi, T. Gernsheimer, M. Michel, D. Provan, D. M. Arnold, J. B. Bussel, D. B. Cines, B. H. Chong, N. Cooper, B. Godeau, K. Lechner, M. G. Mazzucconi, R. McMillan, M. A. Sanz, P. Imbach, V. Blanchette, T. Kuhne, M. Ruggeri, J. N. George. (2009) Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113:11, 2386-2393
CrossRef80
A. Cuker, C. S. Abrams. (2009) Romiplostim: chronic therapy for a chronic disease?. Blood 113:10, 2122-2123
CrossRef81
J. B. Bussel, D. J. Kuter, V. Pullarkat, R. M. Lyons, M. Guo, J. L. Nichol. (2009) Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 113:10, 2161-2171
CrossRef82
B. Godeau. (2009) Les agonistes du récepteur de la thrombopoïétine : vers une révolution du traitement du purpura thrombopénique immunologique ?. La Revue de Médecine Interne 30:3, 203-205
CrossRef83
Jaclyn S. King, Joseph B. Farland, J. Aubrey Waddell, Dominic A. Solimando, Jr. (2009) Cancer Chemotherapy Update - Eltrombopag; Romiplostim. Hospital Pharmacy 44:3, 228-231
CrossRef84
Adrian Newland. (2009) Romiplostim: a breakthrough treatment for the management of immune thrombocytopenic purpura. European Journal of Haematology 82, 20-25
CrossRef85
A. Greinacher, J. Bux, A. Salama. (2009) Autoimmune Thrombozytopenie, Neutropenie und Hämolyse. Der Internist 50:3, 276-290
CrossRef86
David J. Kuter. (2009) Thrombopoietin and Thrombopoietin Mimetics in the Treatment of Thrombocytopenia. Annual Review of Medicine 60:1, 193-206
CrossRef87
Hans L. Tillmann, Keyur Patel, John G. McHutchison. (2009) Role of growth factors and thrombopoietic agents in the treatment of chronic hepatitis C. Current Gastroenterology Reports 11:1, 5-14
CrossRef88
James N. George, Susan D. Mathias, Ronald S. Go, Matthew Guo, David H. Henry, Roger Lyons, Robert L. Redner, Lawrence Rice, Martin R. Schipperus. (2009) Improved quality of life for romiplostim-treated patients with chronic immune thrombocytopenic purpura: results from two randomized, placebo-controlled trials. British Journal of Haematology 144:3, 409-415
CrossRef89
James B Bussel, Drew Provan, Tahir Shamsi, Gregory Cheng, Bethan Psaila, Lidia Kovaleva, Abdulgabar Salama, Julian M Jenkins, Debasish Roychowdhury, Bhabita Mayer, Nicole Stone, Michael Arning. (2009) Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. The Lancet 373:9664, 641-648
CrossRef90
Michelle Perugini, Antiopi Varelias, Timothy Sadlon, Richard J. D’Andrea. (2009) Hematopoietic growth factor mimetics: From concept to clinic. Cytokine & Growth Factor Reviews 20:1, 87-94
CrossRef91
Laura Bonsi, Cosetta Marchionni, Francesco Alviano, Giacomo Lanzoni, Michele Franchina, Roberta Costa, Alberto Grossi, Gian Paolo Bagnara. (2009) Thrombocytopenia with absent radii (TAR) syndrome: from hemopoietic progenitor to mesenchymal stromal cell disease?. Experimental Hematology 37:1, 1-7
CrossRef92
James B. Bussel. (2009) Therapeutic Approaches to Secondary Immune Thrombocytopenic Purpura. Seminars in Hematology 46, S44-S58
CrossRef93
James E. Frampton, Katherine A. Lyseng-Williamson. (2009) Romiplostim. Drugs 69:3, 307-317
CrossRef94
Motonobu Watanabe, Soichiro Murata, Ikuka Hashimoto, Yoritaka Nakano, Osamu Ikeda, Yasuyuki Aoyagi, Ryota Matsuo, Kiyoshi Fukunaga, Hiroshi Yasue, Nobuhiro Ohkohchi. (2009) Platelets contribute to the reduction of liver fibrosis in mice. Journal of Gastroenterology and Hepatology 24:1, 78-89
CrossRef95
Daan Dierickx, Anja De Rycke, Steven Vanderschueren, André Delannoy. (2008) New treatment options for immune-mediated hematological disorders. European Journal of Internal Medicine 19:8, 579-586
CrossRef96
Ewout J. Houwerzijl, Henk Louwes, Wim J. Sluiter, Jan W. Smit, Edo Vellenga, Joost Th.M. Wolf. (2008) Platelet production rate predicts the response to prednisone therapy in patients with idiopathic thrombocytopenic purpura. Annals of Hematology 87:12, 975-983
CrossRef97
Benjamin Levy, Jon E Arnason, James B Bussel. (2008) The use of second-generation thrombopoietic agents for chemotherapy-induced thrombocytopenia. Current Opinion in Oncology 20:6, 690-696
CrossRef98
Douglas B. Cines, Uma Yasothan, Peter Kirkpatrick. (2008) Romiplostim. Nature Reviews Drug Discovery 7:11, 887-888
CrossRef99
M Liem-Moolenaar, D Cerneus, CJ Molloy, D End, KH Brown, ML de Kam, AF Cohen, Y van Hensbergen, J Burggraaf. (2008) Pharmacodynamics and Pharmacokinetics of the Novel Thrombopoietin Mimetic Peptide RWJ-800088 in Humans. Clinical Pharmacology & Therapeutics 84:4, 481-487
CrossRef100
Bethan Psaila, James B. Bussel. (2008) Refractory immune thrombocytopenic purpura: current strategies for investigation and management. British Journal of Haematology 143:1, 16-26
CrossRef101
RACHEL E. BROWN, LISA M. RIMSZA, KAREN PASTOS, LINDA YOUNG, MATTHEW A. SAXONHOUSE, MATTHEW BAILEY, ROBERT M. LAWRENCE, MARTHA C. SOLA-VISNER. (2008) Effects of Sepsis on Neonatal Thrombopoiesis. Pediatric Research 64:4, 399-404
CrossRef102
Karen Peeters, Jean-Marie Stassen, Désiré Collen, Chris Van Geet, Kathleen Freson. (2008) Emerging treatments for thrombocytopenia: Increasing platelet production. Drug Discovery Today 13:17-18, 798-806
CrossRef103
Andrew Wei, Shaun P Jackson. (2008) Boosting platelet production. Nature Medicine 14:9, 917-918
CrossRef104
Jeffrey McCullough, Jeffrey Kahn, John Adamson, Paolo Anderlini, Richard Benjamin, Dennis Confer, Mary Eapen, Betsy Hirsch, David Kuter, Ellen Lazarus, Derwood Pamphilon, David Stroncek, Jeremy Sugarman, Robert Wilson. (2008) Hematopoietic growth factors-use in normal blood and stem cell donors: clinical and ethical issues. Transfusion 48:9, 2008-2025
CrossRef105
James B Bussel, Kristen M Marks. (2008) How effective is eltrombopag for the treatment of thrombocytopenia in patients with HCV infection?. Nature Clinical Practice Gastroenterology & Hepatology 5:8, 424-425
CrossRef106
A. Yamane, T. Nakamura, H. Suzuki, M. Ito, Y. Ohnishi, Y. Ikeda, Y. Miyakawa. (2008) Interferon- 2b-induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes. Blood 112:3, 542-550
CrossRef107
Ramon V Tiu, Mikkael A Sekeres. (2008) The role of AMG-531 in the treatment of thrombocytopenia in idiopathic thrombocytopenic purpura and myelodysplastic syndromes. Expert Opinion on Biological Therapy 8:7, 1021-1030
CrossRef108
Xiaofang Li, Ming Hou. (2008) Emerging drugs for idiopathic thrombocytopenic purpura in adults. Expert Opinion on Emerging Drugs 13:2, 237-254
CrossRef109
Jennifer Wright, Saroj Vadhan-Raj. 2008. Thrombocytopenia and Thrombopoetic Growth Factors. , 1-18.
CrossRef110
Victor Blanchette, Paula Bolton-Maggs. (2008) Childhood Immune Thrombocytopenic Purpura: Diagnosis and Management. Pediatric Clinics of North America 55:2, 393-420
CrossRef111
Adrian Newland. (2008) Emerging strategies to treat chronic immune thrombocytopenic purpura. European Journal of Haematology 80, 27-33
CrossRef112
Francesco Rodeghiero, Marco Ruggeri. (2008) Is splenectomy still the gold standard for the treatment of chronic ITP?. American Journal of Hematology 83:2, 91-91
CrossRef113
Francesco Rodeghiero. (2008) First-line therapies for immune thrombocytopenic purpura: re-evaluating the need to treat. European Journal of Haematology 80, 19-26
CrossRef114
David J. Kuter. (2008) New drugs for familiar therapeutic targets: thrombopoietin receptor agonists and immune thrombocytopenic purpura. European Journal of Haematology 80, 9-18
CrossRef115
David J Kuter, James B Bussel, Roger M Lyons, Vinod Pullarkat, Terry B Gernsheimer, Francis M Senecal, Louis M Aledort, James N George, Craig M Kessler, Miguel A Sanz, Howard A Liebman, Frank T Slovick, J Th M de Wolf, Emmanuelle Bourgeois, Troy H Guthrie, Adrian Newland, Jeffrey S Wasser, Solomon I Hamburg, Carlos Grande, François Lefrère, Alan Eli Lichtin, Michael D Tarantino, Howard R Terebelo, Jean-François Viallard, Francis J Cuevas, Ronald S Go, David H Henry, Robert L Redner, Lawrence Rice, Martin R Schipperus, D Matthew Guo, Janet L Nichol. (2008) Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. The Lancet 371:9610, 395-403
CrossRef116
Ram Kalpatthi, James B Bussel. (2008) Diagnosis, pathophysiology and management of children with refractory immune thrombocytopenic purpura. Current Opinion in Pediatrics 20:1, 8-16
CrossRef117
Bertrand Godeau. (2008) Purpura thrombopénique auto-immun. Revue Francophone des Laboratoires 2008:399, 9-11
CrossRef118
Ara Metjian, Charles S Abrams. (2008) New insights and therapeutics for immune-mediated thrombocytopenia. Expert Review of Cardiovascular Therapy 6:1, 71-84
CrossRef119
James B. Bussel, Andrea Primiani. (2008) Fetal and neonatal alloimmune thrombocytopenia: progress and ongoing debates. Blood Reviews 22:1, 33-52
CrossRef120
T. B. Gernsheimer. (2008) The Pathophysiology of ITP Revisited: Ineffective Thrombopoiesis and the Emerging Role of Thrombopoietin Receptor Agonists in the Management of Chronic Immune Thrombocytopenic Purpura. Hematology 2008:1, 219-226
CrossRef121
Benjamin Leader, Quentin J. Baca, David E. Golan. (2008) Protein therapeutics: a summary and pharmacological classification. Nature Reviews Drug Discovery 7:1, 21-39
CrossRef122
Magda Melchert, Alan List. (2008) Targeted Therapies in Myelodysplastic Syndrome. Seminars in Hematology 45:1, 31-38
CrossRef123
J.A. Stockman. (2008) AMG 531, a Thrombopoiesis-Stimulating Protein, for Chronic ITP. Yearbook of Pediatrics 2008, 62-64
CrossRef124
B. Godeau. (2007) Actualités du purpura thrombopénique immunologique de l’adulte : de la physiopathologie au traitement. La Revue de Médecine Interne 28, S315-S316
CrossRef125
Schwartz, Robert S., . (2007) Immune Thrombocytopenic Purpura — From Agony to Agonist. New England Journal of Medicine 357:22, 2299-2301
Full Text126
Bussel, James B., Cheng, Gregory, Saleh, Mansoor N., Psaila, Bethan, Kovaleva, Lidia, Meddeb, Balkis, Kloczko, Janusz, Hassani, Habib, Mayer, Bhabita, Stone, Nicole L., Arning, Michael, Provan, Drew, Jenkins, Julian M., . (2007) Eltrombopag for the Treatment of Chronic Idiopathic Thrombocytopenic Purpura. New England Journal of Medicine 357:22, 2237-2247
Full Text127
D. M. Boruchov, S. Gururangan, M. C. Driscoll, J. B. Bussel. (2007) Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP). Blood 110:10, 3526-3531
CrossRef128
N. H. AFDHAL, J. G. MCHUTCHISON. (2007) Review article: pharmacological approaches for the treatment of thrombocytopenia in patients with chronic liver disease and hepatitis C infection. Alimentary Pharmacology & Therapeutics 26, 29-39
CrossRef129
Lin Wang, Yuan Li, Ming Hou. (2007) Idiopathic thrombocytopenic purpura and dysmegakaryocytopoiesis. Critical Reviews in Oncology/Hematology 64:2, 83-89
CrossRef130
David J. Kuter, Barbara Bain, Ghulam Mufti, Adam Bagg, Robert P. Hasserjian. (2007) Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres. British Journal of Haematology 139:3, 351-362
CrossRef131
Thomas Kühne, Victor Blanchette, George R. Buchanan, Ugo Ramenghi, Hugo Donato, Rienk Y.J. Tamminga, Johannes Rischewski, Willi Berchtold, Paul Imbach, . (2007) Splenectomy in children with idiopathic thrombocytopenic purpura: A prospective study of 134 children from the Intercontinental Childhood ITP Study Group. Pediatric Blood & Cancer 49:6, 829-834
CrossRef132
Angelo Nascimbene, Matteo Iannacone, Bruno Brando, Andrea De Gasperi. (2007) Acute thrombocytopenia after liver transplant: Role of platelet activation, thrombopoietin deficiency and response to high dose intravenous IgG treatment. Journal of Hepatology 47:5, 651-657
CrossRef133
S. Panzer. (2007) New therapeutic options for adult chronic immune thrombocytopenic purpura: a brief review. Vox Sanguinis 0:0, 071031203718001-???
CrossRef134
K. Kaushansky. (2007) Historical review: megakaryopoiesis and thrombopoiesis. Blood 111:3, 981-986
CrossRef135
E. Shpall, M. de Lima, R. Jones, R. Champlin. (2007) Are 2 cords better than 1?. Blood 110:8, 2789-2790
CrossRef136
Adrian Newland. (2007) Thrombopoietin Mimetic Agents in the Management of Immune Thrombocytopenic Purpura. Seminars in Hematology 44, S35-S45
CrossRef137
Donald M. Arnold, John G. Kelton. (2007) Current Options for the Treatment of Idiopathic Thrombocytopenic Purpura. Seminars in Hematology 44, S12-S23
CrossRef138
R. Y. J. Tamminga, M. C. A. Bruin. (2007) Idiopathische trombocytopenische purpura (itp), capita selecta. Tijdschrift voor kindergeneeskunde 75:5, 188-194
CrossRef139
Biree Andemariam, James Bussel. (2007) New therapies for immune thrombocytopenic purpura. Current Opinion in Hematology 14:5, 427-431
CrossRef140
Bertrand Godeau, Drew Provan, James Bussel. (2007) Immune thrombocytopenic purpura in adults. Current Opinion in Hematology 14:5, 535-556
CrossRef141
Elisabeth M Battinelli, John H Hartwig, Joseph E Italiano. (2007) Delivering new insight into the biology of megakaryopoiesis and thrombopoiesis. Current Opinion in Hematology 14:5, 419-426
CrossRef142
Christof Schweizer, Frederic J. Reu, Anthony D. Ho, Manfred Hensel. (2007) Low rate of long-lasting remissions after successful treatment of immune thrombocytopenic purpura with rituximab. Annals of Hematology 86:10, 711-717
CrossRef143
Bethan Psaila, James B. Bussel. (2007) Immune Thrombocytopenic Purpura. Hematology/Oncology Clinics of North America 21:4, 743-759
CrossRef144
Oliver G. Ottmann, Gesine Bug, Jürgen Krauter. (2007) Current Status of Growth Factors in the Treatment of Acute Myeloid and Lymphoblastic Leukemia. Seminars in Hematology 44:3, 183-192
CrossRef145
Stefan O. Ciurea, Ronald Hoffman. (2007) Cytokines for the Treatment of Thrombocytopenia. Seminars in Hematology 44:3, 166-182
CrossRef146
D. B. Cines. (2007) Pumping out platelets. Blood 109:11, 4591-4592
CrossRef147
J. M. Jenkins, D. Williams, Y. Deng, J. Uhl, V. Kitchen, D. Collins, C. L. Erickson-Miller. (2007) Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist. Blood 109:11, 4739-4741
CrossRef148
Lauren RH Krumpe, Toshiyuki Mori. (2007) Potential of phage-displayed peptide library technology to identify functional targeting peptides. Expert Opinion on Drug Discovery 2:4, 525-537
CrossRef149
(2007) AMG 531 for Chronic ITP. New England Journal of Medicine 356:3, 307-308
Full Text150
B. Andemariam, B. Psaila, J. B. Bussel. (2007) Novel Thrombopoietic Agents. Hematology 2007:1, 106-113
CrossRef151
Ki Lyong Nam, Sang Hee Cho, Sung Wan Yang, Dong Woo Son, In-sang Jeon. (2007) Therapeutic Efficacy of a Single Dose of Anti-D Immunoglobulin 50µg/kg in Childhood Acute Immune Thrombocytopenic Purpura. The Korean Journal of Hematology 42:3, 258
CrossRef152
James N. George, Kiarash Kojouri. 2007. Immune Thrombocytopenic Purpura. , 123-138.
CrossRef153
Bromberg, Michael E., . (2006) Immune Thrombocytopenic Purpura — The Changing Therapeutic Landscape. New England Journal of Medicine 355:16, 1643-1645
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