{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:48:25Z","timestamp":1788306505326,"version":"build-2803163510"},"reference-count":119,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T00:00:00Z","timestamp":1655942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Primary immune thrombocytopenia (ITP) is an autoimmune disorder that causes low platelet counts and subsequent bleeding risk. Although current corticosteroid-based ITP therapies are able to improve platelet counts, up to 70% of subjects with an ITP diagnosis do not achieve a sustained clinical response in the absence of treatment, thus requiring a second-line therapy option as well as additional care to prevent bleeding. Less than 40% of patients treated with thrombopoietin analogs, 60% of those treated with splenectomy, and 20% or fewer of those treated with rituximab or fostamatinib reach sustained remission in the absence of treatment. Therefore, optimizing therapeutic options for ITP management is mandatory. The pathophysiology of ITP is complex and involves several mechanisms that are apparently unrelated. These include the clearance of autoantibody-coated platelets by splenic macrophages or by the complement system, hepatic desialylated platelet destruction, and the inhibition of platelet production from megakaryocytes. The number of pathways involved may challenge treatment, but, at the same time, offer the possibility of unveiling a variety of new targets as the knowledge of the involved mechanisms progresses. The aim of this work, after revising the limitations of the current treatments, is to perform a thorough review of the mechanisms of action, pharmacokinetics\/pharmacodynamics, efficacy, safety, and development stage of the novel ITP therapies under investigation. Hopefully, several of the options included herein may allow us to personalize ITP management according to the needs of each patient in the near future.<\/jats:p>","DOI":"10.3390\/ph15070779","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T22:43:00Z","timestamp":1656024180000},"page":"779","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Novel Therapies to Address Unmet Needs in ITP"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9083-855X","authenticated-orcid":false,"given":"Mar\u00eda Eva","family":"Mingot-Castellano","sequence":"first","affiliation":[{"name":"Hematology Deparment, Hospital Universitario Virgen del Roc\u00edo, Instituto de Biomedicina de Sevilla (IBIS\/CSIC), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8007-3909","authenticated-orcid":false,"given":"Jos\u00e9 Mar\u00eda","family":"Bastida","sequence":"additional","affiliation":[{"name":"Hematology Deparment, Hospital Universitario de Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Caballero-Navarro","sequence":"additional","affiliation":[{"name":"Hematology Deparment, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Entrena Ure\u00f1a","sequence":"additional","affiliation":[{"name":"Hematology Deparment, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2458-2554","authenticated-orcid":false,"given":"Tom\u00e1s Jos\u00e9","family":"Gonz\u00e1lez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Hematology Deparment, Hospital Universitario de Burgos, 09006 Burgos, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Ram\u00f3n","family":"Gonz\u00e1lez-Porras","sequence":"additional","affiliation":[{"name":"Hematology Deparment, Hospital Universitario de Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4601-7150","authenticated-orcid":false,"given":"Nora","family":"Butta","sequence":"additional","affiliation":[{"name":"Hematology Deparment, Hospital Universitario La Paz-Idi-PAZ, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Canaro","sequence":"additional","affiliation":[{"name":"Hematology Deparment, Hospital Son Espases, 07210 Palma, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reyes","family":"Jim\u00e9nez-B\u00e1rcenas","sequence":"additional","affiliation":[{"name":"Hematology Deparment, Hospital Serran\u00eda de Ronda, 29400 Ronda, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda del Carmen","family":"G\u00f3mez del Castillo Solano","sequence":"additional","affiliation":[{"name":"Hematology Deparment, Complexo Hospitalario Universitario A Coru\u00f1a, 15006 A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"S\u00e1nchez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Hematology Deparment, Hospital del Mar, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Pascual-Izquierdo","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hospital Gregorio Mar\u00f1\u00f3n (HGUGM), Instituto de Investigaci\u00f3n Gregorio Mara\u00f1\u00f3n, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the GEPTI","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1002\/ajh.21616","article-title":"The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports","volume":"85","author":"Terrell","year":"2010","journal-title":"Am. J. Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.3324\/haematol.2009.007823","article-title":"Elevated profile of Th17, Th1 and Tc1 cells in patients with immune thrombocytopenic purpura","volume":"94","author":"Zhang","year":"2009","journal-title":"Haematologica"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"220","DOI":"10.3324\/haematol.2019.240440","article-title":"Desialylation of O-glycans on glycoprotein Ib\u03b1 drives receptor signaling and platelet clearance","volume":"106","author":"Wang","year":"2021","journal-title":"Haematologica"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8360","DOI":"10.1073\/pnas.1707662114","article-title":"Sialylation on O-glycans protects platelets from clearance by liver Kupffer cells","volume":"114","author":"Li","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/j.1365-2141.2006.06024.x","article-title":"The pathogenesis of immune thrombocytopaenic purpura","volume":"133","author":"Cooper","year":"2006","journal-title":"Br. J. Haematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1111\/jth.12813","article-title":"Severe bleeding events in adults and children with primary immune thrombocytopenia: A systematic review","volume":"13","author":"Neunert","year":"2015","journal-title":"J. Thromb. Haemost."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Singh, A., Uzun, G., and Bakchoul, T. (2021). Primary Immune Thrombocytopenia: Novel Insights into Pathophysiology and Disease Management. J. Clin. Med., 10.","DOI":"10.3390\/jcm10040789"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.medcli.2021.03.017","article-title":"Guidelines of the Spanish ITP Group for the diagnosis, treatment and follow-up of patients with immune thrombopenia","volume":"157","author":"Lozano","year":"2021","journal-title":"Med. Clin."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1055\/s-0032-1305780","article-title":"Immune Thrombocytopenia: Pathophysiologic and Clinical Update","volume":"38","author":"Stasi","year":"2012","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3780","DOI":"10.1182\/bloodadvances.2019000812","article-title":"Updated international consensus report on the investigation and management of primary immune thrombocytopenia","volume":"3","author":"Provan","year":"2019","journal-title":"Blood Adv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3829","DOI":"10.1182\/bloodadvances.2019000966","article-title":"American Society of Hematology 2019 guidelines for immune thrombocytopenia","volume":"3","author":"Neunert","year":"2019","journal-title":"Blood Adv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1182\/blood.V92.1.4.413k38_4_10","article-title":"Role of c-mpl in Early Hematopoiesis","volume":"92","author":"Solar","year":"1998","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/j.1600-0609.2007.00999.x","article-title":"New drugs for familiar therapeutic targets: Thrombopoietin receptor agonists and immune thrombocytopenic purpura","volume":"80","author":"Kuter","year":"2008","journal-title":"Eur. J. Haematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3444","DOI":"10.1182\/blood.V85.12.3444.bloodjournal85123444","article-title":"Thrombo-poietin induces tyrosine phosphorylation and activation of the Janus kinase, JAK2","volume":"85","author":"Tortolani","year":"1995","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.blre.2010.04.002","article-title":"Thrombopoietic agents","volume":"24","author":"Stasi","year":"2010","journal-title":"Blood Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1055\/s-0038-1676129","article-title":"Thrombopoietin Receptor Agonist Use for Immune Thrombocytopaenia","volume":"39","author":"Neunert","year":"2019","journal-title":"Hamostaseologie"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1055\/s-0039-1700512","article-title":"Immune Thrombocytopenia in Adults: Modern Approaches to Diagnosis and Treatment","volume":"46","author":"Kuter","year":"2020","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1111\/bjh.17872","article-title":"Novel therapies for immune thrombocytopenia","volume":"196","author":"Kuter","year":"2021","journal-title":"Br. J. Haematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1080\/17474086.2020.1850253","article-title":"Romiplostim in adults with newly diagnosed or persistent immune thrombocytopenia","volume":"13","author":"Lozano","year":"2020","journal-title":"Expert Rev. Hematol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/bjh.13266","article-title":"Use of eltrombopag after romiplostim in primary immune thrombocytopenia","volume":"169","author":"Andrade","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"901","DOI":"10.2165\/00003495-200868070-00002","article-title":"Novel thrombopoietic agents: A review of their use in idiopathic thrombocytopenic purpura","volume":"68","author":"Stasi","year":"2008","journal-title":"Drugs"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/S0140-6736(10)60959-2","article-title":"Eltrombopag for management of chronic immune thrombocytopenia (RAISE): A 6-month, randomised, phase 3 study","volume":"377","author":"Cheng","year":"2011","journal-title":"Lancet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/S0140-6736(08)60203-2","article-title":"Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: A double-blind randomised controlled trial","volume":"371","author":"Kuter","year":"2008","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S0140-6736(09)60402-5","article-title":"Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: A randomised, double-blind, placebo-controlled trial","volume":"373","author":"Bussel","year":"2009","journal-title":"Lancet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1111\/bjh.13827","article-title":"Remission and platelet responses with romiplostim in primary immune thrombocytopenia: Final results from a phase 2 study","volume":"172","author":"Newland","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_26","first-page":"E40","article-title":"Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia","volume":"90","author":"Pascual","year":"2015","journal-title":"Am. J. Hematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1007\/s00277-016-2682-2","article-title":"Changes in bone marrow morphology in adults receiving romiplostim for the treatment of thrombocytopenia associated with primary immune thrombocytopenia","volume":"95","author":"Janssens","year":"2016","journal-title":"Ann. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1097\/MBC.0000000000000726","article-title":"Treatment characteristics, efficacy and safety of thrombopoietin analogues in routine management of primary immune thrombocytopenia","volume":"29","year":"2018","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"16680","DOI":"10.1038\/s41598-019-53209-y","article-title":"Deciphering predictive factors for choice of thrombopoietin receptor agonist, treatment free responses, and thrombotic events in immune thrombocytopenia","volume":"9","author":"Lozano","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1056\/NEJMoa1002625","article-title":"Romiplostim or Standard of Care in Patients with Immune Thrombocytopenia","volume":"363","author":"Kuter","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1111\/bjh.15573","article-title":"Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia","volume":"183","author":"Jurczak","year":"2018","journal-title":"Br. J. Haematol."},{"key":"ref_32","unstructured":"GlaxoSmithKline (2017). Promacta (Eltrombopag) [Prescribing Information], GlaxoSmithKline."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1182\/blood-2011-11-393900","article-title":"In vivo effects of eltrombopag on platelet function in immune thrombocytopenia: No evidence of platelet activation","volume":"119","author":"Psaila","year":"2012","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s00277-018-3556-6","article-title":"Platelet aggregation response in immune thrombocytopenia patients treated with romiplostim","volume":"98","author":"Kuter","year":"2019","journal-title":"Ann. Hematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1182\/blood-2008-04-150078","article-title":"Safety and efficacy of long-term treatment with romi-plostim in thrombocytopenic patients with chronic ITP","volume":"113","author":"Bussel","year":"2009","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s12185-015-1837-6","article-title":"Integrated analysis of long-term safety in patients with chronic immune thrombocytopaenia (ITP) treated with the thrombopoietin (TPO) receptor agonist romiplostim","volume":"102","author":"Cines","year":"2015","journal-title":"Int. J. Hematol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3748","DOI":"10.1182\/blood-2009-05-224766","article-title":"Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim","volume":"114","author":"Kuter","year":"2009","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/bjh.16327","article-title":"Safety and efficacy of eltrombopag plus pulsed dexamethasone as first-line therapy for immune thrombocytopenia","volume":"189","author":"Zhang","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1002\/art.22019","article-title":"Regeneration of B cell subsets after transient B cell depletion using anti-CD20 an-tibodies in rheumatoid arthritis","volume":"54","author":"Roll","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.3324\/haematol.2019.218883","article-title":"Rituximab in the treatment of immune thrombocytopenia: What is the role of this agent in 2019?","volume":"104","author":"Lucchini","year":"2019","journal-title":"Haematologica"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1182\/blood-2017-06-789578","article-title":"BAFF and CD4(+) T cells are major survival factors for long-lived splenic plasma cells in a B-cell\u2013depletion context","volume":"131","author":"Thai","year":"2018","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1182\/blood-2013-03-491415","article-title":"Preferential splenic CD8(+) T-cell activation in rituximab-nonresponder patients with immune thrombocytopenia","volume":"122","author":"Audia","year":"2013","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1002\/ajh.25125","article-title":"Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials","volume":"93","author":"Bussel","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1002\/ajh.25444","article-title":"Long-term fostamatinib treatment of adults with immune thrombocytopenia during the phase 3 clinical trial program","volume":"94","author":"Bussel","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1111\/bjh.16959","article-title":"Fostamatinib is an effective second-line therapy in patients with immune thrombocytopenia","volume":"190","author":"Boccia","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.1182\/blood-2004-03-1168","article-title":"Splenectomy for adult patients with idiopathic thrombocytopenic purpura: A systematic review to assess long-term platelet count responses, prediction of response, and surgical complications","volume":"104","author":"Kojouri","year":"2004","journal-title":"Blood"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kwiatkowska, A., Radkowiak, D., Wysocki, M., Torbicz, G., Gajewska, N., Lasek, A., Kulawik, J., Budzy\u0144ski, A., and P\u0119dziwiatr, M. (2019). Prognostic Factors for Immune Thrombocytopenic Purpura Remission after Laparoscopic Splenectomy: A Cohort Study. Medicina, 55.","DOI":"10.3390\/medicina55040112"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1080\/17474086.2019.1636644","article-title":"Current and emerging treatments for immune thrombocytopenia","volume":"12","author":"Dou","year":"2019","journal-title":"Expert Rev. Hematol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1111\/bcpt.12815","article-title":"Safety, Pharmacokinetics and Pharmacodynamics of Hetrombopag Olamine, a Novel TPO-R Agonist, in Healthy Individuals","volume":"121","author":"Zheng","year":"2017","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1111\/bcp.14259","article-title":"Effect of postdose fasting duration on hetrombopag olamine pharmacokinetics and pharmacodynamics in healthy volunteers","volume":"86","author":"Yang","year":"2020","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1016\/j.clinthera.2020.10.002","article-title":"Effect of Food on the Pharmacokinetic and Pharmacodynamic Profiles of Hetrombopag in Healthy Volunteers","volume":"42","author":"Wang","year":"2020","journal-title":"Clin. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5367","DOI":"10.1111\/jcmm.13809","article-title":"Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist","volume":"22","author":"Xie","year":"2018","journal-title":"J. Cell. Mol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1111\/jth.15602","article-title":"Dose tapering to withdrawal stage and long-term efficacy and safety of hetrombopag for the treatment of immune thrombocytopenia: Results from an open-label extension study","volume":"20","author":"Mei","year":"2022","journal-title":"J. Thromb. Haemost."},{"key":"ref_54","unstructured":"Lickliter, J., Wu, Y., Hua, Y., Yuan, I., Dai, G., Li, X., Wang, J., Sai, Y., Sun, Z., and Pan, A. (2016;, January 11\u201316). A Phase I, Randomized, Double Blind, Placebo-Controlled, Dose Escalating Study of the Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of Hmpl 523 in Australian Male Healthy Subjects. Proceedings of the 2016 ACR\/ARHP Annual Meeting, Washington, DC, USA."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1182\/blood-2021-149895","article-title":"Safety, Pharmacokinetics and Preliminary Efficacy of HMPL-523 in Adult Patients with Primary Immune Thrombocytopenia: A Randomized, Double-Blind and Placebo-Controlled Phase 1b Study","volume":"138","author":"Yang","year":"2021","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"668131","DOI":"10.3389\/fcell.2021.668131","article-title":"Targeting Bruton\u2019s Tyrosine Kinase in Inflammatory and Autoimmune Pathologies","volume":"9","author":"Neys","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1111\/bcp.13351","article-title":"A phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton\u2019s tyrosine kinase, in healthy volunteers","volume":"83","author":"Smith","year":"2017","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1182\/blood-2021-145128","article-title":"Updated Phase I\/II Safety and Efficacy Results for Oral Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients with Relapsed\/Refractory Immune Thrombocytopenia","volume":"138","author":"Kuter","year":"2021","journal-title":"Blood"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1056\/NEJMoa2110297","article-title":"Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia","volume":"386","author":"Kuter","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1182\/blood-2021-144504","article-title":"LUNA3 Phase III Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial of the Oral BTK Inhibitor Rilzabrutinib in Adults and Adolescents with Persistent or Chronic Immune Thrombocytopenia","volume":"138","author":"Kuter","year":"2021","journal-title":"Blood"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"CT132","DOI":"10.1158\/1538-7445.AM2020-CT132","article-title":"Orelabrutinib, a potent and selective Bruton\u2019s tyrosine kinase inhibitor with superior safety profile and excellent PK\/PD properties","volume":"80","author":"Zhang","year":"2020","journal-title":"Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3172","DOI":"10.1182\/blood-2021-144691","article-title":"Orelabrutinib, a Selective Bruton\u2019s Tyrosine Kinase (BTK) Inhibitor in the Treatment of Primary Immune Thrombocytopenia (ITP)","volume":"138","author":"Yu","year":"2021","journal-title":"Blood"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"100122","DOI":"10.1016\/j.jtauto.2021.100122","article-title":"Ways in which the neonatal Fc-receptor is involved in autoimmunity","volume":"4","author":"Lamamy","year":"2021","journal-title":"J. Transl. Autoimmun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/ajh.25680","article-title":"Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia","volume":"95","author":"Newland","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1126\/scitranslmed.aan1208","article-title":"The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study","volume":"9","author":"Kiessling","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.autrev.2016.03.018","article-title":"IVIG in autoimmune disease\u2014Potential next generation biologics","volume":"15","author":"Zuercher","year":"2016","journal-title":"Autoimmun. Rev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s10875-016-0272-7","article-title":"The FcgammaR\/IgG Interaction as target for the treatment of autoimmune diseases","volume":"36","author":"Sondermann","year":"2016","journal-title":"J. Clin. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/nrmicro1824","article-title":"Complement evasion by human pathogens","volume":"6","author":"Lambris","year":"2008","journal-title":"Nat. Rev. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1084\/jem.20020552","article-title":"Death by a B cell superantigen: In vivo VH-targeted apoptotic supraclonal B cell deletion by a Staphylococcal Toxin","volume":"197","author":"Goodyear","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/bjh.14985","article-title":"A highly purified form of staphylococcal protein A alleviates murine immune thrombocytopenia (ITP)","volume":"183","author":"Kapur","year":"2018","journal-title":"Br. J. Haematol."},{"key":"ref_71","unstructured":"Bethesda (MD): National Library of Medicine (US) (2021, November 26). 27 March 2015. Identifier NCT02401061. PRTX-100-202 Open-Label, Dose Escalation Study in Adult Patients with ITP. 5 July 2019, Available online: https:\/\/clinicaltrials.gov\/."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1126\/science.1129594","article-title":"Anti-Inflammatory Activity of Immunoglobulin G Resulting from Fc Sialylation","volume":"313","author":"Kaneko","year":"2006","journal-title":"Science"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3389\/fcimb.2012.00016","article-title":"Inferring Reasons for the Failure of Staphylococcus aureus Vaccines in Clinical Trials","volume":"2","author":"Bagnoli","year":"2012","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5430","DOI":"10.7150\/thno.53961","article-title":"Sialylated immunoglobulin G: A promising diagnostic and therapeutic strategy for autoimmune diseases","volume":"11","author":"Li","year":"2021","journal-title":"Theranostics"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"E1297","DOI":"10.1073\/pnas.1422481112","article-title":"Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity","volume":"112","author":"Washburn","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","first-page":"945","article-title":"Infusion of Fc gamma fragments for treatment of children with acute immune thrombocytopenic purpura","volume":"42","author":"Griscelli","year":"1993","journal-title":"Lancet"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/BF00320302","article-title":"Are aggregates of IgG the effective part of high-dose immunoglobulin therapy in adult idiopathic thrombocytopenic purpura (ITP)?","volume":"50","author":"Augener","year":"1985","journal-title":"Blut"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1182\/bloodadvances.2016001917","article-title":"A fully recombinant human IgG1 Fc multimer (GL-2045) inhibits complement-mediated cytotoxicity and induces iC3b","volume":"1","author":"Zhou","year":"2017","journal-title":"Blood Adv."},{"key":"ref_79","unstructured":"Bethesda (MD): National Library of Medicine (US) (2021, November 26). 24 June 2020. Identifier NCT03375606. Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous CSL730 in Healthy Adult Subjects. 30 September 2021, Available online: https:\/\/clinicaltrials.gov\/."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/j.1600-0609.2011.01718.x","article-title":"Autoantibody-mediated complement activation on platelets is a common finding in patients with immune thrombocytopenic purpura (ITP)","volume":"88","author":"Najaoui","year":"2012","journal-title":"Eur. J. Haematol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/cei.13475","article-title":"Complement activation in patients with immune thrombocytopenic purpura according to phases of disease course","volume":"201","author":"Castelli","year":"2020","journal-title":"Clin. Exp. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1111\/bjh.13648","article-title":"Classical complement pathway activation in immune thrombocytopenia purpura: Inhibition by a novel C1s inhibitor","volume":"173","author":"Peerschke","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1182\/blood.V126.23.2253.2253","article-title":"Complement Blockade with C1 Esterase Inhibitor in Refractory Immune Thrombocytopenia","volume":"126","author":"Roesch","year":"2015","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1056\/NEJMoa2027760","article-title":"Sutimlimab in Cold Agglutinin Disease","volume":"384","author":"Barcellini","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1182\/blood-2020-139663","article-title":"Long-Term Safety and Efficacy of Sutimlimab in Patients with Chronic Immune Thrombocytopenia","volume":"136","author":"Broome","year":"2020","journal-title":"Blood"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1038\/nm.2030","article-title":"Dual roles for hepatic lectin receptors in the clearance of chilled platelets","volume":"15","author":"Rumjantseva","year":"2009","journal-title":"Nat. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"S68","DOI":"10.1016\/S0049-3848(16)30370-X","article-title":"Platelet clearance by the hepatic Ashwell-Morrell receptor: Mechanisms and biological significance","volume":"141","author":"Hoffmeister","year":"2016","journal-title":"Thromb. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nm.3770","article-title":"The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling","volume":"21","author":"Grozovsky","year":"2015","journal-title":"Nat. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"7737","DOI":"10.1038\/ncomms8737","article-title":"Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia","volume":"6","author":"Li","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"27445","DOI":"10.1038\/srep27445","article-title":"CD8(+) T cells induce platelet clearance in the liver via platelet desialylation in immune thrombocytopenia","volume":"6","author":"Qiu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1111\/fcp.12213","article-title":"Unexpected platelets elevation in a patient with idiopathic thrombocytopenia treated with oseltamivir for influenza infection","volume":"30","author":"Bigot","year":"2016","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"495","DOI":"10.3109\/09537104.2014.948838","article-title":"Successful treatment with oseltamivir phosphate in a patient with chronic immune thrombocytopenia positive for anti-GPIb\/IX autoantibody","volume":"26","author":"Shao","year":"2015","journal-title":"Platelets"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1080\/09537104.2020.1714576","article-title":"Evaluating the effects of oseltamivir phosphate on platelet counts: A retrospective review","volume":"31","author":"Shaim","year":"2020","journal-title":"Platelets"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e289","DOI":"10.1016\/S2352-3026(21)00030-2","article-title":"Dexamethasone plus oseltamivir versus dexamethasone in treatment-naive primary immune thrombocytopenia: A multicentre, randomised, open-label, phase 2 trial","volume":"8","author":"Sun","year":"2021","journal-title":"Lancet Haematol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-981-15-3532-1_1","article-title":"B Cell Development and Maturation","volume":"1254","author":"Wang","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3653","DOI":"10.1182\/blood-2007-07-101600","article-title":"Antigen-induced clustering of surface CD38 and recruitment of intracellular CD38 to the immunologic synapse","volume":"111","author":"Mittelbrunn","year":"2008","journal-title":"Blood"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.4049\/jimmunol.1003032","article-title":"Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors","volume":"186","author":"Tai","year":"2011","journal-title":"J. Immunol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.drudis.2019.11.008","article-title":"New generation drugs for treatment of multiple myeloma","volume":"25","author":"Alanazi","year":"2019","journal-title":"Drug Discov. Today"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1182\/blood-2021-151410","article-title":"Daratumumab as a Treatment for Adult Immune Thrombocytopenia: A Phase II Study with Safety Run-in (the DART Study)","volume":"138","author":"Tsykunova","year":"2021","journal-title":"Blood"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3198","DOI":"10.3324\/haematol.2021.279232","article-title":"Daratumumab, an original approach for treating multi-refractory autoimmune cytopenia","volume":"106","author":"Crickx","year":"2021","journal-title":"Haematologica"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.clim.2016.07.018","article-title":"The proteasome\u2014Victim or culprit in autoimmunity","volume":"172","author":"Feist","year":"2016","journal-title":"Clin. Immunol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1055\/s-0038-1669921","article-title":"Proteasome Inhibition with Bortezomib Induces Apoptosis of Long-Lived Plasma Cells in Steroid-Resistant or Relapsed Immune Thrombocytopaenia","volume":"118","author":"Li","year":"2018","journal-title":"Thromb. Haemost."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1111\/bjh.12696","article-title":"Bortezomib induces clinical remission and reduction of ADAMTS13 inhibitory antibodies in relapsed refractory idiopathic thrombotic thrombocytopenic purpura","volume":"164","author":"Mazepa","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1111\/bjh.16009","article-title":"Bortezomib and dexamethasone, an original approach for treating multi-refractory warm autoimmune haemolytic anaemia","volume":"187","author":"Fadlallah","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e270","DOI":"10.1097\/MJT.0000000000000517","article-title":"Bortezomib for Refractory Immune-Mediated Thrombocytopenia Purpura","volume":"25","author":"Beckman","year":"2018","journal-title":"Am. J. Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1080\/09537104.2021.2002835","article-title":"Refractory immune thrombocytopenia successfully treated with bortezomib in a child with 22q11.2 deletion syndrome, complicated by Evans syndrome and hypogammaglobulinemia","volume":"33","author":"Conti","year":"2022","journal-title":"Platelets"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"11127","DOI":"10.1021\/acs.jmedchem.8b01201","article-title":"Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2S,3R)-N-((S)-3-(Cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propenamide)","volume":"61","author":"Johnson","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1111\/j.1365-2141.2008.07039.x","article-title":"The effect of anti-CD40 ligand in immune thrombocytopenic purpura","volume":"141","author":"Patel","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1182\/blood-2003-06-2167","article-title":"Effect of a single injection of humanized anti-CD154 monoclonal antibody on the platelet-specific autoimmune response in patients with immune thrombocytopenic purpura","volume":"103","author":"Kuwana","year":"2004","journal-title":"Blood"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/nrd4296","article-title":"Interleukin-21: A double-edged sword with therapeutic potential","volume":"13","author":"Spolski","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/j.1365-2141.2010.08327.x","article-title":"Thrombopoietic effect of VPAC1 inhibition during megakaryopoiesis","volume":"151","author":"Peeters","year":"2010","journal-title":"Br. J. Haematol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s12013-010-9100-5","article-title":"Efficacy of Amifostine in Treating Patients with Idiopathic Thrombocytopenia Purpura","volume":"59","author":"Fan","year":"2011","journal-title":"Cell Biophys."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"3154","DOI":"10.1182\/blood-2008-07-166439","article-title":"Of mice and men: An open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk","volume":"113","author":"Podolanczuk","year":"2009","journal-title":"Blood"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1182\/blood.2020008477","article-title":"Low-dose decitabine modulates T-cell homeostasis and restores immune tolerance in immune thrombocytopenia","volume":"138","author":"Han","year":"2021","journal-title":"Blood"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1182\/blood-2018-05-847624","article-title":"Low-dose chidamide restores immune tolerance in ITP in mice and humans","volume":"133","author":"Zhao","year":"2019","journal-title":"Blood"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"3348","DOI":"10.1172\/JCI26891","article-title":"The biogenesis of platelets from megakaryocyte proplatelets","volume":"115","author":"Patel","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1182\/blood-2005-06-2206","article-title":"Mechanisms of organelle transport and capture along proplatelets during platelet production","volume":"106","author":"Richardson","year":"2005","journal-title":"Blood"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"349ra101","DOI":"10.1126\/scitranslmed.aaf4964","article-title":"Noninvasive low-level laser therapy for thrombocytopenia","volume":"8","author":"Zhang","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"107","DOI":"10.2217\/rme.15.82","article-title":"Photobiomodulation in promoting wound healing: A review","volume":"11","author":"Kuffler","year":"2016","journal-title":"Regen. Med."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/7\/779\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:38:07Z","timestamp":1760139487000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/7\/779"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,23]]},"references-count":119,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ph15070779"],"URL":"https:\/\/doi.org\/10.3390\/ph15070779","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,23]]}}}