An association is determined between the use of oral contraceptives (CC) in iron deficiency patients (ID) and Ischemic stroke (IS). However, it is still unclear as to the underlying mechanisms. With the knowledge that CC and ID upregulate transferrin (Tf) in the blood, this study showed that upregulation causes an increase in thrombin and FXIIa and blocks antithrombin proteases’ interactions leads in turn to hypercoagulability.

An evaluation of Tf levels was done on patients and mice with varied cases of IS, ID, and venous thromboembolism using both in vitro and in vivo methods to study the effects of estrogen and ID. Tf and complexes of Tf-thrombin/FXIIa were detected at high levels in the results. ID upregulated Tf by hypoxia, and estrogen did so through estrogen response elements in regions that enhance Tf genes. Moreover, iron deficiency, exterior estrogen administration, and Tf, and overexpression of Tf generated an excess of platelet-based thrombin and hypercoagulability, which evoked IS. On the other hand, in vivo methods, anti-Tf, peptide inhibitors, and Tf knockdown antibodies fulfill an anti-IS effect.

In conclusion, CC and ID upregulate Tf and cause thromboembolic diseases, and this was a novel finding in terms of IS. Copulatively, there is a correlation between CC, ID, Tf, and thrombosis, and factors that upregulate Tf are a risk for thromboembolic diseases. This study’s results are a basis for developing an anti-IS medicine related to CC and ID, which either targets Tf or blocks interactions of Tf-thrombin/FXIIa.