Predictive Value of Fibrin Fibrinogen Degradation Products-to-Potassium Ratio for Poor Functional Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage: A Retrospective Case–Control Study

Background The relationship of fibrin(ogen) degradation products (FDPs) and potassium with the functional outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH) is still uncertain. This study aims to evaluate the predictive value of a novel combination biomarker, the FDP-to-potassium ratio (FPR), for poor functional outcomes in patients with aSAH. Methods A total of 425 consecutive patients with aSAH at a single center were retrospectively enrolled in our study. An unfavorable outcome was defined as a modified Rankin Scale (mRS) score of 3–6 at 3 months after discharge. Univariate analysis and multivariable logistic regression were performed for baseline information and laboratory parameters recorded at admission. In addition, the receiver operating characteristic curve was plotted, and propensity score matching was performed based on the FPR. Results On the basis of mRS grade, 301 patients were classified as having favorable outcomes, and 124 patients were assessed as having unfavorable outcomes. FPR levels were significantly correlated with mRS grade (r[Spearman] = 0.410; P < 0.001). Multivariate logistic regression analysis showed that age (odds ratio [OR] 1.043, 95% confidence interval [CI] 1.016–1.071; P = 0.002), white blood cell count (OR 1.150, 95% CI 1.044–1.267; P = 0.005), potassium (OR 0.526, 95% CI 0.291–0.949; P = 0.033), World Federation of Neurosurgical Societies grade (OR 1.276, 95% CI 1.055–1.544; P = 0.012), and FPR (OR 1.219, 95% CI 1.102–1.349; P < 0.001) at admission were independently associated with poor functional outcomes. The DeLong test showed that the area under the receiver operating characteristic curve of FPR was higher than that of age, white blood cell count, potassium, World Federation of Neurosurgical Societies grade, or FDP alone, indicating that FPR had better predictive potential than these other variables. After 1:1 propensity score matching (FPR ≥ 1.45 vs. FPR < 1.45), the rate of poor prognosis was still significantly increased in the high-FPR group (48/121 [39.7%] vs. 16/121 [13.2%], P < 0.001). Conclusions Fibrin(ogen) degradation product-to-potassium ratio is an independent predictor of poor outcomes for patients with aSAH and may be a promising tool for clinicians to evaluate patients’ functional prognosis. Supplementary Information The online version contains supplementary material available at 10.1007/s12028-023-01865-4.


Introduction
Aneurysmal subarachnoid hemorrhage (aSAH) is one of the most common causes of stroke worldwide and has higher mortality and morbidity than most neurological diseases [1,2].It is generally believed that early brain injury and delayed cerebral ischemia are the main causes of poor prognosis in patients with aSAH, requiring timely identification and intervention [3].Therefore, timely and accurate prediction of disease progression and functional outcomes is essential for the optimal treatment of patients with aSAH.Many classical scales, such as the World Federation of Neurosurgical Society (WFNS) grade [4] (based on the Glasgow Coma Scale [5]) and the modified Fisher (mFisher) score [6], have been reported to correlate with functional prognosis and are used clinically.However, these scales also have inherent flaws, such as overreliance on clinical manifestations and imaging characteristics [7].Additionally, the application of clinical scales is restricted in some cases, such as when patients receive sedative drugs and mechanical ventilation [8].
With the rapid advances in aSAH treatment and diagnosis, biomarkers are receiving increasing attention.Biomarkers are usually composed of measurable and quantifiable biological parameters.Compared with traditional scales, biomarkers have the advantage of a superior range of application and are readily quantified.In previous studies, biomarkers have been demonstrated to be promising tools in assessing disease risk and predicting prognosis.For example, serum C-reactive protein and the glucose-phosphate ratio predict prognosis, the platelet-Ca 2+ ratio and neutrophil-albumin ratio predict complications, and the glucose-potassium ratio is used to assess mortality in patients with aSAH [9][10][11][12][13][14].Interestingly, the use of combination biomarkers as risk factors or predictive tools is increasingly reported.Combination biomarkers are usually composed of related and inversely varying parameters in a particular disease; therefore, they are usually more sensitive and representative than single markers [15,16].
Previous studies have shown that the coagulation and fibrinolytic systems are usually unbalanced for a period after aSAH and are involved in both early brain injury and delayed ischemia [17].Therefore, biomarkers reflecting coagulation and fibrinolytic activity status may be closely related to disease progression and prognosis.Recently, D-dimer, a fibrinogen degradation product, has been reported as an independent predictor for assessing the complications and prognosis as well as long-term mortality of patients with aSAH [18][19][20][21][22].However, a similar laboratory parameter, the concentration of fibrin fibrin(ogen) degradation products (FDPs), has not been reported in relation to the prognosis of patients with aSAH.In addition, hypokalemia has been reported to be the most common electrolyte disorder after aSAH and is often combined with other clinical parameters as a predictor of poor prognosis and complications with aSAH [7,23,24].In the present study, we found that FDP is positively associated with unfavorable outcomes of aSAH, whereas potassium showed the opposite association.Therefore, we aimed to explore whether the FDP-to-potassium ratio (FPR) is a valuable combination biomarker for predicting the outcomes of patients with aSAH.

Study Design and Population
The study was performed according to the TRIPOD statement [25] and approved by the Ethical Committee of the Affiliated Hospital of North Sichuan Medical College (No. 2021ER126-1).We retrospectively reviewed the data from consecutive patients with aSAH who were admitted to the Affiliated Hospital of North Sichuan Medical College from August 2016 to June 2022.The inclusion criteria were as follows: (1) age > 18 years; (2) time from onset to admission less than 24 h; (3) aSAH confirmed by digital subtraction angiography or computed tomography angiography; and (4) complete surgical and hospitalization management.The exclusion criteria were as follows: (1) patients gave up hospitalization before treatment was completed; (2) a history of primary or secondary central nervous system diseases; (3) preexisting severe dysfunction of the heart, lung, liver, kidney, and other organs; (4) preexisting autoimmune diseases and hematopoietic diseases; (5) anticoagulant or antiplatelet medication drug history; and (6) insufficient clinical, imaging, laboratory parameters, and follow-up information.The flowchart of study population selection and screening is shown in Fig. 1.We collected all available cases within the specified time window to maximize the power and generalizability of the results.In this series of patients, treatments were terminated for numerous postoperative patients because the guardians were either unable to afford further hospitalization or were pessimistic about the prognosis.We defined this condition as giving up hospitalization before treatment was completed.These patients were excluded due to a possible risk of bias.Because we excluded all cases with insufficient information, this is a complete case analysis.

Data Collection
Baseline characteristics and clinical information were collected from the electronic database.Baseline characteristics included demographics (age, sex), adverse lifestyle factors (cigarette smoking and alcohol consumption), aneurysm location (anterior circulation, posterior circulation, or both), admission blood pressure (systolic blood pressure, diastolic blood pressure), and medical history (hypertension, diabetes).The WFNS grade was collected as an indicator of disease severity, and the mFisher score was collected to distinguish the radiographic features of SAH.Admission laboratory parameters with possible and reported predictive value based on previous reports were collected; these parameters included white blood cells (WBCs), neutrophils, lymphocytes, red blood cells, hemoglobin, platelets, FDP, potassium, sodium, calcium, glucose, lactate, fibrinogen, activated partial thromboplastin time, thrombin time, and international normalized ratio.The FPR was calculated by dividing the FDP count by the potassium count.For data accuracy and comparability, only the first laboratory parameters after admission were included.We did Fig. 1 Flow diagram of patients in the study.A total of 425 patients were included in the final study after excluding 700 patients who did not meet the inclusion criteria.We classified the patients according to their 3-month functional outcomes, (mRS 0-2 vs. 3-6).aSAH, aneurysmal subarachnoid hemorrhage, mRS, modified Rankin Scale not extract D-dimer values because most of the included patients were not tested for D-dimer on admission to our hospital.

Outcome Assessment
The primary outcome was functional outcomes at 3 months after discharge and was evaluated using the modified Rankin Scale (mRS), which has a 7-level scoring system.We defined favorable outcomes as mRS 0 to 2 and unfavorable outcomes as mRS 3 to 6. Outpatient clinic visits and telephone interviews were conducted to assess the mRS grades of patients.All assessments were performed in a blinded manner.Additionally, we analyzed delayed cerebral ischemia (DCI) during hospitalization as the secondary outcome.DCI was defined as the appearance of new clinical features (progressive focal defects, decreased level of consciousness) after all other reasons (severe electrolyte disorder, fever, epilepsy, drug application, hydrocephalus or bleeding, etc.) were ruled out and/or by imaging criteria as new low-density lesions on computed tomography scans or diffusion restriction on diffusion-weighted magnetic resonance imaging [26].

Statistical Analysis
Statistical analyses were performed using SPSS Statistics 26 (IBM, Armonk, NY) and MedCalc version 18.2.1 (MedCalc Software, Ostend, Belgium), and a two-sided P < 0.05 was considered significant.Continuous variables were presented as the mean ± standard deviation or median (interquartile range), whereas categorical variables were presented as counts with percentages (n [%]).Normal distribution was assessed by the Shapiro-Wilk normality test.Continuous variables were compared using Student's t test (normal distribution) or the Mann-Whitney U-test (nonnormal distribution).The χ 2 test or Fisher's exact test was used to compare categorical variables.Spearman's rank correlation was used for correlation analysis.We performed a multivariable logistic regression analysis to identify independent predictors of functional outcomes, and only variables that had P values of less than 0.05 in the univariate analysis were included in the final multivariable model.Additionally, variance inflation factors were calculated to assess multicollinearity and ensure that the variance inflation factors of variables were less than 5 in the final multivariable model.
Furthermore, receiver operating characteristic (ROC) curve analysis was performed to estimate the sensitivity and specificity of each independent predictor, and the area under the curve (AUC) was calculated to measure the prediction ability.DeLong tests were conducted to compare the target variables with other predictors.The patients were divided into a high-FPR group and a low-FPR group according to the best cutoff value achieved by ROC analysis.After propensity score matching (1:1 match, caliper 0.02, nearest neighbor approach) for all possible confounders, the rates of poor outcomes and DCI were compared between the two groups.

Baseline Characteristics
After screening according to the inclusion and exclusion criteria, 425 of 1125 adult patients with aSAH were included in this study (Fig. 1).Among the 425 included patients, unfavorable outcomes were documented in 124 patients (29%), and 301 patients (71%) were categorized as having achieved favorable outcomes.There were significant differences in age, WBC, neutrophil, potassium, lactate, FDP, WFNS grade, and mFisher score between the two groups.The differences in the percentage of women, hypertension, diabetes, smoking, alcohol consumption, aneurysm location, and other laboratory data between the groups were not statistically significant (Table 1).
The optimal threshold of FPR was identified at 1.45 to predict the poor outcomes of patients with aSAH (Youden's index = 0.459), in which the sensitivity was 75.81% and the specificity was 70.09% (Table 3).

Propensity Score Matching
The patients were categorized into a high-FPR group (FPR ≥ 1.45 n = 186) and a low-FPR group (FPR < 1.45 n = 239) based on the optimal threshold.Univariate analysis showed that there were significant differences in age, percentage of women, diastolic blood pressure, smoking, WBCs, neutrophil, lymphocyte, red blood cells, hemoglobin, sodium, calcium, WFNS grade, and mFisher score between the two groups (Table 4).After adjusting for potential confounding with propensity score matching (caliper 0.02, ratio 1:1, nearest neighbor approach), the primary functional outcome and secondary outcome still had statistically significant differences between the two groups (mRS 3

Discussion
In this retrospective study, we investigated the association of clotting-related biomarkers with the functional outcome of patients with aSAH.A significant correlation between elevated FDP and FPR levels and unfavorable outcomes (mRS 3-6) was observed.In addition, multivariable regression analyses and propensity score matching confirmed that FPR was an independent predictor of functional outcomes in patients with aSAH.Therefore, we considered serum FPR to be a valuable predictor of aSAH prognosis.To our knowledge, our study is the first to explore the association between FPR and functional outcomes in patients with aSAH.
The results of this study provide new independent and composite biomarkers for predicting clinical outcomes in patients with aSAH.Compared with the clinical grading scale, biomarkers offer the following advantages.
First, the use of biomarkers to predict prognosis relies on objective laboratory parameters and reduces the subjective bias caused by manual assessment.Second, biomarkers can be easily measured by routine equipment.This means that a broader scope of application, including conditions such as sedative drugs and mechanical ventilation, compensates for the inherent flaws of the clinical grading scale.Third, evaluating patient outcomes by biomarkers differs fundamentally from grading scales and offers novel options to recognize critical information on the prognosis of patients.
Following the fact that D-dimer has been reported as an independent predictor of poor prognosis and death in aSAH [18][19][20][21][22], our results indicated that FDP was positively correlated with admission WFNS grade and 3-month mRS in patients with aSAH, suggesting that patients with higher FDP values were more likely to have more severe clinical manifestations and worse prognosis.FDP serves as an indicator of the clotting system fibrinolytic system and mainly reflects the production or degradation of its precursor fibrin(ogen) in the acute phase.Fibrinogen is an acute phase response pleiotropic protein synthesized in the liver and plays a crucial role in coagulation, inflammation, and tissue Fig. 4 The correlation of FDP, potassium, and FPR levels with mRS grade.Scatterplot showing that the FPR increases with mRS grade (Spearman's r = 0.410, P < 0.001).The same trends held with the FDP (Spearman's r = 0.403, P < 0.001) and potassium presented a negative correlation trend with increasing mRS grade (Spearman's r = − 0.201, P < 0.001).FDP, fibrin(ogen) degradation products, FPR, fibrin(ogen) degradation products-to-potassium ratio, mRS, modified Rankin Scale  repair [27,28].In general, fibrinogen circulates as a soluble homodimer form in the blood.When the coagulation cascade is activated, thrombin converts fibrinogen into insoluble fibrin to participate in thrombosis.Finally, fibrin clots degrade into soluble FDP by plasmin, and the significantly increased level of FDP suggests organisms in the hypercoagulative state and hyperfibrinolysis symptoms [29,30].Previous studies have reported that FDP can predict neurological outcomes for patients with cardiac arrest and is associated with the recurrence of chronic subdural hematoma [31,32].When aSAH occurs, the integrity of vascular endothelial cells and the blood-brain barrier are disrupted, leading to secondary coagulation abnormalities and excessive activation of the fibrinolytic system, producing a significant amount of FDPs.Fibrin and fibrinogen are also involved in the onset and progression of neuroinflammation [33,34].Fibrin induces neuroinflammation through microglia activation and recruitment of peripheral inflammatory macrophages into the central nervous system.The neuroinflammatory functions of fibrinogen are mainly mediated by the activation of microglia, resulting in neurological deficits [29,35,36].A large amount of FDP suggests excessive consumption of fibrin(ogen), indicating intense neuroinflammation after the onset of aSAH.In addition, fibrin(ogen) is associated with neurodegenerative disorders by promoting β-amyloid deposition, inducing astrocytes to form glial scars, and inhibiting axonal growth following aSAH.All of these findings support the conjecture that FDP may be related to the prognosis of aSAH.To date, there have been no reports on the relationship between FDP and the prognosis of patients with aSAH.However, because of the lack of D-dimer data, we could not compare the predictive value of FDP and D-dimer for the prognosis of aSAH.Although it has been reported that D-dimer is more specific and stable than FDP, their clinical value in aSAH needs to be further studied and compared [37].The potassium cation is of primary physiological importance in maintaining the acid-base balance and regulating osmotic pressure after aSAH [23].Our research found that patients with unfavorable outcomes were more likely to develop hypokalemia and that potassium levels were negatively associated with 3-month prognosis.This phenomenon was also reported by Jung Fig. 5 Receiver operating characteristic (ROC) curves for predicting functional outcome at 3 months.Variables include FPR, WFNS grade, age, WBC, potassium, and FDP.Delong tests were performed to compare FPR with other predictors, and results showed the AUC of FPR was significantly higher than that of other predictors.AUC, area under the curve, FDP, fibrin(ogen) degradation products, FPR, fibrin(ogen) degradation products-topotassium ratio, WBC, white blood cells, WFNS, World Federation of Neurological Society

Table 4 Characteristics of patients dichotomized to the identified FPR threshold (1.45) before and after PS matching
Bold figures indicate statistical significance and values are expressed as n (%), mean ± SD, and median (25%-75%) respectively.Propensity-score matching (caliper 0.02, ratio 1:1, nearest neighbor approach) was performed according to the following parameters: age, female sex, DBP, smoking, WBC, neutrophil, lymphocyte, RBC, hemoglobin, sodium, calcium, WFNS grade, and mFisher score AC anterior circulation, APTT activated partial thromboplastin time, BP blood pressure, DBP diastolic blood pressure, DCI delayed cerebral ischemia, FDP fibrin(ogen) degradation products, FIB fibrinogen, FPR fibrin(ogen) degradation products to potassium ratio, INR international normalized ratio, mFisher modified fisher, PC post circulation, PS, xxx, RBC red blood cells, SBP systolic blood pressure, SD standard deviation, TT thrombin time, WBC white blood cells, WFNS, World Federation of Neurosurgical Society  [9,14].The reason that patients with aSAH have a lower serum potassium level is due to excessive secretion of catecholamines and β 2 adrenergic hormones, which induce overactivation of the Na + /K + -ATPase pump as well as increased influx of potassium [38][39][40].Additionally, a large amount of potassium deposits in the brain extracellular space because of blood-brain barrier disruption may be associated with the inversion of neurovascular coupling and cause dysfunction of the nervous system [41][42][43].Furthermore, patients with aSAH often lose abundant potassium from the digestive tract because of vomiting due to increased intracranial pressure.Ultimately, these factors collectively promote the occurrence of hypokalemia in patients with aSAH.
Because FDP and potassium levels were positively and negatively correlated with mRS grades in patients with aSAH, we verified the predictive value of the FDP/potassium ratio for functional outcomes.Our results show not only that FPR is independently associated with outcome in patients with aSAH but also that its AUC is significantly higher than those of other independent predictors such as age, WFNS grade, WBCs, and potassium and FDP alone.These results indicate that FPR is an ideal predictor of prognosis in patients with aSAH.Although there is no proven pathophysiological evidence for the relationship between FDP and potassium, they may have an indirect correlation in patients with aSAH.We propose the following conjectures to explain the correlation between FDP and potassium.When aSAH occurs, inflammatory responses and coagulation mechanisms are activated, which cause elevated fibrin(ogen) and correlative FDP.In the acute phase, much fibrin and fibrinogen are rapidly synthesized in the liver.This consumes significant amounts of energy and substrate.Potassium, as the common substrate of protein synthesis and energy generation, is heavily consumed during this period.In addition, catecholamines and β 2 adrenergic hormones are abundantly released, directly promoting potassium influx and fibrin(ogen) synthesis.Regarding the relationship between FDP and potassium, we propose the following conjectures.When aSAH occurs, inflammatory responses and coagulation mechanisms are activated, which cause elevated fibrin(ogen) and correlative FDP.In the acute phase, large amounts of fibrin and fibrinogen are rapidly synthesized in the liver.This consumes significant amounts of energy and substrate.Potassium, as the common substrate of protein synthesis and energy generation, is heavily consumed during this period.In the meantime, catecholamines and β 2 adrenergic hormones are abundantly released, directly promoting potassium influx and fibrin(ogen) synthesis.
Finally, we must stress that although biomarkers have some advantages over grading scales, the function of the grading scale cannot be completely abolished by biomarkers in clinical practice.In this study, although FPR was independently associated with poor prognosis and showed a higher AUC and sensitivity, the specificity Fig. 6 The mRS grade at 3 months for patients with aSAH with FPR level differences (FPR ≥ 1.45 vs. FPR < 1.45) after propensity-score matching.Comparisons of functional outcomes and mortality between the two groups were performed by χ 2 test or Fisher's exact test.aSAH, aneurysmal subarachnoid hemorrhage, FPR, fibrin(ogen) degradation products-to-potassium ratio, mRS, modified Rankin Scale of FPR was lower than that of WBC count and WFNS grade.In addition, in our data, we noted that 30 patients (12.6%) with FPR below the threshold had a poor prognosis, while 92 patients (49.5%) with FPR above the threshold had a good prognosis.This shows the limitation of FPR alone in predicting prognosis because other factors, such as age and WFNS grade, are also independently associated with poor prognosis and have independent predictive value.Therefore, we believe that establishing a comprehensive predictive model including FPR, WFNS grade, age, and WBC count in the future will improve the prediction efficiency and provide better clinical guidance.

Limitations of the Study
We must admit that some limitations exist in this study.First, this was a single-center, retrospective study.Therefore, there may exist unavoidable bias that influences the accuracy of the conclusions.We need a multicenter, prospective study with a large sample size to validate our conclusions.Second, we may have overlooked the influence of some factors, such as nutritional status and financial hardship, on functional outcome.Third, not all laboratory parameters were completely included in our study due to limitations of research conditions, such as D-dimer and C-reactive protein.Finally, because of insufficient data, we merely analyzed the relationship of admission FDP and FPR with prognosis and did not consider the trends in FDP and FPR, which may have caused us to underestimate the role of FDP and FPR in predicting the prognosis of patients with aSAH.

Conclusions
Our research demonstrated that elevated serum FPR levels were related to poor functional outcomes in patients with aSAH at 3 months and that FPR was an independent predictor of poor prognosis.FPR may be a promising biomarker for predicting the prognosis of patients with aSAH.

Table 1 Univariate analysis of patient characteristics and admission laboratory data associated with functional out- comes at 3 months
Bold figures indicate statistical significance, and values are expressed as n (%), mean ± SD, and median (25-75%), respectively AC anterior circulation, APTT activated partial thromboplastin time, BP blood pressure, DBP diastolic blood pressure, FDP fibrin(ogen) degradation products, FIB fibrinogen, INR international normalized ratio, mFisher modified Fisher, PC post circulation, RBC red blood cells, SBP systolic blood pressure, SD standard deviation, TT thrombin time, WBC white blood cells, WFNS World Federation of Neurosurgical Society

Table 2 Multivariable logistic regression analysis of pre- dictors for poor functional outcome at 3 months
Bold figures indicate statistical significanceCI confidence interval, FPR fibrin(ogen) degradation products to potassium ratio, mFisher modified Fisher, OR odds ratio, WBC white blood cells, WFNS World Federation of Neurosurgical Society

Table 3 Area under the curve of baseline patient characteristics associated with poor outcome at 3 months
AUC area under the curve, CI confidence interval, FDP fibrin(ogen) degradation products, FPR fibrin(ogen) degradation products to potassium ratio, WBC white blood cells, WFNS World Federation of Neurosurgical Society