Introduction
Early-onset ischemic stroke presents a significant clinical challenge, often occurring in the absence of traditional vascular risk factors. In approximately 30% to 50% of patients aged 18 to 49, the underlying cause remains undetermined despite extensive diagnostic evaluation, a condition termed cryptogenic ischemic stroke (CIS). Recent evidence has increasingly pointed toward transient triggers, such as acute infections, as potential catalysts for these events. While the link between infection and stroke is well-established in older populations with atherosclerosis, its role in young CIS patients—where thromboinflammatory mechanisms might predominate—has remained less clear. The SECRETO study, a multicenter case-control investigation, provides critical insights into how recent infections and specific coagulation biomarkers contribute to the risk of early-onset CIS.
Highlights
– Recent infections within the week preceding a stroke are associated with a 2.6-fold increase in the risk of cryptogenic ischemic stroke in adults under 50.
– Elevated von Willebrand Factor (VWF) activity and Factor VIII levels are strongly linked to stroke risk specifically in the context of recent infection or fever.
– The association suggests a transient prothrombotic state, or ‘thromboinflammatory window,’ that may be a critical target for preventive interventions in young patients.
The SECRETO Study: Design and Population
The SECRETO study (Search for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome) is a rigorous multicenter case-control study conducted across 19 European centers between 2013 and 2022. The study enrolled 537 first-ever CIS patients aged 18 to 49 years and matched them with age- and sex-matched controls.
To ensure the ‘cryptogenic’ nature of the strokes, all cases underwent standardized, extensive diagnostic workups, including brain imaging (MRI/CT), vascular imaging (CTA/MRA or ultrasound), and cardiac evaluations (transesophageal echocardiography and prolonged rhythm monitoring). Preceding infections within three months were assessed via standardized questionnaires, and blood samples were collected at both baseline and a three-month follow-up to differentiate between acute-phase responses and baseline coagulation profiles.
Key Findings: Infection as a Potent Stroke Trigger
The study found a clear temporal relationship between infection and stroke onset. Patients who reported an infection within the week preceding the event had a significantly higher risk of CIS. Specifically, the multivariable-adjusted odds ratio (OR) was 2.64 (95% CI, 1.34–5.20). When the window was extended to the preceding month, the association remained present but was less pronounced, suggesting that the highest risk period is immediate and transient.
Interestingly, the type of infection (respiratory, gastrointestinal, or other) did not significantly alter the risk, suggesting that the systemic inflammatory response, rather than a specific pathogen, serves as the primary trigger. Fever, a hallmark of systemic inflammation, was also independently associated with increased stroke odds.
Coagulation Biomarkers: The VWF and Factor VIII Connection
A central component of the SECRETO study was the analysis of coagulation biomarkers, including von Willebrand Factor (VWF) activity, Factor VIII (FVIII), fibrinogen, antithrombin III, and protein C. The researchers observed that VWF activity was significantly higher in CIS cases than in controls (122 IU/mL vs. 100 IU/mL; P < 0.001).
The Impact of Infection on Biomarker Levels
Within the case group, those with a recent infection (within one month) exhibited significantly higher VWF activity compared to those without infection (157 IU/mL vs. 121 IU/mL). In contrast, VWF levels in the control group did not vary significantly based on infection status. This discrepancy suggests that young CIS patients may possess an increased sensitivity to inflammatory triggers or a predisposed ‘hyper-reactive’ endothelial response.
Stratified analyses further revealed that for every standard deviation increase in VWF and FVIII levels, the odds of stroke increased significantly more in participants who had recently experienced an infection or fever compared to those who had not. This interaction highlights a synergistic effect between systemic inflammation and the intrinsic coagulation pathway.
Expert Commentary and Mechanistic Insights
The findings from the SECRETO study reinforce the ‘thromboinflammatory’ hypothesis of stroke. In young adults, who typically lack significant atherosclerotic plaque, the stroke mechanism may rely on the transient activation of the endothelium. Infections trigger the release of ultra-large VWF multimers from Weibel-Palade bodies in endothelial cells. These multimers are highly effective at tethering platelets, especially in the microvasculature.
If the ADAMTS13 protease—which normally cleaves these multimers—is overwhelmed or if the inflammatory surge is sufficiently intense, a prothrombotic environment is created. The fact that Factor VIII, which is carried by VWF, was also elevated and associated with higher stroke odds supports the theory that the VWF-FVIII complex is a key mediator of infection-related stroke risk.
Study Limitations
While robust, the study has limitations. The reliance on self-reported infection data introduces potential recall bias, although the use of a standardized questionnaire and matching with controls helps mitigate this. Furthermore, because blood samples were taken after the stroke event, it is difficult to definitively determine whether the elevated biomarkers were solely a result of the preceding infection or were partially influenced by the acute stroke itself. However, the comparison with the three-month follow-up samples helps establish the transient nature of these changes.
Conclusions and Clinical Implications
This multicenter study provides compelling evidence that recent infections act as a potent, transient trigger for cryptogenic ischemic stroke in young adults. By identifying VWF and Factor VIII as key biomarkers in this process, the research opens new avenues for risk stratification and prevention.
For clinicians, these findings suggest that the post-infection period represents a window of vulnerability. While routine anticoagulation for every minor infection is not supported by current data, young patients with a history of CIS or those with known elevations in prothrombotic markers should be monitored more closely during and after febrile illnesses. Future research should explore whether targeted anti-inflammatory or anti-thrombotic strategies—such as the use of low-dose aspirin or VWF-inhibiting agents—could reduce the incidence of stroke during this high-risk period.
Funding and Registration
The SECRETO study was supported by various national research grants from participating European countries. The study is registered at ClinicalTrials.gov with the unique identifier NCT01934725.
References
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