• „ ORIGINAL ARTICLE

Platelet function in patients undergoing surgical and transcatheter aortic valve replacement: a comparative study

Anna Komosa1, Bartłomiej Perek2, Piotr Rzymski3, 4, Barbara Poniedziałek3, Marek Grygier1, Andrzej Siniawski1, Katarzyna Szabatowska1, Jolanta Siller-Matula5, 6, Marek Jemielity2, Marcin Misterski2, Maciej Lesiak1

11st Department of Cardiology, Poznan University of Medical Sciences, Poznań, Poland

2Department of Cardiac Surgery and Transplantology, Poznan University of Medical Sciences, Poznań, Poland

3Department of Facial Malformation, Poznan University of Medical Sciences, Poznań, Poland

4Integrated Science Association (ISA), Universal Scientific Education and Research Network (USERN), Poznań, Poland

5Department of Cardiology, Medical University of Vienna, Vienna, Austria

6Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology CEPT, Medical University of Warsaw, Warszawa, Poland

INTRODUCTION

Aortic stenosis (AS) is the most common valvular heart disease among elderly patients [1]. Symptomatic severe AS is associated with a survival rate of 50% if untreated [2]. Thus, to improve a patient’s prognosis it is crucial to undertake invasive treatment on time. Currently, there are two therapeutic options for patients with severe AS: surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). SAVR is the treatment of choice in symptomatic patients with severe AS [3]. However, TAVR has lately become less invasive although valuable alternative to manage symptomatic patients at intermediate or high risk of surgical procedure [4, 5]. It has already been proven that TAVR is non-inferior to surgery when performed in experienced centers, with respect to the risk of death or stroke within 5 years of follow-up [6, 7]. The estimation has been made that the number of SAVR procedures is expected to decrease significantly due to the growing number of TAVR procedures [8].

Pathophysiology of AS is an overly complex issue. Impaired fibrinolysis, pronounced calcification, coagulation, and platelet activation abnormalities contribute to the progression due to increased fibrin deposition and inflammation [9–11]. Platelet activity has an impact on the development of atherosclerosis. Platelets contribute to the early stage of vascular pathology, such as endothelial dysfunction and rupture of vulnerable plaque [12]. Platelet activation caused by atherosclerotic plaque rupture or erosion of the endothelium contributes to the formation and progression of the atherothrombotic disease [13]. These processes lead to clinically relevant consequences — adverse cardiovascular events such as myocardial infarction or stroke [14, 15]. The influence of platelet activity on the course of AS has been investigated, but results remain unequivocal [16].

Intervention-induced platelet hypercoagulability may pose patients to potentially serious adverse events. It has already been proven that platelets play a significant role in reparation after injury, wound healing, and organ regeneration [17]. The coagulation cascade is initiated at the injured endothelial surface, where platelets migrate and a fibrin-rich clot is formed. Progressive postinjury thrombocytosis induces a hypercoagulable state associated with an increased risk of thromboembolic complications [18]. Postinjury thrombocytosis seems to be an underestimated factor of a hypercoagulable state causing platelet hyperactivity.

As reported in the previous study, both TAVR and SAVR can induce systemic oxidative stress, although the former is associated with a significantly lower redox imbalance and faster recovery of antioxidant capacity [19]. As established experimentally and through observational studies, increased levels of endo- and exogenous reactive oxygen species are important factors triggering platelet activation [20–22]. It is therefore important to understand whether there is an association between platelet-related oxidative stress and platelet function following TAVR and SAVR procedures. In this regard, malondialdehyde (MDA) in platelets appears to be a feasible marker and a link between oxidative stress and platelet activity, since it is a hallmark of lipid peroxidation, a common outcome of cellular redox imbalance [23]. Moreover, it correlates with platelet aggregation in response to arachidonic acid, epinephrine, and collagen [24], and it is, besides thromboxane A2, a product of prostaglandin H2 conversion by thromboxane synthase [25, 26].

This study aimed to assess whether two available methods of AS treatment differ in periprocedural platelet activity caused by iatrogenic injury due to intervention. To this end, the platelet indices and platelet MDA were compared in patients undergoing TAVR and SAVR during the hospital stay.

METHODS

The total number of 24 patients with a mean age (SD) of 71 (13) years who underwent SAVR (n = 12) or TAVR (n = 12) procedures between May 2016 and March 2017 were recruited for the study. The baseline characteristics of the studied group are summarized in Table 1.

Written informed consent was obtained from each patient before participating in the research. The study protocol was approved by the Ethical Committee of the Medical University in Poznan (No. 968/15). All of the studied individuals fulfilled the criteria for high-gradient AS defined according to the current European Societ of Cardiology guidelines [27].

The following parameters were evaluated in all studied patients: (i) platelet indices: total platelet count (PLT), platelet distribution width (PDW) and mean platelet volume (MPV), (ii) MPV/PLT ratio, (iii) platelet level of lipid peroxidation measured by means of its final major product, MDA content and MDA/PLT ratio, and (iv) the percentage variation of PLT, PDW and MPV in relation to the baseline values were also determined [28]. All parameters were measured at 4 time-points: pre-procedure, immediately post-procedure, then 1 and 2 days after the procedure. Subsequently, all values were compared between the two groups at each of the measured time-points: functional parameter (MDA) vs platelet morphological indicators (PLT, MPV, PDW, PLT/MPV). Additionally, the percentage variation of MDA vs PLT values, MDA vs PDW, MDA vs MPV, and MDA vs PLT/MPV ratio, in relation to the baseline values, were calculated.

Malondialdehyde concentration

The content of MDA was measured in isolated platelets. Firstly, the platelet-rich plasma was obtained from the patient’s blood samples by centrifugation at 200 g for 12 minutes. Platelet-rich plasma was then transferred to polypropylene tubes, 1/10 vol acid citrate dextrose was added, centrifuged again at 900 g for 15 minutes. Plasma was aspirated and platelets were suspended in 200 µl of distilled water. The platelet MDA level was assessed using the TBARS Assay kit (Cayman Chemicals, Ann Arbor, MI, USA). The platelets were treated with 300 ml of RIPA Buffer (50 mM Tris-HCl, pH 7.4, 1% Triton X-100, 150 mM NaCl, 1% Tergitol type NP-40, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate) to conduct the lysis of cellular components. The butylated hydroxytoluene was added to the RIPA Buffer to prevent artificial lipid peroxidation during platelet lysis. The samples were then centrifuged at 1600 g for 10 minutes and the resulting 100 µl of supernatants were transferred to new tubes. The 800 µl of thiobarbituric acid was added to generate an MDA-thiobarbituric acid adduct. The reaction was conducted at 95°C for 60 minutes, samples were then placed for 10 minutes on an icebath for inhibition and centrifuged at 1600 g for 10 minutes. The absorbance of the final product was measured at 532 nm using a SynergyHTX multi-mode plate reader (BioTek Instruments, Winooski, VT, USA). The MDA content, given as µM, was calculated by comparing the absorbance values to a calibration curve (r2 = 0.99) prepared using the MDA standard (Cayman Chemicals, Ann Arbor, MI, USA).

Surgical aortic valve replacement

All operations were performed from full median sternotomy with the use of cardio-pulmonary bypass (CPB) in moderate hypothermia (28°C) and cardioplegic cardiac arrest according to St. Thomas Hospital II formula [29]. CPB was conducted through an arterial cannula introduced to the ascending aorta and a two-staged venous cannula to the right atrium. After the ascending aorta was opened, the aortic valve was completely removed and the aortic prosthesis using 2-0 sutures with Teflon pledges was implanted. After aortotomia was closed with 5-0 monofilament suture and de-airing of the left heart was completed, ascending aorta was de-clamped and reperfusion phase of CPB initiated. Successful weaning from CPB was followed by removal of all cannulas, protamine administration, careful hemostasis, and closure of the chest.

Percutaneous aortic valve implantation

Patients were eligible for TAVR based on the institutional heart team’s decision (interventional cardiologist, cardiac surgeon, and echocardiography specialist).

The pre-procedural evaluation included: coronary angiography, transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE); contrast-enhanced computed tomography (CT) with off-line reconstruction to evaluate the aortic valve, and access site (femoral and iliac arteries). The final decision regarding the route of the vascular approach was made based on the results of the CT scan. General anesthesia or deep sedation was used during the procedures. The TTE monitoring was performed and a temporary pacemaker was inserted from the femoral vein for rapid pacing and as a backup in case of iatrogenic atrioventricular block consequences [30].

In patients with the percutaneous femoral approach, two Proglides™ were introduced before insertion of the vascular sheath. The Medtronic CoreValve Evolut R prosthesis was implanted in all cases. Once the prosthesis was correctly positioned, expanded, and deployed, the contrast injection was performed to assess the presence and degree of paravalvular leak. Control angiography of the access site was performed to assess vessel patency and possible bleeding [31].

Data presentation and statistical analysis

First, all continuous variables were checked for normality by means of the Shapiro–Wilk W test. Those meeting the criteria of normal distribution were presented as means with standard deviations and then compared with the use of unpaired Student t-test (between TAVI and SAVR groups) or repeated-measures ANOVA followed by post hoc Tukey HSD test (for time-related changes within groups). Otherwise (i.e., for not normally distributed continuous variables), they were expressed as the medians with interquartile range (IQR: first to third quartile) and then analyzed statistically by non-parametric tests such as Friedman test followed by Dunn’s multiple comparisons of ranks. Qualitative variables were compared by means of Yates’ corrected χ2 test. P-value <0.05 was considered as statistically significant. Analyses were performed with the use of Statistica 10.0 for the Windows package (StatSoft, Tulsa, OK, USA).

RESULTS

PLT count

In both groups, PLT decreased significantly following procedures (P <0.001). However, this drop was more pronounced in the SAVR group (P = 0.02 vs TAVI) because in all postoperative analyses (samples ‘1’ to ‘3’) PLT count was markedly lower than before surgery, whereas in the TAVI group only between two points, before procedure vs 48 hours after it (Table 2).

Interestingly, the intergroup comparison did not show any statistical significance (Figure 1)

.

MPV and PDW

In both groups, these platelet parameters did not change during the periprocedural period (MPV, P = 0.67 and P = 0.26; PDW, P = 0.05 and P = 0.16; respectively for TAVI and SAVR in ANOVA) (Table 3).

Of note, MPV before the procedure was significantly lower in SAVR than in the TAVI group.

MPV/PLT

MPV/PLT ratio increased significantly after procedures in both groups (P = 0.01 in TAVI and P = 0.01 in SAVR), although its value did not differ between groups (Figure 2A).

Post-hoc analysis disclosed that marked increase in MPV/PLT ratio between baseline vs both 24 (P = 0.04) and 48 hours (P = 0.01) after valve implantations in the SAVR group whereas in the TAVI group only between baseline and 48 hours after (P = 0.01) the procedures. These findings encouraged us to perform a more detailed analysis of this parameter. In the next step, a relative increase of this ratio was compared between groups and was found to be more pronounced 24 hours after procedures (Figure 2B).

MDA and MDA/PLT

Multiple comparisons of ranks test revealed that platelet levels of MDA were significantly higher soon after procedures (P = 0.046) and 24 hours (P = 0.02) later in the SAVR group than in the TAVI group (Figure 3A).

The limitations of the present study should also be highlighted. Firstly, the research encompassed a small sample size. It is an effect of the complex protocol including the performance of surgical procedures requiring many preparations, precise timing of blood sample collection at 4 accurate time-points and a proper sample transfer to the experimental laboratory for determination of MDA levels. Furthermore, there is a need to emphasize a significant difference in the age of patients in both studied groups (TAVI vs SAVR; mean 80 years vs 63 years, respectively). It is a consequence of the qualification process by the heart team according to European Society of Cardiology guidelines on the management of patients with severe symptomatic AS. TAVR is a method preferred in elderly and high-risk patients. The findings of the present study cannot be used to modify the antiplatelet therapy, although they lay a foundation for further investigations encompassing larger groups and additional platelet-related parameters.

Standard surgical aortic valve replacement is associated with a more pronounced platelet reaction to intervention-induced injury, as compared to the transcatheter-based technique. The importance of these laboratory findings warrants further investigation focused on early, as well as late, clinical outcomes. Whether these findings are of any significance in terms of selecting the appropriate antiplatelet therapy after SAVR and TAVI requires further investigations.

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