What is already known: The specific mechanisms by which intracranial atherosclerosis (ICAS) leads to large-vessel occlusion stroke (LVOS) remain poorly defined, unlike the well-established causes of cardioembolic stroke.

Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of acute ischemic stroke worldwide, especially in Asian populations, with high recurrent risks (1). The rise in mechanical thrombectomy (MT) for large-vessel occlusion stroke (LVOS) has revealed ICAS as an underlying etiology in approximately 27.7% of cases (2), reaching up to 60% in Chinese populations (3). ICAS-LVOS often leads to larger infarcts, higher disability rates, and increased mortalities. Diagnosing ICAS-related LVOS poses unique challenges, relying on complicating identification during MT procedures in LVOS populations (4). Thus, studies focusing on ICAS-LVOS are scant and demanding. The hypothesis of the mechanism behind ICAS-LVOS was akin to ST-segment-elevation myocardial infarction in cardiac scenarios (5), suggesting that the acute plaque rupture leads to thrombosis and occlusion. Furthermore, given residual stenosis and compromised perfusion, over one-third ICAS-LVOS patients experience intraprocedural reocclusion, 20 times higher than non-ICAS-LVOS cases (2). Achieving and sustaining recanalization often necessitates rescue interventions such as angioplasty, stenting and intra-arterial antiplatelet administration. However, the benefit of intravenous thrombolysis (IVT) remains unclear. Hence, our study aims to identify key factors contributing to or exacerbating ICAS occlusion, shedding light on the mechanism of ICAS- LVOS and exploring more effective therapies.

After screening and exclusions, the final analysis was comprised 70 patients with ICAS-LVOS, 78 patients with AF-LVOS and 131 with sICAS from January 2017 to January 2023. Among the 148 LVOS patients, the mean age was 68.77 ± 12.04 years, with 95 out of 148 (64.2%) being male. In the 201 ICAS patients, the mean age was 64.16 ± 11.97 years, with 152 out of 201 (75.6%) being male, which was consistent with major ICAS trials.

ICAS-LVOS represents a newly recognized condition emerging alongside the widespread use of MT in patients with LVOS (4). Fewer investigations delved into the underlying pathology, particularly why only a subset of patients with ICAS developed LVOS. In our study, we addressed this gap by uncovering the pivotal role of fibrinogen in thrombosis and LVOS occurrence in ICAS patients in real-world practice. Initially, we compared the clinical characteristics and lab results of ICAS-LVOS with AF-LVOS patients and found higher fibrinogen levels significantly associated with ICAS-LVOS. Subsequently, we contrasted ICAS-LVOS with non-LVOS ICAS patients, confirming fibrinogen’s crucial contribution to LVO-associated thrombosis in ICAS. Our analysis of ICAS-LVOS patients with and without extracted thrombi revealed a strong correlation between fibrinogen levels and extensive clot formation. Finally, we investigated the interplay among fibrinogen, IVT, and thrombectomy complexity, discovering that IVT could reduce the number of thrombectomy device passes, particularly in patients with lower fibrinogen levels.

Previous study had figured out the distinct comorbidities between embolism-LVOS and ICAS-LVOS patients (7, 8). In our study, we described the unique characteristics of age, times of stroke, position and distinct levels of fibrinogen in etiologically different patients. In the similar process of thrombosis and LVOS, the reason why the level of fibrinogen was elevated in ICAS-LVOS patients remained uncertain. Retrospectively, numerous studies have identified hyperfibrinogenemia as an independent risk factor for ASCVD and stroke (9, 10). Within the stroke domain, fibrinogen has been associated with etiology classification, clot burden and clinical outcome (11–15). A study has indicated increased fibrinogen in both LAA and CE strokes, with the former accompanied by inflammatory profiles like C-reactive proteins, while the latter by prothrombotic profiles like D-dimers (12), reminding inflammation-driven coagulation in the former and coagulation-driven inflammation in the latter (16). This emphasized the heterogeneous nature of LVOS thrombosis and the need for further understanding and tailored therapeutic approaches.

In our continued efforts to elucidate which subset of ICAS patients would develop LVOS, we conducted a secondary comparison and identified correlations between BMI, WBC counts, and fibrinogen levels in ICAS-associated LVOS compared to non-LVO solitary ICAS patients. It is evident that WBC represents an acute inflammatory response following stroke and is notably higher in LVOS patients (17). Conversely, the influences of BMI and fibrinogen levels can be attributed to the degree of inflammation, particularly chronic aseptic inflammation, given their measurement as stable indicators over a relatively longer period. Fibrinogen, known as coagulation factor I, is converted to fibrin by thrombin, participating in the coagulation cascade, and typically considered as an acute-phase reactant synthesized by the liver under the activation of inflammatory mediator like interleukin-6 (9, 16). However, it was demonstrated that the level of fibrinogen remained stable in the first 24 h after stroke onset, and peaked until over 3 days or longer (14, 15, 18). Therefore, in our study, fibrinogen levels were measured at admission without any treatment, suggesting that they reflect the chronic inflammatory state preceding thrombosis. This underscores the intricate interplay between inflammation, atherosclerosis, and thrombosis, necessitating a comprehensive understanding for effective therapeutic interventions.

As previously discussed, the characteristic of ICAS-LVOS was inflammation-driven coagulation. Consequently, it is plausible to hypothesize that individuals with higher levels of inflammatory could be predisposed to unstable plaque rupture and subsequent LVOS. This hypothesis finds parallels in the realm of acute coronary syndrome (ACS), where those ruptured fibrous cap (RFC) exhibits markedly elevated levels of interleukin-6 and other inflammatory proteome expression compared with intact fibrous cap (IFC) (19). Interestingly, RFC-associated ACS involves plaque rupture, while IFC-associated ACS is attributed to plaque erosion, leading to different clot characteristics (20). A case report detailing the occlusion of the basilar artery in ICAS- LVOS has indicated a similar mechanism of IFC. Regretfully, the widespread prevalence of this phenomenon in ICAS-associated LVOS remains unknown (21). Future research endeavors should prioritize elucidating this aspect, as it holds implications for tailored therapeutic strategies. It has been proved that plaques exhibiting IFC may benefit more from anti-thrombotic therapies (22).

Moreover, our study identified hypertension as a key factor associated with greater thrombus burden in ICAS-LVOS. On one hand, hypertension fosters a systemic pro-inflammatory state, which upregulates fibrinogen synthesis (23). The environment of elevated fibrinogen levels have been demonstrated to confer mechanical stability to clots, increasing their rigidity and impairing permeability (24). It correlated with the poor clinical outcomes following IVT in higher fibrinogen levels (14, 15). On the other hand, hypertension may directly promote a pro-thrombotic state, contributing to the formation of clots with a more compact fibrin network and a predisposition toward hypofibrinolysis (25). These unfavorably altered fibrin clot properties can contribute to a higher thrombus burden. Therefore, rigorous management of hypertension and elevated fibrinogen levels emerges as a potential therapeutic strategy to mitigate thrombus burden and possibly improve EVT outcomes in ICAS-LVOS.

The challenges of early and recurrent reocclusion persist in the endovascular treatment. Several retrospective studies have revealed the potential rescue therapies (26). Nevertheless, the utility of pretreatment before thrombectomy remains uncertain. While direct thrombectomy has not proven inferior to bridging thrombectomy with IVT (27), Asian patients, who exhibit a higher prevalence of ICAS-LVOS, may derive greater benefit from bridging therapy (28). Latest study has demonstrated the prevailage of IVT with tenecteplase before thrombectomy (29). Our study also observed a signal that the reduction in thrombectomy device passes associated with IVT appeared more pronounced in the subgroup of ICAS-LVOS patients with lower fibrinogen levels, although it is critical to note that this subgroup analysis was underpowered due to the small sample size. Lower fibrinogen levels might enhance the penetration and efficacy of thrombolytic agents, facilitating early clot lysis and leading to fewer device passes, which aligns with the established role of IVT in promoting early recanalization (27). Conversely, the observed attenuated effect in patients with high fibrinogen levels suggests that fibrinogen might act as a barrier to thrombolysis. This exploratory observation raises the possibility that future therapeutic strategies, such as the use of fibrinogen-lowering agents (e.g., fibrinogenase (30)) or anti-inflammatory therapies, could be investigated to potentially improve outcomes in this specific patient population. However, any such implications are speculative at this stage and require rigorous future validation.

Our study had several limitations. Firstly, classification accuracy relied on diagnostic tests (CTA/DSA) and varied strategies of MT by different interventionalists. Potentially introducing misclassification biases. Secondly, being a cross-sectional study, it lacked longitudinal research on the association, thereby limiting the convincement of the causal link between fibrinogen and ICAS to some extent. Therefore, cohort studies are crucial to fully establish this relationship in the future. Thirdly, the analysis of IVT’s effect on MT in ICAS-LVOS patients was limited by the small number of recruited patients. Adjusting for other confounding factors, such as onset-to-door time and the use of antiplatelet and heparins therapies, was not possible. Lastly, our study primarily focused on fibrinogen in the pathophysiology of ICAS-LVOS, but lifestyle factors, comorbidities, plaque characteristics, and inflammatory levels are also pivotal and should be included in forthcoming studies.

In summary, this observational study highlights the role of fibrinogen in facilitating thrombosis and occurrence of LVOS in ICAS patients. The higher level of fibrinogen observed in ICAS-LVOS patients compared to AF-LVOS patients suggest two distinct mechanisms of thrombosis and provide a method of prediagnosis. Additionally, elevated fibrinogen levels in ICAS-LVOS patients compared to sICAS-non-LVOS patients indicate fibrinogen’s contribution to thrombosis in this subgroup. Furthermore, fibrinogen levels correlate with thrombus burden, suggesting that IVT may alleviate the challenges of thrombectomy in patients with lower fibrinogen burden. These findings underscore the importance of fibrinogen as a potential target in the assessment and treatment strategies for ICAS-LVOS. Therapeutic interventions aimed at reducing fibrinogen levels, such as anti-inflammatory approaches to inhibit synthesis or fibrinogenase to degrade existing fibrinogen, hold promise for future benefits.