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. 2026 Feb 20;105(8):e47589. doi: 10.1097/MD.0000000000047589

The impact of different intensities of physical activity on the risk of venous thromboembolism: A Mendelian randomization study

Yongjin Xie a, Jintuo Zhou b, Yanting Zhu b, Yingling Xie c,*
PMCID: PMC12928901  PMID: 41731807

Abstract

Venous thromboembolism (VTE) is a leading cause of cardiovascular disease, which seriously threatens human health. Physical activity (PA) has multiple benefits for health and well-being, while whether PA is associated with the risk of VTE remains debated. A 2-sample Mendelian randomization (MR) analysis was conducted to evaluate the causal relationship between different intensities of PA and the risk of VTE. Genetic instruments associated with PA were sourced from the UK Biobank, and VTE data came from the latest publicly released R10 data of the FinnGen study. The primary statistical method employed was the inverse variance weighted approach. MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier tests were then used to evaluate the robustness of the results. Data of 4,12,181 individuals with VTE from FinnGen and 13,35,561 participants with 3 intensities of PA from UK Biobank were obtained. Our study revealed a significant association between vigorous PA and a reduced risk of VTE (OR = 0.727, 95% CI = 0.576–0.920, P < .017). Regarding the impact of light and moderate PA on VTE risk, these associations did not achieve statistical significance (P > .017). However, at a relaxed significance level (0.017 < P < .05), the inverse variance weighted method identified suggestive evidence of an association between light PA and a reduced risk of VTE (OR = 0.778, 95% CI = 0.610–0.994, P = .045). This study revealed a significant association between vigorous PA and a reduced risk of VTE, providing constructive suggestions for VTE preventive and intervention strategies.

Keywords: Mendelian randomization, physical activity, risk, venous thromboembolism

1. Introduction

Venous thromboembolism (VTE) is a leading cause of cardiovascular disease (CVD) with severe complications and potentially fatal outcomes. In China, the incidence of VTE among hospitalized patients, especially in high-risk populations, has significantly increased over time.[1] This may be partly attributed to advances in VTE detection technology,[2] and also a higher prevalence of obesity and a less active lifestyle in the population.[3] VTE poses an increasing global health burden due to the increased morbidity, mortality and hospitalization.[4] Risk factors for VTE include hospitalization, malignancy, trauma, surgery, congestive heart failure, estrogen supplementation, and central venous access, however, about a quarter to half of patients have no predisposing risk factors.[5]

Physical activity (PA) was defined as the number of activities a participant performed in a week that were sufficient to sweat. PA has multiple benefits for health and well-being, and its opposite effects on CVD are well documented.[6] PA has a positive role in physiological and metabolic processes and may reduce vascular risk by improving endothelial function, reducing cardiovascular risk factor levels,[7] enhancing cardiac function,[8] and exerting anti-inflammatory effects.[9] There is evidence that PA can stimulate hemostasis and fibrinolytic systems,[10] and prolonged sedentary was regarded as a promoter for VTE events.[11] According to a recent meta-analysis, an association between high-intensity PA and thrombosis has been reported in some studies, but not all.[12] Further research is warranted to clarify the relationship between high level PA and VTE.

Mendelian randomization (MR), an epidemiological method that uses genetic variation as an instrumental variable (IV), is increasingly being applied to assess the causal relationships between risk factors and outcomes.[13] There are 3 main reasons why MR has been widely used recent years: inherent defects of traditional design, namely, the possibility of reverse causality and confounding factors cannot be completely excluded in current observational studies, which may lead to biased conclusions; randomized controlled studies are difficult in practice because they require a lot of human resources and time-consuming follow-up[14]; in MR approach, the random distribution of genotypes during meiosis can avoid reverse causality and minimize confusion.[15]

In this study, we employed 2-sample MR analysis to evaluate the causal relationship between different intensities of PA and the risk of VTE, providing constructive suggestions for VTE preventive and intervention strategies.

2. Materials and methods

Our study conformed to the Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization (STROBE-MR) guidelines. Since all data used in this MR study were sourced from publicly available GWAS datasets, ethical approval and written informed consent were not required.

2.1. Study design

In this study, we conducted a 2-sample MR analysis to evaluate the causal relationship between different intensities of PA and the risk of VTE. This MR design was based on 3 key assumptions: the selected IVs must have a strong association with the exposure (walking, moderate PA, vigorous PA), the IVs must be independent of any confounding factors, and the IVs must influence the outcome (VTE) solely through the exposure (walking, moderate PA, vigorous PA), without any alternative pathways. A schematic view of the study design is shown in Figure 1.

Figure 1.

Figure 1.

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The assumptions of this Mendelian randomization study. SNP= single-nucleotide polymorphism, VTE = venous thromboembolism.

2.2. Data source

The genetic instruments for 3 intensities of PA were sourced from the UK Biobank (UKbiobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age). Specifically, light PA was defined as the number of days per week walked for 10 or more minutes (N = 4,54,783, ukb-b-4886); moderate PA was defined as the number of days per week of moderate PA for 10 or more minutes (N = 4,40,266, ukb-b-4710); vigorous PA was defined as the number of days per week of vigorous PA for 10 or more minutes (N = 4,40,512, ukb-b-151). These data can be downloaded from the IEU OpenGWAS database (https://gwas.mrcieu.ac.uk/). The summary-level GWAS data for VTE (21,021 cases, 3,91,160 controls) were obtained from the latest publicly released R10 data of the FinnGen study (Release 10, https://finngen.gitbook.io/documentation/data-download), which combines genotype data from Finnish biobanks with digital health record data from Finnish health registries. The detail information of data sources is shown in Table 1.

Table 1.

Data sources and IDs.

GWAS-ID Phenotype Sample size Ancestry
ukb-b-4886 Walking 4,54,783 European
ukb-b-4710 Moderate PA 4,40,266 European
ukb-b-151 Vigorous PA 4,40,512 European
finngen_R10_I9_VTE Venous thromboembolism 4,12,181 (21,021 cases, 3,91,160 controls) European
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PA = physical activity, VTE = Venous thromboembolism.

2.3. Instrumental variable selection

In this study, single-nucleotide polymorphisms (SNPs) were used as IVs for conducting MR analysis. To select robust IVs, we first identified SNPs significantly associated with PA at genome-wide significance (P < 5E−08). We then conducted linkage disequilibrium tests to identify independent SNPs (r2 < 0.001 within a 10,000 kb window) using the European 1000 Genomes Project reference panel and PLINK clumping method. These SNPs were identified in the GWAS of VTE, and palindromic SNPs with intermediate allele frequencies were excluded during the harmonization process. The F-statistic (F = β2/se2) was calculated for these SNPs, and those with a value significantly below 10 were excluded.

2.4. Mendelian randomization analysis

The primary statistical method employed was the inverse variance weighted (IVW) approach. Additionally, MR-Egger regression, weighted median, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) tests were conducted to assess the robustness of the results. In MR-Egger regression, a P-value > .05 for the intercept indicates no horizontal pleiotropy. The MR-PRESSO test was employed to identify significant outliers and mitigate the effects of horizontal pleiotropy by excluding them. Cochran’s Q statistic was used to assess potential heterogeneity of SNP estimates in IVW method. A P-value < .05 indicates significant heterogeneity; thus, a random-effects IVW model was utilized. We performed a leave-one-out analysis to evaluate the stability of these genetic variants by excluding 1 SNP at a time. Given the multiple tests in our main analyses, we applied a Bonferroni-corrected threshold of P < .017 (calculated as 0.05 divided by 3 exposures). P values falling within the range of .017 to .05 were considered suggestive correlations. All analyses were conducted using the “TwoSampleMR” and “MRPRESSO” packages in R software version 4.3.2 (R Foundation, Vienna).

3. Results

3.1. Genetic IVs selection

In total, we selected 17 SNPs for light PA, 15 SNPs for moderate PA, 11 SNPs for vigorous PA. Each of these SNPs had an F-statistic value >10, indicating robust instruments with no evidence of weakness. Detailed information on the IVs used in the MR analysis is provided in Table S1, Supplemental Digital Content, https://links.lww.com/MD/R373.

3.2. Causal relationship between PA and VTE

The MR analysis using the IVW method revealed a significant association between vigorous PA and a reduced risk of VTE (OR = 0.727, 95% CI = 0.576–0.920, P < .017). Regarding the impact of light and moderate PA on VTE risk, these associations did not achieve statistical significance (P > .017). However, at a relaxed significance level (0.017 < P < .05), the IVW method identified suggestive evidence of an association between light PA and a reduced risk of VTE (OR = 0.778, 95% CI = 0.610–0.994, P = .045). Similarly, MR-Egger regression suggested that moderate PA reduces the risk of VTE (OR = 0.288, 95% CI = 0.095–0.870, P = .046) at a relaxed significance threshold (0.017 < P < .05), however, this finding was not supported by our primary estimator, the IVW method. The directions of the weighted median and MR-Egger MR estimates aligned with the IVW estimates, indicating the robustness of the findings (Figs. 2 and 3, Table 2).

Figure 2.

Figure 2.

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Forest plots of MR estimates of the causal relationship between light-intensity PA, moderate-intensity PA, vigorous-intensity PA and VTE. CI = confidence interval, IVW, inverse-variance weighted, MR = Mendelian randomization, OR = odds ratio, PA = physical activity, VTE = venous thromboembolism.

Figure 3.

Figure 3.

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MR forest plots for physical activity intensity and VTE risk. The plots show the causal effect estimates (odds ratios) of individual genetic variants (instrumental variables, IVs) and the overall inverse-variance weighted estimate. (A) Light-intensity PA, (B) Moderate-intensity PA, (C) Vigorous-intensity PA. IV = instrumental variables, MR = Mendelian randomization, PA = physical activity; SNP = single-nucleotide polymorphism, VTE = venous thromboembolism.

Table 2.

Effects of different intensities of PA on VTE.

Exposure Method SNP (n) B SE P-value IVW MR-PRESSO P-value Egger_intercept P-value
Q P-value
Light PA IVW 17 −0.25 0.125 .045 25.33 .064 28.7 .068 −.004 .918
MR-Egger 17 −0.096 1.489 .949
Weighted median 17 −0.252 0.1454 .082
Moderate PA IVW 15 −0.055 0.089 .535 18.1 .202 20.925 .197 .04 .052
MR-Egger 15 −1.244 0.564 .046
Weighted median 15 −0.111 0.13 .39
Vigorous PA IVW 11 −0.318 0.12 .008 13.25 .209 16.13 .23 .045 .166
MR-Egger 11 −1.865 1.035 .105
Weighted median 11 −0.269 0.182 .139
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IVW = inverse-variance-weighted, MR = Mendelian randomization, MR-PRESSO = Mendelian randomization pleiotropy residual sum and outlier, PA = physical activity, SNP = single-nucleotide polymorphism, VTE = Venous thromboembolism.

3.3. Sensitivity analysis

Cochran’s Q statistics revealed no significant heterogeneity among the selected IVs (P > .05 in the IVW method; Fig. 4 and Table 2). Additionally, no evidence of pleiotropy was detected in both MR-Egger and MR-PRESSO global tests (P > .05; Fig. 5 and Table 2). The leave-one-out sensitivity analysis further highlighted that none of the identified causal associations were driven by any individual SNP (Fig. 6).

Figure 4.

Figure 4.

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Assessment of pleiotropy via funnel plots for physical activity intensity on VTE risk. Funnel plots visualize the distribution of causal effect estimates from individual genetic instruments (SNPs) to assess potential heterogeneity or directional pleiotropy in the MR analyses. (A) Light-intensity PA, (B) Moderate-intensity PA, (C) Vigorous-intensity PA. Symmetry around the pooled estimate (dashed line) suggests the absence of significant pleiotropy. IVW = inverse variance weighted, MR = Mendelian randomization, PA = physical activity, SNP = single-nucleotide polymorphism, VTE = venous thromboembolism.

Figure 5.

Figure 5.

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Scatter plots of genetic associations for MR analyses. The plots visualize the relationship between the single-nucleotide polymorphism (SNP) association with physical activity intensity (exposure; x-axis) and VTE risk (outcome; y-axis). (A) light-intensity PA, (B) Moderate-intensity PA, (C) Vigorous-intensity activity PA. Each point represents 1 instrumental variable (SNP). The slope of the regression line (blue) through the origin represents the causal odds ratio estimated by the inverse-variance weighted MR method. M = Mendelian randomization, PA = physical activity, SNP = single-nucleotide polymorphism, VTE = venous thromboembolism.

Figure 6.

Figure 6.

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Leave-one-out sensitivity analysis for the causal effect of PA intensity on VTE risk. The plot displays the overall causal estimate (red horizontal line) alongside the estimate recomputed after sequentially removing each individual instrumental variable (SNP). The stability of the point estimates (black dots) and confidence intervals (horizontal lines) across all iterations indicates the overall MR result is not driven by any single influential genetic variant. (A) Light-intensity PA, (B) Moderate-intensity PA, (C) Vigorous-intensity PA. MR = Mendelian randomization, PA = physical activity, SNP = single-nucleotide polymorphism, VTE = venous thromboembolism.

4. Discussion

MR is developed in recent years to infer the causal relationship between exposure and outcome. MR simulates randomized controlled trials by using genotype as IVs or a proxy for the exposure of interest, can exclude the external confounding factors.[13,16] The current 2-sample MR study used FinnGen data from 4,12,181 individuals with VTE and UK Biobank data from 13,35,561 participants with 3 intensities of PA. The main significance of this study was to provide evidence of an association between PA and a reduced risk of VTE, especially regarding a lower risk of VTE with exercise on a high level. Of note, the long-term effect of PA on the onset of VTE might be extrapolated since genetic instruments represent lifelong exposure.

According to the World Health Organization, at least 150 minutes of moderate-intensity PA or at least 75 minutes of vigorous-intensity PA per week is recommended.[17] Beneficial effects of PA on coronary heart disease and stroke have been observed.[18] Conversely, one of the clinically harmful outcomes of poor activity awareness is potentially costly VTE prevention in hospitalized patients.[19,20] Thrombosis involves different etiologies, such as inflammation, endothelial dysfunction, altered blood flow, and hypercoagulable states,[21,22] and although PA was known to have beneficial effects on some of these states,[23,24] whether the risk of thrombosis is associated with PA remains controversial.

Numerous studies have shown that increasing PA can significantly reduce the risk of VTE. Regular sports activities was proved to reduce the risk of VTE by stimulating the blood flow.[25] A study from the American Heart Association to track the population’s cardiovascular health showed that ideal PA and body mass index (BMI) were associated with a lower risk of VTE.[26] In a population-based cohort, PA (≥1 h/wk) was associated with a reduced risk of TVE in overall, especially in older adults.[27] A single-center cohort study based on residents of the Tromsø municipality in Norway showed that habitual PA prior to VTE occurrence was not associated with a risk of recurrence, while active exercise after thrombosis might reduce mortality.[28] Greater PA was found association with lower VTE risk in a demographic adjusted model, however this association became insignificant after adjusting for BMI.[29] A meta-analysis conducted in 2020 revealed that engaging in regular PA was significantly associated with a lower risk of VTE compared to sedentary or inactive, and this association did not appear to be mediated or confounded by BMI.[30] Some studies have demonstrated that being physically active is not associated with a reduced risk of VTE. A study conducted in Norway suggested that moderate intensity PA did not have a significant impact on the risk of VTE in a general population.[31] Similarly, in a recent univariate and multivariate MR analysis, moderate to vigorous PA was shown to have no causal relationship with VTE in the general population.[32] One study has found quite the opposite. Increased exercise seemed to have a tendency to induce the risk of VTE.[33] Some studies demonstrated a U-shaped association. It has been reported that, regular moderate to high intensity physical exercise in leisure time had no significant effect on the risk of VTE in the general population; Moderate PA reduced the risk of VTE in people under 60 years of old, while high PA (≥3 h/wk) had a potential of inducing VTE risk in elderly and obese people.[31] A Cardiovascular Health Study conducted in United States suggested that, strenuous exercise led to a higher risk of VTE in older adults than no exercise at all.[34] In line with this, a large prospective study in the United Kingdom reported that moderately active women had a significantly lower risk of VTE compared to inactive women. However, women who exercised vigorously every day had a higher risk of VTE than women who exercised moderately (2–3 times a week).[35] Other studies have described differences in the incidence of VTE by age and sex, revealing the highest incidence of VTE in older women.[36] The reported risk factors for VTE in women include smoking, physically inactive, overweight and diabetic.[37] A prospective population-based cohort study found that increasing PA might reduce the risk of first-time VTE in women.[38] Conversely, in a cohort of men followed for 27 years, vigorous exercise was positively associated with a higher risk of VTE.[39]

In the current MR analysis, we assessed the relationship between different intensities of PA and the risk of VTE. Only high-intensity exercise was significantly associated with a reduced risk of VTE, while light and moderate exercise were not. This is consistent with the findings of more than half of the studies included in a systematic review, in which increasing PA was associated with a reduced risk of VTE.[12] Previous studies have found some conflicting results regarding the relationship between PA and VTE, and the main reasons may include the following: differences in study design and specific study populations, such as on men only, women only, or older adults only; ddifferences in measuring PA and whether the existing measurements are suitable for capturing more vigorous activity; VTE may occur long after exercise, resulting in an association that is not always obvious; and fatigue after strenuous exercise can easily be dismissed as normal and DVT can be overlooked, leading to delayed diagnosis. Therefore, more objective, well-designed studies, as well as more precise methods for assessing PA, are needed before the most plausible explanation of the association between vigorous PA and the risk of VTE can be obtained.

The mechanisms underlying the beneficial effects of PA on VTE risk might involve: increasing blood flow, which may create an antithrombotic environment and avoid the occurrence of VTE[40-42]; increasing endothelial nitric oxide syntheses level, thereby enhancing endothelial function.[43]; and decreasing the level of fibrinogen, plasma viscosity, and platelet aggregation.[44] However, it has been reported that different intensities of PA may lead to a higher risk of injury and may also lead to some immediate changes in the hemostatic system, all of which may lead to an increased risk of VTE.[45,46]

5. Strengths and limitations

There are several strengths of this study: the MR method we used can simulate RCTs under observation conditions and can also overcome the confounding effects between the exposure and outcome, making the operation more convenient and the results more objective. The GWAS data for VTE we used were obtained from the latest publicly released R10 data of the FinnGen study, based on which no MR analysis of the relationship between PA and VTE risk has been reported. We comprehensively analyzed the causal relationship between different intensities of PA (light, moderate, and vigorous) and the risk of VTE, providing constructive suggestions for VTE preventive and intervention strategies.

There are several limitations of this study: the GWAS data were mainly from the European populations, and given the disparities in the distribution of genetic factors for VTE among different ethnic groups,[47] the present findings are not suitable to generalize to other ethnicities. Defects in the objectivity and accuracy of PA assessment: PA was assessed by self-report, which was easily affected by subjective factors; existing PA assessment methods are not accurate enough to assess strenuous exercise. As previously reported, the effect of PA on VTE risk varied by sex, but due to the lack of detail on gender composition in the GWAS data, no further gender subgroup analysis was performed in this study. Some individuals of UK Biobank were in both the exposure and outcome datasets, which might introduce sample overlap bias. Therefore, we used a good strength of the genetic IVs for the exposures (F statistic > 10) to mitigate this bias.

6. Conclusions

In conclusion, knowledge of the relationship between PA and the risk of thrombosis is of clinical significance for VTE preventive and intervention. This study found that high intensity exercise was associated with a reduced risk of VTE. Although this conclusion remains controversial, PA should be promoted based on its recognized beneficial effects in reducing the cardiovascular mortality from any cause.

Acknowledgments

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. No writing assistance was utilized in the production of this manuscript.

Author contributions

Conceptualization: Yingling Xie.

Data curation: Jintuo Zhou, Yanting Zhu.

Formal analysis: Yongjin Xie, Jintuo Zhou.

Methodology: Yongjin Xie, Jintuo Zhou, Yanting Zhu.

Validation: Yingling Xie.

Writing – original draft: Yongjin Xie.

Writing – review & editing: Yingling Xie.

Supplementary Material

medi-105-e47589-s001.docx (25.1KB, docx)
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Abbreviations:

BMI
body mass index
CVD
cardiovascular disease
IV
instrumental variable
IVW
inverse variance weighted
MR
Mendelian randomization
MR-PRESSO
Mendelian randomization pleiotropy residual sum and outlier
PA
physical activity
SNP
single-nucleotide polymorphism
VTE
venous thromboembolism

This work was supported by Startup Fund for Scientific Research, Fujian Medical University (grant numbers 2024QH1197, 2024QH1199, and 2024QH1229).

The authors have no conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Supplemental Digital Content is available for this article.

How to cite this article: Xie Y, Zhou J, Zhu Y, Xie Y. The impact of different intensities of physical activity on the risk of venous thromboembolism: A Mendelian randomization study. Medicine 2026;105:8(e47589).

YX and JZ contributed to this article equally.

Contributor Information

Yongjin Xie, Email: 807292480@qq.com.

Jintuo Zhou, Email: 973486647@qq.com.

Yanting Zhu, Email: 971657721@qq.com.

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