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Editorials
Figure 1. Rates of thrombocytosis and thrombosis among patients with iron-deficiency anemia. Rates of thrombocytosis and thrombosis in a recent large clinical database study of over six million patients, supported by extensive chart review to exclude alternative confounding causes of thrombocytosis and confirm thrombotic events.4
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ciency with a number of clinical conditions with known thrombotic risk such as inflammatory bowel disease and cancer, this animal model clearly demonstrates that iron deficiency alone increases thrombotic tendency, consis- tent with the findings of aforementioned human studies. Perhaps even more importantly, treatment with ferric car- boxymaltose (an intravenous iron formulation) reversed the prothrombotic changes in the rats, including throm- bocytosis, changes in platelet function, and iron deficien- cy-associated increases in thrombus size in both venous and arterial models of thrombosis.
The development of a high quality animal model to lend support to the longstanding observation of iron deficiency mediated-thrombocytosis leading to a significantly higher risk of thrombosis is an important advance. Without strat- ifying for iron deficiency or its successful abatement by intravenous iron, the observation of a marked increment in thromboses in erythropoiesis stimulating agent-treated patients with cancer and chemotherapy-induced anemia and anemia associated with both non-dialysis and dialy- sis-dependent chronic kidney disease led to the near pro- scription of the use of a treatment which unqualifiedly leads to improvements in energy, activity and quality of life in a cohort with debilitating chronic illness. Despite a litany of prospective, randomized, placebo-controlled studies failing to show harm with the use of erythro- poiesis-stimulating agents, especially in cancer and chemotherapy-induced anemia,6 extreme caution with their use remains the order of the day.
A now growing body of inferential evidence supports the use of intravenous iron as the preferred route of administra- tion in most of the described conditions. This new animal model provides evidence that intravenous iron replenish- ment may have additional advantages in mitigating the thrombogenic potential of iron deficiency. It also suggests that intravenous iron might preferentially provide an important adjunctive therapy to mitigate the hypercoagula- bility associated with iron-deficiency states comorbid with multiple disorders in humans, such as cancer, inflammatory bowel disease, after bariatric surgery, abnormal uterine bleeding and pregnancy. Given that iron-deficiency anemia affects approximately 20% of the human population at any given point in time,7 even a modestly increased thrombotic risk imparted by iron deficiency has profound public health implications. Additionally, synergism of multiple thrombot- ic risk factors is well-documented,8 raising the specter of a potentially even greater thrombotic impact of this common problem given its frequent comorbidities. Thankfully, addi- tional avenues of investigation to better understand these risks are open, as this animal model also suggests that criti- cal biomarkers can now be explored and can then be corre- lated with objective in vivo events. Such biomarkers could also include the hypoxia-inducible factors HIF-1 and HIF-2, whose target genes include erythropoietin, the transferrin receptor and vascular endothelial growth factor. These tar- gets are also associated with increased thrombogenesis.
Despite the overwhelming preponderance of published evidence supporting the safety and efficacy of intra-
haematologica | 2021; 106(3)