Thrombocytopenia After Aortic Valve Replacement: Comparison Between Sutureless Perceval S Valve and Perimount Magna Ease Bioprosthesis

Introduction The incidence of postoperative thrombocytopenia after aortic valve replacement (AVR) with the Perceval S Sutureless bioprosthesis remains unclear. The aim of this study was to report thrombocytopenia associated with the use of sutureless AVR. Methods The data was collected retrospectively for patients who had isolated AVR with sutureless Perceval S valve (Group A: 72 patients) and was compared with patients who underwent isolated sutured AVR with Perimount Magna Ease Bioprosthesis (Group B: 101 patients) in our institution between June 2014 and January 2017. Results Cardiopulmonary bypass and cross-clamp time were significantly shorter in group A. Maximum drop in platelet count was 58% mean (day 2.3) in group A versus 44% mean (day 1.7) in group B (P=0.0001). Absolute platelet count on postoperative day 1-6 in group A was significantly less than in group B (P≤0.05). Platelet count recovered to preoperative value in 44% patients in group B versus only in 26% patients in group A at discharge (P=0.018). Moderate thrombocytopenia occurs more often in group A (41% vs. 26%) (P=0.008) while severe thrombocytopenia (<50 x 109) was observed in 6% in group A but never in group B. Platelets (P=0.007) and packed red blood cells (P=0.009) transfusion was significantly higher in the group A. Conclusion The implantation of sutureless Perceval aortic valves was associated with a significant drop in platelet count postoperatively with slow recovery and higher platelets and packed red blood cells transfusion requirements. A prospective randomised trial is needed to confirm our findings.


INTRODUCTION
Surgical aortic valve replacement (AVR) still represents the gold standard in patients with severe aortic valve stenosis [1] . Owing to increasing age of the patient population in the Western world, there has been an increase in the prevalence of patients with valvular heart disease eligible for AVR [2] . Given the increasing number of co-morbidities and the increasing age of patients, a tendency has emerged to use biological valve implants thus avoiding the need for long-term anticoagulation therapy. Although the concept of transcatheter aortic valve implantation (TAVI) appears attractive, the calcified aortic valve is not removed during this procedure. Therefore, paravalvular leakage remains an important issue with this technique [3] . Other important concerns are access site-related problems and device malpositioning.
The recent introduction of sutureless bioprostheses may offer an additional tool in the therapeutic armamentarium as these valves do not need to be sutured into place resulting in shorter cross-clamp and cardiopulmonary bypass (CPB) durations which may be beneficial in older patients with comorbid conditions. Moreover, due to the absence of a sewing ring, these valves exhibit favourable hemodynamic properties. Excellent outcomes have been demonstrated with sutureless AVR in minimally invasive surgical setting [4] .
was collapsed in a side table and placed into the manufacturer's holder. The three guiding sutures were passed through the three green holes arising from the annular ring of the prosthesis, which was consequently seated on the debrided annulus. Once the delivery system is in position, the stent is deployed by turning the release screw and leaving the valve in place. The delivery system and the guiding sutures are removed. The field was rinsed with warm saline, and the prosthesis was dilated at four atmospheres for 30 seconds.
On first postoperative day, patients were started on aspirin 150 mg orally and low molecular weight heparin subcutaneously for deep vein thrombosis prophylaxis.

Statistical Analysis
All data has been extracted from the Dendrite PATS CS2010F SCTS v4.1.2 database. Date of data extract was 25.07.17 to cover the period from 01.06.2014 to 31.01.17. Analysis was performed using MS Excel. Numerical values were compared using an independent t-Test, with a two-tailed distribution assuming unequal variances. Categorical variables were compared using Chi Square χ2 analysis.

RESULTS
The preoperative characteristics of patients are depicted in Tables 1 and 2 Greater number of L and XL size valves was implanted in Perceval valve group, and of 23 and 25 mm prosthesis in Perimount Magna Ease group (Table 3).
When Perceval valve sizes S, M, L and XL were compared with their counterpart Perimount Magna Ease valve sizes, there was more significant thrombocytopenia in Perceval group (Table 4). Haematology data is depicted in Tables 5, 6 and 7. Among the Perceval valve group, 5 (6%) patients had severe thrombocytopenia. Their peak reduction was on day 3 with 58% of their preoperative platelet value. While in Perimount Magna group none of them had severe thrombocytopenia. Their peak reduction was on day 2 with 44% of preoperative value which is significantly less then Perceval valve group. Perceval valve group required more blood (1.5 vs. 0.7 units) (P=0.009) and platelet (0.3 vs. 0.1 platelets pools; P=0.007) transfusion. No significant difference in absolute platelet count between two groups on preoperative and operation days was observed. Platelet count was significantly reduced in Perceval group from day 1-6 and 20% patients came back to preoperative level at discharge. Fortyfour percent of Perimount patients came back to preoperative value at the time of discharge. Forty-one percent of Perimount group had moderate thrombocytopenia while this value was 26% in Perceval valve group.
We noticed that sutureless valves are associated with greater drops in postoperative platelet counts compared to sutured valves. Albacker [5] reported this phenomenon with sutureless AVR and the aim of this study was to investigate this observation and try to find an explanation for its occurrence.

Patients
It is a retrospective, observational study. All the patients who underwent isolated sutureless Perceval AVR between June 2014 and November 2016 were compared with patients who had isolated AVR with Carpentier-Edwards Perimount Magna Ease valve between June 2015 and January 2017. Any nonisolated AVR cases i.e.: coronary artery bypass grafting, mitral and tricuspid valve surgery, myomectomy, ascending aorta surgery were excluded. Moreover, all the redo, emergency and infective endocarditis patients were excluded.
All the sutureless AVRs were performed by the six different surgeons in our institution during that period. Data was collected on all the patients who underwent sutured AVR by the same surgeons during the same time period (101 patients) as a control group.
A total of 72 patients received isolated Perceval bioprosthesis and 101 patients had Perimount Magna Ease valve. The Percevel S valve sizes were small, medium, large and extra-large. For statistical purposes they were taken as equivalent to 19-21, 23, 25 and 27 mm Perimount Magna Ease sizes, respectively.
Severe thrombocytopenia was defined as a platelet count <50x10 9 /Lit during the postoperative period. The platelet count was determined preoperatively, day of surgery and every day until day 5 in the postoperative period. In-hospital mortality was defined as any death occurring within first 30 days after surgery. Aspirin and clopidogrel was discontinued 7 days before surgery and warfarin was stopped 5 days before operation.

Surgical Approach
A complete median sternotomy was performed and extracorporeal circulation (ECC) with moderate hypothermia (34°C) was employed in every patient. Antegrade cold blood cardioplegia was administered after application of cross clamp. The choice of prosthesis implanted was made by the surgeon. Perioperative transesophageal echocardiogram was performed routinely to confirm correct position of the valve, exclude any paravalvular leak and evaluate valve hemodynamics.
The Perimount Magna Ease valve was rinsed with normal saline for 3 minutes before implantation while Perceval valve does not require any rinsing before implantation. Perimount Magna Ease valves were intra implanted with interrupted or semi continuous 2/0 prolene sutures.
The Perceval valve is a surgical bioprosthetic heart valve consists of glutaraldehyde-fixed bovine pericardium treated with homocysteic acid in order to remove the free aldehyde residues and prevent the calcification process. It is fixed in a metal cage made up of an alloy of nickel and titanium, known as nitinol.
Three 4/0 polypropylene guiding sutures were passed at the nadir of the aortic annulus. An appropriately sized prosthesis   significant difference in postoperative neurological dysfunction, renal impairment, atrial fibrillation, permanent pacemaker requirement or mortality could be observed.

DISCUSSION
Our retrospective study showed that there is a relationship between Perceval S valve implantation and severe thrombocytopenia. Severe thrombocytopenia in our study was  In our study, the drop-in platelet count started to occur during the 3 rd POD with very slow recovery toward the 7 th to 10 th POD. The lowest drop in platelet count was down to 22% of the preoperative baseline level and occurred in patients implanted with the Perceval valve. As shown in other studies, there were no other clinical consequences associated with thrombocytopenia that was transient but resulted in more transfusion requirements.
The bovine pericardium leaflets of both Perceval S valve and Mitroflow bioprosthesis are fixed in a process using gluteraldehyde. The Mitroflow prosthesis is stored in a solution of gluteraldehyde and needs rinsing before it is used. On the other side, the Perceval S prosthesis and Freedom Solo prosthesis are detoxified with homocysteic acid to eliminate any residual aldehyde and then stored in an aldehyde free solution; so, it does not require rinsing prior to use. Homocysteic acid can have a damaging effect on vessel endothelial cells and can precipitate platelet aggregation resulting in both thrombocytopenia and thrombotic complications [15] . These valves are carefully washed after detoxification with a homocysteic acid-free solution and then stored in jars filled with a homocysteic acid-free storage solution. Consequently, the residual amount of homocysteic acid, which could be transferred to the patient during the valve implantation, is negligible and the resulting concentration in blood is extremely low, so cannot be blamed for the postoperative thrombocytopenia. Moreover, the same solution is used for other bioprosthesis [16] , without causing higher incidence of thrombocytopenia.
Mechanical stress and hemodynamic turbulence have also been proposed as a cause of thrombocytopenia after Freedom Solo prosthesis [10] .
Small valve sizes have been described as causing some turbulence across the valve resulting in platelet activation or destruction, and consequently postoperative thrombocytopenia [7,9,14] . However, sutureless valves are well known for their superior hemodynamic performance and this hypothesis is quite unlikely.
Non-specific activation of platelets leading to diffuse consumption and thrombocytopenia after AVR with both mechanical and bioprosthetic aortic valves was suggested by Leguyader et al. [17] . Platelet activation could also result from valve manipulation or the presence of the metal stent.
The Perceval S valve has metal structure that serves as an anchoring system to the aortic valve, which could be the cause of turbulent flow, platelet rupture and mechanical structure. The metal stent may play a role in platelet activation and the possibility of paravalvular leaks may also trigger platelet activation and consumption. Moreover, the metal stents of these valves could interfere with the quality of images and could conceal or underestimate the degree of some paravalvular leaks [5] .
Long CPB duration has been suggested by other studies to be associated with postoperative thrombocytopenia [14] . In our study the CPB durations were shorter in the sutureless group not associated with higher mortality and morbidity, and none of these deaths was related to severe thrombocytopenia.
Sánchez et al. [6] compared the incidence of thrombocytopenia after AVR with Perceval S Sutureless Bioprosthesis (n=27) and Mitroflow prostheses (n=50). The incidence of severe thrombocytopenia was significantly higher (P=0.046) in Perceval S patients than in Mitroflow patients. The platelet count recovered in all patients with severe thrombocytopenia.
The biological structure of the Perceval S valve and Freedom Solo stentless bioprosthesis are very similar [6] .
Hilker et al. [7] compared the postoperative courses of platelet counts in patients having had AVR with stentless prostheses (Sorin Biomedica Freedom Solo [SOLO]) or stented prostheses (Carpentier Edwards Perimount [PM]). A higher occurrence of platelet levels below 100 Gpt/l between the second and the fifth postoperative day (POD) was found in the SOLO-group (71.9%) compared with the other biological substitute PM (36.6%).
Miceli et al. [8] evaluated the postoperative evolution of platelet count and function after AVR in 116 patients undergoing isolated stentless biological AVR with Freedom Solo and compared with 206 patients who received stented biological valves. Freedom Solo implantation was associated with a higher incidence of thrombocytopenia compared with the control group (24.1% vs. 4.4%, P<0.0001).
Piccardo et al. [9] also studied the incidence and clinical impact of thrombocytopenia in patients receiving AVR with Freedom Solo bioprosthesis and Carpentier-Edwards Perimount pericardial prosthesis. They reported that severe thrombocytopenia occurred in 25% and 3% of patients with Freedom Solo and Perimount bioprostheses, respectively (P<0.0001).
Yerebakan et al. [10] compared platelet counts within 2 weeks after implantation of either a stentless (Sorin Freedom Solo) or a stented (Sorin Mitroflow) bovine pericardial bioprosthesis. In the Mitroflow group, the mean platelet count moderately dropped to a minimum of 60% of the initial value on 3 rd POD and fully recovered on 8 th POD. In the Freedom Solo group, platelet loss was significantly more severe (minimum relative value 25% on 4 th POD) with no recovery during follow-up. However, there were no other complications reported in association with thrombocytopenia related to the use of these Freedom Solo valves and the phenomenon was transient and resolved without clinical consequences or hemodynamic dysfunction [9,10] .
Platelet count decrease has also been reported after percutaneous coronary intervention [11] . Gallet et al. [12] studied the effect of transcatheter (via femoral artery) aortic valve implantation (TAVI) on platelet count. They observed that platelet count systematically decreased after TAVI, with an average decrease of 34±15%, and a decrease in platelet count reported to be associated with in-hospital major adverse cardiovascular events and strongly influenced patient outcome. In the setting of TAVI procedures platelet activation can be caused by endothelial damage caused by prosthesis implantation, fibrinogen binding on metallic armatures, and shear stress modifications due to prosthesis implantation [13] .
Van Straten et al. [14] compared thrombocytopenia after AVR with mechanical and biological valves. They concluded than the sutured one so it cannot be responsible for postoperative thrombocytopenia.
Severe thrombocytopenia is a common complication in patients who undergo cardiac surgery with ECC. It occurs as result of structural changes and activation of platelets, hemodilution, platelet aggregation and bleeding [18] .

Limitations
The main limitation of our study is due to its observational, non-randomized and retrospective characteristics. Heparin induced thrombocytopenia was not investigated as a possible cause of thrombocytopenia, as it appears after the 5 th postoperative day [18] .

CONCLUSION
It seems to be an association between sutureless Perceval valve and severe thrombocytopenia, although it does not affect patient's mortality and morbidity. These patients had also higher rate of blood and platelets transfusion. A prospective randomised trial is needed to confirm our findings.