Iron deficiency-induced thrombocytosis increases thrombotic tendency in rats

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 thrombotic 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 histologically and by high frequency ultrasound in the venous model. ID consistently 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 correlated with the final thrombus size, with thrombi in iron-deficient animals having the largest platelet areas. Platelet function was also evaluated in surgically-naive rats. Coagulability, determined by thromboelastography, 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 aggregation 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 prevention 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 kidney disease, or cancer.