Relationship between the first pass effect and the platelet-lymphocyte ratio in acute ischemic stroke

Abstract

Purpose

The aim of this study was to evaluate the relationship between platelet-lymphocyte ratio (PLR) and first pass effect (FPE) in patients with acute ischemic stroke (AIS). Our secondary goal was to investigate other laboratory, demographic or technical parameters that may be related to FPE and to search for independent predictors of FPE.

Materials and methods

Patients who underwent mechanical thrombectomy (MT) in our hospital between January 2017 and February 2020 were reviewed. Patients were divided into two groups: FPE and non-FPE. Demographic features, laboratory parameters, pretreatment imaging and clinical features, angiographic and clinical outcomes were recorded and compared between the two groups. Logistic regression analysis was performed to analyze the independent predictors and a predictive model was produced for demonstrating the possibility to achieve FPE.

Results

The study consisted of 83 patients (37 female, 46 male; mean age 62.69 ± 15.16) who were treated by MT. FPE was achieved in 32 patients (32/83, 38.6%). PLR was higher in the non-FPE group (195.35 ± 101.49) when compared to the FPE group (103.17 ± 37.06). A PLR value of <126.3 and female sex were found as independent predictors of FPE. Our predictive model estimated the chance of FPE as 77.9% in female patients who had PLR values lower than 126.3 while it was 77.1% when only using the PLR cutoff value.

Conclusions

High levels of PLR were associated with the failure of FPE. High values of PLR may be considered as a negative predictor for FPE achievement prior to MT in patients with AIS.

Introduction

Stroke is one of the main causes of disability and death. ¹ The effectiveness of endovascular treatment in acute ischemic stroke (AIS) has been demonstrated by important trials. ² New devices and techniques have been developed recently to strengthen both the recanalization rates and the clinical outcomes of mechanical thrombectomy (MT).^3–6 Even though complete or near-complete reperfusion has been related with better clinical outcomes in patients with AIS,^7,8 several passes and extended procedure time may induce endothelial damage and cause poor outcomes.^9,10

A new definition, first pass effect (FPE), has been introduced and researched in AIS patients who underwent MT in recent years.^11–14 FPE is described as complete antegrade reperfusion of the previously occluded target artery ischemic territory (Modified Thrombolysis in Cerebral Infarction [mTICI] 3) with a single pass. ¹¹ Currently published studies demonstrated that FPE is significantly associated with better clinical outcomes and concluded that the main goal should be to obtain FPE in MT. ¹² The variables associated with FPE may become a big field of interest in the near future considering the increase of patients with AIS and developing techniques in MT.

Platelet-lymphocyte ratio (PLR) is a practical laboratory biomarker that can show an increased systemic inflammatory process. ¹⁵ Different reports have searched the association between PLR and chronic inflammation in various clinical entities.^16–18 In AIS, inflammatory response aggravates intravascular thrombus formation by platelet activation and cytokine secretion, which may directly affect the success of FPE. ¹⁹ Although the use of PLR in clinical practice is feasible and easy, its association with FPE has not been described before. Hence, the aim of this study was to determine the relationship between PLR and FPE in patients with AIS. Our secondary goal was to investigate any other laboratory, demographic or technical parameters that may be related to FPE.

Materials and methods

Population and data collection

Local ethics committee approval was obtained for this retrospective single-center study. Patients with AIS who underwent MT in our hospital between January 2017 and February 2020 were retrospectively examined. Inclusion criteria were as follows: patients older than 18 years, anterior or posterior circulation large vessel occlusion without intracranial hemorrhage, ASPECT score of ≥6 for anterior circulation stroke, and baseline NIHSS score of ≥6. Patients with insufficient laboratory or clinical data (n = 8), tandem occlusions which predominantly consisted of extracranial stenosis or occlusion (n = 11), carotid artery dissections (n = 2), and spontaneous revascularization after intravenous tPA (n = 2) were excluded. The flowchart of the study was demonstrated in Figure 1. In patients with recognized symptom onset, MT was performed within 6 hours. In ten patients with unknown time of symptom onset, the mismatch between an apparent acute lesion on diffusion-weighted imaging (DWI) and the lack of parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR) images (DWI–FLAIR mismatch) was used. ²⁰ Patients in a 4.5-hour onset-to-groin puncture window were treated with intravenous tissue plasminogen activator (tPA) unless there was a contraindication. ²¹ For posterior circulation, onset to treatment time was extended to 10 hours. ²² Written informed consent was obtained from all patients for the use of all imaging and clinical data prior to the endovascular treatment.

Figure 1.

Flowchart of the study.

ASPECT: Alberta Stroke Program Early CT; NIHSS: National Institutes of Health Stroke Scale; tPA: tissue tissue plasminogen activator.

Age, sex, and comorbidities of the patients were noted. Laboratory parameters of venous blood sampling taken at the time of admission to the emergency department were recorded. PLR was calculated by using the formula “absolute platelet count/absolute lymphocyte count” according to the complete blood count test results of the venous blood sample.

Pretreatment evaluation and endovascular treatment

A non-contrast brain computed tomography (CT) was done to exclude hemorrhage and to assess the Alberta Stroke Program Early computed tomography (ASPECT) score. Then, a CT angiogram was performed to evaluate of the vascular system as well as the collaterals. The baseline ASPECT scores were evaluated in consensus by two blinded observers, a 5-year experienced radiologist and a 5-year experienced neurologist. Magnetic resonance imaging was performed in wake-up stroke and in patients with unknown time of symptom onset to search for the DWI–FLAIR mismatch. ²⁰ A consultant neurologist with 7-year experience in interventional neurology examined all patients, recorded all National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores prior to the procedure.

Written informed consent was obtained prior to the endovascular treatment. Endovascular procedures were performed by a 20-year experienced interventional radiologist and a 7-year experienced interventional neurologist. Mechanical thrombectomies were performed under conscious sedation or general anesthesia (determined by the interventionist and anesthesiologist in consensus depending on the clinical situation of the patient), with an intravenous heparin bolus of 2000 IU initially. A first-line aspiration with a large-bore aspiration catheter or a stent retriever with manual aspiration during stent retrieval was performed by a triaxial system (8 F balloon guiding catheter with an intermediate catheter). The choice of thrombectomy technique varied depending on the operator's preference. In case of partial or no response, the operator decided to pass to another technique or repeat the initial maneuver. The goal was to finish the procedure when successful reperfusion (TICI 2 b/3) was observed. ⁶ The consensus in our institution was to end the procedure if unsuccessful recanalization was noticed after six passes.

Image analysis and clinical outcome

All angiographic images were reviewed retrospectively to examine the target downstream territory, the technique, and the mTICI score by the same blinded observers who evaluated the initial ASPECT scores. Successful reperfusion was defined as TICI 2 b or TICI 3 flow on the latest angiography. ²³ FPE was described as the mTICI score of 3 after a single technique. The angiographic revascularization grades were determined based on recommendations of the Cerebral Angiographic Revascularization Grading collaborators. ²⁴ Disagreements were solved by consensus. Periprocedural complications including dissection, distal embolism in the same territory or in a new territory, and arterial perforation were recorded. Lastly, the procedure time (puncture to end of the procedure) was evaluated.

Non-contrast brain CT was obtained 24 hours after the intervention to assess hemorrhagic transformation. Symptomatic intracerebral hemorrhage (sICH) was described as hemorrhage with clinical worsening of ≥4 points on the NIHSS score at 24 hours. ²⁵ CT scan was performed earlier when the clinical condition got worse. The mRS at the third month was used to evaluate the clinical outcome. A mRS ≤2 at the third month was determined as a good clinical outcome. ²⁶ mRS scores were recorded from the data of our stroke outpatient clinic.

Statistical analysis

Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 22.0 (SPSS Inc., Chicago, IL, USA). Continuous data were expressed as means ± standard deviation (SD) and categorical variables as percentages. The distribution of variables was assessed by the Kolmogorov-Smirnov test. Patients were divided into two groups: FPE and non-FPE. Chi-square test or Fisher’s exact test was used for categorical variables. Mann-Whitney U test or independent t-test was performed to compare continuous variables. Receiver operating characteristic (ROC) curve analyses were performed for each statistically significant parameter to evaluate the performance of predicting FPE. Logistic regression analysis using a backward stepwise selection procedure was performed to analyze the independent predictors for FPE. Lastly, a predictive model was built up for demonstrating the possibility to achieve FPE using the variables in the logistic model. P-values less than 0.05 were considered statistically significant.

Results

Demographic and laboratory parameters

The study consisted of 83 patients (37 female, 46 male; mean age 62.69 ± 15.16) who underwent MT. The demographic and laboratory data were displayed in Table 1. No significant difference was noticed in demographic data except sex. FPE was observed in 21 of 37 female patients (p = 0.002).

Table 1.

Comparative analysis of demographic data and laboratory parameters.

	All of the patients (n = 83)	FPE group(n = 32)	Non-FPE group (n = 51)	P value
Age (years)	62.69 ± 15.16	65.03 ± 2.86	61.22 ± 14.44	0.131
Female/male	37/46	21/11	16/35	0.002
Hypertension	53 (63.9%)	20 (62.5%)	33 (64.7%)	0.839
Diabetes mellitus	26 (31.3%)	8 (25.0%)	18 (35.2%)	0.325
Hyperlipidemia	36 (43.4%)	17 (53.1%)	19 (37.2%)	0.156
Congestive heart failure	24 (28.9%)	10 (31.2%)	14 (27.4%)	0.710
Coronary artery disease	35 (42.1%)	12 (37.5%)	23 (45.0%)	0.310
Previous stroke/Transient ischemic attack	11 (13.3%)	6 (18.7%)	5 (9.8%)	0.242
Atrial fibrillation	31 (37.3%)	16 (50.0%)	15 (29.4%)	0.059
Smoking	42 (50.6%)	14 (43.7%)	28 (54.9%)	0.256
Hemoglobin (g/dL)	13.14 ± 1.90	12.85 ± 2.01	12.94 ± 1.99	0.247
Hematocrit (%)	39.85 ± 5.42	39.38 ± 5.74	39.31 ± 5.92	0.534
White cell count (109/L)	9.64 ± 2.82	9.00 ± 2.02	8.96 ± 2.88	0.099
Neutrophils (109/L)	6.56 ± 2.50	5.83 ± 1.91	6.31 ± 2.44	0.037
Lymphocytes (109/L)	1.98 ± 0.90	2.36 ± 0.85	1.62 ± 0.67	0.001
Platelets (109/L)	251.97 ± 77.05	222.37 ± 57.37	269.78 ± 64.36	0.007
PLR	155.36 ± 92.09	103.17 ± 37.06	195.35 ± 101.49	<0.001
NLR	4.55 ± 3.95	2.96 ± 1.94	5.55 ± 4.55	0.003

Note: bold values indicate statistically significant.

FPE: first pass effect; PLR: platelet-lymphocyte ratio; NLR: neutrophil-lymphocyte ratio.

Platelets, lymphocytes, neutrophils, neutrophil-lymphocyte ratio (NLR), and PLR seemed significantly different between the FPE and non-FPE groups. Among these, PLR was the most significant parameter (p < 0.001). PLR was higher in the non-FPE group (195.35 ± 101.49) when compared to the FPE group (103.17 ± 37.06).

Clinical presentation features, periprocedural and clinical outcomes

Clinical presentation and angiographic parameters were summarized in Table 2. FPE was achieved in 32 patients (32/83, 38.6%) in the present study. The mean ASPECT score at admission was significantly higher in the FPE group (p = 0.002). Although time from onset to puncture was shorter in the FPE group (219 versus 237 minutes), no statistical significance was observed (p = 0.151). Neither of the techniques (aspiration was initially performed in 26 patients while stent retriever was initially used in 57 patients) demonstrated a higher percentage in the FPE group. In the failure of aspiration (n = 19), a stent retriever was used for the mechanical thrombectomy. Aspiration was performed as the second technique in 10 of 32 (31.2%) cases who initially had unsuccessful recanalization with stent retrievers. The procedure time was shorter in the FPE group (47 versus 89 minutes; p < 0.001).

Table 2.

Clinical presentation, technical, and angiographic features.

	All of the patients (n = 83)	FPE group(n = 32)	Non-FPE group(n = 51)	P value
ASPECT score at admission	8.76 ± 0.94	9.22 ± 0.89	8.61 ± 0.89	0.002
NIHSS score at admission	16.31 ± 5.00	15.52 ± 4.71	17.17 ± 4.59	0.225
Anterior/posterior circulation stroke	67/16	29/3	38/13	0.090
Intravenous tPA	18 (21.6%)	7 (21.8%)	11 (21.5%)	0.974
Time from onset to puncture (minute)	229.60 ± 56.33	219.03 ± 42.05	237.49 ± 63.71	0.151
Procedure time (minute)	73.23 ± 33.17	47.91 ± 16.04	89.12 ± 31.25	<0.001
Technique				0.141
Aspiration	26 (31.3%)	7 (26.9%)	19 (73.1%)
Stent retriever	57 (68.7%)	25 (43.9%)	32 (56.1%)

Note: bold values indicate statistically significant.

ASPECT: Alberta Stroke Program Early computed tomography; NIHSS: National Institutes of Health Stroke Scale; tPA: tissue plasminogen activator; FPE: first pass effect.

The occluded arteries were: middle cerebral artery in 50 patients (60.2%), internal carotid artery (ICA) terminus in 17 patients (20.5%), basilar artery in 11 patients (13.3%), and posterior cerebral artery in 5 patients (6.0%). No relation with FPE was observed regarding the clot location. Successful reperfusion (TICI 2 b/3) was obtained in 65 patients (78.3%) at the end. Distal embolization and embolization into a new territory rates were 5/83 (6.0%) and 3/83 (3.6%), respectively. Arterial perforation was observed in one patient (1.2%).

The mean mRS score at 90 days was 2.42 ± 2.17. Clinical outcomes, mortality rates, and sICH rates were summarized in Table 3. The subjects with FPE had superior clinical and functional outcomes (mRS ≤ 2) at the third month (p = 0.001). The rates of sICH were higher in the non-FPE group (p = 0.047). In addition, we did not observe any relation between higher PLR values and sICH (p = 0.279) or mortality (p = 0.502).

Table 3.

Clinical outcomes.

	All of the patients (n = 83)	FPE group(n = 32)	Non-FPE group (n = 51)	P value
mRS at 90 days (≤2)	49 (59.0%)	26 (81.3%)	23 (45.1%)	0.001
sICH	17 (20.5%)	3 (9.4%)	14 (27.5%)	0.047
Mortality	13 (15.7%)	3 (9.4%)	10 (19.6%)	0.352

Note: bold values indicate statistically significant.

mRS: modified Rankin Scale; sICH: symptomatic intracerebral hemorrhage; FPE: first pass effect.

Predictors of FPE

The diagnostic performances of the related variables to predict FPE were displayed in Table 4 with the cutoff values and diagnostic accuracies. PLR showed the highest diagnostic performance with a sensitivity of 81%, a specificity of 77%, and a diagnostic accuracy of 77.1% among the variables associated with FPE. ROC curve analysis determined an optimal cutoff value of PLR as 126.3 for predicting FPE (Figure 2). The area under the curve was 0.847. In the logistic regression analysis, only female sex (odds ratio [OR], 2.9; 95% confidence interval [CI], 0.894–9.699; p = 0.076) and the PLR value of <126.3 (OR, 11.9; 95% CI, 3.597–39.635; p < 0.001) were found as independent predictors of FPE.

Table 4.

Diagnostic performances of variables associated with FPE.

	AUROC	95% CI	Cutoffvalue	Sensitivity(%)	Specificity(%)	p value	Diagnostic accuracy (%)
Sex	–	–	–	65	68	0.002	67.5
PLR	0.847	0.762–0.932	<126.3	81	77	<0.001	77.1
NLR	0.730	0.619–0.841	<3.22	72	63	<0.001	66.3
ASPECT score at admission	0.710	0.584–0.836	>8.5	75	59	0.003	66.2

FPE: first pass effect; AUROC: Area under the curve; CI: confidence interval; PLR: platelet-lymphocyte ratio; NLR: neutrophil-lymphocyte ratio.

Figure 2.

ROC analysis of platelet-lymphocyte ratio (PLR) for the first pass effect.

Our predictive model estimated the chance of FPE as 77.9% when using a combined-model which included a PLR cutoff value of <126.3, an NLR cutoff value of <3.22, and an ASPECT score of >8. Moreover, the likelihood of FPE rate did not change when using the NLR cutoff value was excluded. Besides, the diagnostic accuracy was still the same after ignoring the ASPECT score. Lastly, the possibility of achieving FPE was 77.9% in female patients who had PLR values lower than 126.3 while it was 77.1% when only using the PLR cutoff value.

Discussion

In this study, we found increased PLR values in the failure of FPE in patients who underwent MT. Moreover, a PLR value of < 126.3 was demonstrated to be an independent predictor of FPE. In our predictive model, we showed that using only PLR values displayed 77.1% accuracy in predicting FPE, and adding female sex to it increased the rate to 77.9%. The findings of this study reveal the influence of PLR on FPE in patients with AIS.

Platelets are proven to have an active role in thrombosis and inflammation by interacting with endothelium and activating cytokine discharge. ²⁷ Lymphocytes also take part in the inflammatory process and lower values were illustrated as an independent predictor of cardiovascular events. ²⁸ In AIS, lymphocytes participate in the pathophysiological process by penetrating to the ischemic tissue. ²⁹ Although higher values of PLR have been demonstrated in several ischemic conditions,^30–32 the relationship with FPE in patients with AIS has not been evaluated before. To our knowledge, this is the first study in the literature evaluating the impact of PLR on FPE and forming a model to estimate FPE in patients with AIS.

In a retrospective study consisting of 57 patients, authors demonstrated that patients with lower PLR had better successful recanalization (TICI 2 b/3) rates. ¹⁷ In the present study, we investigated the association of PLR with FPE and found lower PLR values in the FPE group. It might be hypothesized that the higher the PLR values are, the more severe the inflammatory response gets. Hence, it might be difficult to take out the thrombus at once considering the severity of inflammation. Douglas et al. ³³ demonstrated that platelet-rich clots were associated with worse recanalization rates. However, they did not find any difference in clot formation between the FPE and non-FPE group. This may suggest that not only platelet increase in the clot but complicated inflammatory processes play a role in the failure of the FPE.

Female sex and a PLR value of <126.3 were the independent factors for FPE in our study. Close to our results, Zaidat et al. ¹¹ found that the FPE rate was higher in women. But, this finding was not an independent factor for FPE in their research. Contrary to this, Gonzalez et al. ³⁴ found that the success rate of FPE was lower in women in patients with anterior circulation stroke. These inconstant findings may be due to ethnical and genetic features, or unknown multifactorial variables, which require further investigation in the future.

In the model we created, the accuracy rate reached up to 77.9% when all variables affecting FPE were included. However, we found that the rate stayed the same after excluding the cutoff value of NLR and the baseline ASPECT score of >8. We can speculate from this finding that NLR, which has been commonly used as an alternative inflammation marker in different conditions,^16,35 has not a substantial effect on FPE when compared to using only PLR. In the acute phase of stroke, both neutrophils and platelets play a role in the inflammatory process concomitantly. Neutrophils contribute to the neuronal death by injuring endothelial cells and supporting the thrombus formation with platelets. ¹⁹ Although the exact reason could not be explained clearly in the literature, PLR was found to be more significant in predicting the inflammation compared to NLR,^36,37 which is similar to our results. We also observed that excluding the baseline ASPECT score of >8, like NLR, did not make a difference in estimating FPE. We can conclude that interventionists have a better chance to obtain FPE in female patients with lower PLR values with a rate of 77.9%. However, only using a PLR value of 126.3 has the ability to estimate FPE with a possibility of 77.1%. Considering these results, we can easily propose that PLR has the biggest impact on FPE among our sample. A PLR value lower than 126.3 may be used alone as a predictor for FPE with a rate of 77.1% in daily practice.

Baseline ASPECT scores were found to be higher in patients with FPE in this study. Similarly, admission DWI-ASPECT score was higher in the FPE group and also found as an independent predictor of FPE in a large prospective population. ³⁸ The association between higher ASPECT score and FPE may be explained by the fact that fewer thrombus burden results with higher ASPECT score compared to longer thrombus possibly affecting more perforators. ³⁹ Accordingly, it might be easier to take out the thrombus at once.

FPE group had greater functional outcomes at 90 days, and the sICH rates were fewer. Our results were comparable to the North American Solitaire Acute Stroke (NASA) Registry database. ¹¹ Zaidat et al. ¹¹ demonstrated better clinical outcomes as well as lower mortality rates in the FPE group. Although we did not observe a statistical difference in mortality rates, there was a substantial difference quantitively. The reason for that could be the relatively small number of the study population. In another recent study, patients with complete reperfusion (mTICI 3) after a single pass and patients with mTICI 3 after multiple passes were compared to evaluate the true FPE. ¹² They as well concluded that FPE was an independent factor for good clinical outcome. Although evaluating the factors associated with clinical outcome was not the purpose of this study, our results validate the importance of FPE in patients with AIS.

Our study had several limitations. Firstly, the study design was retrospective, and the sample size was relatively small. Secondly, two different techniques were performed during the procedures. However, this issue has given the opportunity to see if there was an interaction between the treatment modality and FPE. Thirdly, the procedures were not performed by the same operator. We think that operator experience may affect the success of the FPE. Fourthly, we did not know the conditions which might have affected the platelet and lymphocyte counts such as infection, hematological diseases, and thrombophilia at the time of admission.

In conclusion, high levels of PLR can be associated with the failure of FPE. According to our results, using only a cutoff value of PLR has an equal diagnostic performance to estimate the FPE when compared to its combination with other laboratory and clinical parameters. We anticipate that PLR may be used as a practical marker before treatment if our results are validated with further studies.