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Vitamin K-antagonism impairs the bone marrow microenvironment and hematopoiesis

Divij Verma, Rahul Kumar, Raquel S. Pereira, Christina Karantanou, Costanza Zanetti, Valentina R. Minciacchi, Keertik Fulzele, Kathrin Kunz, Soraya Hoelper, Sara Zia-Chahabi, Marie-Joëlle Jabagi, Joseph Emmerich, Rosemary Dray-Spira, Franziska Kuhlee, Karl Hackmann, Evelin Schroeck, Philip Wenzel, Stefan Müller, Natalie Filmann, Michaela Fontenay, Paola Divieti-Pajevic and Daniela S. Krause

Key Points

  • - Warfarin impairs murine hematopoiesis via reduction of macrophagic secretion of functional periostin binding to integrin β3 on HSC

  • - Vitamin K antagonism impairs human HSC engraftment and, in humans, associates with modestly reduced leukocyte counts and MDS

Abstract

Vitamin K antagonists (VKA) have been used in 1% of the world's population for prophylaxis or treatment of thromboembolic events for 64 years. Impairment of osteoblast function and osteoporosis has been described in patients on VKA. Given the involvement of cells of the bone marrow microenvironment (BMM), such as mesenchymal stem cells (MSC) and macrophages, as well as other factors like the extracellular matrix for the maintenance of normal hematopoietic stem cells (HSC), we investigated a possible impact of VKA on hematopoiesis via the BMM. Using various transplantation and in vitro assays we show here that VKA alter parameters of bone physiology and reduce functional HSC 8- fold. We implicate impairment of the functional, secreted, vitamin K-dependent, γ-carboxylated form of periostin by macrophages and - to a lesser extent - MSC of the BMM and integrin β3-AKT signaling in HSC as at least partly causative of this effect, with VKA not being directly toxic to HSC. In patients, VKA use associates with modestly reduced leukocyte and monocyte counts, albeit within the normal reference range. VKA decrease human HSC engraftment in immunosuppressed mice. Following published examples that alteration of the BMM can lead to hematological malignancies in mice, we describe - without providing a causal link - that the odds of VKA use is higher in patients with versus without a diagnosis of myelodysplastic syndrome (MDS). These results demonstrate that VKA treatment impairs HSC function via impairment of the BMM and the periostin/integrin β3 axis, possibly associating with increased MDS risk.

  • Submitted September 12, 2018.
  • Revision received April 5, 2019.
  • Accepted April 4, 2019.