Acute ischemic stroke (AIS) is a leading cause of mortality and long-term disability worldwide, particularly among older adults (1, 2). Accurate early prognostication is essential for optimizing treatment decisions and poststroke care. Although clinical tools such as the national institutes of health stroke scale (NIHSS) and the modified Rankin scale (mRS) are widely used to assess neurological deficits and outcomes (3), these assessments may be limited by timing and lack of biological insight. Moreover, a recent study revealed that the inclusion of the NIHSS score and mRS score contributes only modestly to the prediction of 30-day unplanned readmission or mortality following stroke (4). In this context, hematologic biomarkers such as the neutrophil-to-lymphocyte ratio (NLR) (5), monocyte-to-lymphocyte ratio (MLR) (6), and systemic immune-inflammation index (SII) (7) have received increasing attention because of their clinical accessibility, cost-effectiveness, and reported associations with poor outcomes in patients with AIS.

Among these, the platelet-to-hemoglobin ratio (PHR) (8, 9), which is derived from routine complete blood counts, has emerged as a novel composite indicator. Platelet (10) and hemoglobin levels (11) are independently associated with stroke outcomes, and elevated PHR has been linked to adverse outcomes in cardiovascular and systemic conditions such as myocardial infarction (8), heart failure (9), pulmonary embolism (12), and cancer (13). However, its prognostic value in AIS remains uncertain.

Therefore, this study aimed to investigate the associations between PHR and 3-month functional outcomes in a large cohort of older patients with AIS. In addition, we investigated whether high-sensitivity C-reactive protein (hs-CRP), a well-established marker of systemic inflammation (14), mediates this association, with the aim of elucidating potential biological pathways linking the PHR to stroke prognosis.

In this large-scale cohort study of older patients with AIS, we identified a significant inverse association between the PHR and 3-month unfavorable outcomes. A nonlinear relationship was observed between the PHR and poor prognosis. Furthermore, mediation analysis revealed that hs-CRP partially mediated the association between the PHR and functional outcome, suggesting that an inflammatory component underlies this relationship. These results indicate that systemic inflammation and dysregulation of hematologic components may jointly contribute to stroke prognosis, suggesting potential targets for intervention.

The platelet-to-hemoglobin ratio (PHR) is a simple and cost-effective biomarker derived from routine blood tests. It combines the platelet count, which reflects prothrombotic and inflammatory activity, with the hemoglobin concentration, which indicates oxygen-carrying capacity and nutritional status. PHR has been reported to be significantly associated with adverse clinical outcomes in various diseases (8, 9, 12). For example, Ozbeyaz et al. identified the PHR as an independent predictor of in-hospital mortality in patients with acute pulmonary embolism (12). It has also demonstrated prognostic value in conditions such as ST-segment elevation myocardial infarction (8), congestive heart failure (9), rheumatoid arthritis (18), and colorectal cancer (13), suggesting broad applicability across disease types. Moreover, its individual components—platelet count and hemoglobin level—have been independently linked to stroke severity and prognosis. A 2024 study revealed a U-shaped relationship between platelet count and mortality in hemorrhagic stroke patients (10), and Kanazawa et al. reported that the baseline platelet count predicted early neurological deterioration in IS patients (19). However, another study of 281 first-ever IS patients indicated that while an elevated PLT increased stroke risk, it was not significantly associated with poststroke functional outcomes (20). In terms of hemoglobin, a large cohort study involving 14,159 patients with AIS or TIA revealed that both anemia and elevated hemoglobin levels were positively associated with mortality and poor functional outcomes (11). Furthermore, a two-sample Mendelian randomization study using UK Biobank data suggested that anemia may be a risk factor for stroke (21). Although the platelet count and hemoglobin level have been shown to individually influence stroke prognosis, research directly examining the prognostic value of the PHR in AIS patients remains limited.

On the basis of data from Seoul National University Hospital, this study investigated the association between the PHR and 3-month unfavorable outcomes in older patients with AIS. We identified a significant positive nonlinear relationship, with an inflection point at approximately 1.217. When the PHR exceeded this threshold, each one-unit increase was associated with a 47.9% greater risk of poor functional outcome, even after full adjustment for confounders. However, no significant associations were observed below this threshold. This dose–response pattern is consistent with previous findings in heart failure patients (9). The observed relationship likely reflects complex interactions among thrombogenicity, oxygen-carrying capacity, and systemic inflammation within the context of AIS. Inflammation is a well-recognized feature of AIS (22), and elevated levels of proinflammatory mediators can stimulate megakaryocyte proliferation and platelet production (23–25), indicating a heightened prothrombotic state (26). Furlan et al. found that increased platelet count in AIS patients was significantly associated with 30-day and 90-day mortality (27). A study by Yang et al., which analyzed 16,842 patients with ischemic stroke or transient ischemic attack, found that higher platelet counts were associated with an increased risk of recurrent stroke, all-cause mortality, and functional impairment within 1 year (28). Concurrently, low hemoglobin levels may exacerbate cerebral hypoxia and tissue damage following AIS, thereby affecting neuronal survival and functional recovery (29). Kimberly et al. observed that lower hemoglobin levels in AIS patients were significantly correlated with larger infarct volumes and infarct expansion (30). Other studies have also shown that low hemoglobin levels are significantly associated with increased mortality, functional disability, and recurrent stroke risk following AIS (11). Furthermore, it has been suggested that the recovery of hemoglobin levels may help reduce hospitalization time and improve functional recovery in stroke patients (31). Moreover, anemia is often accompanied by systemic inflammation, with elevated markers such as fibrinogen and von Willebrand factor enhancing platelet reactivity (32, 33). Compensatory bone marrow hyperactivity in response to anemia may also contribute to increased platelet counts (34). Collectively, these findings suggest that an elevated PHR may reflect an adverse pathophysiologic state and serve as a potential prognostic biomarker for risk stratification in older patients with AIS. In support of this finding, ROC analysis demonstrated that the PHR had a greater AUC for predicting 3-month unfavorable outcomes than the platelet count or hemoglobin alone did, indicating superior discriminative ability. As an integrated hematologic index, the PHR may therefore provide more robust prognostic insight than its individual components. Although traditional clinical tools such as NIHSS and mRS are crucial for assessing stroke severity, they primarily rely on clinical symptoms and may not fully capture the underlying biological processes that influence stroke prognosis. The PHR, a simple and cost-effective biomarker, provides additional biological insights into factors such as thrombosis, oxygen-carrying capacity, and inflammation, all of which play important roles in stroke prognosis. By integrating PLT and HGB levels, PHR serves as a complementary tool that offers early risk stratification information beyond what traditional tools alone can provide. Incorporating PHR into clinical decision-making allows healthcare providers to perform early risk stratification and implement timely interventions for high-risk patients, potentially improving patient outcomes.

Subgroup analysis revealed a significantly stronger association between the PHR and poor outcomes in patients with hyperlipidemia, suggesting that the PHR may have greater prognostic value in this population. Hyperlipidemia is known to aggravate ischemic injury through mechanisms such as endothelial dysfunction (35), heightened systemic inflammation (36), and a prothrombotic state (37), which may in turn amplify the prognostic relevance of the PHR. As a composite index incorporating the platelet count and hemoglobin level, the PHR may reflect the combined effects of inflammation, thrombogenicity, and anemia—factors that are implicated in stroke progression and outcome. Therefore, in AIS patients with concomitant hyperlipidemia, the PHR may serve as a more informative and clinically meaningful prognostic biomarker. Additionally, our mediation analysis revealed that hs-CRP significantly mediates the association between the PHR and AIS, suggesting that systemic inflammation is a key pathway linking the PHR to stroke outcomes. Elevated hs-CRP, a well-established marker of inflammation and vascular risk, has been linked to increased mortality, recurrence, and poor prognosis in AIS patients (38). These findings underscore the central role of inflammation in AIS pathophysiology and support the prognostic relevance of the PHR, which integrates both platelet activity and hemoglobin levels—components potentially modulated by inflammatory states. Our findings provide novel insights into the relationship between hematologic markers and AIS outcomes, warranting further studies to elucidate the underlying biological mechanisms.

This study is the first to demonstrate a significant nonlinear association between the PHR and 3-month functional outcomes in older patients with AIS. Notably, this relationship was more apparent in individuals with hyperlipidemia. Furthermore, mediation analysis indicated that hs-CRP partially mediated the effect of the PHR on clinical outcomes, suggesting that systemic inflammation may be an intermediate pathway. Given its simplicity, accessibility, and low cost, the PHR holds potential as a clinically applicable prognostic marker in AIS. However, several limitations of this study should be acknowledged. First, although the mRS is a widely accepted tool for assessing post-stroke functional outcomes, reliance on a single outcome measure may limit the assessment of comprehensive neurological recovery. Second, important treatment-related variables—such as intravenous thrombolysis and endovascular therapy—that may affect outcomes were not included in the present analysis. Future studies should incorporate these therapeutic factors to reduce residual confounding. Third, this study utilized the 3-month mRS as the primary endpoint, as it is a critical time point for assessing functional recovery in AIS. However, the 3-month mRS may not fully reflect long-term outcomes, as patients may experience continued recovery or deterioration beyond this period. Due to the absence of 6–12 month follow-up data, the long-term prognostic durability remains uncertain. This limitation highlights the need for future studies with extended follow-up to assess the predictive value of the 3-month mRS outcomes. Future studies should explore longitudinal outcomes at 6 months or 1 year to assess prognostic durability. Fourth, laboratory parameters such as neutrophils and lymphocytes were not included in our study, which prevented us from calculating the NLR and SII indices. In future research, we aim to incorporate a broader range of laboratory parameters to enhance the prediction of stroke outcomes. Fifth, the study cohort consisted exclusively of Korean patients, and the generalizability of these findings to other populations remains uncertain. Multicenter studies across diverse populations are needed to confirm the external validity of these results. Finally, further mechanistic research is needed to elucidate the biological pathways underlying the association between elevated PHR and adverse AIS outcomes.

This study revealed a nonlinear association between the PHR and 3-month unfavorable outcomes in older patients with AIS. The prognostic value of the PHR was more pronounced in patients with hyperlipidemia, and hs-CRP partially mediated this association. These findings support the potential utility of the PHR as a simple and accessible biomarker for outcome prediction in AIS patients.