Clinical Neurology and Neurosurgery 190 (2020) 105739

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Clinical Neurology and Neurosurgery

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The effects of changes in platelet-to-neutrophil ratios 24 hours after T

intravenous thrombolysis on prognosis in acute ischemic stroke patients
Hong Pana, Mei Fua, Wanqian Geb, Chengye Zhoub,*
a
Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
b
Department of Rehabilitation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

A R T I C LE I N FO A B S T R A C T

Keywords: Objective: To investigate the prognostic value of Platelet-to-Neutrophil ratio on admission (PNR on admission)
PNR and 24 h after intravenous thrombolysis (24 h PNR) in acute ischemic stroke patients (AIS) patients.
24h PNR Patients and Methods: One hundred fifty-one ischemic stroke patients receiving intravenous thrombolysis were
Acute ischemic stroke retrospectively recruited in this study. Complete blood count evaluations for PNR were conducted on admission
Prognosis
and 24 h after the treatment of thrombolysis. The poor outcome at 3months was defined as the modified Rankin
Intravenous thrombolysis
Scale of 3–6.
Results: In multivariate logistic regression, PNR on admission (odds ratio [OR] = 0.967, 95 % confidence in-
terval [CI] = 0.939-0.996; P = 0.028), and 24 h PNR(OR = 0.933, 95 %CI = 0.895-0.972; P = 0.004) were all
independent indicators for the 3-month poor prognosis in ischemic stroke patients receiving intravenous
thrombolysis. The area under the curve of PNR on admission to predict poor functional outcomes at 3 months
was 0.645 (95 %CI = 0.558–0.732; P < 0.001), and the best predictive PNR on admission value was 41.35. After
the treatment of thrombolysis, the area under the curve of 24 h PNR to predict poor functional outcomes at 3
months was 0.796 (95 %CI = 0.722–0.858; P < 0.001), and the best predictive 24 h PNR value was 31.03.
Conclusions: Both the PNR on admission and 24 h PNR were independently associated with poor functional
outcomes. Compared with the PNR on admission, 24 h PNR may serve as a more reliable marker for a poor
prognosis in ischemic stroke patients receiving intravenous thrombolysis.

1. Introduction with infections but also in sterile inflammation [7]. The interaction
between the platelets and neutrophils is increasingly recognized as a
Stroke is a major cause of disability according to the World Health driver of inflammation and thrombosis [8]. Recent studies reported that
Organization’s Global Health estimates. Of all strokes, the ischemic increased platelet-to-neutrophil ratio (PNR) appeared to induce a hy-
stroke accounts for 87 % [1,2]. Current strategies for treating acute percoagulable state and might affect the occurrence of gastric cancer-
ischemic stroke (AIS) include intravenous recombinant tissue plasmi- related ischemic stroke [9]. However, the association between PNR and
nogen activator (rt-PA) and mechanical endovascular treatment [3]. the outcome of AIS patients receiving thrombolysis has not been fully
Although the great superiority of thrombectomy has been showed in the clarified. The purpose of this study was to observe the association be-
treatment of the AIS [4], thrombolysis with rt-PA will still remain an tween the changes of the levels of PNR and the prognosis in AIS patients
important treatment due to the uncertainties of the thrombectomy [5]. treated with thrombolysis.
It is vital to understand the pathogenic mechanisms of stroke and
control risk factors as soon as possible, which is imperative for the 2. Materials and methods
prognosis of patients.
Inflammation has been recognized as an important contributor to 2.1. Study patients
the pathophysiology of stroke. It is well known that platelets possess the
ability of hemostatic function and play a key role in inflammation and From January 2016 to October 2018, we consecutively recruited
immune response [6]. Neutrophils, indicator of inflammation and im- 217 patients who suffered AIS within 4.5 h from the symptoms onset
mune response, act as a fundamental defensive in diseases correlated and received intravenous thrombolysis (IVT) in the First Affiliated

⁎
Corresponding author.
E-mail addresses: [email protected] (H. Pan), [email protected] (M. Fu), [email protected] (W. Ge), [email protected] (C. Zhou).

https://doi.org/10.1016/j.clineuro.2020.105739
Received 1 July 2019; Received in revised form 3 February 2020; Accepted 16 February 2020
Available online 17 February 2020
0303-8467/ © 2020 Published by Elsevier B.V.
H. Pan, et al. Clinical Neurology and Neurosurgery 190 (2020) 105739

Hospital of Wenzhou Medical University. The diagnosis of AIS was Student's t-test was used for the comparison of normally distributed
according to the World Health Organization Criteria [10]. Emergency variables and the Mann–Whitney U test for the asymmetrically dis-
computed tomography (CT) was served to exclude cerebral hemorrhage tributed continuous variables. Chi-square test was used to compare
and subarachnoid hemorrhage before receiving rt-PA. Intravenous rt- categorical variables. If the expected frequency is 5 or less than 5, the
PA (0.9 mg/kg up to a maximum of 90 mg) was used with 10 % of the Fisher exact-test was used. The correlation between NIHSS and PNR, 24
total dosage as a bolus and the rest over 1 h. h NIHSS and 24 h PNR were analyzed with Spearman rank correlation.
After adjusting for the confounders in the univariate analyses, the as-
2.2. Exclusion criteria sociation between the probable predictors and the 3-month outcome
was then using the stepwise multivariate logistic regression analysis.
Exclusion criteria were as follows: patients with no history of he- The receiver operating characteristic (ROC) curves were used to eval-
matologic disorders, no immunosuppressant drug use (n = 5), no in- uate the accuracy of the prognosis of the PNR, 24 h PNR, Neutrophil
fection history within 2 weeks before onset of stroke (n = 20), no within 24 h after thrombolysis (24 h Neutrophil) and Platelet within 24
baseline characteristics (n = 18) and no modified Rankin Scale score at h after thrombolysis (24 h Platelet) for the 3-month outcome of AIS
3-months (n = 23). Ultimately, a total of 151 patients were included in patients receiving thrombolysis.
this study. This study was approved by the Ethics Committee of The Affiliated
Hospital of Wenzhou Medical University. All patients or proxies signed
2.3. Laboratory assay and clinical data the informed consent.

Laboratory indicators such as white blood cell, neutrophil, platelet 3. Results

(PLT), lymphocyte, serum creatinine (Scr), red blood cell distribution
width (RDW), and platelet distribution width (PDW), and fasting blood 3.1. Baseline characteristics
glucose (FBG) were collected on admission and within 24 h after
thrombolysis. Lipid profile including total cholesterol, triglyceride, low- Based on the selection criteria, a total of 151 participants were
density lipoprotein cholesterol (LDL) and high-density lipoprotein enrolled in this study, which consisted of 97 males (64.2 %) and 54
cholesterol (HDL) were measured within 24 h after thrombolysis. females (35.8 %). Their mean age was 68 years old (Table 1). According
Baseline demographic and clinical information including age, to the 3-month mRS score, all participants were divided into two
gender, hypertension, diabetes mellitus, drinking history, smoking groups: Good Prognosis (GP) and Poor prognosis (PP). The baseline
history and atrial fibrillation (AF) were collected on admission. characteristic data and laboratory data of the patients in GP and PP
Hypertension was defined as the use of antihypertensive medication or were presented in Table 1. Age, AF, NHISS score on admission, PNR on
the blood pressure reading of ≥140/90 mmHg on repeated measure- admission, red blood cell width distribution to platelet ratio (RDW/PLT
ment at least 1 week after stroke onset; diabetes mellitus was defined as ratio), 24 h NIHSS score, 24 h PNR, platelet-to-white ratio within 24 h
the use of diabetic medication or a fasting glucose level ≥7mmol/L; the after thrombolysis (24 h PWR), platelet-to-lymphocyte ratio within 24 h
history of AF was defined as the previous history of AF episode or after thrombolysis (24 h PLR), red blood cell distribution width to
electrocardiogram of AF recorded in the hospital; Smoking history was platelet ratio within 24 h after thrombolysis(24 h RDW/PLT ratio), and
defined as smoking more than 1 cigarettes a day for 6 months and neutrophil-to-lymphocyte ratio within 24 h after thrombolysis (24 h
drinking history was defined as the average drinking 2 U/d for male or NLR) and platelet distribution width within 24 h after thrombolysis (24
1 U/d for female [11]. h PDW) were notably different in the GP and PP(P ＜ 0.001). Mean-
The severity of the stroke was assessed by professional clinicians on while, there were also significant differences in lymphocyte, red blood
admission and within 24 h after thrombolysis using the National cell (RBC), Triglyceride, Scr, PLT, Platelet-to-White ratio (PWR), neu-
Institutes of Health Stroke Scale (NIHSS) score. The subtypes of stroke trophil-to-lymphocyte ratio (NLR), and FBG.
were classified as large-artery atherosclerosis (LAA), cardioembolism
(CE), small-vessel disease (SVD), other determined etiology and un-
determined etiology [12]. PNR on admission was defined as the ratio of 3.2. The correlation between PNR on admission, 24 h PNR and the severity
platelets and neutrophils in peripheral blood samples on admission. 24 of AIS
h PNR was defined as the ratio of platelets and neutrophils in peripheral
blood samples within 24 h after thrombolysis. The Spearman rank correlation showed that there were inverse
correlations between PNR on admission and NIHSS score on admission
2.4. The evaluation of the 3-month outcome (r = −0.19, p = 0.018) just as shown on Fig. 1, and 24 h PNR and 24 h
NIHSS after thrombolysis (r = −0.38, p < 0.001) shown on Fig. 2.
Stroke severity was assessed by NIHSS score on admission and 24 h
after thrombolysis(24 h NIHSS). The functional outcome was evaluated 3.3. The correlation between PNR, 24 h PNR and 3-month outcome
by the modified Rankin Scale (mRS) at 3months. Poor prognosis was
defined as mRS≥3; Good prognosis was defined as mRS＜3. All the The univariate logistic regression analysis showed that NIHSS score,
participants were divided into 2 groups: Good Prognosis (GP) and Poor age, AF, Triglyceride, Scr, PNR, PWR, NLR, RDW/PDW ratio, 24 h
prognosis (PP) according to the mRS score. RDW/PDW ratio, 24 h PLR, 24 h PDW, 24 h NIHSS, 24 h NLR, 24 h
PWR, and 24 h PNR were prognostic indicators of functional outcome.
2.5. Statistical analyses After the confounding factors were controlled, multivariate logistic
regression analysis showed that PNR, 24 h PNR were independent
All statistical analyses were generated using SPSS Statistics 22.0 predictors of 3-month prognosis with AIS after thrombolysis (OR =
software (SPSS Inc., Chicago, IL) and MedCale software version 15.2.2 0.967, 95 %CI = 0.939-0.996; P = 0.028; OR = 0.933, 95 %CI =
(Health Care Computer Systems Ltd. Data-Med, P.O. Box 148). P value 0.895-0.972; P = 0.004), as shown in the Table 2 and Table 3. In the
＜0.05 was considered to be statistically significant. Data for con- Table 4, 24 h PNR was independently correlated with a poor outcome in
tinuous variables were exhibited as mean ± standard deviation or AIS patients receiving thrombolysis compared with PNR on admission.
medians and interquartile range according to the normality of data In addition, 24 h NIHSS and Scr were also the independent predictors of
distribution which was tested by Kolmogorov-Smirnov test. Categorical 3-month prognosis in AIS patients receiving intravenous thrombolysis
variables were expressed as relative frequencies and percentages. (Table 4).

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H. Pan, et al. Clinical Neurology and Neurosurgery 190 (2020) 105739

Table 1
Demographic characteristics of AIS patients with different prognosis.
Characteristics Patients Good prognosis Poor prognosis P value

N 151 82 69
Age 68(59–74) 64.5(52–70) 71(62–78) ＜0.001
Male 97(64.2 %) 52(63.4 %) 45(65.2 %) 0.818
Systolic BP mmHg 149.8 ± 21.6 149.5 ± 19.7 150.2 ± 23.9 0.838
Diastolic BP mmHg 84.7 ± 14.6 84.9 ± 13.6 84.4 ± 15.7 0.824
Hpertension 98(64.9 %) 48(58.5 %) 50(72.5 %) 0.074
Diabetses 28(18.5 %) 15(18.3 %) 13(18.8 %) 0.931
AF 46(30.5 %) 17(20.7 %) 29(42.0 %) ＜0.001
Toast
LAA 91(60.3 %) 47(57.3 %) 44(63.8 %) 0.420
CE 27(17.9 %) 12(14.6 %) 15(21.7 %) 0.256
SVD 7(4.6 %) 7(8.5 %) 0(0) 0.017
Other reasons 26(17.2 %) 16(19.5 %) 10(14.5 %) 0.416
Smoking 55(36.4 %) 32(39.0 %) 23(33.3 %) 0.469
Alcohol drinking 39(25.8 %) 22(26.8 %) 17(24.6 %) 0.759
NIHSS score 9(6–14) 6(4–8) 14(10–18) ＜0.001
WBC(109/L) 8.1(6.5–10.4) 8.1(6.4–10.0) 8.1(6.5–10.5) 0.656
Neutrophils(109/L) 5.5(4.0–8.3) 5.2(3.8–7.6) 5.8(4.3–8.5) 0.264
Lymphocytes(109/L) 1.6(1.2–2.0) 1.7(1.4–2.0) 1.4(0.9–1.9) 0.024
RBC(109/L) 4.7(4.3–5.1) 4.8(4.4–5.2) 4.6(4.2–5.0) 0.008
FBG(mmol/L) 7.4(6.1–8.8) 7.0(6.0–8.0) 7.8(6.4–9.4) 0.01
PLT(109/L) 204.0(165.5–246.0) 225.0(182.0–259.0) 185.0(155.8–222.0) 0.001
PNR 38.5(23.9–51.7) 42.4(26.1–56.1) 30.3(22.3–45.8) ＜0.001
NLR 3.7(1.9–6.9) 2.9(1.8–5.4) 5.1(2.4–7.9) 0.004
PWR 24.1(18.6–32.1) 26.9(20.3–35.6) 20.7(17.6–27.7) 0.001
RDW(%) 13.6(13.0–14.1) 13.5(13.0–14.0) 13.8(13.0–14.1) 0.346
PLR 133.8(95.6–182.0) 131.9(93.4–168.1) 137.5(100.6–193.6) 0.530
RDW/PLT 6.57(5.55–8.30) 5.94(5.30–7.71) 7.01(5.88–8.80) ＜0.001
PDW 15.5(11.6–16.9) 16.2(11.6–17.0) 15.3(11.5–16.8) 0.397
24 h PNR 38.5 (23.9–51.7) 46.2(34.8–55.9) 24.7(18.5–37.9) ＜0.001
24 h NLR 3.8 (2.5–7.4) 2.9(2.1–4.1) 7.1(3.6–24.0) ＜0.001
24 h PWR 26.5 (19.2–33.6) 30.2(24.5–37.1) 20.7(15.8–37.2) ＜0.001
24 h RDW(%) 13.1(12.7–13.6) 13.1(12.6–13.6) 13.2(12.8–13.8) 0.510
24 h PLR 137.3(110.9–222.7) 127.9(105.2–172.2) 195.0(124.2–261.7) ＜0.001
24 h RDW/PLT 6.39(5.38–7.91) 5.74(4.99–7.12) 7.01(5.88–8.80) ＜0.001
24 h PDW 13.4(12.2–15.6) 12.8(11.8–14.9) 14.2(12.9–16.1) 0.003
LDL 3.0(2.3–3.5) 3.1(2.4–3.5) 3.1(2.2–3.6) 0.646
HDL 1.2(.9–1.4) 1.1(.9–1.3) 1.2(.9–1.4) 0.869
TG 1.3(.9–2.9) 1.4(1.0–3.1) 1.2(.7–2.6) 0.022
TC 5.03 ± 1.29 5.10 ± 1.18 4.95 ± 1.41 0.482
Scr(mg/dl) 69(59–85) 66(57.3–76.8) 75(61–87) 0.030

Abbreviations: ORodds ratio; CIconfidence interval; BPblood pressure; AFatrial fibrillation; NIHSSNational Institutes of Health Stroke Scale; LAAlarge-artery
atherosclerosis; CEcardioembolism; SVDsmall-vessel disease; WBCwhite blood cell; RBCred blood cell; FBG: fasting blood glucose; PNRplatelet-to-neutrophil ratio;
NLRneutrophil-to-lymphocyte ratio; PWRplatelet-to-white ratio; PLRplatelet-to-lymphocyte ratio; RDWred blood cell distribution width; PDWplatelet distribution
width; RDW/PLTred blood cell distribution width to platelet ratio; 24 h NIHSSNational Institutes of Health Stroke Scale within 24 h after thrombolysis; 24 h
PNRplatelet-to-neutrophil ratio within 24 h after thrombolysis; 24 h NLRneutrophil-to-lymphocyte ratio within 24 h after thrombolysis; 24 h PWRplatelet-to-white
ratio within 24 h after thrombolysis; 24 h PLRplatelet-to-lymphocyte ratio within 24 h after thrombolysis; 24 h RDWred blood cell distribution width within 24 h
after thrombolysis; 24 h RDW/PLTred blood cell distribution width to platelet ratio within 24 h after thrombolysis; 24 h PDWplatelet distribution width within 24 h
after thrombolysis; FBGfasting blood glucose; TGtriglycerides; TCtotal cholesterol; HDLhigh-density lipoproteins; LDLlow-density lipoproteins; Scrserum creatinine.

Fig. 2. Correlation between 24 hPNR and 24 h NIHSS score.

Fig. 1. Correlation between PNR and NIHSS score on admission.

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Table 2
The univariate logistic regression analysis and multivariate logistic regression analysis for outcome.
Univariate Analysis Multivariate Analysis

OR 95 %CI P value OR 95 %CI P value

Age 1.058 1.027-1.091 ＜0.001

Male 0.924 0.474-1.805 0.818
Systolic BP mmHg 1.002 0.987-1.017 0.836
Diastolic BP mmHg 0.998 0.976-1.020 0.822
Hpertension 2.022 0.998-4.099 0.051
Diabetses 1.079 0.473-2.465 0.856
AF 2.772 1.354-5.676 0.005
Smoking 0.781 0.400-1.525 0.470
Alcohol drinking 0.877 0.421-1.828 0.726
NIHSS score 1.443 1.288-1.617 ＜0.001 1.517 1.317-1.747 ＜0.001
RBC(109/L) 0.725 0.392-1.343 0.307
PNR 0.968 0.949-0.987 0.001 0.967 0.939-0.996 0.028
NLR 1.155 1.046-1.275 0.004
PWR 0.944 0.909-0.981 0.003
PLR 1.004 0.999-1.008 0.087
RDW 1.125 0.814-1.557 0.475
RDW/PLT 1.339 1.124-1.596 0.001
PDW 0.971 0.884-1.067 0.544
LDL 0.928 0.676-1.273 0.643
HDL 1.083 0.421-2.785 0.868
FBG(mmol/L) 1.210 1.053-1.394 0.007
Triglyceride 0.587 0.362-0.953 0.031 0.497 0.289-0.853 0.011
Cholesterol 0.912 0.706-1.178 0.480
Creatinine(mg/dl) 1.019 1.002-1.036 0.027 1.038 1.010-1.066 0.007

3.4. PNR on admission, 24 h PNR, 24 h Neutrophil and 24 h Platelet to serve as a more reliable marker for a poor prognosis in ischemic stroke
predict the prognosis of AIS patients at 3months patients receiving intravenous thrombolysis.
The roles of platelets and neutrophils are indispensable in the de-
ROC curves of PNR on admission, 24 h PNR, 24 h Neutrophil and 24 velopment of ischemic stroke. On the one hand, platelets form in-
h Platelet were respectively shown on the Fig. 3 and Fig. 4. According to travascular thrombosis after atherosclerotic plaque erosion or rupture
the ROC curves, the area under the curve (AUC) were 0.645 for PNR (95 once the stroke occurs [13]. On the other hand, the activated platelets
% CI: 0.558-0.732, P = 0.001), 0.796 for 24 h PNR (95 % CI:0.722- express and release different inflammatory mediators to cause the da-
0.858,P < 0.001), 0.725 for 24 h Neutrophil(95 % CI: 0.645-0.796, mage to the brain in all stages of the ischemic cascade [14–16]. Neu-
P < 0.001) and 0.685 for 24 h Platelet (95 % CI: 0.603-0.795, trophils, important components of white leukocytes, were the first cells
P < 0.001) just as shown in the Table 5.Therefore, the 24 h PNR had to migrate from the peripheral vessel into the brain ischemic zone after
higher accuracy than PNR on admission, 24 h Neutrophil and 24 h cerebral infarctions [17]. Johanna et al. proposed a significant corre-
Platelet. lation between the neutrophils and the formation of thrombosis, the
inflammation response and the release of neutrophil extracellular trap,
all of which could destruct the brain tissue [18]. Indeed, a growing
4. Discussion body of studies showed that neutrophils were linked to the 3-month
outcome of AIS patients after thrombolysis [19,20].
In this study, we firstly explored the effects of PNR on admission PNR was an indicator which integrated platelets and neutrophils
and 24 h PNR on the prognosis of AIS patients receiving thrombolysis, into a single index. Recently, a considerable number of studies showed
and identified the accuracy of PNR on admission and 24 h PNR in that increased levels of PNR were related to the no reflow phenomenon
predicting prognosis. Ultimately, we found that both the PNR on ad- and poor prognosis in acute myocardial infarction [21,22]. Jin et.al also
mission and 24 h PNR were independently associated with poor func- found that the indicator of PNR was an independent risk factor for 3-
tional outcomes. Compared with the PNR on admission, 24 h PNR may

Table 3
The univariate logistic regression analysis and multivariate logistic regression analysis of post-thrombolysis indicators for outcome.
Univariate Analysis Multivariate Analysis

OR 95 %CI P value OR 95 %CI P value

Age 1.058 1.027-1.091 ＜0.001

24 h NIHSS score 1.481 1.313-1.670 ＜0.001 1.672 1.373-2.037 ＜0.001
24 h PNR 0.929 0.905-0.955 ＜0.001 0.933 0.895-0.972 0.004
24 h NLR 1.406 1.225-1.614 ＜0.001
24 h PWR 0.897 0.858-0.936 ＜0.001
24 h PLR 1.008 1.004-1.012 ＜0.001
24 h RDW/PLT 1.399 1.160-1.688 ＜0.001
24 h PDW 1.218 1.057-1.404 0.006
FBG(mmol/L) 1.210 1.053-1.394 0.007
AF 2.772 1.354-5.676 0.005
Triglyceride 0.587 0.362-0.953 0.031
Creatinine(mg/dl) 1.019 1.002-1.036 0.027 1.045 1.014-1.078 0.001

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Table 4
The univariate logistic regression analysis and multivariate logistic regression analysis of independent indicators for outcome.
Univariate Analysis Multivariate Analysis

OR 95 %CI P value OR 95 %CI P value

24 h NIHSS score 1.481 1.313-1.670 ＜0.001 1.651 1.351-2.018 ＜0.001

24 h PNR 0.929 0.905-0.955 ＜0.001 0.935 0.897-0.975 ＜0.001
PNR 0.968 0.949-0.987 0.001
NIHSS score 1.443 1.288-1.617 ＜0.001
Creatinine(mg/dl) 1.019 1.002-1.036 0.027 1.046 1.016-1.078 0.003

receiving thrombolysis.
In addition, we also found that 24 h PNR was an autocephaly in-
dicator for the poor outcome compared with PNR on admission, and the
ROC curves also showed 24 h PNR had higher accuracy than PNR on
admission. The possibility underlying this phenomenon might be those:
for one thing, the possibility of the progression of the AIS was un-
certain, and the symptoms could get aggravated within 2 weeks espe-
cially 24 h. For another, combined with the thrombolysis, the symp-
toms could get worsen more easier due to the symptomatic intracranial
hemorrhage. A mount of studies revealed that decreased platelets and
increased neutrophils could account for symptomatic intracranial he-
morrhage [19,24,25]. In addition, the correlation between 24 h PNR
and the 24 h NIHSS was higher inversely correlated, which indicated
Fig. 3. Receiver operating characteristic curve (ROC) of platelet-to-neutrophil that the 24 h PNR could reflect the stroke severity better, and the 24 h
ratio (PNR) and 24 h PNR on the prognosis of AIS patients treated with PNR also had higher accuracy and specificity than 24 h Neutrophil and
thrombolysis. 24 h Platelet. Thus, we concluded that 24 h PNR might be a useful
indicator for the 3-month outcome of AIS patients receiving thrombo-
lysis.
In this study, we also analyzed other indicators such as NLR, RDW,
RDW/PLT ratio, PLR, 24 h RDW, 24 h RDW/PLT ratio and so on.
Similar as the acute myocardial infarction, previous study observed that
in the process of intravenous thrombolysis, the reperfusion injury or
inadequate restoration of flow in the microvasculature could result in
the no-reflow phenomenon, which was highly correlated with the
mortality [26]. Celik et.al revealed that RDW/PLT ratio was in-
dependently associated with no-reflow phenomenon in acute myo-
cardial infarction undergoing primary percutaneous coronary inter-
vention [27]. In addition, other blood count parameters such as NLR,
PLR and RDW could also predict the no-reflow phenomenon in acute
myocardial infarction [28,29]. However, our study did not observe the
independent associations between these indicators and the poor out-
Fig. 4. Receiver operating characteristic curve (ROC) of 24 h PNR, 24 h come of AIS patients. This discrepancy may be due to the different
Neutrophil, 24 h Platelet on the prognosis of AIS patients treated with throm- designs and sample heterogeneity.
bolysis. Above all, in clinical practice, the AIS patients with low levels of
PNR on admission should be treated with thrombolysis carefully.
month outcome in AIS patients [23]. Besides, the platelet–neutrophil Besides, if the patients treated with thrombolysis, we should focus on
crosstalk is being increasingly recognized as a driver of inflammation the dynamic changes of PNR levels. Once the 24 h PNR became more
and thrombosis [8], and in the process of the acute ischemic stroke, the lower compared with the PNR on admission, we emphasize the im-
form of the intravascular thrombosis and the inflammation response portance of evaluating the severity of the disease and the symptoms
could cause the decrease of platelets and the increase of neutrophils, may get worsen. Previous study had shown that the AIS patients after
which ultimately accounted for the decrease of PNR levels. Therefore, thrombolysis could also suffer the progression of ischemia progression
we reasonably found that the low levels of PNR were independently or recurrence, brain edema, and symptomatic hemorrhage [30]. Hence,
associated with the poor outcome for AIS patients. Thus, the indicator the dynamic changes of PNR levels especially 24 h PNR may help
of PNR may be a novel predictor for the prognosis of AIS patients clinicians to identify the early neurological deterioration of the patients

Table 5
Prediction of PNR, 24 h PNR,24 h Neutrophil, 24 h Platelet for AIS patients outcome at 3months.
Prediction AUC 95 %CI Sensitivity Specificity cut-off P value

PNR 0.645 0.558-0.732 68.12 52.44 ＜41.35 0.001

24 h PNR 0.796 0.722-0.858 63.60 83.70 ＜31.03 ＜0.001
24 h Neutrophil 0.725 0.645-0.796 74.20 65.00 > 5.45 ＜0.001
24 h Platelet 0.685 0.603-0.795 69.70 63.70 < 209 ＜0.001

Abbreviations: 24 h Neutrophil: Neutrophil within 24 h after thrombolysis; 24 h Platelet:Platelet within 24 h after thrombolysis.

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and thus conduct appropriate therapy. [8] A. Garcia-Culebras, V. Duran-Laforet, C. Pena-Martinez, et al., Myeloid cells as
However, this study had several limitations. Firstly, part of data was therapeutic targets in neuroinflammation after stroke: specific roles of neutrophils
and neutrophil-platelet interactions, J. Cereb. Blood Flow Metab. 38 (2018)
retrospectively collected and the research was a single center study. 2150–2164.
Secondly, the sample size was relatively small to represent the crowd [9] H. Long, K. Qin, J. Chen, et al., Biomarkers of gastric cancer-related ischemic stroke
and we just recorded the PNR on admission and 24 h after thrombolysis and its underlying pathogenesis, Medicine 97 (2018) e0493.
[10] T. Brott, H.P. Adams Jr., C.P. Olinger, et al., Measurements of acute cerebral in-
which should be collected at many time points. Thus, further line large farction: a clinical examination scale, Stroke 20 (1989) 864–870.
sample, prospective research will provide more clinical guidance. [11] R. Fu, Y. Wang, Y. Wang, et al., The development of cortical microinfarcts is as-
sociated with intracranial atherosclerosis: data from the chinese intracranial
atherosclerosis study, J. Stroke Cerebrovasc. Dis. 24 (2015) 2447–2454.
5. Conclusion [12] H.P. Adams Jr., B.H. Bendixen, L.J. Kappelle, et al., Classification of subtype of
acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST.
In summary, this study highlights the value of PNR as a potential Trial of Org 10172 in Acute Stroke Treatment, Stroke 24 (1993) 35–41.
[13] S. Greisenegger, G. Endler, K. Hsieh, et al., Is elevated mean platelet volume as-
indicator for the outcomes in AIS patients receiving intravenous
sociated with a worse outcome in patients with acute ischemic cerebrovascular
thrombolysis. Besides, Low levels of 24 h PNR may provide better events? Stroke 35 (2004) 1688–1691.
prediction value for the ischemic stroke patients treated with in- [14] G. Shi, C.N. Morrell, Platelets as initiators and mediators of inflammation at the
travenous thrombolysis. vessel wall, Thromb. Res. 127 (2011) 387–390.
[15] F. Boehlen, K.J. Clemetson, Platelet chemokines and their receptors: what is their
relevance to platelet storage and transfusion practice? Transfus. Med. 11 (2001)
Credit author statement 403–417.
[16] S.S. Smyth, R.P. McEver, A.S. Weyrich, et al., Platelet functions beyond hemostasis,
J. Thromb. Haemost. 7 (2009) 1759–1766.
Hong Pan conceived the idea. [17] J.Y. Kim, J. Park, J.Y. Chang, et al., Inflammation after ischemic stroke: the role of
Mei Fu analyzed the data. leukocytes and glial cells, Exp. Neurobiol. 25 (2016) 241–251.
Draft manuscript was prepared by Hong Pan and Wanqian Ge. [18] J. Ruhnau, J. Schulze, A. Dressel, et al., Thrombosis, neuroinflammation, and
poststroke infection: the multifaceted role of neutrophils in stroke, J. Immunol. Res.
Chengye Zhou revised the manuscript. 2017 (2017) 5140679.
All authors made contribution to data interpretation and writing of [19] I. Maestrini, D. Strbian, S. Gautier, et al., Higher neutrophil counts before throm-
the draft manuscript. bolysis for cerebral ischemia predict worse outcomes, Neurology 85 (2015)
1408–1416.
[20] J. Shi, H. Peng, S. You, et al., Increase in neutrophils after recombinant tissue
Declaration of Competing Interest plasminogen activator thrombolysis predicts poor functional outcome of ischaemic
stroke: a longitudinal study, Eur. J. Neurol. 25 (2018) e687-e645.
[21] G.Y. Huang, L.J. Yang, X.H. Wang, et al., Relationship between platelet-leukocyte
The authors declare no financial or other conflicts of interest.
aggregation and myocardial perfusion in patients with ST-segment elevation myo-
cardial infarction after primary percutaneous coronary intervention, Heart & Lung:
Acknowledgements J. Critical Care 45 (2016) 429–433.
[22] F. Ren, N. Mu, X. Zhang, et al., Increased platelet-leukocyte aggregates are asso-
ciated with myocardial No-reflow in patients with ST elevation myocardial in-
We are grateful to all patients and their relatives for their co- farction, Am. J. Med. Sci. 352 (2016) 261–266.
operation and support. [23] P. Jin, X. Li, J. Chen, et al., Platelet-to-neutrophil ratio is a prognostic marker for
90-days outcome in acute ischemic stroke, J. Clin. Neurosci. 63 (2019) 110–115.
[24] S.M. Desai, A. Mehta, A.A. Morrison, et al., Endovascular thrombectomy, platelet
References count, and intracranial hemorrhage, World Neurosurg. (2019).
[25] S. Monch, T. Boeckh-Behrens, K. Kreiser, et al., Thrombocytopenia and declines in
[1] Tissue plasminogen activator for acute ischemic stroke, N. Engl. J. Med. 333 (1995) platelet counts: predictors of mortality and outcome after mechanical throm-
1581–1588. bectomy, J. Neurol. (2019).
[2] D. Mozaffarian, E.J. Benjamin, A.S. Go, et al., Heart disease and stroke Statistics- [26] T. Dalkara, E.M. Arsava, Can restoring incomplete microcirculatory reperfusion
2016 update: a report from the american heart association, Circulation 133 (2016) improve stroke outcome after thrombolysis? J. Cerebral. Blood Flow & Metabolism.
e38–e360. 32 (2012) 2091–2099.
[3] O. Altintas, M.O. Altintas, A. Tasal, et al., The relationship of platelet-to-lymphocyte [27] T. Celik, S. Balta, M. Demir, A.O. Yildirim, et al., Predictive value of admission red
ratio with clinical outcome and final infarct core in acute ischemic stroke patients cell distribution width-platelet ratio for no-reflow phenomenon in acute ST segment
who have undergone endovascular therapy, Neurol. Res. 38 (2016) 759–765. elevation myocardial infarction undergoing primary percutaneous coronary inter-
[4] M. Goyal, B.K. Menon, W.H. van Zwam, et al., Endovascular thrombectomy after vention, Cardiology journal 23 (2016) 84–92.
large-vessel ischaemic stroke: a meta-analysis of individual patient data from five [28] T. Celik, S. Balta, C. Ozturk, et al., Predictors of No-Reflow phenomenon in young
randomised trials, Lancet (London, England) 387 (2016) 1723–1731. patients with acute ST-Segment elevation myocardial infarction undergoing pri-
[5] Y. Xiong, B. Manwani, M. Fisher, Management of acute ischemic stroke, Am. J. Med. mary percutaneous coronary intervention, Angiology 67 (2015) 683–689.
132 (2019) 286–291. [29] T. Celik, S. Balta, D.P. Mikhailidis, et al., The relation between No-Reflow phe-
[6] J.W. Semple, J.E. Italiano Jr., J. Freedman, Platelets and the immune continuum, nomenon and complete blood count parameters, Angiology 68 (2017) 381–388.
Nat. Rev. Immunol. 11 (2011) 264–274. [30] J.M. Kim, J. Moon, S.W. Ahn, H.W. Shin, et al., The etiologies of early neurological
[7] P.H. Leliefeld, C.M. Wessels, L.P. Leenen, et al., The role of neutrophils in immune deterioration after thrombolysis and risk factors of ischemia progression, J. stroke
dysfunction during severe inflammation, Crit. Care 20 (2016) 73. and cerebrovascular diseases 25 (2016) 383–388.