The authors emphasized that the findings identify differences at admission rather than predict which unruptured aneurysms will rupture in the future. Intracranial aneurysms are pathological focal dilations of arteries within the skull, and their rupture is a leading cause of spontaneous subarachnoid hemorrhage, in which blood enters the space surrounding the brain. Rupture can produce rapid clinical deterioration and is associated with substantial mortality and disability.

Existing assessments of unruptured aneurysms commonly focus on demographic and anatomical information, including aneurysm size, location and shape, through systems such as the PHASES score. The study examined whether adding routine blood markers could help distinguish aneurysms that were already ruptured from those that remained unruptured when patients arrived at the hospital. The researchers assembled data from electronic medical records at the Department of Neurosurgery of Renmin Hospital, Hubei University of Medicine, for patients admitted between January 2020 and September 2025.

Of 333 cases initially screened, 167 met the inclusion criteria. An aneurysm had to be confirmed by digital subtraction angiography, computed tomography angiography or magnetic resonance angiography, and each patient needed complete imaging, admission laboratory and clinical data. Patients were excluded if they had conditions that could independently affect inflammatory or coagulation measurements, including infectious, dissecting or pseudoaneurysms; malignant tumors, primary blood diseases, severe liver or kidney dysfunction; or previous aneurysm treatment.

Rupture status was assigned from preoperative imaging and intraoperative findings. A patient was placed in the ruptured group if the aneurysm corresponded to a spontaneous subarachnoid hemorrhage, imaging showed a defect in its wall, or surgery directly revealed rupture and bleeding. Otherwise, the patient entered the unruptured group.

The researchers collected age, sex, medical history, aneurysm location and dimensions, aspect ratio, shape, vascular stenosis and arteriosclerosis, together with inflammatory and coagulation measures from the first venous sample obtained on admission. White blood cell count was considered elevated above 9.5 × 10⁹/L, neutrophil count above 6.3 × 10⁹/L, lymphocyte count below 1.0 × 10⁹/L and D-dimer above 0.5 mg/L. Irregular aneurysms were markedly more common among patients with rupture, occurring in 110 of 119 cases, or 92.44%, compared with 11 of 48, or 22.92%, among those without rupture.

Multiple aneurysms were also more frequent in the ruptured group, at 40.34% versus 20.83%. Elevated white blood cell count was present in 73.11% of ruptured cases but only 4.17% of unruptured cases, while increased D-dimer occurred in 55.46% and 6.25%, respectively. Reduced lymphocyte counts were also significantly more common in the ruptured group.

By contrast, age, sex, hypertension, coronary heart disease, smoking, drinking, aneurysm location, diameter, aspect ratio and conventional coagulation times did not differ significantly between the groups. The investigators used LASSO regression with 10-fold cross-validation for initial variable screening, followed by multivariable logistic regression and checks for collinearity. In the conventional model, irregular morphology was associated with an odds ratio of 37.13 for ruptured status, elevated white blood cell count with an odds ratio of 15.34, elevated neutrophil count with 9.69 and increased D-dimer with 12.27; all four had p values below 0.001.

Those estimates had wide 95% confidence intervals, which the authors said could reflect quasi-complete separation and small-sample bias. They therefore repeated the analysis with Firth-penalized logistic regression, a method intended to reduce bias in sparse or separated data. Under the Firth model, the three strongest remaining associations were irregular aneurysm morphology, with an odds ratio of 24.70 and 95% confidence interval of 3.67 to 166.02; elevated white blood cell count, with an odds ratio of 17.19 and interval of 1.44 to 205.17; and increased D-dimer, with an odds ratio of 15.53 and interval of 1.94 to 124.49.

Elevated neutrophil count lost statistical significance, with an odds ratio of 6.15, a 95% confidence interval of 0.86 to 44.09 and p = 0.071. This was consistent with its strong correlation with white blood cell count because neutrophils constitute much of the circulating leukocyte population. The investigators retained the irregular morphology, white blood cell and D-dimer model while excluding the collinear neutrophil measure.

Model performance improved as the three retained indicators were added together. A model containing morphology alone produced an area under the ROC curve of 0.85, with a 95% confidence interval of 0.78 to 0.91. Adding D-dimer increased the value to 0.91, with an interval of 0.87 to 0.96, while the full model combining morphology, D-dimer and white blood cell count reached 0.96, with an interval of 0.94 to 0.99.

The investigators also constructed a nomogram to estimate the probability of rupture from the three predictors. Bootstrap internal validation using 1,000 resamples produced a mean absolute calibration error of 0.017, and decision-curve analysis suggested favorable clinical net benefit over a reasonable range of threshold probabilities. These analyses assess discrimination, agreement between estimated and observed outcomes, and modeled decision benefit within the study data; they do not establish real-world clinical benefit.

Several features of the evidence limit how the findings should be interpreted. The investigation was retrospective, conducted at one center and restricted to patients who received surgery or embolization, creating risks of selection bias and limiting generalizability. The cohort was small, particularly its 48 unruptured cases, and laboratory testing was not uniformly available for every patient.

Continuous measurements were converted into abnormal or normal categories, which discarded some quantitative and potentially nonlinear information. The researchers also did not include hemodynamic or vascular microstructural variables and could not examine interactions between morphology and hypertension in adequately powered subgroup analyses. Most importantly, blood samples in ruptured cases were collected after hemorrhage had occurred.

Elevated leukocytes and D-dimer may therefore reflect acute systemic stress or tissue injury rather than pre-existing conditions that caused the aneurysm to rupture. The results therefore support irregular morphology, high white blood cell count and elevated D-dimer as objective correlates of rupture status at hospital admission, not as validated predictors of future rupture. Their potential value lies in combining structural information from imaging with two routine laboratory tests, potentially helping emergency teams distinguish already-ruptured aneurysms from unruptured ones.

That distinction is important because post-rupture blood markers can be consequences of hemorrhage, while imaging shape may reflect structural vulnerability.

Subject of Research: Admission biomarkers associated with ruptured versus unruptured intracranial aneurysms

Article Title: Biomarkers associated with admission rupture status of intracranial aneurysms: a combined analysis of morphological, inflammatory and coagulation indicators

Article References: Liu, P., Wang, Y., Zhao, Z., Liu, X., Ren, Q., Tang, Z., & Luo, J. (2026). Biomarkers associated with admission rupture status of intracranial aneurysms: a combined analysis of morphological, inflammatory and coagulation indicators. Frontiers in Neurology, 17, 1934306. https://doi.org/10.3389/fneur.2026.1934306

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1934306

Keywords: intracranial aneurysm, rupture status, subarachnoid hemorrhage, D-dimer, white blood cell count, aneurysm morphology, inflammation, coagulation biomarkers, diagnostic model, retrospective study, Biomarkers, associated