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Thromb Haemost
DOI: 10.1055/a-2733-6331
Invited Editorial Focus

Obesity and Tissue Factor Driven Thrombin Generation: A Thick Connection

Authors

  • Qi Luo

    1   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
    2   Department of Biochemistry, Cardiovascular Research Maastricht University, Maastricht, the Netherlands
    3   German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany

  • Philip Wenzel 

    1   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
    3   German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
    4   Medical Clinic I - Cardiology and Internal Intensive Care Medicine, Darmstadt Hospital, Darmstadt, Germany

Funding Q.L. was supported by the European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie grant Agreement TICARDIO No. 813409. P.W. was supported by the German Research Foundation (grant DFG WE WE4361/14-1), the Clusters for Future grant curATime (BMBF [Bundesministerium für Bildung und Forschung] grant 03ZU1202HB) and the Center for Thrombosis and Hemostasis (BMBF 01EO1003).
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Obesity, a chronic disease characterized by a body mass index (BMI) exceeding 30 kg/m2, has become a worldwide epidemic with devastating health and economic burdens. It is strongly associated with an increased risk of thrombotic events,[1] [2] [3] cardiovascular disease, type 2 diabetes mellitus (T2DM), dyslipidemia, and certain cancers.[4] [5] [6] Emerging evidence suggests that the underlying pathological mechanisms are partly driven by an imbalance in plasma procoagulants, in particular hypercoagulability. Routine laboratory tests (e.g., PT, APTT) are often insufficient to detect this hypercoagulability. The calibrated automated thrombogram (CAT) assay, which measures in vitro thrombin generation (TG), represents a promising approach to evaluate an individual's hypercoagulability.[7] It is widely known that endogenous thrombin potential (ETP) is elevated in obese patients, particularly those with metabolic syndrome, and is positively correlated with severity of obesity. However, results regarding thrombin generation at the initial phase (parameter shown as lag time) in overweight/obese patients have reported conflicting results,[2] [8] underscoring a gap in our understanding of coagulation initiation in obesity.

Tissue factor (TF) is a membrane-bound glycoprotein that is exposed at sites of vascular injury. Exposed TF binds circulating FVIIa and generates FXa, which converts prothrombin to thrombin. TF is a key trigger for initial thrombin generation. An increasing number of studies have shown that TF also plays an important role in the development of obesity and metabolic syndrome.[9] [10] [11] TF is overexpressed in obesity due to chronic inflammation and adipose tissue dysfunction, resulting in a pro-thrombotic tendency. The initial TG driven by the TF pathway is likely to relate to the hypercoagulability observed in obesity.

In line with this concept, the journal Thrombosis and Haemostasis features a study from Kamikubo and colleagues,[12] who have developed a highly sensitive fluorescent assay method focusing on measuring initial TG in healthy/overweight subjects. Furthermore, they tested male Tsumura Suzuki obese diabetic (TSOD) mice, a mouse model of spontaneous type 2 diabetes and obesity. In the human study, initial TG levels in PPP did not differ significantly between healthy and overweight individuals under stimulation with exogenous TF and phospholipids. Notably, in the absence of exogenous TF, overweight individuals showed markedly elevated TG levels, but this phenomenon was blocked by anti-TF antibodies, suggesting that the core factor of the initial TG was endogenous TF activity. Parallel observations in TSOD mice revealed that initial TG driven by the TF pathway in TSOD mice was significantly increased. The authors further confirmed that the procoagulant TF in the PPP of TSOD mice was mainly derived from microvesicles (TF-MVs) (Graphical Abstract). Furthermore, the study identified sex-based differences in initial TG among healthy subjects, consistent with the classic continuous TG measurement. The authors integrated both human and animal data to prove that hypercoagulability in obesity and even pre-obesity was associated with elevated initial TG driven by endogenous TF.

However, open questions remain to be addressed in the future. The population size of overweight individuals was limited, which may have affected the statistical power and extrapolation of the study. A large population cohort study would be necessary to confirm the observations. It would also be interesting to include the study of initial TG levels in patients with different degrees of obesity (based on BMI) or in other populations (e.g., patients with diabetes, metabolic syndrome, or arterial hypertension). Interestingly, a role for FXI-dependent thrombin generation in platelet-rich plasma (PRP) was identified in arterial hypertension, and patients with uncontrolled blood pressure have significantly higher TG levels in their PRP compared to controls.[13] Longitudinal studies would be particularly valuable to check whether this marker has predictive value as an early warning indicator for actual thrombotic events or responds to interventions such as weight loss or pharmacologic therapy. Taken together, the study by Kamikubo and colleagues provides a rapid and precise tool for studying the early mechanism of obesity-related hypercoagulability, elucidating to some extent the interplay between TF, hypercoagulability, and obesity, and might open new windows for risk assessment and therapeutic monitoring in obesity-related thrombosis.



Publication History

Received: 27 October 2025

Accepted: 28 October 2025

Accepted Manuscript online:
29 October 2025

Article published online:
28 November 2025

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