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James B. Bussel - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms and therapeutic prospects of thrombopoietin receptor agonists.
Seminars in Hematology, 2019Co-Authors: James B. Bussel, Austin G. Kulasekararaj, Nichola Cooper, Amit Verma, Ulrich Steidl, John W. Semple, Britta WillAbstract:The second-generation thrombopoietin (TPO) receptor agonists eltrombopag and romiplostim are potent activators of megakaryopoiesis and represent a growing treatment option for patients with thrombocytopenic hematological disorders. Both TPO receptor agonists have been approved worldwide for the treatment of children and adults with chronic immune Thrombocytopenia. In the EU and USA, eltrombopag is approved for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy and in the USA for the first-line treatment of severe aplastic anemia in combination with immunosuppressive therapy. Eltrombopag has also shown efficacy in several other disease settings, for example, chemotherapy-induced Thrombocytopenia, selected inherited Thrombocytopenias, and myelodysplastic syndromes. While both TPO receptor agonists stimulate TPO receptor signaling and enhance megakaryopoiesis, their vastly different biochemical structures bestow upon them markedly different molecular and functional properties. Here, we review and discuss results from preclinical and clinical studies on the functional and molecular mechanisms of action of this new class of drug.
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106 American Society of Hematology Novel Thrombopoietic Agents
2015Co-Authors: Biree Andemariam, James B. Bussel, Bethan Psaila, Pier M. MannucciAbstract:Thrombocytopenia is a primary manifestation of immune thrombocytopenic purpura (ITP) and may occur as a result of hepatitis C, malignancy, and treatment with chemotherapy. There is a need for additional means to treat Thrombocytopenia in these settings. Recombinant thrombopoietin-like agents became available after the cloning of thrombopoietin in 1994. In clinical trials, these agents showed some efficacy in chemotherapy-induced Thrombocytopenia, but their use was ultimately discontinued due to the development of neutralizing antibodies that cross-reacted with endogenous thrombopoietin and caused Thrombocytopenia in healthy blood donors and other recipients. Subsequently, “second-generation” thrombopoietic agents without homology to thrombopoietin were developed. In the past 5 years, these second-generation thrombopoeitic growth factors have undergone substantial clinical develop-ment and have demonstrated safety, tolerability and efficacy in subjects with ITP and hepatitis C–related Thrombocytopenia. These completed studies, many of which are available only in abstract form, and other ongoing studies suggest that thrombopoietic agents will enhance the hematologist’s ability to manage these and other causes of Thrombocytopenia
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thrombopoietin receptor agonists
Current Opinion in Hematology, 2012Co-Authors: Paul A Basciano, James B. BusselAbstract:Purpose of review Thrombopoietin-receptor agonists (TPO-RAs) have been approved for use in immune Thrombocytopenia (ITP) after showing safety and efficacy. There is increasing interest to expand the role of TPO-RAs, both in ITP as well as in other thrombocytopenic disorders. Recent findings In ITP, more studies are providing evidence of TPO-RA efficacy and safety, as well as their applicability to various patient groups, including children. Use of TPO-RAs in hepatitis C has shown early success in allowing treatments in patients who would otherwise be excluded due to Thrombocytopenia. Use in congenital Thrombocytopenias has also shown early success. The use of TPO-RAs in myelodysplastic syndrome (MDS) is questionable after reports of increasing blasts and leukemic transformation, whereas in other chemotherapy-induced Thrombocytopenias (C-ITs) reports are few. Bone marrow fibrosis remains an area of active study, although the data to date suggest this is seen in a small minority of patients, and is reversible and of questionable clinical relevance. Thrombotic complications are also an area of concern and need further close follow-up. Summary The use of TPO-RAs continues to grow as more evidence of safety and efficacy is found. More studies are needed to determine their utility in other diseases as well as to better characterize adverse events observed to date.
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the immune thrombocytopenic purpura itp bleeding score assessment of bleeding in patients with itp
British Journal of Haematology, 2007Co-Authors: Lemke K Page, Bethan Psaila, Martin Lesser, Drew Provan, Michael J Hamilton, Julian Jenkins, Andrew S Elish, James B. BusselAbstract:A method for objective quantification of bleeding symptoms in immune thrombocytopenic purpura (ITP) has not been established. The ITP Bleeding Scale (IBLS) is a novel bleeding assessment system comprising 11 site-specific grades. Implementation of the IBLS on 100 patient visits revealed that although platelet count and large platelet count correlated well with bleeding symptoms overall, this relationship disappeared in marked Thrombocytopenia. The IBLS is a useful clinical tool for monitoring bleeding and may be used to aid the development of laboratory parameters that correlate with underlying bleeding propensity in Thrombocytopenia.
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clinical and diagnostic comparison of neonatal alloimmune Thrombocytopenia to non immune cases of Thrombocytopenia
Pediatric Blood & Cancer, 2005Co-Authors: James B. Bussel, Stergios Zacharoulis, Kim Kramer, Janice G Mcfarland, Joanne Pauliny, C KaplanAbstract:BACKGROUND: Affected patients with neonatal alloimmune Thrombocytopenia (AIT) are often severely thrombocytopenic and, if so, may suffer an intracranial hemorrhage (ICH). This study was undertaken to compare the outcome of cases of AIT to cases of neonatal Thrombocytopenia shown not to be AIT and to identify clinical features that would facilitate the diagnosis. PROCEDURE: Two hundred twenty two cases of neonatal Thrombocytopenia for which serologic testing was obtained by the referring physician were accrued for this study from 11 testing laboratories. The relevant clinical information was pursued. RESULTS: The mean birth platelet count in 110 neonates with AIT was 26,000/mm(3) x 10(9)/L and the rate of ICH was 11% (not all neonates had head sonos). Three criteria distinguished cases of AIT from other causes of neonatal Thrombocytopenia (n = 56): (1) severe Thrombocytopenia 5, birthweight >2,200 g, grade >1, antenatal occurrence, or signs of bleeding, that is, petechiae, ecchymoses; and (3) no additional, non-hemorrhagic neonatal medical problems. CONCLUSIONS: AIT is a unique type of neonatal Thrombocytopenia with significant hemorrhagic consequences. Identification of AIT at the bedside should guide institution of appropriate treatment and lead to serologic testing for confirmation.
Janice G Mcfarland - One of the best experts on this subject based on the ideXlab platform.
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clinical and diagnostic comparison of neonatal alloimmune Thrombocytopenia to non immune cases of Thrombocytopenia
Pediatric Blood & Cancer, 2005Co-Authors: James B. Bussel, Stergios Zacharoulis, Kim Kramer, Janice G Mcfarland, Joanne Pauliny, C KaplanAbstract:BACKGROUND: Affected patients with neonatal alloimmune Thrombocytopenia (AIT) are often severely thrombocytopenic and, if so, may suffer an intracranial hemorrhage (ICH). This study was undertaken to compare the outcome of cases of AIT to cases of neonatal Thrombocytopenia shown not to be AIT and to identify clinical features that would facilitate the diagnosis. PROCEDURE: Two hundred twenty two cases of neonatal Thrombocytopenia for which serologic testing was obtained by the referring physician were accrued for this study from 11 testing laboratories. The relevant clinical information was pursued. RESULTS: The mean birth platelet count in 110 neonates with AIT was 26,000/mm(3) x 10(9)/L and the rate of ICH was 11% (not all neonates had head sonos). Three criteria distinguished cases of AIT from other causes of neonatal Thrombocytopenia (n = 56): (1) severe Thrombocytopenia 5, birthweight >2,200 g, grade >1, antenatal occurrence, or signs of bleeding, that is, petechiae, ecchymoses; and (3) no additional, non-hemorrhagic neonatal medical problems. CONCLUSIONS: AIT is a unique type of neonatal Thrombocytopenia with significant hemorrhagic consequences. Identification of AIT at the bedside should guide institution of appropriate treatment and lead to serologic testing for confirmation.
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antenatal management of alloimmune Thrombocytopenia with intravenous γ globulin a randomized trial of the addition of low dose steroid to intravenous γ globulin
American Journal of Obstetrics and Gynecology, 1996Co-Authors: James B. Bussel, Richard L Berkowitz, Lauren Lynch, Martin Lesser, Michael J Paidas, Carol L Huang, Janice G McfarlandAbstract:Abstract OBJECTIVES: Our purposes were to investigate maternal infusions of intravenous γ -globulin used to increase the platelet count in thrombocytopenic fetuses with alloimmune Thrombocytopenia, to prevent intracranial hemorrhage, and to determine whether 1.5 mg dexamethasone and 60 mg prednisone per day add to the effect of intravenous γ -globulin. STUDY DESIGN: Fifty-four women with alloimmune Thrombocytopenia and thrombocytopenic fetuses were randomized to intravenous γ -globulin 1 gm/kg per week with or without dexamethasone. Nonresponders after 4 to 6 weeks received continued intravenous γ -globulin plus 60 mg of prednisone per day ("salvage"). RESULTS: Dexamethasone did not add to the effect of intravenous γ -globulin. Overall, there was a mean platelet increase from the first to the second fetal blood sampling of 36,000/μl ( n = 47) and from the first fetal blood sampling to birth of 69,000/μl ( n = 54). A total of 62% to 85% of fetuses responded. There were no intracranial hemorrhages. "Salvage" increased the platelet count in 5 of 10 nonresponders to intravenous γ -globulin. CONCLUSION: Intravenous γ -globulin treatment is appropriate for thrombocytopenic fetuses with alloimmune Thrombocytopenia before use of weekly in utero platelet transfusions, even in severe Thrombocytopenia. (AM J OBSTET GYNECOL 1996;174:1414-23.)
Simon J Hambidge - One of the best experts on this subject based on the ideXlab platform.
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a population based multisite cohort study of the predictors of chronic idiopathic thrombocytopenic purpura in children
Pediatrics, 2008Co-Authors: Jason M Glanz, Taru Hayes, Simon J HambidgeAbstract:OBJECTIVE. The objective of this study was to identify risk factors for developing chronic idiopathic thrombocytopenic purpura in a cohort of pediatric patients with idiopathic thrombocytopenic purpura. METHODS. We conducted a retrospective cohort analysis of 259 children who were diagnosed with idiopathic thrombocytopenic purpura between 1991 and 2000 at 1 of 8 managed care organizations that comprise the Vaccine Safety Datalink. We reviewed the charts of 595 potential patients with idiopathic thrombocytopenic purpura from the 8 Vaccine Safety Datalink sites and excluded patients with known causes of Thrombocytopenia. Chronic idiopathic thrombocytopenic purpura was defined as having Thrombocytopenia for 6 months beyond the initial diagnosis. The risk for developing chronic idiopathic thrombocytopenic purpura was assessed using simple and multivariable analyses. RESULTS. Of the 259 cases of idiopathic thrombocytopenic purpura, 197 (76%) were acute, 60 (23%) were chronic, and 2 (1%) could not be determined. Among the acute cases, the mean duration of illness was 22 days. There was 1 serious bleeding outcome in the cohort. In multivariable regression analysis, the patients with chronic illness were older, less likely to present with mucosal bleeding, less likely to have had an acute illness before diagnosis, and more likely to present with a platelet count >20000/μL than children with acute idiopathic thrombocytopenic purpura. In particular, children whose illness was diagnosed at ≥10 years of age and who had platelet counts ≥20000/μL had an approximate fivefold risk for progressing to chronic disease when compared with children who presented at ≤2 years of age with platelet counts CONCLUSIONS. Although idiopathic thrombocytopenic purpura tends to be a benign and self-limited condition, acute and chronic idiopathic thrombocytopenic purpura seem to be distinct illnesses defined by age, platelet count, bleeding symptoms, and the presence of acute illness before diagnosis. Physicians should be aware of these differences when advising their patients and families.
Donald M Arnold - One of the best experts on this subject based on the ideXlab platform.
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autoantibodies to thrombopoietin and the thrombopoietin receptor in patients with immune Thrombocytopenia
British Journal of Haematology, 2018Co-Authors: Ishac Nazy, John G Kelton, Jane C Moore, Rumi Clare, Peter Horsewood, James W Smith, Nikola Ivetic, Vanessa Dsouza, Donald M ArnoldAbstract:Autoantibodies to thrombopoietin (TPO, also termed THPO) or the TPO receptor (cMpl, also termed MPL) could play a pathological role in immune Thrombocytopenia (ITP). In this study, we tested for autoantibodies against TPO, cMpl, or the TPO/cMpl complex in ITP and other thrombocytopenic disorders. Using an inhibition step with excess TPO in fluid-phase to improve binding specificity, the prevalence of anti-TPO autoantibodies was: active ITP: 9/32 (28%); remission ITP: 0/14 (0%); non-immune Thrombocytopenias: 1/10 (10%); and healthy controls: 1/11 (9%). Similarly, using an inhibition step with excess cMpl, the prevalence of specific anti-cMpl autoantibodies was: active ITP: 7/32 (22%); remission ITP: 1/14 (7%); non-immune Thrombocytopenias: 3/10 (30%); and healthy controls: 0/11 (0%). Two active ITP patients had autoantibodies against the TPO/cMpl complex, but not against TPO or cMpl alone. Anti-TPO or anti-cMpl autoantibodies were found in 44% of ITP patients, and in 40% of patients with other thrombocytopenic disorders. These autoantibodies did not correlate with ITP disease severity or number of ITP treatments received; however, in this cohort, 3 patients failed to respond to TPO receptor agonist medications, and of those, 2 had anti-TPO autoantibodies. This suggests that anti-TPO and anti-cMpl autoantibodies are associated with Thrombocytopenia, and may be clinically relevant in a subset of ITP patients.
James R. Scott - One of the best experts on this subject based on the ideXlab platform.
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neonatal alloimmune Thrombocytopenia antenatal management
American Journal of Obstetrics and Gynecology, 2000Co-Authors: Robert M Silver, Flint T Porter, Sean M Esplin, Ware D Branch, James R. ScottAbstract:Abstract Objective: The optimal management of pregnancies at risk for neonatal alloimmune Thrombocytopenia is debated. Proposed management includes the administration of intravenous immunoglobulin and serial determination of the fetal platelet count. The aims of our study were to determine the effectiveness and likely mechanism of action of intravenous immunoglobulin and to evaluate the safety of cordocentesis in cases of neonatal alloimmune Thrombocytopenia. Study Design: Eighteen mother-infant pairs were studied. All were at risk for neonatal alloimmune Thrombocytopenia on the basis of delivery of a previously affected infant and confirmation of specific maternal antiplatelet antibodies. The pertinent antigen was HPA-1a in 13 cases, HPA-3a in 2 cases, and undetermined in 3 cases. Serial cordocenteses were used to determine fetal platelet counts. If the platelet count was Results: Seven (39%) fetuses had adequate platelet counts, were not treated, and were delivered of infants with normal platelet counts. Eleven (61%) fetuses were thrombocytopenic. Eight thrombocytopenic infants were treated with maternally administered intravenous immunoglobulin. In 6 (75%) of 8 cases the fetal platelet count increased after administration of intravenous immunoglobulin, but 2 fetuses remained severely thrombocytopenic. Two thrombocytopenic fetuses were treated with intravenous immunoglobulin infusion directly into the umbilical vein; both remained thrombocytopenic. Moreover, fetal immunoglobulin G levels did not correlate well with the response to intravenous immunoglobulin. Two (5.3%) of 38 cordocenteses were complicated by hemorrhagic complications, necessitating immediate cesarean delivery despite the use of prophylactic platelet transfusion in one case. Conclusion: Severe fetal alloimmune Thrombocytopenia does not always occur in subsequent fetuses. Thus either fetal antigen status or platelet counts or both of these are necessary to determine whether treatment is needed. The effect of intravenous immunoglobulin on raising the fetal platelet count is inconsistent and appears to be caused by maternal or placental factors rather than a direct inhibition of fetal platelet destruction by immunoglobulin. The risk of hemorrhagic complications from cordocentesis in pregnancies complicated by neonatal alloimmune Thrombocytopenia is higher than generally appreciated and is not always avoided by platelet transfusion at the time of the procedure. (Am J Obstet Gynecol 2000;182:1233-8.)