This study reveals 'the multi-layered and complex associations between CBC parameters and stroke risk,' finding that red blood cell distribution width, hematocrit, hemoglobin, and mean corpuscular hemoglobin are independent predictors of stroke, with Mendelian randomization suggesting potential causal links between specific CBC parameters and stroke.
Key Findings
Results
CBC parameters including red blood cell distribution width (LBXRDW), hematocrit (LBXHCT), hemoglobin (LBXHGB), and mean corpuscular hemoglobin (LBXMCHSI) emerged as independent predictors of stroke.
Analysis was conducted on 6736 participants from the NHANES dataset covering years 2011–2016
Stroke cases were ascertained using a dedicated questionnaire
Multivariable logistic regression was used to identify these parameters as independent predictors
A broad spectrum of covariates was considered including age, race, socioeconomic status, BMI, lifestyle factors (smoking, alcohol consumption, physical activity), serum calcium levels, hypertension, and diabetes
Results
WQS regression demonstrated a positive association between CBC indices and stroke risk, which was attenuated after adjusting for confounders.
Weighted Quantile Sum (WQS) regression was applied to assess the combined link between blood cell metrics and stroke
The positive association between CBC parameters and stroke risk was present but became attenuated upon full covariate adjustment
This suggests that confounding factors such as hypertension and diabetes partially explain the CBC-stroke relationship
Results
Restricted cubic spline analysis revealed significant nonlinear correlations between LBXRDW (red blood cell distribution width) and LBXMCHSI (mean corpuscular hemoglobin) with stroke events.
Nonlinear relationships were specifically identified for LBXRDW and LBXMCHSI
Other CBC parameters did not show the same nonlinear pattern
This nonlinear finding suggests that the relationship between these hematological markers and stroke risk is not simply linear across all values
Results
Mendelian randomization suggested potential causal links between specific CBC parameters, including mean erythrocyte hemoglobin concentration and red blood cell distribution width, and stroke, with variable correlation directions.
A two-step multivariable Mendelian randomization design was employed
The causal associations identified included mean erythrocyte hemoglobin concentration and red blood cell distribution width
The 'variable correlation directions' indicate that different CBC parameters may have opposing causal effects on stroke risk
Sensitivity analyses including heterogeneity inspection and pleiotropy testing were performed to reinforce robustness of findings
Results
Initial descriptive analysis revealed significant disparities in age, education, income, hypertension, and diabetes between the stroke and nonstroke cohorts.
The study population comprised 6736 NHANES participants from 2011 to 2016
Stroke and nonstroke groups differed significantly across demographic and clinical characteristics
Hypertension and diabetes were among the key distinguishing factors between groups, consistent with their known roles in stroke pathogenesis
Results
Sensitivity analyses reinforced the robustness of the Mendelian randomization findings.
Heterogeneity inspection was conducted as part of sensitivity analysis
Pleiotropy testing was also performed
These analyses were described as reinforcing the robustness of the causal findings
What This Means
This research suggests that routine blood count measurements — specifically red blood cell distribution width, hematocrit, hemoglobin levels, and mean corpuscular hemoglobin — are associated with stroke risk in a large sample of over 6,700 American adults. The study used both traditional statistical methods and a genetic approach called Mendelian randomization, which helps determine whether these associations are likely causal rather than simply correlational. The genetic analysis pointed to red blood cell distribution width and mean erythrocyte hemoglobin concentration as having potential causal relationships with stroke, though the directions of these relationships varied across different blood markers.
One notable finding is that the relationship between some of these blood markers and stroke is not straightforward or linear — for red blood cell distribution width and mean corpuscular hemoglobin, the risk pattern curves in ways that cannot be captured by simple statistical models. Additionally, while a combined blood count index showed a positive association with stroke risk, this association was weakened when factors like hypertension, diabetes, age, and lifestyle habits were taken into account, suggesting these conditions partially mediate or confound the relationship.
This research suggests that the complete blood count — already a widely available and inexpensive clinical test — may contain useful information for identifying individuals at elevated stroke risk. If future research confirms these causal relationships, it could support the use of routine blood count parameters as early screening tools or as targets for understanding the biological mechanisms behind stroke development. The authors emphasize that hematological characteristics must be interpreted alongside a broad range of confounding factors in stroke research.
Chen T, Li Y, Cai L, Liu Y, Kuang P, Zou L, et al.. (2026). Mediators of the Association Between Stroke and Blood Cells: A Two-Step Multivariable Mendelian Randomization Study.. CNS neuroscience & therapeutics. https://doi.org/10.1002/cns.70903