Inflammatory Biomarkers in Cerebral Venous Thrombosis: Prognostic Insights from the CLOT-VENUS Substudy and Meta-Analyses

Highlights

• Elevated admission inflammatory markers, specifically Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Monocyte-to-Lymphocyte Ratio (MLR), and Systemic Immune-Inflammation Index (SII), are robust predictors of 6-month functional disability (mRS 3–6) in CVT patients.
• PLR and SII demonstrate particularly high prognostic value for mortality, with PLR >161.04 associated with a seven-fold increase in 6-month mortality risk.
• A systematic review of nearly 19,000 patients confirms that NLR is among the most frequently reported and statistically significant blood-based biomarkers for predicting CVT outcomes.
• Despite their prognostic utility, these markers do not appear to correlate with early venous recanalization or the radiological evolution of brain lesions, suggesting they reflect systemic stress or the underlying pathophysiology of neuro-inflammation.

Background

Cerebral venous thrombosis (CVT) is a distinct and often underdiagnosed form of stroke, predominantly affecting younger adults and females. While the overall prognosis is generally more favorable than arterial stroke, a significant subset of patients (approximately 15–20%) still suffers from death or long-term functional dependency. Early identification of these high-risk individuals is a clinical priority but remains challenging due to the heterogeneity of CVT presentation and the lack of specific, readily available prognostic tools.

Inflammation plays a dual role in the pathogenesis of CVT. It serves both as a trigger for thrombus formation and as a downstream response to venous congestion, blood-brain barrier (BBB) disruption, and subsequent parenchymal injury. Recently, serum-based inflammatory indices derived from the complete blood count (CBC)—such as NLR, PLR, and SII—have emerged as promising, cost-effective biomarkers in various cerebrovascular conditions. However, their specific utility in CVT has only recently been validated through large-scale registry substudies like CLOT-VENUS and comprehensive meta-analyses.

Key Content

Evolution of Evidence: From Pilot Studies to Meta-Analysis

The understanding of inflammatory markers in CVT has progressed from small prospective cohorts to large-scale data synthesis. Early work, such as the PRIORITy-CVT study (2021), laid the groundwork by demonstrating that Interleukin-6 (IL-6), NLR, and C-reactive protein (CRP) were elevated at admission in CVT patients compared to healthy controls. While this multicenter study (n=62) was relatively small, it established a crucial link: baseline IL-6 and NLR were significantly associated with unfavorable functional outcomes at 90 days, even though they did not predict the rate of venous recanalization or lesion growth.

Building on this, a massive systematic review and meta-analysis published in 2025 analyzed 64 studies involving 18,958 participants. This analysis identified NLR as a premier prognostic factor (log OR = 1.72), alongside classic risk factors such as coma (OR 11.60), deep venous involvement (OR 6.30), and malignancy (OR 3.87). The meta-regression confirmed that the impact of NLR on outcomes increases as the severity of the Modified Rankin Scale (mRS) score worsens, reinforcing its role as a continuous marker of disease severity.

The CLOT-VENUS Substudy: Refining Thresholds

The CLOT-VENUS substudy (Cruz-Criollo et al., 2026) provides the most granular data to date regarding specific inflammatory thresholds in an international cohort (n=339). By utilizing the CLOT-VENUS registry (2004–2024), researchers identified the following optimal cutoffs for predicting poor functional outcome (mRS 3–6) at 6 months:

• NLR >4.88: aOR 2.19 (P=0.044)
• MLR >0.54: aOR 2.32 (P=0.027)
• PLR >161.04: aOR 3.33 (P=0.003)
• SII >1388.58: aOR 2.03 (P=0.049)

Crucially, PLR and SII emerged as superior predictors of mortality. Patients with a PLR above 161.04 faced a staggering 7.19-fold increase in 6-month mortality risk, while an elevated SII carried a 4.69-fold increase. These findings suggest that the integration of platelet and neutrophil counts (as seen in SII) provides a more comprehensive snapshot of the pro-thrombotic and hyper-inflammatory state than individual cell counts alone.

Pathophysiological and Translational Insights

The prognostic power of these indices is rooted in the biology of neurovascular inflammation.

• Neutrophils: These are the first responders to ischemia and venous stasis. They release neutrophil extracellular traps (NETs), which provide a scaffold for fibrin and platelets, thereby stabilizing the venous thrombus and promoting its propagation.
• Lymphocytes: Lower lymphocyte counts often reflect increased physiological stress and cortisol release, or immune exhaustion following a significant insult. A low lymphocyte count combined with high neutrophil/platelet counts (high NLR/PLR) indicates a shift toward a pro-inflammatory, tissue-damaging milieu.
• Platelets: Beyond their role in primary hemostasis, platelets interact with leukocytes to release pro-inflammatory cytokines, further compromising the BBB and exacerbating cerebral edema.

Expert Commentary

From a clinical perspective, the primary advantage of NLR, PLR, and SII is their accessibility. Most patients with suspected CVT receive a CBC upon admission; calculating these ratios requires no additional cost or specialized laboratory equipment.

However, several nuances must be considered:

1. Timing of Measurement: Biomarker levels fluctuate rapidly in the acute phase. Evidence suggests that admission levels are most predictive, but serial measurements might offer insights into treatment response (e.g., response to anticoagulation or endovascular therapy).
2. Specificity: These markers are non-specific and can be elevated by concurrent infections, systemic inflammatory diseases, or the use of corticosteroids. Clinicians must interpret these values in the context of the patient’s overall clinical picture.
3. Clinical Integration: While these markers are independently associated with outcomes, they should not be used in isolation. They are most powerful when integrated into multi-variable models that include age, consciousness level (GCS), and radiological features (e.g., deep venous involvement or intracranial hemorrhage).

One significant controversy remains: whether these inflammatory markers are merely indicators of severe injury or active contributors to poor outcomes. If inflammation is a driver, there may be a therapeutic window for adjunctive anti-inflammatory treatments in patients with high SII or NLR, though this currently lacks randomized controlled evidence in the CVT population.

Conclusion

The synthesis of evidence from the CLOT-VENUS substudy and recent meta-analyses confirms that admission inflammatory biomarkers—specifically NLR, PLR, and SII—are valuable, independent predictors of functional outcome and mortality in acute CVT. PLR and SII, in particular, offer high-resolution prognostic data regarding mortality risk. While these markers do not replace clinical and radiological assessment, they serve as a powerful adjunct for early risk stratification and personalized management. Future research should focus on whether these biomarkers can guide the selection of patients for more aggressive interventions, such as mechanical thrombectomy or targeted anti-inflammatory adjuncts.

References

• Cruz-Criollo L, et al. Early Inflammatory Biomarkers Associated With Functional Outcomes in Acute Cerebral Venous Thrombosis: CLOT-VENUS Substudy. Stroke. 2026. PMID: 42017277.
• Key prognostic risk factors linked to poor functional outcomes in cerebral venous sinus thrombosis: a systematic review and meta-analysis. BMC Neurol. 2025. PMID: 39915720.
• Blood biomarkers associated with inflammation predict poor prognosis in cerebral venous thrombosis: a multicenter prospective observational study. Eur J Neurol. 2021. PMID: 32918842.