Shujie YanI; Sizhe GaoI; Song LouI; Qiaoni ZhangI; Yuefu WangII; Bingyang JiI
ABSTRACTIntroduction: Postoperative thrombocytopenia is common in cardiac surgery with cardiopulmonary bypass, and its risk factors are unclear.
ACT = Activated clotting time
AKI = Acute kidney injury
BMI = Body mass index
BSA = Body surface area
BUN = Blood urea nitrogen
CABG = Coronary artery bypass grafting
CI = Confidence interval
CPB = Cardiopulmonary bypass
CRRT = Continuous renal replacement therapy
ECMO = Extracorporeal membrane oxygenation
EuroSCORE = European System for Cardiac Operative Risk Evaluation
FFP = Fresh frozen plasma
HIT = Heparin-induced thrombocytopenia
IABP = Intra-aortic balloon pump
ICU = Intensive care unit
INR = International normalized ratio
LVEF = Left ventricular ejection fraction
OR = Odds ratio
PT-INR = Prothrombin time-international normalized ratio
RBC = Red blood cell
VAVD = Vacuum-assisted venous drainage
Postoperative thrombocytopenia is common in cardiac surgery with cardiopulmonary bypass (CPB), leading to increased postoperative blood loss. The etiology of thrombocytopenia in cardiac surgery is related to blood destruction, hemodilution, and platelet activation during CPB.
The incidence of postoperative thrombocytopenia is about 10-40% according to different criteria of thrombocytopenia[2, 3, 4]. Postoperative thrombocytopenia was reported to be associated with postoperative adverse outcomes, including acute kidney injury (AKI), stroke, and death[5, 6, 7]. However, risk factors of postoperative thrombocytopenia are unclear. A study including 42 patients identifed preoperative platelet count, age, and intraoperative blood transfusion as independent predictors for postoperative thrombocytopenia. Given the small sample size, the conclusion was not convincing enough.
The present retrospective study was aimed to describe the distribution of postoperative thrombocytopenia in patients undergoing cardiac surgery with CPB, investigate the relationship between postoperative thrombocytopenia and outcomes, and identify risk factors of postoperative thrombocytopenia.
Study Design and Population
This retrospective study was approved by our institutional review board (approval number 2020-1288), and the need for informed consent was waived. Data were extracted from the CPB database (2017-2018). Only valve surgeries were included to exclude the impact of perioperative antiplatelet drugs on platelet counts in coronary artery bypass grafting (CABG) and minimize surgical heterogeneity. The inclusion criteria were: (1) age > 18 years and (2) undergoing valve replacement or repair surgery from January 1, 2017 to December 30, 2018. The exclusion criteria included: (1) combined CABG, aortic surgery, or other surgery; (2) preoperative antiplatelet treatment; (3) previous cardiac surgery within six months; and (4) emergency surgery.
Platelet counts were extracted from blood routine tests at three time points: (1) last test before surgery (preoperative platelet count); (2) first test after surgery, immediately after admission to intensive care unit (ICU) (postoperative platelet count); and (3) last test before discharge from hospital (before-discharge platelet count).
Postoperative thrombocytopenia was defined as a postoperative platelet count below the 10th quantile of all the enrolled patients, referring to Kertai MD’s method. Platelet count recovery was defined as before-discharge platelet counts ≥125×109/L or the preoperative level.
Risk factors of postoperative thrombocytopenia were assessed. Variables contained demographic information, body surface area (BSA), comorbidity, European System for Cardiac Operative Risk Evaluation (EuroSCORE), preoperative laboratory tests, surgical information (including valve position, valve numbers, valve replacement or repair, and mechanical or bioprosthetic valve), CPB circuit, CPB time, aortic cross-clamping time, CPB temperature, and total heparin dose.
Outcomes were compared between patients with and without postoperative thrombocytopenia. The primary outcome was in-hospital mortality. Secondary outcomes included chest drainage volume, postoperative blood transfusion, re-thoracotomy, platelet count recovery, cerebrovascular accidents (defined as the diagnosis of stroke or intracranial hemorrhage), AKI (defined as a postoperative increase in serum creatinine levels to more than two times baseline within a month or to > 354 mmol/l postoperatively), postoperative myocardial infarction (defined as an increase in creatine kinase to > 240 IU/l within 48 hours postoperatively), intraaortic balloon pump, and extracorporeal membrane oxygenation, mechanical ventilation time, and ICU length of stay. The postoperative red blood cell transfusion threshold was 8 g/L. Platelets were transfused when the level was < 50×109/L. Fresh frozen plasma was transfused at excessive bleeding/chest drainage circumstances, with laboratory evidence suggesting coagulopathy.
Cardiac surgery was performed with mild hypothermic CPB (32-34ºC) under general anesthesia. CPB flow was maintained at 2.2-2.6 L/min/BSA (m2). A conventional or minimized CPB circuit was used according to the patient’s preoperative hemoglobin level and the perfusionists’ preference. A conventional CPB circuit consisted of a roller pump, a hollow-fiber oxygenator, an arterial flter, and an uncoated polyvinyl chloride circuit, with a priming volume of 1600 ml. A mini circuit, with 900-ml priming volume, consisted of a hollow-fiber oxygenator integrated with arterial flter, smaller tubes, and vacuum-assisted venous reservoir drainage.
Unfractionated heparin (400 U/kg) was given to achieve activated clotting time (ACT) ≥ 410 seconds before CPB. ACT was maintained ≥ 410 seconds during CPB. After CPB was weaned of, protamine sulfate was administered for heparin reversal (1 mg protamine vs. 100 units heparin).
Variables were retrospectively collected from electric records. Continuous variables were presented as median (P25-P75) and were compared with the non-parametric test, according to its abnormal distribution. Categorical variables were presented as n (%) and compared with the x2 test for equal proportion. Logistic regression of multiple risk factors was performed to identify risk factors of postoperative thrombocytopenia. Univariable associations with P<0.10 and clinical significance were evaluated by a forward stepwise method to establish a logistic regression model of multiple risk factors. Nonlinear continuous variables were transformed into categorical variables, including age, preoperative platelet count, blood urea nitrogen (BUN), and international normalized ratio (INR). The variables with strong collinearity were chosen according to clinical significance. For example, prosthetic valve type (mechanical or bioprosthetic valve) was not put into the logistic regression analysis due to its strong correlation with age. The ft of the logistic regression analysis was evaluated by the Hosmer-Lemeshow test.
Two sensitivity analyses were also performed to determine if the risk factors of thrombocytopenia were afected by preoperative thrombocytopenia and intraoperative platelet transfusion. We excluded patients with preoperative platelet counts ≤ 125×109/L and patients who received intraoperative platelet transfusion, respectively. All statistical testing was two-sided, and a P-value < 0.05 was considered significant. All statistical analyses were performed using IBM Corp. Released 2015, IBM SPSS Statistics for Windows, Version 23.0, Armonk, NY: IBM Corp. The study was presented following the Strengthening the Reporting of Observational Studies in Epidemiology (or STROBE) guidelines.
Patients and Postoperative Platelet Count
According to the inclusion and exclusion criteria, 3,175 patients were enrolled (Figure 1). The mean age was 54 years, and 1,735 (54.6%) were male. More than half of the patients’ first postoperative platelet counts were < 125×109/L (reference value in normal healthy individuals), 10% were < 75×109/L, and 1% were < 50×109/L. The 10th, 25th, 50th, and 75th quantile of postoperative platelet count were 75×109/L, 94×109/L, 117×109/L, and 146×109/L, respectively (Figure 2). The threshold for postoperative thrombocytopenia was defined as 75×109/L. The incidence of postoperative thrombocytopenia was 10.2% (n=324), and 85% of the patients had platelet recovery at hospital discharge.
Pre and Intraoperative Information
Patients with postoperative thrombocytopenia were older (59.93 [51.92-65.94] vs. 54.15 [46.12-62.28] years, P<0.001), had lower body mass index (23 [21-25] vs. 24 [22-27] kg/m2, P<0.001), smaller BSA (1.64 [1.53-1.76] vs. 1.7 [1.58-1.85] m2, P<0.001), higher EuroSCORE (3 [2-4] vs. 2 [2-3], P<0.001), lower preoperative platelet count (131 [110-152] vs. 203 [170-240] × 109/L, P<0.001), lower preoperative hemoglobin level (136 [125-149] vs. 139 [127-150] g/L, P=0.04), higher BUN (6.6 [5.3-8.12] vs. 6.21 [5.1-7.6] mmol/L, P=0.003), and higher INR (1.07 [1.01-1.15] vs. 1.02 [0.98-1.08], P<0.001) level (Table 1).
|No postoperative thrombocytopenia (n=2851)||Postoperative thrombocytopenia (n=324)||P-value|
|Age (years)||54.15 (46.12-62.28)||59.93 (51.92-65.94)||< 0.001|
|Male, n (%)||1558 (54.6%)||177 (54.6%)||0.995|
|BMI (kg/m2)||24 (22-27)||23 (21-25)||< 0.001|
|BSA (m2)||1.7 (1.58-1.85)||1.64 (1.53-1.76)||< 0.001|
|Diabetes, n (%)||184 (6.5%)||24 (7.4%)||0.511|
|Hypertension, n (%)||823 (28.9%)||83 (25.6%)||0.22|
|Hyperlipidemia, n (%)||1066 (37.4%)||116 (35.8%)||0.575|
|Chronic kidney disease, n (%)||8 (0.3%)||1 (0.3%)||1|
|Smoker, n (%)||868 (30.4%)||100 (30.9%)||0.877|
|EuroSCORE||2 (2-3)||3 (2-4)||< 0.001|
|Preoperative LVEF (%)||60 (58-65)||60 (58-65)||0.413|
|Preoperative laboratory test|
|Platelet count (×109/L)||203 (170-240)||131 (110-152)||< 0.001|
|Hemoglobin (g/L)||139 (127-150)||136 (125-149)||0.04|
|Creatinine (μmol/L)||80.47 (70-93)||81.48 (70.55-94.67)||0.215|
|Blood urea nitrogen (mmol/L)||6.21 (5.1-7.6)||6.6 (5.3-8.12)||0.003|
|Alanine transaminase (U/L)||18 (13-28)||18 (13-26)||0.747|
|Albumin (g/L)||41.8 (39.2-44.6)||41.5 (38.65-44.2)||0.161|
|PT-INR||1.02 (0.98-1.08)||1.07 (1.01-1.15)||< 0.001|
|Preoperative RBC transfusion (U)||0 (0-0)||0 (0-0)||0.061|
|Preoperative anticoagulants, n (%)||1205 (42.3%)||158 (48.8%)||0.025|
In regard to valve surgical position and type, more patients in the postoperative thrombocytopenia group underwent multivalve surgery (59.9% vs. 43.6%, P<0.001) and bioprosthetic valve replacement surgery (32.7% vs. 19.2%, P<0.001). More patients in the non-thrombocytopenia group underwent isolated mitral valve surgery (21% vs. 7.1%, P<0.001) and valve repair surgery (18.8% vs. 9%, P<0.001). In addition, postoperative thrombocytopenia was associated with longer CPB (114 [86-147] vs. 93 [74-121] minutes, P<0.001) and aortic cross-clamping times (85 [61-110] vs. 67 [52-89] minutes, P<0.001), lower nadir temperature (31.8 [30.9-32.6] vs. 32.1 [31.3-32.7] ºC, P<0.001), lower heparin dosage (30000 [26800-34400] vs. 32400 [28400-36800] IU, P<0.001), and more allogeneic blood transfusion during the surgery (Table 2).
|No postoperative thrombocytopenia (n=2851)||Postoperative thrombocytopenia (n=324)||P-value|
|Valve position||< 0.001|
|Mitral valve, n (%)||598 (21%)||23 (7.1%)||< 0.001|
|Tricuspid valve, n (%)||63 (2.2%)||7 (2.2%)||0.954|
|Aortic valve, n (%)||948 (33.3%)||100 (30.9%)||0.387|
|Mitral and tricuspid valves, n (%)||751 (26.3%)||94 (29%)||0.303|
|Mitral and aortic valves, n (%)||179 (6.3%)||31 (9.6%)||0.024|
|Aortic and tricuspid valves, n (%)||19 (0.7%)||4 (1.2%)||0.253|
|Mitral, aortic, and tricuspid valves, n (%)||293 (10.3%)||65 (20.1%)||< 0.001|
|Valve type*||< 0.001|
|Valve repair, n (%)||536 (18.8%)||29 (9%)||< 0.001|
|Valve replacement (mechanical valve), n (%)||1768 (62%)||189 (58.3%)||0.197|
|Valve replacement (bioprosthetic valve), n (%)||547 (19.2%)||106 (32.7%)||< 0.001|
|Multivalve, n (%)||1242 (43.6%)||194 (59.9%)||< 0.001|
|Thoracoscopic procedure, n (%)||19 (0.7%)||0 (0%)||0.25|
|Valvular vegetation, n (%)||16 (0.6%)||2 (0.6%)||0.705|
|Perivalvular leakage, n (%)||6 (0.2%)||2 (0.6%)||0.193|
|Conventional circuit, n (%)||2607 (92.6%)||295 (92.5%)|
|Mini circuit with VAVD, n (%)||178 (6.3%)||21 (6.6%)|
|Mini circuit without VAVD, n (%)||31 (1.1%)||3 (0.9%)|
|Cardiopulmonary bypass time (minutes)||93 (74-121)||114 (86-147)||< 0.001|
|Aortic cross-clamping time (minutes)||67 (52-89)||85 (61-110)||< 0.001|
|Nadir nasal temperature (ºC)||32.1 (31.3-32.7)||31.8 (30.9-32.6)||< 0.001|
|Nadir bladder temperature (ºC)||33 (32.1-33.7)||32.5 (31.5-33.3)||< 0.001|
|Ultrafltration volume (ml)||1000 (0-1500)||1000 (0-2000)||0.001|
|Heparan dose (U)||32400 (28400-36800)||30000 (26800-34400)||< 0.001|
|Intraoperative RBC transfusion (U)||0 (0-0)||0 (0-4)||< 0.001|
|Intraoperative FFP transfusion (ml)||0 (0-0)||0 (0-400)||< 0.001|
|Intraoperative platelet transfusion (U)||0 (0-0)||0 (0-0)||< 0.001|
Outcomes were compared between patients with and without postoperative thrombocytopenia. In-hospital mortality was comparable between non- thrombocytopenia and thrombocytopenia groups (0.6% vs. 0.9%, P=0.343). Patients with postoperative thrombocytopenia had more chest drainage volume (735 [550-1080] vs. 560 [430-730] ml, P<0.001), higher rates of postoperative blood transfusion (5.9% vs. 3.2%, P=0.014), and lower frequency of platelet recovery at hospital discharge (66.2% vs. 88.5%, P<0.001). In addition, postoperative thrombocytopenia was associated with adverse outcomes including AKI (12.3% vs. 4.2%, P<0.001), longer mechanical ventilation (19 [15-35] vs. 16 [12-20] hours, P<0.001), and longer ICU length of stay (3 [2-4] vs. 2 [1-4] days, P=0.001) (Table 3).
|No postoperative thrombocytopenia (n=2851)||Postoperative thrombocytopenia (n=324)||P-value|
|In-hospital mortality, n (%)||16 (0.6%)||3 (0.9%)||0.434|
|Platelet recovery, n (%)||2475 (88.5%)||208 (66.2%)||< 0.001|
|Chest drainage volume (ml)||560 (430-730)||735 (550-1080)||< 0.001|
|Postoperative transfusion, n (%)||92 (3.2%)||19 (5.9%)||0.014|
|RBC, n (%)||80 (2.8%)||18 (5.6%)||0.007|
|FFP, n (%)||41 (1.4%)||11 (3.4%)||0.009|
|Platelet, n (%)||15 (0.5%)||6 (1.5%)||0.043|
|Re-thoracotomy, n (%)||47 (1.6%)||10 (3.1%)||0.065|
|Stroke, n (%)||11 (0.4%)||3 (0.9%)||0.165|
|Myocardial infarction, n (%)||4 (0.1%)||1 (0.3%)||0.416|
|Hepatic failure, n (%)||19 (0.7%)||9 (2.8%)||0.001|
|Acute kidney injury, n (%)||121 (4.2%)||40 (12.3%)||< 0.001|
|CRRT, n (%)||13 (0.5%)||3 (0.9%)||0.219|
|IABP, n (%)||9 (0.3%)||2 (0.6%)||0.311|
|ECMO, n (%)||3 (0.1%)||0 (0%)||1|
|Prolonged mechanical ventilation, n (%)||140 (4.9%)||46 (14.2%)||< 0.001|
|ICU length of stay (days)||2 (1-4)||3 (2-4)||0.001|
|Mechanical ventilation time (hours)||16 (12-20)||19 (15-35)||< 0.001|
Risk Factors of Postoperative Thrombocytopenia
Logistic regression of multiple risk factors was performed to identify risk factors of postoperative thrombocytopenia. Fifteen covariables were selected: age, BSA, EuroSCORE, preoperative platelet count, BUN, INR, preoperative blood transfusion, preoperative anticoagulant use, CPB time, valve position, valve repair/replacement, nasal nadir temperature, intraoperative ultrafltration volume, and intraoperative heparin dose. According to the logistic regression analysis, age > 60 years (odds ratio [OR] 2.25, 95% confidence interval [CI] 1.345-3.765, P=0.002), preoperative thrombocytopenia (OR 18.671, 95% CI 13.649-25.542, P<0.001), and CPB time (OR 1.088, 95% CI 1.059-1.117, P<0.001) were positive predictors for postoperative thrombocytopenia (Table 4). BSA (OR 0.247, 95% CI 0.114-0.538) and isolated mitral valve surgery (OR 0.475, 95% CI 0.294-0.77) were negative predictors for postoperative thrombocytopenia. These five risk factors were confirmed by sensitivity analyses excluding patients with preoperative platelet counts ≤ 125×109/L and patients who received intraoperative platelet transfusion (Table 5).
|OR (95% CI)||P-value|
|> 60||2.25 (1.345-3.765)||0.002|
|Body surface area||0.247 (0.114-0.538)||< 0.001|
|Cardiopulmonary bypass time (per 10-minute increase)||1.088 (1.059-1.117)||< 0.001|
|Isolated mitral valve||0.475 (0.294-0.77)||0.002|
|Preoperative thrombocytopenia||18.671 (13.649-25.542)||< 0.001|
|OR (95% CI)||P-value|
|Patients with intraoperative platelet transfusion excluded*|
|> 60||2.049 (1.191-3.525)||0.01|
|Body surface area||0.213 (0.093-0.488)||< 0.001|
|Cardiopulmonary bypass time (per 10-minute increase)||1.086 (1.053-1.121)||< 0.001|
|Isolated mitral valve||0.431 (0.256-0.723)||0.001|
|Preoperative thrombocytopenia||21.959 (15.541-31.028)||< 0.001|
|Patients with preoperative thrombocytopenia excluded#|
|> 60||2.864 (1.561-5.254)||0.001|
|Body surface area||0.172 (0.068-0.439)||< 0.001|
|Cardiopulmonary bypass time (per 10-minute increase)||1.1 (1.067-1.134)||< 0.001|
|Isolated mitral valve||0.575 (0.341-0.968)||0.037|
*The final multivariable logistic analysis was based on n=2748 due to missing data of 254 subjects. Predictive ability of the model was 92%. P-value of Hosmer-Lemeshow test was 0.607. #The final multivariable logistic analysis was based on n=2668 due to missing data of 217 subjects. Predictive ability of the model was 94.2%. P-value of Hosmer-Lemeshow test was 0.552. CI=confidence interval; OR=odds ratio
This retrospective study gave an overview of postoperative thrombocytopenia after cardiac surgery. In-hospital mortality was not increased in the thrombocytopenia group. Patients with postoperative thrombocytopenia tended to have more postoperative bleeding and required more blood transfusion. In addition, postoperative thrombocytopenia was accompanied by a series of complications, including AKI. Predictors for postoperative thrombocytopenia included age > 60 years, BSA, preoperative thrombocytopenia, CPB time, and isolated mitral valve surgery.
There is no universally accepted definition of postoperative thrombocytopenia in cardiac surgery. Platelet count decline was typical in patients after cardiac surgery with CPB, and many patients’ platelet counts were below the reference value in normal healthy individuals. But the threshold of platelet count with the most crucial clinical significance was undetermined. The definition of postoperative thrombocytopenia in the present study was < 75×109/L, which was the 10th quantile of the study population. Two previous large studies also took 75×109 as the threshold of postoperative thrombocytopenia[5,6]. They reported that postoperative platelet count < 75×109 was associated with adverse outcomes, including mortality, AKI, and prolonged ICU length of stay[5,6].
The present study did not find an association between postoperative thrombocytopenia and in-hospital mortality. But our study demonstrated that patients with postoperative thrombocytopenia had a higher incidence of AKI and longer mechanical ventilation time and ICU length of stay, which was consistent with the abovementioned two studies. We also found the relationship between postoperative thrombocytopenia with transfusion and bleeding. Previous studies reported similar results.
The mechanism under the relationship between thrombocytopenia and adverse outcomes is unclear. Thrombocytopenia has also been identifed as a risk factor of multi-organ failure in critically ill patients[10, 11, 12, 13]. Postoperative thrombocytopenia might be coupled with massive platelet-derived chemokines, which were associated with multi-organ injury[14,15]. Besides, postoperative thrombocytopenia and other adverse outcomes might be both the consequences of prolonged CPB and some underlying situations (i.e., microvascular thrombosis). Another possible assumption was that postoperative thrombocytopenia led to more bleeding and transfusions, which increased the risks of AKI and other adverse outcome[17,18].
Platelet consumption and hemodilution were considered as the leading causes of platelet count decline after cardiac surgery with CPB. Platelet was an essential modulator in infammation and hemostasis. Once CPB was started, platelets were activated by mechanical shear stress and artificial surface contact, and platelet activation cascade was induced. High shear stress could also induce platelet apoptosis. In addition, hemolysis during CPB enhanced platelet aggregation. Our study identifed age > 60 years, BSA, preoperative thrombocytopenia, and CPB time as independent risk factors of postoperative thrombocytopenia. These factors were related to platelet consumption and hemodilution. Patients with small BSA had more hemodilution during CPB. Prolonged CPB indicated more platelet activation. Older age was reported to be associated with platelet hyperreactivity and enhanced aggregation. Therefore, we guessed older patients might have more platelet activation during cardiac surgery. In addition, older individuals had fewer platelet counts than younger people.
In addition, the present study found a relationship between valve surgical information and postoperative thrombocytopenia. Isolated mitral valve surgery was a negative predictor for thrombocytopenia. The reasons might be stated as follows. Firstly, compared to multivalve surgeries, isolated mitral valve surgeries usually required shorter CPB time and therefore caused less platelet consumption. Secondly, compared to isolated aortic valve surgeries, a larger proportion of isolated mitral valve surgeries was valve repair surgery. Prosthetic valves would lead to increased platelet activation.
For patients with high risks of postoperative thrombocytopenia, an active platelet preservation strategy might be applied. Heparinbonded cardiopulmonary circuit reduced platelet activation compared to standard uncoated circuit. Several potential agents have been reported, including nitric oxide. More research is required to obtain comprehensive recognition of platelet preservation during CPB.
Heparin-induced thrombocytopenia (HIT) was also a big concern in postoperative thrombocytopenia. A biphasic platelet count pattern was typical of HIT, while early-onset thrombocytopenia was mainly related to CPB. In the present study, postoperative thrombocytopenia was defined with the first platelet count test after surgery, and hence HIT was not the primary concern. We screened all the patients with postoperative thrombocytopenia and those who received postoperative platelet transfusion retrospectively. Only three patients were suspected with HIT, but not confirmed as anti-PF4/heparin antibody test was not available in our institute.
This study had several limitations, mainly due to its retrospective nature. Firstly, postoperative platelet count was affected by intraoperative platelet transfusion. However, a sensitivity analysis excluding patients with intraoperative platelet transfusion was performed and obtained similar results. Secondly, the result might be influenced by the definition of postoperative thrombocytopenia. Thirdly, platelet function and markers of platelet activation were not tested. Fourthly, other factors (i.e., redo surgery and valve brands), which might be associated with postoperative thrombocytopenia, were not included in risk factor analysis.
Thrombocytopenia was common after cardiac surgery. The risk factors of postoperative thrombocytopenia included age > 60 years, BSA, preoperative thrombocytopenia, and CPB time. Patients with postoperative thrombocytopenia tended to have more postoperative bleeding and required more blood transfusion, and post thrombocytopenia was associated with a series of complications.
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Authors’Roles & Responsibilities
SY= Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published
SG= Substantial contributions to the acquisition, analysis and interpretation of data for the work; revising the work critically for important intellectual content; final approval of the version to be published
SL= Revising the work critically for important intellectual content; final approval of the version to be published
QZ= Substantial contributions to the acquisition of data for the work; final approval of the version to be published
YW= Revising the work critically for important intellectual content; final approval of the version to be published
BJ= Revising the work critically for important intellectual content; final approval of the version to be published
Article receive on Thursday, June 17, 2021
Article accepted on Tuesday, November 2, 2021