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Ferrata Storti Foundation
Haematologica 2021 Volume 106(3):782-794
Iron Metabolism and its Disorders
Iron deficiency-induced thrombocytosis increases thrombotic tendency in rats
Kristine Jimenez,1 Florentina Leitner,1 Aran Leitner,1 Gisela Scharbert,2 Philipp Schwabl,1 Anne-Margarethe Kramer,3 Anita Krnjic,1 Joachim Friske,4 Thomas Helbich,4 Rayko Evstatiev,1 Vineeta Khare1 and Christoph Gasche1
1Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna; 2Department of Special Anesthesiology and Pain Management, General Intensive Care and Pain Control, Medical University of Vienna; 3Department of Biomedical Research, Medical University of Vienna and 4Department of Biomedical Imaging and Image-guided Therapy, Division of Gender and Molecular Imaging, Medical University of Vienna, Vienna, Austria
ABSTRACT
Iron deficiency (ID) is globally prevalent, and apart from anemia is associated with thrombocytosis. While considered benign, studies linking thrombotic events with prior ID anemia suggest otherwise. In this study we used animal models to assess the influence of ID on throm- botic tendency. Sprague-Dawley rats were fed control or iron-deficient diets and ferric carboxymaltose was used to reverse ID. Thrombosis was induced by stenosis of the inferior vena cava or damage to the right carotid artery using ferric chloride. Thrombi were evaluated histological- ly and by high frequency ultrasound in the venous model. ID consistent- ly induced thrombocytosis alongside anemia. The growth of venous thrombi and the final dimensions of both arterial and venous thrombi were greater in animals with ID. In both models, platelet numbers corre- lated with the final thrombus size, with thrombi in iron-deficient ani- mals having the largest platelet areas. Platelet function was also evaluat- ed in surgically-naïve rats. Coagulability, determined by thromboelasto- graphy, and hemostasis, evaluated by tail transection, were enhanced in the animals with ID. Platelet P-selectin expression and plasma P-selectin levels were both higher in animals with ID. Platelet adhesion and aggre- gation in ID was impaired under shear flow but was intact in static assays. Iron replacement therapy reversed all ID-related changes in hematologic parameters, thrombus dimensions, and platelet assays. In summary, ID alone increases thrombotic tendency. Iron replacement therapy reverses these changes, making it a viable strategy for the pre- vention of ID-related thrombotic disease. This may be of importance in patients with chronic illnesses who may already be at increased risk of thrombosis, such as those with inflammatory bowel disease, chronic kid- ney disease, or cancer.
Introduction
Iron-deficiency anemia (IDA) affects over 1.2 billion people worldwide, with per- haps just as many having iron deficiency (ID) without manifest anemia.1 Iron is essential, being vital to oxygen transport via hemoglobin, mitochondrial function, DNA replication and repair, cellular metabolism and signaling, and it even plays a role in host defenses.2 Thus, apart from anemia, ID has been connected to impaired cognition and muscular function, and is detrimental in the context of cardiovascu- lar disease.1,3 ID is also a known cause of thrombocytosis, although the pathological consequences of this phenomenon have not been well studied.4
Numerous studies have linked thrombotic events with prior IDA.5-11 In adults, patients with ischemic stroke or venous thromboembolism (VTE) were about 1.4 times more likely to have had prior IDA.10,11 In children, in whom ID is more com- mon, prior IDA was 3.8 to 10 times more likely in those who suffered a stroke.8,9 Platelet counts were also higher in patients with stroke and IDA. In one prospective
Correspondence:
CHRISTOPH GASCHE
christoph.gasche@meduniwien.ac.at
Received: December 13, 2019. Accepted: February 17, 2020. Pre-published: February 20, 2020.
https://doi.org/10.3324/haematol.2019.245092
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