Thrombogenicity and endothelial progenitor cells function during Acute myocardial infarction - comparison of Prasugrel versus Ticagrelor

Abstract

Background: Thrombin generation (TG), platelet function and circulating endothelial progenitor cells (EPCs) have an important role in the pathophysiology of coronary artery disease (CAD). To date, the effect of novel P2Y₁₂ inhibitors on these aspects has mostly been studied in the sub-acute phase following myocardial infarction. Objectives: Comparing the effects of prasugrel and ticagrelor on TG and EPCs in the acute phase of ST-segment elevation myocardial infarction (STEMI). Methods: STEMI patients were randomized to either ticagrelor or prasugrel treatment. TG, platelet reactivity and EPCs were evaluated prior to P2Y₁₂ inhibitor loading dose (T0), and one day following (T1). Results: Between December 2018 - July 2021, 83 consecutive STEMI patients were randomized to ticagrelor (N = 42) or prasugrel (N = 41) treatment. No differences were observed at T0 for all measurements. P2Y₁₂ reactivity units (PRU) at T1 did not differ as well (prasugrel 13.2 [5.5–20.8] vs. ticagrelor 15.8 [4.0-26.3], p = 0.40). At T1, prasugrel was a significantly more potent TG inhibitor, with longer lag time to TG initiation (7.7 ± 7.5 vs. 3.9 ± 2.1 min, p < 0.01), longer time to peak (14.1 ± 12.6 vs. 8.3 ± 9.7 min, p = 0.03) and a lower endogenous thrombin potential (AUC 2186.1 ± 1123.1 vs. 3362.5 ± 2108.5 nM, p < 0.01). Furthermore, EPCs measured by percentage of cells expressing CD34 (2.6 ± 4.1 vs. 1.1 ± 1.1, p = 0.01) and CD133 (2.3 ± 1.8 vs. 1.4 ± 1.5, p = 0.01) and number of colony forming units (CFU, 2.1 ± 1.5 vs. 1.1 ± 1.0, p < 0.01) were significantly higher in the prasugrel group. Conclusion: Among STEMI patients, prasugrel as compared to ticagrelor was associated with more potent TG inhibition and improved EPCs count and function.

Graphical abstract

Introduction

Dual anti-platelet therapy (DAPT) with aspirin and a P2Y₁₂ inhibitor is the recommended guideline-directed medical treatment for acute coronary syndrome (ACS). The 2017 European Society of Cardiology (ESC) guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation (STEMI) recommend ticagrelor or prasugrel, as P2Y₁₂ inhibitor treatment, in patients presenting with STEMI and treated with primary percutaneous coronary intervention (PPCI) [1]. Both ticagrelor and prasugrel have been proven to decrease recurrent ischemic events following ACS and stent implantation [2, 3]. The superiority of one over the other is still debated.

The biological milieu in which P2Y₁₂ inhibitors operate, and which they affect, in turn, is complex and includes interaction with platelets, endothelial cells and various coagulation factors. Endothelial cells play a major role in the biomechanics of coronary blood flow, primary prevention of ischemic events, and endothelial recovery following myocardial infarction [4–6]. Endothelial progenitor cells (EPCs) originate from the bone marrow and have the potential to migrate into the blood stream and assist in the process of re-endothelization, following ischemia or damage to blood vessel, thus contributing to the healing of damaged blood vessels. Importantly, EPCs exposure to platelets improves their colony formation capability and chemotaxis, two key parameters of EPCs function assessment [7]. However, so far these effects have mostly been studied in the sub-acute phase following ACS with subsequent PCI.

Thrombin is a key enzyme in the coagulation cascade and a strong platelet activator via activation of protease-activated receptors (PAR1 and 4) on the cell membrane of the platelet, thus potentially acting as an important mediator in the procoagulant-prothrombotic state during acute myocardial infarction (AMI) [8]. Increased thrombin generation (TG) during AMI, as previously reported, is associated with a poor prognosis [9–12]. Thrombin is also associated with recruitment of bone marrow hematopoietic stem cells [13], including EPCs, thus serving as a key mediator in platelet function and hemostasis [7, 14]. Yet, little is known regarding the impact of the new P2Y₁₂ inhibitors on the generation of thrombin and on EPCs. Accordingly, we aimed to examine the acute effects of prasugrel versus ticagrelor on TG, and its correlation to platelet function and EPCs count and function in patients with AMI.

Methods

Study design

Patients, over the age of 18 years, diagnosed with STEMI undergoing PPCI at the Rabin Medical Center between December 2018 and July 2021 were included in this study. Prior to arriving at the catheterization laboratory, all patients received aspirin loading dose (300 mg) and intravenous heparin (weight adjusted dose). Prior to P2Y₁₂ inhibitor loading, patients were randomized to either prasugrel (60 mg loading dose, 10 mg once daily maintenance) or ticagrelor (180 mg loading dose, 90 mg twice daily thereafter). The study was randomized and single blinded - randomization was unblinded to the medical team during the acute care (admission, catheterization lab and cardiac intensive care unit), but these choices were blinded at the level of the investigators - i.e., those performing the TG and EPC measurments. Patients were excluded from the trial if they were: (a) already treated with a P2Y₁₂ inhibitor; (b) treated with anticoagulation for any reason (hence also expected to receive a post-PCI regimen that includes clopidogrel rather than prasugrel or ticagrelor); (c) had a recent major gastrointestinal or cerebral bleeding; (d) diagnosed with end stage malignant disease; (e) had any other contra-indications for prasugrel or ticagrelor treatment; or (f) tested positive for COVID-19 infection.

We hypothesized better TG inhibition with prasugrel, compared with ticagrelor. We also expect better EPCs count and function among patients treated with prasugrel, compared to ticagrelor.

All clinical investigations were conducted according to the principles of the Declaration of Helsinki and were approved by the institutional ethics board. All patients signed an informed consent before inclusion.

Blood sampling

Blood samples were drawn at two time points: at baseline (prior to PPCI and P2Y₁₂ inhibitor loading) through the arterial access catheter, and 24 h thereafter (post PPCI and P2Y₁₂ inhibitor loading dose), through a venous puncture.

Isolation of EPCs

EPCs were isolated from heparinized tubes. Peripheral mononuclear cells (PMNCs) were fractionated using Ficoll density-gradient centrifugation. The mononuclear cells were isolated and washed with phosphate-buffered saline after red cell lysis.

Quantification of EPCs

Aliquots of PMNCs were incubated with monoclonal antibodies against VEGFR-2 (FITC labeled, R&D, Minneapolis, USA), CD133 (PE-labeled, Miltenyi Biotech, Auburn, CA, USA) and CD34 (PE-labled, Miltenyi Biotech). Isotype-identical antibodies was used as controls. After incubation cells were washed with phosphate-buffered saline and analyzed with a flow cytometer (FACSCalibur, Becton Dickinson). Each analysis included 100,000 events, after selection for viability and CD45 positive cells and exclusion of debris and platelets. In the next step gated CD34 or CD133 positive cells were examined for the expression of VEGFR-2. Results were presented as the percentage of cells co-expressing either VEGFR-2 and CD133, or VEGFR-2 and CD34 [15, 16].

Functional evaluation of EPCs

Functional aspects of EPCs were evaluated by measurement of colony forming units (CFU) and MTT assay.

Isolated PMNCs were re-suspended with medium 199 (Invitrogen, Carlsbad, CA, USA) supplemented with 20% fetal calf serum (Gibco BRL Life Tech, Gaithersburg, MD, USA) and plated on 6-well plates coated with human fibronectin at a concentration of 5 * 10⁶ cells per well [17]. EPC colonies were counted using an inverted microscope 7 days after plating [18, 19]. An EPC colony was defined as a cluster of at least 100 flat cells surrounding a cluster of rounded cells, as previously described [17]. Results are expressed as the mean number of CFUs per microscopic field.

The MTT assay was performed to evaluate viability of the cultured EPCs. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) measures mitochondrial activity in living cells. After 7 days of culture, 1 mg/mL MTT (Sigma, St. Louis, USA) was added to the EPC medium culture, and incubated for an additional 3–4 h. After the incubation, the medium was removed and the cells were solubilized in isopropanol. Mitochondrial dehydrogenases of viable cells cleave the tetrazolium ring, yielding purple MTT crystals, which can be dissolved in isopropanol. The amount of the dye released from the cells was measured with a spectrophotometer at 570 nm and subtracted background at 690 nm. An increase in the number of viable cells results in an increased amount of MTT formed and, therefore, in absorbance. Therefore, optical density is directly correlated with viable cell quantity [20].

Thrombin generation

TG was measured using a commercially available fluorogenic assay kit (Technothrombin®, Vienna, Austria) on a fully automated coagulation analyser (Ceveron®, Alpha, Technoclone, Vienna, Austria). Blood was drawn in citrated tubes, centrifuged in 3000 rpm for 10 min to obtain platelet poor plasma and kept at -70 degrees Celsius until analysis. Samples were thawed and hepzyme (Dade® Hepzyme® freeze-dried preparation of purified bacterial heparinase I > 125 IU/ml with added stabilizers) was added to T0 samples in order to remove heparin. TG was then initiated through the addition of tissue factor 0.3 pmol/L and phospholipids 3 pmol/L. The concentration of thrombin was measured with a fluorescent peptide substrate, which is cleaved by thrombin to release a fluorophore. The rate of thrombin generation is measured over time resulting in a thrombin formation curve. The following parameters of thrombin activity were recorded: (a) lag time until thrombin generation initiation (minutes); (b) peak thrombin generation – the maximal concentration of thrombin formed (nM); (c) time to peak thrombin generated (minutes); (d) endogenous thrombin potential (ETP) which equals the area under the curve (AUC) and represents the total amount of thrombin generated (nM) [21].

Platelet response to P2Y₁₂ inhibitors and bleeding events

Response to prasugrel or ticargrelor was measured in citrated blood by the VerifyNow P2Y₁₂ assay (Accumetrics California). Results are reported as P2Y₁₂ reaction units (PRU) [22]. In addition, patients were monitored for events of bleeding according to the Bleeding Academic Research Consortium (BARC) definitions of bleeding events [23] in the first 30 days following PPCI.

Study size

The study size calculation assumed differences of 700 nM in the AUC of thrombin generation between the two different medications, and at 80% power and a standard deviation of 1000 nM, a sample size of approximately 35 patients per group are required to reject the null hypothesis at an alpha level of 0.05.

Statistical analysis

Patients’ characteristics were presented as n (%) for categorical variables, and as mean ± standard deviation (SD) or median [interquartile range - IQR] for symmetrically or asymmetrically distributed continuous variables, respectively. Continuous variables following a normal distribution were compared using Student’s t-test, whereas those not following a normal distribution are presented as median and interquartile range and were compared using the Mann-Whitney U test. Categorical variables are reported as counts and percentages. The valid percent was reported. Comparing variables at T0 versus T1 were done using paired t-test. All tests were conducted at a two-sided alpha level of 0.05 which was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 28.0 (Armonk, NY: IBM Corp, 2021).

Results

Between December 2018 and July 2021, a total of 83 consecutive STEMI diagnosed patients referred to PPCI were enrolled. Patients were randomized into two treatment groups, 41 were treated with prasugrel and 42 with ticagrelor (Fig. 1).

Fig. 1.

Patient selection flowchart

Baseline characteristics are shown in Table 1. Average age at enrollment was 61.5 years with male predominance in both groups. There was no difference in body-mass index (BMI), the frequency of the traditional coronary artery disease (CAD) risk factors – diabetes mellitus, hypertension or smoking, nor in the rate of either peripheral vascular disease (PVD) or chronic obstructive pulmonary disease (COPD). There were also no differences in the initial blood tests, including Hs-Troponin levels both at T0 and T1, nor in the baseline medical treatment. Left ventricular estimated ejection fraction at baseline did not differ between groups as well.

Table 1.

Baseline Characteristics

Variable	Prasugrel N = 41	Ticagrelor N = 42	P value
Age (years)	61.5 ± 11.3	61.3 ± 10.9	0.46
Female gender (n(%)]	11 (27)	16 (38)	0.14
BMI (kg/m2)	28.7 ± 4.4	28.1 ± 4.5	0.26
Smoking [n(%)]	19 (46)	14 (33)	0.23
Diabetes mellitus [n(%)]	16 (39)	16 (38)	0.93
Hypertension [n(%)]	20 (49)	24 (57)	0.45
PVD [n(%)]	2 (5)	3 (7)	0.67
CAD [n(%)]	10 (24)	13 (31)	0.51
COPD [n(%)]	7 (17)	6 (14)	0.73
LVEF (%)	48.8 ± 8.1	50.4 ± 6.8	0.34
Hemoglobin (g/dL)	14.4 ± 1.2	14.2 ± 2.1	0.52
WBC count (K/micl)	11.1 ± 4.2	10.1 ± 3.0	0.23
Platelets (K/micl)	244.3 ± 56.3	247.5 ± 55.9	0.79
MPV (FL)	9.6 ± 1.1	9.8 ± 1.2	0.48
Creatinine (mg/dL)	0.9 ± 0.2	0.9 ± 0.2	0.60
Glucose (mg/dL)	173 ± 90	156 ± 68	0.33
Hs-Troponin (T0, ng/L)	1297 ± 2631	1467 ± 5400	0.85
Hs-Troponin (T1, ng/L)	2588 ± 3221	2885 ± 5261	0.76
Aspirin [n(%)]	14 (34)	18 (43)	0.42
Statin [n(%)]	23 (56)	24 (57)	0.92
Beta blocker [n(%)]	10 (24)	9 (21)	0.75
ACEI [n(%)]	14 (34)	15 (35)	0.88

Thrombin generation

Lag time to TG initiation, time to peak, peak levels, and AUC did not differ between the groups prior to P2Y₁₂ inhibitors loading at T0 (Table 2). However, significant differences were observed between prasugrel treatment and ticagrelor the day after PPCI and P2Y₁₂ loading dose (T1): the lag time to TG initiation, as well as the time to thrombin peak level, were significantly longer in the prasugrel group (Fig. 2). Thrombin peak levels were lower in the prasugrel group, though not reaching statistical significance. The AUC was significantly smaller in the prasugrel group (Table 2; Fig. 3).

Table 2.

Thrombin generation outcomes at T0 and T1 for prasugrel compared with ticagrelor

Variable	Prasugrel N = 41		Ticagrelor N = 42		P value
	T0	T1	T0	T1	T0	T1
Lag time a (min)	6.2 ± 2.6	7.7 ± 7.5	6.8 ± 4.3	3.9 ± 2.1	0.46	< 0.01
Time to peak thrombin level (min)	13.6 ± 10	14.1 ± 12.6	15.2 ± 12.7	8.3 ± 9.7	0.57	0.03
Peak thrombin level (nM)	257.3 ± 118.9	319.5 ± 237.7	244.9 ± 169.3	433.5 ± 264.3	0.71	0.06
AUC (nM)	2650.3 ± 551.2	2186.1 ± 1123.1	2525.5 ± 883.4	3362.5 ± 2108.5	0.45	< 0.01

^a Lag time to thrombin generation initiation

Fig. 2.

Thrombin generation outcomes compared at T0 and T1

Fig. 3.

Thrombin generation outcomes compared at T0 and T1

Lag time to TG initiation, as well as the time to thrombin peak level, are significantly longer in the prasugrel compared with the ticagrelor group (7.7 ± 7.5 min vs. 3.9 ± 2.1 min, p < 0.01, 14.1 ± 12.6 min vs. 8.3 ± 9.7 min, p = 0.03, respectively). No difference was observed in T0.

The endogenous thrombin potential (ETP) which equals the area under curve is significantly lower in the prasugrel versus ticagrelor treatment group (AUC 2186.1 ± 1123.1 nM vs. 3362.5 ± 2108.5 nM, p < 0.01). Thrombin peak levels were also lower in the prasugrel group, though not statistically significant (319.5 ± 237.7 nM vs. 433.5 ± 264.3 nM, p = 0.06).

For the full cohort, thrombin peak levels increased significantly at T1 versus T0, while no significant changes were noted for lag time to initiation, time to peak thrombin level or AUC (supplementary Table 1). We also did not observe any differences in TG measurments at T0 versus T1 for each medication (supplementary Table 2).

EPCs count and function

EPCs count estimated by the amount of cells expressing CD34 and CD133 were significantly higher at T1 in the prasugrel treatment group, as compared to the ticagrelor group (Table 3; Fig. 4). EPCs function as estimated by CFU showed significantly higher CFU per microscopic field in the prasugrel group at T1, while the MTT assay results at T1 did not differ between the groups (Table 3; Fig. 4). There were also no signifcant differences in EPCs counts and function between T1 and T0 for the whole cohort (supplementary Table 3) as well as for each medication (supplementary Table 4).

Table 3.

EPCs ^a count and function at T0 and T1 for prasugrel compared with ticagrelor

Variable	Prasugrel N = 41		Ticagrelor N = 42		P value
	T0	T1	To	T1	T0	T1
CD34 b	0.7 ± 0.6	2.6 ± 4.1	0.9 ± 1.2	1.1 ± 1.1	0.20	0.01
CD133 b	0.6 ± 0.5	2.3 ± 1.8	0.8 ± 1.9	1.4 ± 1.5	0.20	0.01
CFU c	1.1 ± 0.9	2.1 ± 1.5	1.4 ± 1.3	1.1 ± 1.0	0.11	< 0.01
MTT d	0.1 ± 0.2	0.5 ± 0.6	0.1 ± 0.1	0.6 ± 0.8	0.09	0.19

^a EPC = endothelial progenitor cell

^b Results are presented as the percentage of cells co-expressing either VEGFR-2 and CD133, or VEGFR-2 and CD34.

^c Colony forming unit; Results are expressed as the mean number of CFUs per microscopic field

^d MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) measures mitochondrial activity in living cells. Results are expressed as the amount of MTT formed represented by optical density (OD) 570 nm

Fig. 4.

EPCs count and function compared at T0 and T1

EPCs counts presented as the percentage of cells expressing CD34 (2.6 ± 4.1 vs. 1.1 ± 1.1, p = 0.01) and CD133 (2.3 ± 1.8 vs. 1.4 ± 1.5, p = 0.01) were significantly higher in the prasugrel versus the ticagrelor group at T1. EPCs function presented by mean CFU per microscopic field and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay expressed as the amount of MTT formed represented by optical density (OD) 570 nm. In the prasugrel group there were significantly more CFUs at T1 (2.1 ± 1.5 vs. 1.1 ± 1.0, p < 0.01), while there was no difference in the MTT assay results (0.5 ± 0.6 vs. 0.6 ± 0.8, p = 0.19).

Platelet function, response to ADP blockers and bleeding events

The VerifyNow™ PRUTest™ results, reported as P2Y₁₂ reactivity units (PRU), did not differ between groups at T1 (13.2 [IQR 5.5–20.8] for prasugrel vs. 15.8 [IQR 4.0-26.3] for ticagrelor, p = 0.40, supplementary Table 5). Bleeding events occurred in equal rates between the two medications (supplementary Table 6). All were BARC 1–2. There was no correlation to TG or EPCs count.

Discussion

In our study, among STEMI patients we found prasugrel to be significantly more potent in attenuating thrombin generation and an overall better EPCs responsive profile, compared to ticagrelor, one day after PPCI. Importantly, platelet response to the two P2Y₁₂ inhibitors was not different, suggesting an independent effect of these medications on TG and EPCs. Consistent with previous studies, we did not find a difference between the groups in the PRU measured 24 h post P2Y₁₂ inhibitors loading [22, 24, 25]. Nor were there any differences in bleeding events. However, this study was not powered to assess clinical outcomes.

Our study is the first, to our knowledge, to compare prasugrel and ticagrelor effects on TG and EPC count and function in a prospective cohort of STEMI patients only, specifically in the first 24 h post PPCI and subsequent P2Y₁₂ inhibitors loading dose. These findings might be relevant clinically and are discussed herein.

Recent studies have compared the efficacy and safety of these two novel P2Y₁₂ inhibitors in patients with AMI, and have not reached consensus on clinical superiority. A retrospective analysis of the SWEDEHEART registry of AMI patients treated with PCI followed by prasugrel or ticagrelor based DAPT, showed no significant differences in a composite of death, MI or stroke after one year [26], similarly to the results from the PRAGUE-18 trial [27]. The ISAR-REACT 5 trial was the first prospective study to show superior “hard” outcomes (composite of death, MI or stroke at 1 year) with prasugrel vs. ticagrelor among ACS patients [28]. This difference was mainly driven by a higher incidence of MI in the ticagrelor group. As to the possible mechanism for the differences observed, in a small cohort of type 2 diabetic patients with non-ST segment elevatin myocardial infarction (NSTEMI) randomized to prasugrel compared with ticagrelor, Jeong et al. found that ticagrelor significantly decreased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha and increased circulating EPCs, as well as a trend for better inhibited platelet activity [29]. In a multicenter randomized study, Diego-Nieto et al. found no difference in the levels of EPC among patients with NSTEMI treated with ticagrelor compared with clopidogrel [30], though prasugrel was not included. In our study of a larger cohort of STEMI patients, with or without diabetes, the results favor the effects of prasugrel rather than ticagrelor. In a way, Diego-Nieto et al. findings support our finding, considering their results suggest similar effect for ticagrelor and clopidogrel on EPCs count. The discrepancies with Jeong et al’s findings may be explained by the fact that we compared EPCs levels in the acute phase while Jeong et al. examined late effects, and by the fact that Jeong et al. included diabetic patients only. Jeong et al. suggested that the effect exerted by ticagrelor is P2Y₁₂-independent as compared with the P2Y₁₂ dependent effect of prasugrel, which may be more prominent among diabetic patients.

A more recent work by Schnorbus et al. observed similar results to our study [31]. Ninety patients with unstable angina or NSTEMI undergoing PCI were randomized to receive either clopidogrel, prasugrel or ticagrelor in a 1:1:1 ratio. Endothelial function (using conduit artery flow mediated dilation) response to ADP blockers (assessed by adenosine diphosphate-induced aggregation in vitro) and inflammatory biomarkers were measured at screening, 2 h after loading dose (which was later amended to 2 h after PCI), 1 day, 1 week and 1 month after stenting. Platelet aggregation 2 h after loading dose and at all later time points was significantly more inhibited in NSTEMI patient treated with prasugrel. They have also found that one day after PCI, prasugrel prevented the endothelial dysfunction associated with stenting, whereas this effect disappeared when drugs were administered immediately after PCI. These results may explain the ISAR-REACT 5 trial findings as well as our findings suggesting that prasugrel might be a more potent pharmacotherapy in the inflammatory-platelet activation-endothelial function cascade triggered in AMI.

However, it is important to note that the impact of both medications on the vascular environment which is unrelated to the anti-P2Y₁₂ effect, the so called “pleitrophic” of these newer effects P2y12 inhibitors, is debatable still. In addition to the findings of Diego-Nieto et al.[30], Ariotti et al. have also studied these additional effects of P2Y₁₂ inhibitors, and demonstrated no benefit for one over the other with respect to endothelial function or adenosine plasma levels post ACS [32]. Importantly, van Leeuwen et al. have recently demonstrated that ticagrelor was not superior to prasugrel in preventing microvascular injury 1 month after STEMI [33].

Prasugrel and ticagrelor differ in metabolism and mechanism of action, specifically regarding their binding to P2Y₁₂ receptors (irreversibly vs. reversibly, respectively). Furthermore, prasugrel’s loading dose is six times the maintenance dose, while ticagrelor’s loading dose is only two-fold higher than the maintenance dose. This may explain, in part, the stronger TG inhibition and favorable EPC profile observed in the prasugrel group, considering that T1 samples were taken 24 h post loading dose and prior to maintenance dose. It is also important to consider as previously suggested that these pleiotropic effects may be P2Y₁₂-independent, and rather mediated by other signaling pathways, which lead to increased EPCs number [29, 30, 34] and TG inhibition.

Study limitations

Our study has several limitations; First, it is a single-centered study. Second, while treatment to either prasugrel or ticagrelor was randomized, the choice was not blinded to the medical teams. Nevertheless, the researchers performing the TG and EPCs tests were indeed blinded to the grouping. Moreover, there were no crossovers in the first 24 h. Third, we did not include a significant number of COVID-19 patients in the study, mainly since patients with COVID-19 were referred to a dedicated COVID-19 hospital with a dedicated catheterization lab [35]. Fourth, the pleotropic differences demonstrated in this study occurred one day after loading dose. The long-term effect of the drugs on TG and EPCs was not evaluated.

Conclusion

Among patients treated with PPCI due to STEMI, medical treatment with prasugrel as compared to ticagrelor is associated with more potent inhibition of thrombin generation and improved EPCs count and function one day after PCI. This unique observation may argue in favour of prasugrel over ticagrelor for STEMI patients.

Abbreviations

ACEI

angiotensin converting enzyme inhibitor

CAD

coronary artery disease

COPD

chronic obstructive pulmonry disease

Hs

high sensitivity

LVEF

left ventricular ejection fraction

MPV

mean platelet volume

PVD

peripheral vascular disease

WBC

white blood cell.

Authors Contribution

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Maya Wiessman, Mark Kheifetz, Nili Schamroth Pravda, Dorit Leshem Lev, Eti Ziv and Leor Perl. The first draft of the manuscript was written by Maya Wiessman and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

The authors did not receive support from any organization for the submitted work.

Declarations

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Rabin Medical Center.

Concent to participate

Informed consent was obtained from all individual participants included in the study.