In this prospective hospital-based nationwide stroke registry in China, we found that high fibrinogen levels were associated with increased risks of short-term and long-term poor functional outcome, but not stroke recurrence, ischemic stroke recurrence, and composite vascular events in patients with acute ischemic stroke or TIA.
Although previous studies confirmed that a high fibrinogen level was associated with first-ever cardiovascular disease [5, 6], the association between fibrinogen and ischemic stroke is contradictory. A large meta-analysis involving 154 211 participants proved that moderately strong associations were found between plasma fibrinogen and the risk of first stroke in healthy middle-aged adults . However, subsequent studies investigating the association between fibrinogen and initial ischemic stroke showed inconsistent results [7, 27–29]. In contrast, only a few studies indicated that fibrinogen level was associated with stroke recurrence in recent TIA or minor ischemic stroke [12, 30] A preliminary study showed that fibrinogen combined with tissue-type plasminogen activator and von Willebrand factor was associated with coronary events, but not stroke recurrence among patients with recent TIA or ischemic stroke . In addition, previous studies have indicated that the association between fibrinogen and a new vascular event was no longer significant after adjustment for confounding risk factors in patients with acute stroke [10, 11]. On the contrary, the association between fibrinogen and poor functional outcome is less established. It was previously suggested that fibrinogen was associated with poor functional outcome after adjusted simple risk factors, but further adjustment for potential factors eliminated this association . Previous studies suggested that patients with lower initial fibrinogen levels had good functional outcome after acute stroke, indicating that the independent association between fibrinogen levels and functional outcomes need to be verified using a larger acute stroke dataset . In the present study, the associations of fibrinogen with poor functional outcome and stroke recurrence were assessed base on a large-scale stroke registry study in China. Furthermore, D-dimer, hsCRP, and complications during hospitalization were considered in addition to the baseline NIHSS score and stroke subtype according to the Trial of Org 10172 in Acute Stroke Treatment.
In our analysis, high fibrinogen levels were associated with an increased risk of poor functional outcome. This association was independent of the stroke severity, stroke subtype, complications, D-dimer, and hsCRP. Our findings indicate that this association might depend on other potential mechanisms of fibrinogen. One possible explanation is that high fibrinogen level may affect the structure of the fibrin clot. Previous studies have suggested that high fibrinogen levels might be related to the formation of more stable fibrin clots, which determine the efficacy of arterial recanalization . Another potential explanation is that high fibrinogen levels cause high blood viscosity, which could potentially compromise the microvascular blood flow in marginally perfused brain areas . An additional explanation is that fibrinogen plays a critical role in interfering with tissue repair .Blood–brain barrier permeability increases after ischemia and reperfusion , and fibrinogen enters the brain tissue, thus participating in acute tissue necrosis and causing secondary tissue damage [35, 36]. Based on our findings, high fibrinogen levels independently predict poor functional outcome, which suggest that fibrinogen might be a targeted therapeutic after acute ischemic stroke or TIA.
Consistent with previous studies, we observed no association between fibrinogen and a new vascular event in the multivariate model . Potential explanation might be that fibrinogen levels were associated with other risk factors. Although fibrinogen is the most common hemostatic factor, its role in the development of atherosclerosis and vascular disease extends to a key proinflammatory player . The Canakinumab Antiinflammatory Thrombosis Outcome Study showed that antiinflammatory therapy led to the reduction in hsCRP and fibrinogen, indicating that fibrinogen had potentially plays dual roles as both an acute-phase reactant and a mediator of coagulation . Previous studies proved that there was a strong association between fibrinogen and hsCRP . In addition, it has been suggested that hsCRP was more related to the risk of new cardiovascular events after acute ischemic stroke than fibrinogen . Therefore, our findings suggest that fibrinogen might be involved in stroke recurrence through other critical risk factors.
Our study has several limitations. First, our study only included the D-dimer and hsCRP levels in addition to the fibrinogen levels, while other related coagulation or inflammatory factors may also be associated with stroke outcomes. Future studies focusing on the coagulation or inflammatory pathway could help to reveal the molecular mechanism underlying stroke outcomes. Second, this study obtained one-point fibrinogen measurements. Since fibrinogen levels persistently increase from the acute phase to the stable phase in patients after stroke [8, 9], dynamic change might be necessary to confirm its predictive value. Third, 4648 (30.6%) of the 15166 patients did not provide blood samples and were excluded because their fibrinogen levels were not measured. Although the baseline characteristics of the patients included and those excluded were well balanced, some deviation in the analysis of the associations between the fibrinogen levels and outcomes may exist. Finally, all enrolled patients were Chinese adults with acute ischemic stroke or TIA, and these results may not be generalizable to patients of other ethnicities.