Thrombopoietin receptor agonists in conjunction with oseltamivir for immune thrombocytopenia

Abstract

We present a case of a HIV-positive patient with immune thrombocytopenia (ITP) refractory to treatment with intravenous immunoglobulin (IVIG) and corticosteroids, as well as to several second-line treatments. Complete response was achieved with the combination of a thrombopoietin receptor agonist (TPORA) and the neuraminidase inhibitor oseltamivir. A 51-year-old man presented mucocutaneous hemorrhaging 24 h after onset. His platelet count was 7×109/l with leukocytes and hemoglobin within normal ranges. A peripheral blood smear showed neither schistocytes nor dysplastic features. The medical history indicated HCV treated to an undetectable viral load, and an HIV infection since 1988, with the patient currently undergoing antiretroviral treatment with tenofovir disoproxil difumarate, raltegravir and eravirine. He also had dyslipidemia secondary to the antiretroviral treatment under good control and type 2 diabetes mellitus secondary to pentamidine and was on insulin treatment. In the last check-up 10 days before the hospitalization, the patient presented a CD4+ level of 26% (447 cells/μl) and an undetectable viral load. Thrombocytopenia in patients with HIV infection is usually mild, and lower counts usually occur in advanced stages of the disease, with CD4+ cell counts below 200 cells/μl. It is therefore unlikely that this thrombocytopenia was secondary to the HIV infection. ITP is an autoimmune disease mediated by antibodies against platelet membrane glycoproteins (GP). Platelet destruction mechanism differs according to the GP against which the antibodies are directed. Antibodies against GPIIb/IIIa caused opsonization of platelets that are destroyed through the binding of the constant fraction of immunoglobulins to their receptors present in the spleen macrophages. Antibodies against GPIb/IX [1–3] produce a translocation of the neuraminidase from the granules to platelet surface, which causes a loss of sialic acid in the GPIb/IX. These platelets without sialic acid are taken up by the Ashwell–Morell receptors of the hepatocytes, where they are destroyed [4,5]. This is significant from the therapeutic standpoint, because, when the destruction is independent of the binding to the Fc receptor for immunoglobulin, the blocking of this receptor with IVIG will be ineffective. Patient platelet count and therapeutic treatments along time are shown in Fig. 1a. Up to 40–70% of patients with ITP respond to first-line corticosteroid treatment; however, our case did not and showed hemorrhagic symptoms. We started second-line treatment in the persistent ITP phase with the TPORA eltrombopag because recent studies have shown higher response rates (up to 93%) when the agonist treatment is started in persistent ITP. Owing to the lack of response, we started treatment with the anti-CD20 monoclonal antibody because of the diagnostic suspicion of a splenic lymphoma. After three doses of rituximab, the platelet count did not rise, and the patient had WHO grade 3 hemorrhagic symptoms. Owing to the high risk of bleeding, we performed a partial splenic embolization, which also failed to increase platelet count. Although we were unable to perform a platelet kinetics study due to our patient's thrombocytopenia, we believe that there might be a platelet elimination mechanism other than the splenic destruction. Thus, we began treatment with oseltamivir to inhibit neuraminidase, improve the sialylation of platelet membrane GPs and, consequently, avoid platelet interaction with Ashwell–Morell receptors of the hepatocytes. Platelet count only increased after simultaneous treatment of oseltamivir and TPORA.Fig. 1: (a) Platelet count, bleeding episodes and therapeutic treatments along time.Arrows indicate single therapeutic interventions and green lines periods receiving drug treatments. (b and c) Surface expression of platelet activation markers evaluated by flow cytometry. Platelets from healthy controls and from the patient before and after responding to treatment were stimulated with TRAP (PAR-1 receptor agonist) and ADP and the binding of FITC-PAC1, antibody that recognizes the activated conformation of fibrinogen receptor (b) and FITC-anti-P-selectin antibody were assayed (c). DX, dexamethasone; DZ, danazol; ETPG, eltrombopag; PRD, prednisone; RTXB, rituximab.Few cases have been published on the management of patients with ITP using oseltamivir and none with the combination of this drug and a TPORA as we performed for our patient [6]. In the studies conducted for our patient, oseltamivir restored platelet function (Fig. 1b and c), in contrast to what occurs in patients treated only with TPORA [7], and slightly improved membrane glycoprotein sialylation (data not shown). The combined use of a TPORA (romiplostim) which increases platelet production and another (such as oseltamivir) that re-establishes membrane glycoprotein sialylation can be useful for patients with combined splenic and hepatic destruction mechanisms. Acknowledgements This work was supported by a grant from the ISCIII –Feder, PI12/01831 (N.V.B.). N.V.B. holds a Miguel Servet II tenure track grant from FIS. Conflicts of interest There are no conflicts of interest.