From April 10 to 11, 2026, the Annual Academic Meeting of the Hematology Branch of the China International Exchange and Promotive Association for Medical and Health Care (CPAM), together with the “Huatuo Project” MDT Workshop, was held in Changsha.During the conference, Professor Yu Hou from Qilu Hospital of Shandong University was invited by Hematology Frontier to share his perspectives. Drawing on extensive clinical experience and the latest advances in the field, he provided a systematic overview of the definition, clinical challenges, and diagnostic strategies for refractory primary immune thrombocytopenia (ITP), offering valuable guidance for early recognition, accurate diagnosis, and clinical management.
Q1: Definition and Current Status of Refractory ITP
It is well recognized that a subset of patients with ITP continue to experience persistently low platelet counts and/or ongoing bleeding symptoms. How is refractory ITP currently defined, and what are its clinical characteristics in China?
Professor Yu Hou: Refractory primary immune thrombocytopenia (ITP) represents one of the most challenging subgroups within the ITP spectrum. At present, there is no universally accepted definition of refractory ITP across international and domestic guidelines. In China, clinical practice generally follows the updated Chinese Guidelines for the Diagnosis and Treatment of Adult Primary Immune Thrombocytopenia (2025 edition).
According to these guidelines, refractory ITP refers to patients who fail to respond to first-line and subsequent therapies, including high-dose glucocorticoids, intravenous immunoglobulin (IVIg), thrombopoietin receptor agonists, and rituximab (RTX), or those in whom splenectomy is ineffective or relapse occurs after surgery. Importantly, the diagnosis should be confirmed only after re-evaluation to ensure that alternative causes have been excluded.
This definition underscores that identifying refractory ITP is typically a prolonged and stepwise process, requiring the sequential exclusion of multiple therapeutic options. As a result, it imposes a considerable burden on both patients and clinicians in terms of time, effort, and healthcare costs. Diagnostic delays are therefore common, which in turn limit subsequent treatment choices. In current clinical practice, patients with refractory ITP are often encouraged to participate in clinical trials of novel therapies, which may offer access to more effective treatment strategies.
Q2: Early Identification and Diagnostic Accuracy
Early recognition of refractory ITP is essential for optimizing treatment strategies. What are the key considerations for early diagnosis, and how can diagnostic accuracy be improved?
Professor Yu Hou: Early diagnosis of refractory ITP remains highly challenging. First, it is important to emphasize that ITP itself is a diagnosis of exclusion, as there is no definitive laboratory gold standard.
Certain laboratory tests may provide supportive evidence. For instance, platelet-associated autoantibodies can be detected using assays such as the monoclonal antibody immobilization of platelet antigens (MAIPA) or flow cytometric immunobead array (FCIA). However, due to their limited sensitivity and specificity, these tests cannot serve as definitive diagnostic criteria.
Reticulated platelet counts are often elevated in ITP, reflecting increased platelet turnover due to peripheral destruction. These measurements can be obtained through flow cytometry or certain automated hematology analyzers and are conceptually analogous to reticulocyte counts in red blood cells. In addition, plasma thrombopoietin levels may offer some diagnostic insight: they are typically elevated in hypoproliferative disorders but tend to remain within the normal range in ITP. Nevertheless, these markers lack disease specificity.
From a pathophysiological standpoint, emerging evidence suggests that refractory or chronic ITP is closely associated with cytotoxic CD8-positive T cells, particularly terminally differentiated effector memory T cells exhibiting clonal expansion. These cells are believed to play a central role in platelet destruction. Furthermore, relapse following B-cell–depleting therapies—such as splenectomy, anti-CD20 monoclonal antibodies, anti-CD38 antibodies, or Bruton tyrosine kinase (BTK) inhibitors—may be driven by long-lived plasma cells in the bone marrow, which continue to produce pathogenic antibodies.
Q3: Differential Diagnosis and Essential Evaluations
Given the absence of definitive diagnostic tests, distinguishing refractory ITP from other conditions can be challenging. What diseases should be considered in the differential diagnosis, and which investigations are essential?
Professor Yu Hou: The diagnosis of suspected ITP or refractory ITP is fundamentally a process of exclusion. The primary objective is to differentiate it from systemic autoimmune diseases and other hematologic disorders that may cause thrombocytopenia.
The first diagnostic step is to confirm isolated thrombocytopenia on a peripheral blood count, typically defined as a platelet count below 100 × 10⁹/L, with other blood cell lineages remaining normal. A peripheral blood smear should be carefully examined to assess cellular morphology. The presence of abnormal cells may suggest alternative diagnoses, particularly hematologic malignancies.
Further evaluation should include screening for circulating autoantibodies, such as antinuclear antibodies, anticardiolipin antibodies, lupus anticoagulant, and rheumatoid factor, in order to exclude systemic autoimmune diseases affecting the hematologic system. Routine viral screening is also essential, as infections such as hepatitis C virus (HCV), human immunodeficiency virus (HIV), cytomegalovirus (CMV), and Epstein–Barr virus (EBV) can result in secondary thrombocytopenia. Testing for Helicobacter pylori infection should also be included. In addition, thyroid function testing is recommended to identify autoimmune thyroid disorders that may be associated with thrombocytopenia.
In China, bone marrow examination is commonly recommended at the time of initial diagnosis. This allows for evaluation of megakaryocyte number and maturation, and helps exclude other hematologic malignancies by assessing for abnormal blasts or immature cells. However, international guidelines differ in their recommendations. For younger patients, bone marrow examination is not always routinely required during initial evaluation, whereas in older patients presenting with thrombocytopenia, it is generally advised to exclude underlying malignancies.
Expert Profile
Yu Hou Qilu Hospital of Shandong University
Professor, Doctoral Supervisor; Researcher / Associate Chief Physician
Recipient of the National Excellent Young Scientists Fund Recipient of the Shandong Provincial Outstanding Young Scientists Fund Taishan Scholar Young Expert, Shandong Province Distinguished Young and Middle-Aged Scholar, Shandong University
Deputy Director, Department of Hematology, Qilu Hospital of Shandong University
Deputy Head, Youth Committee, Hematology Branch, Chinese Medical Association Member, Thrombosis and Hemostasis Group, Hematology Branch, Chinese Medical Association Member, Experimental Hematology Committee, Chinese Society of Pathophysiology Member, Hematology Branch, Shandong Medical Association
He has long been engaged in basic and translational research on the molecular immunoregulation of immune thrombocytopenia (ITP). As first or corresponding author (including co-authorship), he has published 17 top-tier (CAS Zone 1) papers in leading journals such as Blood (7 articles), The Lancet Haematology, and Cellular & Molecular Immunology. He has led eight national and provincial research projects and was awarded the First Prize of the Ministry of Education Science and Technology Progress Award (second contributor).
