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Interact CardioVasc Thorac Surg 2008;7:616-620. doi:10.1510/icvts.2007.169326 © 2008 European Association of Cardio-Thoracic Surgery
Thrombocytopenia after aortic valve replacement with the Freedom Solo stentless bioprosthesis
a Department of Cardiac Surgery, Medical Faculty, University of Rostock, Schillingallee 35, 18057 Rostock, Germany Received 1 October 2007; received in revised form 16 April 2008; accepted 22 April 2008
*Corresponding author. Tel.: +49-381-494-6101; fax:+49-381-494-6102.
Stentless bioprostheses have been considered to achieve superior hemodynamics over stented bioprostheses for aortic valve replacement with improved long-term performance. We observed severe thrombocytopenia in patients who received the Sorin Freedom Solo aortic stentless pericardial bioprosthesis within the first days after implantation. Absolute and relative platelet counts within 2 weeks after implantation of either a stentless (Sorin Freedom Solo) or a stented (Sorin Mitroflow) bovine pericardial bioprosthesis were compared in a matched-pairs analysis in 40 patients. Except the preoperative values, absolute platelet count was higher at all time points in the Mitroflow group. In the Mitroflow group, the mean platelet count moderately dropped to a minimum of 60% of the initial value on POD 3 and fully recovered by POD 8. In the Freedom Solo group, platelet loss was significantly more severe (minimum relative value 25% on POD 4) with no recovery during follow-up (60% on POD 13). Eight patients of the Freedom Solo group experienced a critical platelet drop towards <20% of their initial values, in five of them absolute numbers decreased below 30,000/µl. No bleeding complications or other morbidity occurred. Attention should focus on the platelet count after implantation of the Freedom Solo bioprosthesis, especially in patients who are supposed to receive platelet inhibitors. However, the described phenomenon remains unexplained.
Key Words: Aortic valve, replacement; Heart valve, stentless; Heart valve, bioprosthesis; Blood coagulation
Stentless bioprosthesis for aortic valve replacement (AVR) have proven advantages over stented valves including better hemodynamic performance [1], improved left ventricular remodeling [2] and superior survival [3]. The requirement for two suture lines for secure implantation in the aortic root for stentless bioprosthesis and consequently prolonged cross-clamp time has led to the development of the Freedom Solo (FS) valve which was released by the Sorin company in June 2004. For implantation of this valve in the supraannular position, only one continuous suture line is required [4]. FS valve had been used in our Department since 2005 for AVR. After encouraging initial experience with this type of stentless bioprosthesis regarding easy and fast implantation technique and early postoperative results, we encountered a significant decrease in platelet count in several cases within the early postoperative days. The aim of this study was to statistically prove our clinical observation, that reduction of platelet count in patients receiving a FS valve was more severe than in patients who were implanted with a standard stented bovine pericardial bioprosthesis.
2.1. Patients Individual patient consent was not required because individual patients were not identified in the study. Between February 2006 and February 2007, 20 patients (14 males, 6 females, mean age 70.3±7.5 years, range: 56–83 years) requiring AVR received Freedom Solo valves (Sorin Group, Saluggia, Italy). Implantation of the FS valve was performed by only two experienced surgeons. These patients were retrospectively matched with 20 patients (14 males, 6 females, mean age 71.7±5.2, range: 63–82) who were implanted with a Mitroflow (MF) stented bioprosthesis (Sorin Group, Saluggia, Italy) between January 2006 and May 2007. The implantation of the MF valve was performed by five different surgeons, including those who implanted the FS bioprosthesis. The implantation of the MF bioprosthesis was supervised by one of the surgeons who implanted the FS bioprostheses. There was no difference in the strategy of the operation, except the technique of the implantation as described below. The indications for AVR were aortic stenosis or regurgitation. There were no emergency cases. Only one patient in the FS group had aortic valve endocarditis who was operated electively. All operations were performed only at the department of cardiac surgery of the University of Rostock. Baseline preoperative and perioperative data with comparison of both groups are shown in Table 1.
2.2. Surgical technique After the institution of general anesthesia and median sternotomy, cardiopulmonary bypass with moderate hypothermia (32–34 °C) was begun. Intermitted cold blood cardioplegia was applied via coronary ostia after transverse aortotomy. Inspection of the valve, leaflet resection and decalcification of the annulus followed. The FS valve is made of two sheets of bovine pericardium which is fixed in a glutaraldehyde-based process. The prosthesis is treated for the elimination and neutralization of aldehyde residues and stored in a buffer solution without aldehydes. Therefore, according to the manufacturer's recommendation rinsing of the FS valve is not required. FS valve was implanted with a continuous supraannular suture line technique using three 4-0 prolene monofilament running sutures starting at the base of each sinus valsalva and proceeding to the top of the commisures. Sutures were tied outside of the aorta without reinforcement. Our implantation technique was consistent with the recommendations of the valve manufacturer. After deairing of the left ventricle and aorta, cross-clamp was released and cardiopulmonary bypass cessation followed. The surgical procedure for MF valve replacement differed from the above described manner only regarding valve implantation technique. MF valve was implanted to the annulus using 12–16 double needled interrupted braided pledgeted sutures to take place in the supraannular position. All patients received subcutaneous weight adapted high-molecular heparin until establishment of oral anticoagulation with phenprocoumon which was initiated on POD 2 or 3 and advised to be continued for 3 months. In cases of concomitant coronary artery bypass surgery (CABG), aspirin was continued on the first postoperative day with 100 mg per day following a single intravenous infusion of 500 mg six hours postoperatively. According to surgeon's preference, aspirin was replaced with clopidogrel in six patients in the FS group after the institution of oral anticoagulation on POD 3. Heparin induced thrombocytopenia (HIT) was investigated in ten (50%) of the patients in the FS group because of the reduction in platelet count using a special enzyme immuno assay (GTI Diagnostics, PF4 enhanced, Wisconsin, USA). In all cases with suspicion of HIT, but two, Danaparoid was begun with the same time of cessation of heparin. In one case in the MF group oral anticoagulation was postponed because of hemorrhoidal bleeding following hemorrhoidectomy. The summary of postoperative medical management is presented in Table 2.
2.4. Statistical analysis All data were stored and analyzed using the SPSS statistical package 14.0 (SPSS Inc. Chicago, IL, USA).
The creation of groups was established by matching regarding age and sex. Descriptive statistics were computed for variables of interest. The statistics computed included mean and standard deviations of continuous variables, frequencies and relative frequencies of categorical factors. Testing for differences of continuous variables between two study groups created by therapy was accomplished by analysis of covariance adjusted for the covariate plavix. For binary variables, comparisons were realized by using the Mantel–Haenszel test combining two separate tables created by plavix. All P-values resulted from two-sided statistical tests in the sense that sufficiently large departures from the null hypothesis in either direction will be judged significant and generally P
There was no difference in most of group demographics, medication and perioperative data (Tables 1, 2). No significant difference was observed between the groups regarding the concomitant procedures performed with AVR. No mortality was observed. In the MF group, the mean platelet count moderately dropped to a minimum of 60% of the initial count on POD 3 with full recovery by POD 8. In the Freedom Solo group, platelet loss was significantly more severe (minimum relative value of 25% on POD 4) showing no recovery during follow-up (60% on POD 13). In five patients (25%) of the FS group, the platelet count was critically decreased below the value of 30,000/µl, whereas in eight patients the relative number of platelets was reduced up to 20% of the preoperative value between 3–5 postoperative days. The absolute platelet count was not different in both groups preoperatively but from the day of the operation it decreased more clearly in the FS group in comparison to the MF group. Except the initial values, absolute platelet count was higher at all time points in the MF group. In consideration of Bonferroni correction, the differences between the two groups were significant at the 3rd, 5th, 6th and 8th postoperative day and at the 1st, 2nd, 4th, 12th and 13th postoperative day, P-values were <0.05. The change in platelet count was similar in the subgroup of patients who received concomitant CABG surgery with AVR. No significant bleeding or thrombembolic complication occurred in either group. No major cardiovascular event was encountered in the early postoperative period. HIT was investigated in 10 patients (50%) of the FS group using the enzyme immune assay and was negative in all subjects. Red blood cell concentrates were given in a total number of eight and six packs in the FS and MF group, respectively, in the early postoperative period. No fresh frozen plasma was needed in the MF group, whereas one patient in the FS group needed six packs. There was no significant difference regarding blood product delivery between the groups. Table 3 shows the absolute platelet number preoperatively, at day of operation and at 13 postoperative days, and Fig. 1 presents percentage differences of platelet counts at the day of operation and during the first 13 postoperative days compared with the preoperative situation in both groups. In consideration of Bonferroni correction at the 3rd, 5th, 6th and at the 8th postoperative day, these percentage decreases were significantly greater in the FS group in comparison to the MF group, and at the 2nd, 4th, 12th and 13th days P<0.05 because of the small number of subjects. The peak and mean gradients between the MF and FS groups revealed no difference in the echocardiographic control within the first postoperative week. Furthermore, there was no difference in the body surface area or in the size of the implanted valve (Table 4).
Stentless bioprostheses for AVR have been considered superior regarding their hemodynamic properties, effect on the left ventricular remodeling and survival [1–3] in comparison to stented prostheses. The FS valve is made of bovine pericardium and was developed to overcome certain disadvantages of the prior stentless bioprostheses [5]. This valve especially needs a single continuous suture line and no rinsing before implantation [4]. Since the first FS stentless bioprostheses were implanted in our Department, we encountered severe reduction of platelet count in several patients. After assurance of other factors, such as HIT or other possible toxic agents on thrombocytes, we decided to systematically address this observation. In a matched-pairs analysis, we aimed to show that the platelet count in the FS valve group was lower than the MF valve group in the early postoperative period. Even when concomitant procedures, such as CABG and mitral valve replacement have been performed the percentage of these patients in both groups did not differ significantly. Furthermore, the higher incidence of aortic valve regurgitation in the FS group may be attributed that the FS valve has preferably chosen for patients with sole aortic insufficiency and with less aortic valve annulus calcifications. In total, 50% of patients of the FS valve group were investigated for suspected HIT. In the enzyme immuno-assay, no HIT antibodies were detected in these patients. Danaparoid therapy was instituted in eight (40%) patients in the FS group before awaiting the laboratory evidence for HIT. The change of anticoagulation had no effect on the course of the platelet count. To the author's knowledge, no report has been published about postoperative thrombocytopenia in patients after FS valve implantation yet. This is the first report of such an occurrence. Similar but not published observations in other cardiac surgical centers occurred with the same type of valve (personal communications). Currently, the reason for the occurrence of the thrombocytopenia is ambiguous. One possible reason may be a transitory direct toxic effect on platelets originating from the FS valve. This hypothesis is corroborated by the acute decrease of the platelet count immediately after AVR and slow trend towards recovery in the second postoperative week. A possible toxic effect on the platelets cannot be eliminated by rinsing of the valve in similar manner, such as glutaraldehyde-fixed bioprostheses, which usually have not been detoxificated, such as the FS valve (not published observation). The inclusion of clopidogrel in six subjects happened after the POD 3 without a loading dose. The time point of severe reduction in platelet count was before the initiation of clopidogrel. Given 75 mg daily without a loading dose, this agent needs several days to exert any effect on platelet function. Moreover, we adjusted our statistical analysis regarding the difference of clopidogrel administration between the groups. In comparison to other patients, no correlation with the severity of platelet reduction was observed in patients who received clopidogrel. A second consideration would be the mechanical stress on platelets which cannot be disproved with our data, but is either improbable considering superior hemodynamic properties of the FS valve. Postoperative echocardiographic data did not indicate any dysfunction of the FS valve in our patients. Although no data are available of the aortic valve annulus size before implantation, implanted valve size did not differ significantly between the groups. In echocardiographic analysis after AVR, the peak gradient and the mean gradients were 21.6±7.66 mmHg and 10.8±4.13 mmHg, respectively. These results are comparable to other studies in the literature [5, 6]. Although no bleeding complication has occurred in patients with severe thrombocytopenia, this complication is still to be considered possible, especially patients who are treated with platelet inhibitors with higher risk of bleeding. Therefore, close meshed monitoring of the platelet count after AVR with the FS valve prosthesis is essential. Further studies are needed to clarify the mechanisms and consequences of platelet reduction after the implantation of the FS bioprosthesis. A prospective, randomized study is planned in our Department for the explanation of the thrombocytopenia patients undergoing AVR with the FS stentless bioprosthesis.
The prospective comparison of single AVR would have eliminated any possible group or procedure related effect on the platelet count. In patients with thrombocytopenia, no further evaluation, such as bone marrow aspirates or platelet smears, were available. The number of subjects is limited due to the frequency of the implantation of the FS prosthesis in our department. After our report, the experience of other departments with a larger sample of patients should be awaited to strengthen our conclusion. Moreover, we provide only up to three months follow-up of our patients postoperatively. After discharge from our clinic no morbidity or mortality was reported from secondary health care institutions in this period. However, to date no further follow-up of the platelet count than presented is available.
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Abstract
1. Introduction
0.05 was considered to be statistically significant. For the 15 multiple comparisons of platelet counts, Bonferroni correction was made to control experiment-wise type I error. That means, we work with a lower critical significance probability and in Table 
