Sialidase inhibition to increase platelet counts: A new treatment option for thrombocytopenia
Authors: Arend Jan Gerard Jansen, Jun Peng, Hong‐Guo Zhao, Ming Hou, Heyu Ni
Journal: American Journal of Hematology (2015)

Recent studies revealed that platelets normally gradually loose surface sialic acid as they circulate and age through cleavage by sialidases 1. It has been shown in vitro that desialylation of the platelet von Willebrand Factor Receptor Complex triggers platelet clearance and primes glycoprotein (GP)Ibα and GPV for metalloproteinase dependent cleavage, which could be circumvented with a sialidase inhibitor 2. Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-induced platelet destruction, often resulting in mild bleeding symptoms, but may also lead to severe bleeding manifestations such as intracranial hemorrhage 3. Many ITP patients, particularly patients with anti-GP Ib-IX autoantibodies, do not respond to conventional treatments such as steroids, intravenous immunoglobulins, or splenectomy 4-8. Also the role of new therapies like thrombopoietin agonist are unclear and not without risks 9. Oseltamivir phosphate, the ethyl ester prodrug of oseltamivir carboxylate that conventionally serves as an antiviral sialidase inhibitor, has been prescribed worldwide for the treatment of patients with influenza 10. Sporadic case reports showed a significant response on platelet count in patients with chronic ITP who were treated with oseltamivir 6, 11. We hypothesized that oseltamivir treatment leads to an increase in platelet count due to its inhibition of sialidases. To investigate this, we performed a retrospective observational study in consecutive patients from the Erasmus Medical Center, Rotterdam, The Netherlands. From January 2011 till May 2013, a total of 175 patients were prescribed oseltamivir (Tamiflu) because of suspicion of influenza and 204 patients were tested positive for influenza. Patients were divided into patients with oseltamivir treatment with proven influenza (N = 117), and without influenza (N = 58) and patients without oseltamivir with proven influenza (N = 87). Mean age was 52.2, 51.3, and 54.4 years, respectively. The mean amount of days of oseltamivir treatment was 4.3 and 6.0 for patients without and with influenza. Platelet count of 109 patients was available on Day 1: patients with oseltamivir treatment without influenza (N = 24), patients with oseltamivir treatment with influenza (N = 53) and patients with influenza without oseltamivir treatment (N = 32). Figure 1A shows an increase in mean platelet count during treatment with oseltamivir. Although not significant this increase was larger in patients without influenza. After 5 days of treatment, a significant increase in platelet count was found in patients treated with oseltamivir compared to patients who did not use oseltamivir (Fig. 1B). No significant differences were found between patients treated with oseltamivir with and without influenza. A: Platelet count in patients with and without treatment with oseltamivir. A trend to increase in platelet count was found in patients with oseltamivir treatment with and without influenza, but statistical significance was not reached (P > 0.05). Mean and s.e.m. are given. B: Percentage of increase in platelet count 5 days after start of treatment with oseltamivir. Percentage of increase in platelet count 5 days after treatment with oseltamivir in patients with and without influenza and in patients with influenza without oseltamivir treatment. *P < 0.05 compared to patients with influenza without oseltamivir (measured with the non-parametric Mann–Whitney test). This is the first study that investigates the effect of oseltamivir, a sialidase inhibitor, on platelet counts. We found a significant increase in platelet counts in a large cohort of patients who used oseltamivir. This was independent whether influenza was diagnosed, which is in concordance with the positive effects on platelet counts in patients with chronic ITP and influenza. This study is a proof of principle that sialidase inhibition increases platelet count in humans, probably by decreasing clearance of platelets. This might provide a bans for a new treatment option for patients with thrombocytopenia refractory to current treatment regimens. Further (prospective) research is needed to investigate the role of oseltamivir in treatment of patients with thrombocytopenia or platelet transfusion. AJGJ designed and performed research, collected and analyzed data, interpreted results, and wrote the manuscript. JP, HGZ, and MH designed research, interpreted results, and participated in discussions. HN designed research, interpreted results, and assisted in writing the paper. All authors have read and approved the manuscript for submission. Arend Jan Gerard Jansen,1,2* Jun Peng,3,4 Hong-Guo Zhao,5 Ming Hou,3,4 Heyu Ni,6,7,8,9 1Department of Hematology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands; 2Department of Plasma Proteins, Sanquin-AMC Landsteiner Laboratory, Amsterdam, The Netherlands; 3Department of Hematology, Qilu Hospital, Shandong University, Jinan, China; 4Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China; 5Department of Hematology, the Affiliated Hospital of Qingdao University Medical College, Qingdao, China; 6Toronto Platelet Immunobiology Group, Toronto, Ontario, Canada; 7Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada; 8Canadian Blood Services; 9Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada