Iron deficiency-induced thrombocytosis increases thrombotic tendency in rats

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. Herein we used animal models to assess the influence of ID on thrombotic tendency. Sprague-Dawley rats were fed control or iron deficient diets and ferric carboxymaltose was used to reverse ID. Thrombosis was induced via stenosis of the inferior vena cava or damage to the right carotid artery using ferric chloride. Thrombi were evaluated histologically and via high frequency ultrasound in the venous model. ID consistently induced thrombocytosis alongside anemia. Venous thrombus growth and final dimensions in both arterial and venous thrombi were largest in ID. In both models, platelet numbers correlated with the final thrombus size, with ID thrombi having the largest platelet areas. Platelet function was also evaluated in surgically naïve rats. Coagulability on thromboelastography and hemostasis on tail transection were augmented in ID. Platelet and plasma Pselectin expression were both higher in ID. Platelet adhesion and aggregation in ID was impaired under shear flow but was intact on static assays. Iron replacement therapy reversed all ID-related changes in hematological 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 prevention of ID-related thrombotic disease. This may be of importance in patients with chronic illnesses which may already be at increased risk for thrombosis such as inflammatory bowel disease, chronic kidney disease, or cancer.

The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis?

“…In addition, platelet adhesion and aggregation were impaired. Taking into account data obtained in this model, the authors concluded that anemia of inflammation, caused by HAMP-mediated iron sequestration in the liver, spleen and macrophages, as possibly occurs in COVID-19 patients, may be considered a functional iron deficiency (ID) and patients affected by this condition should be treated as patients with high risk of thrombosis [139].…”

Characterization of the rate, predictors, and thrombotic complications of thrombocytosis in iron deficiency anemia

“…Iron deficiency anemia itself has been shown to be associated with thrombotic events in several small retrospective studies 13‐16 . Although recent animal studies demonstrated an elevated thrombotic risk in iron deficient mice with thrombus size correlating with platelet count 17 , whether the elevated thrombotic risk in IDA can be attributed to thrombocytosis has not been clearly elucidated in human analyses. There are numerous case reports describing thrombotic events (particularly in unusual sites) in patients with thrombocytosis reactive to IDA and no other thrombotic risks suggesting a possible relationship 18,19 .…”

Recognition of thrombotic risk of thrombocytosis in iron deficiency

“…In this issue of Haematologica, Jimenez and colleagues describe an animal model of iron deficiency, using Sprague-Dawley rats, which could offer unique opportunities to explore multiple pathophysiological mechanisms for thrombocytosis and venous thrombogenesis. 5 Furthermore, using sensitive histological and sophisticated high-frequency ultrasound techniques, the investigators were able to track the development and progression of thrombus formation. They were then able to correlate those changes with the generation of ex vivo biomarkers of platelet activation and indicators of global hemostasis.…”