The Iron Uptake Receptor Transferrin Receptor 1 (TfR1) Is Required for Proper Platelet and Megakaryocyte Function in Mice

T. Vögtle¹, A. Deuschel¹, L.I. Schober¹, A. Geier², H.M. Hermanns², A. Braun¹, B. Nieswandt¹

¹Institute of Experimental Biomedicine, University Hospital Würzburg and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany, ²Medical Clinic II, Division of Hepatology, University Hospital Würzburg, Würzburg, Germany

Abstract Number: PB1703

Meeting: ISTH 2020 Congress

Theme: Platelets and Megakaryocytes » Platelet Function and Interactions

Background: Dysregulated iron uptake is a risk factor for the development of thrombotic disorders in humans. Abnormal platelet production is frequently detected in patients with iron deficiency anemia (IDA) which can be normalized with iron supplementation. Although a mouse model of IDA showed partially defective megakaryopoiesis, the underlying molecular mechanisms of cellular iron uptake in megakaryocytes have not been established. Transferrin receptor 1 (TfR1) has been proposed to regulate cellular iron uptake in mammalian cells. Recently, a missense mutation in TfR1 was identified in patients presenting combined immunodeficiency and thrombocytopenia, indicating an essential role of TfR1 in the hematopoietic system.

Aims: To assess the role of TfR1 in platelet and megakaryocyte function.

Methods: We utilized megakaryocyte- and platelet-specific TfR1 knockout mice (Tfrc^{fl/fl-Pf4-Cre}) and investigated the role of TfR1 in various in vitro experiments of platelet function. Ploidy levels of in vitro differentiated MKs were measured by flow cytometry

Results: Similar to human patients, Tfrc^{fl/fl-Pf4-Cre} mice developed a thrombocytopenia, while the mean platelet volume was unaltered. This might be a consequence of impaired platelet production, since MKs that were differentiated from Tfrc^{fl/fl-Pf4-Cre} bone marrow showed fewer cells of high ploidy as compared to their wild-type counterparts. Upon activation, platelets from TfR1-deficient mice showed defective activation in response to GPCR and (hem)ITAM-coupled receptor agonists. Notably, agonist-induced Ca²⁺ influx, as well as thapsigargin-triggered store-operated Ca²⁺ entry was strongly impaired in platelets lacking TfR1, directly linking iron and Ca²⁺ homeostasis.

Conclusions: These results establish a regulatory role for iron homeostasis in general and for TfR1 in particular in platelet function. This may have implications for patients with iron disorders.

To cite this abstract in AMA style:

Vögtle T, Deuschel A, Schober LI, Geier A, Hermanns HM, Braun A, Nieswandt B. The Iron Uptake Receptor Transferrin Receptor 1 (TfR1) Is Required for Proper Platelet and Megakaryocyte Function in Mice [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/the-iron-uptake-receptor-transferrin-receptor-1-tfr1-is-required-for-proper-platelet-and-megakaryocyte-function-in-mice/. Accessed September 29, 2023.

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