Novel Platelet Function Analyzer 200 Predicts Blood Transfusion After Elective Cardiac Surgery in Patients Suspended on Dual Antiplatelet Therapy

Abstract

The value of platelet function test in timing of cardiac surgery remains uncertain. Researches on correlation between Platelet Function Analyzer 200 (PFA-200) and bleeding after elective cardiac surgery are still inadequate. The objective of this study was to investigate the predictive value of PFA-200 in blood transfusion after cardiac surgery. A total of 71 patients on aspirin and P2Y12 receptor inhibitors undergoing cardiac surgery in Fuwai Hospital were enrolled. Platelet function after discontinuing of antiplatelet drugs was assessed by PFA-200 using closure time (CT). PFA-200 results before surgery were included in the statistics. The primary endpoint was postoperative blood transfusion. Seventeen patients (21.9%) received blood transfusion after cardiac surgery. The preoperative PFA-200 CT value in the transfused group was significantly higher than that in the non-transfused group (147.24 ± 85.54 s vs 98.06 ± 61.59 s, P = .011). Using 106 seconds as the dividing point, the incidence of blood transfusion in the elevated PFA-200 (CT > 106 s) group was significantly higher than those in normal PFA-200 (CT ≤ 106 s) group (10/24 patients, 41.9% vs 7/47 patients, 14.7%, P = .012). Multivariate logistic regression analysis showed that PFA-200 CT value > 106 s was an independent predictor of postoperative blood transfusion (OR: 4.05, 95%CI: 1.19-13.86, P = .026). The platelet function test PFA-200 had a predictive value for postoperative blood transfusion in elective cardiac surgery and had a promising prospect in the timing of cardiac surgery.

Keywords

platelet function test PFA-200 cardiac surgery transfusion

Perioperative bleeding is one of the most common complications of cardiac surgery, and a considerable proportion of patients require blood transfusion for this reason.^1,2 Several studies have shown³ that blood transfusion after cardiac surgery can increase the risk of infection, renal failure, re-thoracotomy and stroke, leading to poor prognosis of patients.^4,5 In order to reduce the risk of postoperative bleeding, current guidelines support to discontinue P2Y12 receptor inhibitors before cardiac surgery.⁶ Guidelines for dual antiplatelet therapy (DAPT) issued by the ESC in 2017 recommended stopping clopidogrel at least 5 days and ticagrelor at least 3 days before non-urgent cardiac surgery. However, it also suggested that the risk of bleeding and thrombosis should be carefully weighed when deciding the time of drug withdrawal and the timing of surgery.⁷

Platelet function tests have long since been utilized in clinical practice and recommended in previous guidelines. Updated guidelines issued by the Society of Thoracic Surgeons recommended platelet function test before emergent cardiac surgery in patients taking antiplatelet drugs (Class IIa),⁸ while as for non-urgent cardiac surgery platelet function tests were also considered to be beneficial (Class IIb).⁹ It is endorsed that platelet function test is of broad prospect in the management of cardiac surgery. However, relevant evidence is still insufficient and specific effective platelet function testing methods have not been recommended.

As a relatively new platelet function detection system, PFA-200 has rarely been studied on the prediction value of bleeding following cardiac surgery and the cut-off value remains uncertain.¹⁰ PFA-200 is a novel platelet function detection method,^11,12 which is characterized by simple operation and fast results.¹³ The result was reported as closure time (CT). PFA-200 is very sensitive to measure platelet function during antiplatelet therapy of P2Y12 receptors like clopidogrel and ticagrelor.^14,15 The purpose of this study was to explore the association between PFA-200 results and bleeding as well as blood transfusion after cardiac surgery and to investigate the using of platelet function test in the timing of non-urgent cardiac surgery.

Materials and Methods

A total of 88 patients received cardiac surgery in Fuwai Hospital from March 2016 to February 2018 agreed to participate in this study. The inclusion criteria were aging between 18-75 years old. The exclusion criteria were: congenital heart disease, hepatic cirrhosis, renal insufficiency requiring renal replacement therapy, malignant tumors, hematologic diseases, preoperative hemoglobin < 100 g/L, and abnormal platelet count (>300 * [10]^9 or <150 * [10]^9) . In the end, a sum of 71 patients were enrolled and all the patients signed informed consent for the study.

For patients undergoing cardiac surgery, P2Y12 receptor antagonist and aspirin were discontinued at the same time under the guidance of the cardiac surgeons. Blood was drawn 1 day before discontinuation and 1, 3, and 5 days after discontinuation of antiplatelet drugs then the platelet function test is performed using the INNOVANCE ® PFA P2Y kit of PFA-200 (Siemens, Marburg, Germany). The timing of the operation is determined by the cardiac surgeon taking into account the combined risks of bleeding and ischemia. Researchers have no interference with the timing of surgery. The last PFA-200 results before surgery were recorded and included in the statistics. Clinical information of the patients was recorded, including age, sex, body mass index (BMI), relevant medical history. The following data was collected: blood routine test, liver and kidney function, coagulation function test, ultrasonic cardiogram, intraoperative application of cardiopulmonary bypass (CPB), postoperative blood transfusion and pleural drainage volume.

It is assumed that for the same patient longer discontinuation time means better platelet function, thus the last PFA-200 closure time results represented the platelet function of patients before surgery and were introduced in the statistics. The primary endpoint was postoperative blood transfusion (blood product such as red blood cells, fresh-frozen plasma and platelets transfusion after sternal closure) and the secondary end points were 24-h and total chest tube drainage volume. Doctors of postoperative management who are blinded of the PFA-200 results used unified standards to make decisions on whether to transfuse blood products based on patient drainage volume, postoperative blood routine tests, and other relative results. In this study, we choose 106 s (suggested in instruction book) as the threshold of PFA-200 closure time results, and the patients were divided into two groups: patients with closure time greater than 106 s and patients with closure time less or equal to 106 s according to the last PFA-200 results before surgery.

Statistical Analysis

The continuous data are expressed as mean ± standard deviation, and independent samples t-test or Mann–Whitney U test were used to determine differences of continuous data between the groups. The categorical data are presented as absolute and relative frequencies. The Chi-squared test was performed for the comparison of categorical variables between the groups. Univariate and multivariate logistic regressions were used to identify independent associations between various risk factors and post-surgery transfusion. P value < .05 was considered as statistically significant. Statistical analysis was performed using Statistical Package for Social Sciences Version 22 (IBM SPSS Statistics, Chicago, IL).

Results

A total of 71 patients undergoing cardiac surgery were included, among which 68 patients received coronary artery bypass grafting (CABG), one patient undertook aortic valve replacement and two patients underwent Morrow surgery. Fifty-nine (83.1%) patients were males and 12 (16.9%) patients were females. The average age was 59.55 ± 8.33 years. The mean BMI was 26.20 ± 3.37 kg/m². Sixteen (22.5%) patients sustained acute coronary syndrome. CPB was applied during surgery in 38 (53.5%) patients. All patients were on aspirin before withdrawing of antiplatelet drugs, as for P2Y12 receptor inhibitors, 12 (16.9%) patients were on ticagrelor while 59 (83.1%) patients were on clopidogrel before surgery.

Blood Transfusion and Chest Drainage in Elevated and Normal PFA-200 Groups

According to the closure time (CT) of last PFA-200 test results before surgery, the patients were divided into two groups: the elevated PFA-200 group with CT value > 106 s comprised of 24 (33.8%) patients and the normal PFA-200 group with CT value ≤ 106 s comprised of 47 (66.2%) patients. There was no significant difference in gender, age, BMI, rates of ACS, rates of hypertension, rates of diabetes mellitus, preoperative hemoglobin, platelets count, active partial thromboplastin time (APTT), serum creatinine, left ventricular ejection fraction (LVEF) and preoperative medications between the two groups (Table 1). The mean CT value of elevated PFA-200 group was 185.58 ± 74.98 s while the mean CT value of normal PFA-200 group was 71.15 ± 16.16 s. Ten patients (10/24, 41.9%) of elevated PFA-200 group sustained postoperative blood transfusion, and 7 patients (7/47, 14.7%) of normal PFA-200 group sustained postoperative blood transfusion. There was a significance difference in postoperative blood transfusion rates between the two groups (P = .012). As for different blood components, patients with elevated PFA-200 required more fresh frozen plasma after surgery (P = .021), whereas platelets and red blood cells usage after surgery showed no difference between the two groups. No significant difference was seen in 24-h postoperative chest tube drainage (537.55 ± 206.39 ml vs 702.08 ± 397.36 ml, P = .075) or the overall drainage (834.8 ± 328.19 ml vs1034.17 ± 514.02 ml, P = .093) between the two groups (Table 2).

Table 1.

Clinical Characteristics in Elevated and Normal PFA-200 Groups.

Variables	Total	CT ≤ 106	CT > 106	P
Variables	N = 71	N = 47	N = 24	P
Males，N (%)		40 (85.1)	19 (79.2)	.528
Age (yr), mean ± SD		60.09 ± 7.68	58.50 ± 9.56	.452
BMI(kg/m²), mean ± SD		25.81 ± 3.21	26.96 ± 3.61	.175
Patients on bypass, N (%)		22 (46.8)	16 (66.7)	.113
CABG, N (%)		46 (97.9)	22 (91.6)	.262
Acute coronary syndrome, N (%)		11 (23.4)	5 (20.8)	.806
Old myocardial infarction, N (%)		12 (25.5)	6 (25.0)	.961
Hypertension, N (%)		31 (65.9)	18 (75.0)	.436
Diabetes mellitus, N (%)		17 (36.2)	12 (50.0)	.262
PCI, N（%）		9 (19.1)	7 (29.2)	.339
HGB (g/L), mean ± SD		136.00 ± 13.53	132.63 ± 17.84	.376
PLT (10⁹), mean ± SD		224.13 ± 59.90	209.75 ± 55.57	.331
APTT (seconds), mean ± SD		37.79 ± 7.44	38.43 ± 6.17	.719
Creatinine (μmol/L), mean ± SD		76.65 ± 13.94	78.41 ± 17.69	.647
LVEF(%), mean ± SD		59.40 ± 7.91	59.96 ± 9.36	.794
ACEI or ARB, N (%)		32 (68.1)	15 (62.5)	.638
Βeta-blocker, N (%)		45 (95.7)	23 (95.8)	.986
Calcium channel blocker, N (%)		15 (31.9)	10 (41.7)	.416
Statin, N (%)		47 (100)	24 (100)	.999
Diuretics, N (%)		5 (10.6)	6 (20.5)	.114
PFA value (seconds), mean ± SD		71.15 ± 16.16	185.58 ± 74.98	<.001
Transfusion after surgery, N (%)		7 (14.9)	10 (41.7)	.012

Abbreviations: CT, closure time; s, seconds; SD, standard deviation; BMI, body mass index; CABG, coronary artery bypass graft; PCI, percutaneous coronary artery intervention; HGB, hemoglobin; PLT, platelet counts; APTT, activated partial thromboplastin time; LVEF, left ventricular ejaculation fraction; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers.

Table 2.

Blood Transfusion and Chest Drainage in Elevated and Normal PFA-200 Groups.

Variables	Total	CT ≤ 106 s	CT > 106 s	P
Variables	N = 71	N = 47	N = 24	P
PFA value(s), mean ± SD		71.15 ± 16.16	185.58 ± 74.98	<.001
Transfusion after surgery, N (%)		7 (14.9)	10 (41.7)	.012
Fresh frozen plasma (ml)		25.53 ± 98.83	166.67 ± 331.88	.021
Red blood cells (units)		0.38 ± 1.01	0.83 ± 1.55	.153
Platelet (units)		0	0.04 ± 0.20	.162
Drainage in 24 hours		537.55 ± 206.39	702.08 ± 397.36	.067
Total drainage		834.89 ± 328.19	1034.17 ± 514.02	.093

Abbreviations: CT, closure time; s, seconds.

Comparison of PFA-200 Between Transfusion Group and Non-Transfusion Group

Seventeen patients (23.9%) in all undergone postoperative blood transfusion after surgery while other 54 patients (76.1%) did not. The mean PFA-200 closure time of transfusion group was 147.24 ± 85.54 s whereas the mean PFA-200 closure time of non-transfusion group was 98.06 ± 61.59 s. There was a significance difference in preoperative PFA-200 closure time between transfusion group and non-transfusion group (147.24 ± 85.54 s vs 98.06 ± 61.59 s, P = .011).

Analysis of Postoperative Blood Transfusion Risk Factors

Variables that were considered clinically relevant such as gender, age, and BMI were selected into multivariate regression. CPB and PFA-200 which both manifested a univariate relationship with outcome were included into multivariate regression model. Univariate logistic regression analysis showed (Table 3) that elevated PFA-200 (closure time > 106 s) increased the risk of postoperative transfusion (OR = 4.08, 95%CI: 1.30-12.78, P = .016). While application of CPB during surgery was also associated with a higher risk of postoperative transfusion (OR = 3.77, 95%CI: 1.09-13.05, P = .036).

Table 3.

Univariate Logistic Regression Analysis of Postoperative Bleeding.

Variables	Univariate
Variables	OR (95%CI)	P
PFA-200 > 106 s	4.08 (1.30-12.78)	.016
CPB in surgery	3.77 (1.09-13.05)	.036
Sex (male/female)	0.57 (0.15-2.18)	.407
Age	1.01 (0.95-1.08)	.695
BMI (kg/m²)	0.94 (0.79-1.12)	.496
Acute coronary syndrome	2.40 (0.72-8.04)	.156
Old myocardial infarction	2.74 (0.85-8.83)	.092
Hypertension	0.77 (0.24-2.45)	.660
Diabetes mellitus	1.02 (0.34-3.08)	.975
PCI	2.40 (0.72-8.04)	.156
HGB	0.99 (0.95-1.03)	.730
PLT	1.00 (0.99-1.01)	.662
APTT	1.04 (0.96-1.12)	.338
Creatinine	1.11 (0.98-1.05)	.331
LVEF%	0.97 (0.91-1.03)	.321
ACEI or ARB	0.66 (0.21-2.02)	.463
Calcium channel blocker	0.48 (0.14-1.68)	.253
Diuretics	1.23 (0.29-5.28)	.779

Abbreviations: CT, closure time; s, seconds; SD, standard deviation; CPB, cardiopulmonary bypass; BMI, body mass index; CABG, coronary artery bypass graft; PCI, percutaneous coronary artery intervention; HGB, hemoglobin; PLT, platelet counts; APTT, activated partial thromboplastin time; LVEF, left ventricular ejaculation fraction; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers.

In the case of multivariate logistic regression analysis (Table 4), the multivariate logistic regression model was established by introducing age, gender, BMI, PFA-200 before surgery (dichotomized into elevated PFA-200 and normal PFA-200 using 106 s as the cut off value) and application of CPB during operation. The results presented (Table 4) that elevated PFA-200 (closure time > 106 s) was an independent risk factor of postoperative blood transfusion in patients undergoing selective cardiac surgery (OR = 4.05, 95%CI: 1.19-13.86, P = .026).

Table 4.

Multivariate Logistic Regression Analysis of Postoperative Bleeding.

	Multivariate
	OR (95%CI)	P
Sex (male/female)	1.00 (0.21-4.86)	.997
Age	1.01 (0.93-1.08)	.872
BMI	0.91 (0.75-1.11)	.348
CPB in surgery	3.08 (0.82-11.56)	.095
PFA-200 > 106 s	4.05 (1.19-13.86)	.026

Abbreviations: s, seconds; BMI, body mass index; CPB, cardiopulmonary bypass.

Discussion

This study investigated the correlation between preoperative PFA-200 and postoperative blood transfusion in patients undergoing selective cardiac surgery.

Patients with elevated PFA-200 had worse platelet function which can lead to increase in pleural drainage after cardiac surgery, in clinical practice, postoperative management doctors tend to correct the tendency of excessive pleural drainage by transfusing fresh frozen plasma. This could explain why elevated PFA-200 group accepted more fresh frozen plasma. The results showed that elevated PFA-200 before cardiac surgery was an independent risk factor for postoperative blood transfusion, patients with elevated PFA-200 (CT > 106 s) had a 4.05-fold transfusion risk after cardiac surgery. Thus, the platelet function test PFA-200 had a predictive value for bleeding after cardiac surgery and a promising prospect in the timing of cardiac surgery.

Our study reports for the first time that the use of a novel platelet function test PFA-200 before elective cardiac surgery (including CPB or non-CPB) can predict the risk of postoperative blood transfusion, providing meaningful clinical data for precise drug withdrawal strategy before cardiac surgery. A number of literatures concerning the value of platelet function tests in cardiac and non-cardiac postoperative bleeding management demonstrated that PFA-200 and other kinds of platelet function tests had a broad scope of clinical application.¹⁶ In a research aimed only at patients with off pump cardiac surgery reported by Mannacio et al,¹⁷ three equally matched groups undergoing off-pump CABG were compared, scheduling surgery after PFA closure time < 106 s in patients withdrawn DAPT significantly reduces postoperative bleeding and blood consumption, and had a shorter waiting time for operation than current clinical practice. However, this study included only patients undergoing off-pump cardiac surgery and CPB was considered to increase the bleeding risk during cardiac surgery, the predictive value of PFA-200 for bleeding in on-pump cardiac surgery was not answered. Our results showed that preoperative PFA-200 > 106 s could predict postoperative bleeding independently of CPB, which further expanded the application of PFA-200 to both on-pump and off-pump cardiac surgery.

In the study targeting patients of emergent CABG surgery, Mahla et al included 149 patients on DAPT within 48 h, compared to patients with PFA-200 ≥ 300 s those with PFA-200 > 300 s had a lower incidence of bleeding and lower transfusion rates of RBCs and platelets, which identified the predictive value of PFA-200 for bleeding after urgent CABG.¹⁸ Our study introduced different cut-off value 106 s regarding our patients went through elective cardiac surgery other than emergent cardiac surgery hence had a longer waiting time after DAPT withdrawing and the results proved that PFA-200 was beneficial in bleeding risk management in elective cardiac surgery.

PFA-200 was also investigated in predicting bleeding in non-cardiac surgery, Mahla et al included 197 patients who underwent non-cardiac surgery and measure platelet function with light transmittance aggregometry (LTA), PFA-200 and so on, the results presented that LTA was significantly associated with postoperative bleeding, but PFA-200 using the cut-off value 300 s did not show a significant correlation with postoperative bleeding.¹⁹ We reckon that 300 s is not a proper threshold because the group with PFA-200 below 300 s contained both normal and abnormal platelet function patients thus the bleeding rate was influenced. Our study used 106 s as the cut-off value and obtained positive results that certified 106 s could be the optimal cut-off value of PFA-200 when it comes to postoperative bleeding risk management.

In addition to PFA-200, available literatures had reported other platelet function tests for cardiac surgery timing. Nakashima et al planned CABG the next working day after normalization of platelet reactivity assessed by Multiplate Analyzer, that strategy significantly shortened the waiting time for CABG, reduced hospital costs compared to patients with standard of care while did not increase perioperative bleeding.²⁰ As mentioned above, a growing body of evidence supported that the application of platelet function test such as PFA-200 in optimizing of DAPT withdrawing and operation scheduling had a promising prospect. 2018 ESC/EACST guidelines on myocardial revascularization recommended that platelet function test before cardiac surgery might be a probable beneficial option (Class IIb),⁹ indicating that platelet function test such as PFA-200 in cardiac surgery timing still need further research.

As a relatively new platelet function test system, PFA-200 has the advantages of convenient operation and rapid detection, which takes merely about 4-8 minutes to obtain results.¹³ Moreover, it has been proved to be efficient in prognosticate bleeding in urgent or elective cardiac surgery and non-cardiac surgery. Our research demonstrated that application of PFA-200 with the threshold 106 s in elective cardiac surgery can successfully predict postoperative transfusion thus provided further evidence for its use in cardiac surgery. And the closure time > 106 s was preliminarily inquired as the cut-off value in elective cardiac surgery.

This study has limitations: this is a single-center and small sample study. Reliable results are obtained despite the limited sample size. Multi-center and large-scale research are needed in the future to further probe the safety and effectiveness of PFA-200 in individual cardiac surgery timing.

Conclusions

Our study reported that the novel platelet function test method PFA-200 has predictive value for postoperative bleeding after elective cardiac surgery. PFA-200 > 106 s was an independent risk factor for blood transfusion after cardiac surgery. For patients under DAPT, the detection of PFA-200 before cardiac surgery can help to identify patients at high risk of postoperative bleeding and provide individualized guidance for waiting time before elective cardiac surgery. And our results verified that PFA-200 has an auspicious clinical application prospect.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the CS Optimizing Antithrombotic Research Fund, CAMS Innovation Fund for Medical Sciences (CIFMS) (grant number BJUHFCSOARF201801-06, 2020-I2M-C&T-B-052).

Ethical Approval

Ethical approval to report this case was obtained from Ethics Committee of Fuwai Hospital (2015-712).

Written informed consent was obtained from the patients for their anonymized information to be published in this article.

ORCID iDs

Jinqing Yuan

Xueyan Zhao

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