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Combined oral contraceptives are used by millions of people globally and contain progestin, a synthetic progesterone, and synthetic oestrogen in the form of ethinylestradiol which act to prevent ovulation. The use of combined oral contraceptives is associated with an increased risk of venous clot formation. A key inhibitor of the clotting response, activated protein C (APC), has reduced efficacy in users of oral contraceptives - the users develop APC resistance. The mechanism behind this APC resistance is not fully understood; we turned to mathematical models to explore how biological changes induced by oral contraceptives are linked to APC resistance.

Clot formation occurs as the result of a complex network of interactions between cells and proteins in the blood. This process can be modelled mathematically by writing differential equations governing the concentration of each of these factors. The model can then be solved to give the time evolution of each factor given specified input values. Clinical studies have shown the oral contraceptives alter the levels of some of the key factors in the clotting pathway. By combining established models with clinical data, we can begin to learn about potential reasons for APC resistance.

Based on the clinical data, we generated a large virtual population of patients which matched the real patient baseline data. Using the reported changes induced in factor levels by oral contraceptives, we explored the differences in the clotting response, both for individuals and across the population. We were able to identify key factor levels which led to the most extreme changes in clotting response following the use of oral contraceptives. For all virtual patients, we found that the changes in factor levels alone were sufficient to cause reduced sensitivity to APC.

Graphs of used patient factor level data to simulate a virtual population of patients

Figure: We used patient factor level data to simulate a virtual population of patients. Combined oral contraceptives impact these factor levels. Incorporating this into our modelling, we can simulate the coagulation process in each virtual patient.

This project started at the 2022 Collaborative Workshop for Women in Mathematical Biology: Mathematical Approaches to Support Women’s Health, hosted by the Institute of Mathematics and its Applications at the University of Minnesota and United Health Group Optum. The researchers involved are Suzanne Sindi, Melissa Stadt, Ivy Xiong, Anna Nelson, Amy Kent, Ying Zhang and Karin Leiderman. Amy Kent is a postdoctoral research associate in Oxford Mathematics.


Lidegaard, Øjvind, et al. "Hormonal contraception and venous thromboembolism." Acta obstetricia et gynecologica Scandinavica 91.7 (2012): 769-778.

Middeldorp, Saskia, et al. "Effects on coagulation of levonorgestrel-and desogestrel-containing low dose oral contraceptives: a cross-over study." Thrombosis and haemostasis 84.07 (2000): 4-8.

Fogelson, Aaron L., and Nessy Tania. "Coagulation under flow: the influence of flow-mediated transport on the initiation and inhibition of coagulation.Pathophysiology of haemostasis and thrombosis 34.2-3 (2005): 91-108.

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