Drug-induced thrombocytopenia (DITP) is a rare but potentially serious adverse reaction encountered in clinical practice. Its pathogenesis is complex, diagnosis is challenging, and treatment options remain limited. In recent years, advances in our understanding of immune regulation have led to important progress in this field. Oncology Frontier – Hematology Frontier invited Professor Heyu Ni of the University of Toronto, Canada, to discuss recent findings from his team's research on heparin-induced thrombocytopenia (HIT) and atorvastatin-induced thrombocytopenia. He shares new insights that extend beyond hemostatic homeostasis to encompass immune regulation, as well as the potential for clinical translation.Oncology Frontier-Hematology Frontier：You explored novel mechanisms of drug-induced thrombocytopenia from the perspective of immune regulation, extending beyond hemostatic homeostasis. How does this new research framework challenge or reshape our traditional understanding of these disorders?
Professor Heyu Ni：Our team has completed two important studies in collaboration with Chinese researchers. The first was conducted in collaboration with Professor Shen Chuanbin and his team at Ocean University of China, focusing on the mechanisms underlying heparin-induced thrombocytopenia (HIT). We found that heparin suppresses the hepatic production of histidine-rich glycoprotein (HRG). Reduced HRG levels may increase the risk of thrombosis and promote the formation of heparin-PF4 complexes, thereby exacerbating the pathological processes associated with HIT. Given that HIT can lead to severe thrombotic complications, this finding has important implications.
This discovery also has potential clinical translational value. On the one hand, HRG may serve as a potential biomarker for HIT risk assessment or as an aid to diagnosis, helping clinicians identify patients at risk of developing HIT. On the other hand, whether HRG supplementation or modulation could be used to prevent or treat HIT warrants further investigation. The findings have been published in Blood under the title “The hepatic FGFR-ERK-HRG axis regulates heparin-induced thrombocytopenia with thrombosis” . To my understanding, the journal may also consider selecting it for the cover.
The second study focuses on atorvastatin-induced thrombocytopenia. This study has not yet been published, but we hope to publish the findings in Blood or another high-impact journal in the future. Atorvastatin is a widely used statin, with approximately 29 million users in the United States alone and a substantial number of users in China. Although thrombocytopenia associated with atorvastatin is rarely reported in clinical practice, cases have been documented in several countries worldwide. Professor Zhou Yan, who previously worked in my lab as a visiting scholar and is affiliated with the Nanning Blood Center (Nanning Institute of Transfusion Medicine), identified a patient whose platelet counts decreased after starting atorvastatin, recovered after discontinuation, and dropped rapidly again upon re-exposure. The patient was unfortunately passed away due to to intracranial hemorrhage.
Our further investigations revealed that atorvastatin can directly bind to platelet glycoprotein GPIIb/IIIa. Although it required high concentration of atorvastatin to inhibit fibrinogen binding, it can significantly inhibit thrombus growth at low dose at high shear. This finding may provide important mechanistic insights into the role of atorvastatin in preventing atherothrombotic events.
Oncology Frontier-Hematology Frontier：Drug-induced thrombocytopenia can present with considerable clinical heterogeneity, and some patients may face both thrombocytopenia and an increased risk of thrombosis. Based on the novel mechanisms you presented, what new insights could help improve the clinical recognition and diagnosis of these conditions?
Professor Heyu Ni：As mentioned earlier, based on our research on HIT, HRG may have potential applications in assessing the risk of HIT. For atorvastatin-induced thrombocytopenia and other forms of drug-induced thrombocytopenia, there may be considerable interindividual variability. This heterogeneity may be associated with differences in the major histocompatibility complex (MHC) among individuals. Differences in the ability of MHC molecules to present antigenic epitopes may lead to variations in T-cell immune responses. Consequently, some patients may develop drug-induced immune thrombocytopenia, whereas most individuals exposed to the same medications do not experience this reaction. This also makes these conditions more challenging to recognize and diagnose in clinical practice.
Currently, several diagnostic tests are available for certain forms of drug-induced thrombocytopenia. For example, tests can detect antibodies against specific platelet surface proteins, as well as drug-dependent platelet-binding antibodies, helping to establish the relationship between the immune response and drug exposure and supporting clinical diagnosis. Furthermore, investigating the mechanisms underlying the interactions between these antibodies and platelets may help identify targets for blocking the associated pathological processes and facilitate the exploration of potentially therapeutic interventions.
Oncology Frontier-Hematology Frontier：What targeted therapeutic strategies might emerge from these mechanistic discoveries in the future, and how could they help improve the diagnosis, treatment, and clinical outcomes of patients with drug-induced immune thrombocytopenia?
Professor Heyu Ni：This has already been addressed in the first two questions. Overall, research into drug-induced thrombocytopenia needs to be further strengthened. On the one hand, sustained research funding is needed to support basic scientists in elucidating the underlying mechanisms of the disease. On the other hand, closer collaboration between basic researchers and clinicians is essential. Taking atorvastatin-induced thrombocytopenia as an example, without the clinical case provided by Professor Zhou Yan, a former visiting scholar in our team, we might never have been able to investigate this condition, and the significance of the interaction between atorvastatin and integrins might never have been reported. Therefore, I encourage stronger collaboration between basic researchers and clinicians to jointly advance the development of diagnostic tools and therapeutic strategies. The former can facilitate early diagnosis and prognostic assessment, while the latter may offer effective treatment options for patients with drug-induced thrombocytopenia by targeting key pathological mechanisms.
It is important to emphasize that although drug-induced thrombocytopenia has a relatively low incidence, its consequences can be extremely serious and may even be life-threatening. Therefore, greater investment in research funding and human resources is of considerable importance. I would also like to invite young researchers and students who are interested in this field to join us in exploring this area of research, which holds both scientific and clinical significance.
Expert Profile
Professor Heyu Ni
University of Toronto, Canada
- Full Professor in three departments at the University of Toronto: the Department of Medicine, the Department of Physiology, and the Department of Laboratory Medicine and Pathobiology.
- Senior Scientist at Canadian Blood Services.
- Director of the Hematology-Oncology-Immunological Diseases Platform at St. Michael’s Hospital, affiliated with the University of Toronto.
- Founder of CCOA Therapeutics.
In recognition of his groundbreaking research in thrombosis and bleeding disorders, thrombotic thrombocytopenic purpura, and fetal and neonatal alloimmune thrombocytopenia (FNAIT), as well as his outstanding contributions to medical science, Professor Ni was elected a Fellow of the Canadian Academy of Health Sciences in 2020.
