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Recognition of thrombotic risk of thrombocytosis in iron deficiency
Hanny Al-Samkari,1 Craig M. Kessler2 and Michael Auerbach2
1Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA and 2Department of Medicine, Georgetown University School of Medicine, Washington, DC, USA
E-mail: MICHAEL AUERBACH - mauerbachmd@abhemonc.com doi:10.3324/haematol.2020.270496
In 1999, Loo and Beguin examined the effect of recom- binant human erythropoietin on megakaryopoiesis, noting that iron-replete and iron-overloaded rats treat- ed with recombinant human erythropoietin demonstrat- ed a one-third decreased duration of thrombocytosis compared with normal rats.1 The putative explanation given for the increased duration in the normal rats was erythropoietin-induced, iron-deficient erythropoiesis. This provocative hypothesis was subsequently supported by the findings of a post-hoc analysis2 of a large prospec- tive study of oral versus intravenous or no iron as adjunc- tive therapy for erythropoiesis-stimulating agent-treated patients with cancer and chemotherapy-induced anemia.3 This study demonstrated that intravenous, but not oral, iron repletion resulted in marked improvements in hemo- globin and hematopoietic responses and also re-demon- strated the known associations of increased thromboses and thrombocytosis among patients with cancer receiv- ing erythropoiesis-stimulating agents. Of 187 patients treated with an erythropoiesis-stimulating agent, 19 developed 29 venous thromboembolic events and those with platelet counts greater than 350,000 per microliter were three times more likely to develop venous throm- boembolism. Notably, there was a reduced incidence of thrombocytosis and thrombotic complications in those treated with intravenous iron compared with those who were not.
Further corroborating evidence pointing to iron-restrict- ed erythropoiesis resulting in reactive thrombocytosis and thrombosis was derived from a recently published study describing the rate, predictors, and thrombotic complications of thrombocytosis in patients with iron- deficiency anemia.4 Utilizing queries of an institutional database containing clinical information on more than six
million patients over a 40-year time period (1979-2019), supported by extensive manual chart reviews, thrombo- cytosis was observed in 32.6% of patients with iron-defi- ciency anemia, in whom 15.8% developed thrombotic complications. In contrast, thromboses occurred in 7.8% of those with iron deficiency but without thrombocytosis (Figure 1).
The etiological explanation for why iron-restricted ery- thropoiesis increases hypercoagulability has remained somewhat obscure. In this issue of Haematologica, Jimenez and colleagues describe an animal model of iron deficien- cy, using Sprague-Dawley rats, which could offer unique opportunities to explore multiple pathophysiological mechanisms for thrombocytosis and venous thromboge- nesis.5 Furthermore, using sensitive histological and sophisticated high-frequency ultrasound techniques, the investigators were able to track the development and pro- gression of thrombus formation. They were then able to correlate those changes with the generation of ex vivo bio- markers of platelet activation and indicators of global hemostasis. The potential use of this rat model to detect important targets that could be exploited therapeutically to mitigate the association of iron deficiency with throm- bocytosis and thromboembolism is promising and encouraging.
In their elegant description of iron deficiency-induced augmentation of coagulability on thromboelastography and hemostasis following rat tail resection, prominent correlates of increased platelet adhesion and aggregation were clearly described. Using in vitro assays of platelet aggregation, the authors were able to postulate that not only is platelet activation an ongoing process in inflam- matory conditions but in iron deficiency as well. Importantly, given the frequent comorbidity of iron defi-
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