Interferon Alpha Therapy Increases Pro-Thrombotic Biomarkers in Patients with Myeloproliferative Neoplasms.

Dorothée Faille,Nadine Ajzenberg,Marie-Charlotte Bourrienne,Sawsaneh Alkhaier,Bruno Cassinat,Lamia Lamrani,Jérôme Debus,Marie-Geneviève Huisse,Yacine Boulaftali,Christine Dosquet,Martine Jandrot-Perrus,Christine Chomienne,Stéphane Loyau

doi:10.3390/cancers12040992

Abstract

Myeloproliferative neoplasms (MPN) are associated with an increased risk of arterial and venous thrombosis. Pegylated-interferon alpha (IFN) and hydroxyurea (HU) are commonly used to treat MPN, but their effect on hemostasis has not yet been studied. The aim of our study was to determine whether IFN and HU impact the biological hemostatic profile of MPN patients by studying markers of endothelial, platelet, and coagulation activation. A total of 85 patients (50 polycythemia vera and 35 essential thrombocythemia) were included: 28 treated with IFN, 35 with HU, and 22 with no cytoreductive drug (non-treated, NT). Von Willebrand factor, shear-induced platelet aggregation, factor VIII coagulant activity (FVIII:C), fibrinogen, and thrombin generation with and without exogenous thrombomodulin were significantly higher in IFN-treated patients compared to NT patients, while protein S anticoagulant activity was lower. In 10 patients in whom IFN therapy was discontinued, these hemostatic biomarkers returned to the values observed in NT patients, strongly suggesting an impact of IFN therapy on endothelial and coagulation activation. Overall, our study shows that treatment with IFN is associated with significant and reversible effects on the biological hemostatic profile of MPN patients. Whether they could be associated with an increased thrombotic risk remains to be determined in further randomized clinical studies.

Highlights

Myeloproliferative neoplasms (MPN) are clonal diseases resulting from the dysregulated production of mature myeloid cells by hematopoietic stem cells affected by a molecular defect.BCR-ABL-negative MPN include polycythemia vera (PV), essential thrombocytemia (ET), and primary myelofibrosis
As platelet aggregation under high shear conditions is dependent of von Willebrand factor (vWF), we evaluated shear-induced platelet aggregation (SIPA) at 4000 s−1 in all patients
Our study shows that the treatment with interferon alpha (IFN) is associated with significant and reversible effects on the biological hemostatic profile of MPN patients

Summary

Introduction

BCR-ABL-negative MPN include polycythemia vera (PV), essential thrombocytemia (ET), and primary myelofibrosis. They are associated with somatic mutations in 3 driver genes: JAK2, CALR, and MPL in more than 90% of patients. The most frequent one is JAK2V617F mutation [1]. Cancers 2020, 12, 992 mutation, the hyperactivation of JAK2-STAT signaling has a central role in MPN pathophysiology [2,3]. MPN are characterized by a predisposition to thrombotic events that significantly affect patient morbidity and mortality. Thrombotic events at diagnosis and during follow up are more frequent in PV than in ET, with the prevalence of major thrombosis at diagnosis ranging from 19% to 38% and from 7%

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