Hepatocellular carcinoma (HCC) accounts for the vast majority of liver cancer cases and fatalities. It has become a growing disease burden on a global scale in recent decades (McGlynn, Petrick, and El-Serag, 2021; Singal, Lampertico, and Nahon, 2020; Fitzmaurice et al. 2019.). The World Health Organization estimates an annual rise in the mortality rate of liver cancer patients, exceeding one million by 2030 (Villanueva, 2019). Hepatitis B infections are at present the main risk factors for HCC. Moreover, the presence of cirrhosis, metabolic disorders, and autoimmune diseases as well as genetic predisposition are factors increasing the risk of HCC (Shetty and Kellarai, 2022). Surgical resection represents the established therapeutic approach for HCC patients with good liver function and no obvious vascular invasion or distant metastasis. Although the rate of HCC relapse or development of new tumors has declined due to the development of locoregional and systemic therapies in these years, the rate is over 75% (Siegel et al. 2021; Heimbach et al. 2018; Marrero et al. 2018). HCC is associated with a significant pain and a substantial economic burden. Hence, it is of the utmost importance to identify as yet unknown causes and apply preventive measures to reduce the growing incidence rate.
Aspirin, warfarin, and heparin are common antithrombotic agents. Aspirin, whose active principle is acetylsalicylic acid, is a commonly used medication against inflammatory and antiplatelet diseases (DiNicolantonio Jj Fau - O'Keefe, O'Keefe Jh Fau - Lavie, and Lavie, 2012). So far, no primary prevention trials have been conducted to evaluate the use of Aspirin on HCC risk, but basic and clinical research demonstrates preventive or therapeutic properties against cancer (Drew and Chan, 2021). HCC is classified as an inflammation-associated malignancy involving a series of interconnected processes, including hepatocyte injury, inflammation, necrosis, and subsequent regeneration. These processes lead to a state of chronic inflammation, fibrosis, cirrhosis, and genomic instability, contributing to the development and progression of HCC (Kumar, Zhao X Fau - Wang, and Wang, 2011). Platelets play a pivotal role throughout the necro-inflammatory process in the liver by stimulating the increase of inflammatory and immune cells, increasing risk of liver damage and cancer, and promoting the development of a fibrogenic microenvironment (Iannacone et al. 2005; Maini and Schurich, 2012; Pavlovic et al. 2019). Therefore, the use of antithrombotic agents has been associated with a decreased risk of HCC. Rebecca W. Zeng et al. used a random effects model pooling multivariable-adjusted hazard ratios for HCC using the Medline and Embase databases, revealing that the use of aspirin is associated with the risk of HCC, although its degree of significance is not yet clear (Zeng et al. 2023). Although many observational studies showed an inverse association between the use of antithrombotic agents and HCC risk, few have directly assessed the association between antithrombotic agents and HCC. Therefore, a randomized controlled trial would be the ideal study design to identify the effect of the use of antithrombotic agents on HCC risk.
Significant advances were performed during the last decade on large-scale genome-wide association studies (GWASs) and on the powerful statistical tool mendelian randomization (MR). These progresses provide valuable opportunities to comprehensively and cost-effectively evaluate the causal relationship among various phenotypes (Wu et al. 2019). MR is a scientific approach that uses genetic variations as instrumental variables (IVs) to assess whether the observed association between risk factors and outcomes indicates a causal relationship (Burgess, Daniel, et al. 2015). MR analysis overcomes the influence of confounding factors, including behavioral and environmental factors (Burgess, Butterworth A Fau - Malarstig, et al. 2012; Smith and Ebrahim, 2004). Furthermore, it provides reliable evidence on causal relationships between risk factors and diseases, simultaneously guiding the performance of clinical trials and the development of pharmaceutical interventions (Davies, Holmes, and Davey Smith, 2012; Burgess, Butterworth A Fau - Malarstig, et al. 2018).
Therefore, our study make use of two-sample MR to evaluate the causal relationship between the use of antithrombotic agents and HCC risk. The latest drug GWAS data that cover a wide range of populations were used, and accessing the dependability of MR results was evaluated. Our result might provide new evidence being in favor of the causal relationships between the use of antithrombotic agents and HCC risk, providing potential direction for future drug trials.