Differences in the recovery of platelet counts after biological aortic valve replacement

Transcription

1 doi: /icvts Interactive CardioVascular and Thoracic Surgery 8 (2009) Institutional report - Valves Differences in the recovery of platelet counts after biological aortic valve replacement a, b a a a Lutz Hilker *, Michael Wodny, Mario Ginesta, Hans-Georg Wollert, Lothar Eckel a Clinic for Thoracic and Cardiovascular Surgery, Klinikum Karlsburg, Heart and Diabetes Center Mecklenburg-Vorpommern, Karlsburg, Germany b Institute of Biometry and Medical Informatics, Ernst Moritz Arndt University Greifswald, Germany Received 16 July 2008; received in revised form 15 September 2008; accepted 16 September Abstract Observations among Karlsburg patients in 2006 revealed that the majority of very low platelet levels inducing postoperative heparininduced-thrombocytopenia (HIT)-diagnostics with at the end negative results appeared related to aortic valve replacement (AVR) with stentless bioprostheses. We compared the postoperative courses of platelet counts in patients having had AVR with stentless prostheses (Sorin Biomedica Freedom Solo wsolox) or stented prostheses (Carpentier Edwards Perimount wpmx). Between February 2005 and April 2007, 209 patients received AVR with SOLO, in 137 patients a PM-prosthesis was implanted. The mean platelet levels were compared from the first up to the fifth postoperative day. A higher occurrence of platelet levels below 100 Gptyl between the second and the fifth postoperative day was found in the SOLO-group (71.9%) compared with the other biological substitute PM (36.6%). Differences in platelet counts between SOLO- and PM-subgroups were measured for day 2 (Ps0.03), day 3 (Ps0.0004) day 4 (Ps0.0007), day 5 (Ps0.0002) and at discharge (P ). Following intervention with conventional biological AVR, differences in the postoperative recovery of platelet counts can be detected, depending on the prosthesis used. The causes for and the clinical implications of this phenomenon are not yet assessed Published by European Association for Cardio-Thoracic Surgery. All rights reserved. Keywords: Platelets; Biological valve replacement; Stentless prostheses 1. Introduction After the introduction of a new generation of pericardial stentless prostheses (Sorin Biomedica Freedom Solo wsolox), with extreme pliability and very satisfying clinical and hemodynamic results w1x, the Clinic of Karlsburg took up the implantation of this valve in February Until April 2007, 209 of these prostheses in aortic position were implanted. During the same period, 197 stented biological prostheses were implanted (137 Carpentier Edwards Perimount wpmx, 36 Sorin Mitroflow wmfx and 24 St Jude Medical Biocor wbiocorx). Observations of a higher number of HITdiagnostics with negative results in terms of a postoperative decrease of platelet levels throughout 2005y2006, led to more detailed data analysis. This revealed that most of these cases were patients after aortic valve replacement with SOLO-prostheses. Further investigations were conducted into retrospective analyses of pre- and postoperative platelet counts; this included clinical data of all patients with biological prostheses. Has been presented as a poster presentation at The Houston Aortic Symposium: Frontiers in Cardiovascular Diseases, Houston, Texas, April *Corresponding author. Klinikum Karlsburg, Klinik für Herz-Thorax und Gefäßchirurgie, Greifswalder Straße 11, Karlsburg, Germany. Tel.: q (Ms. Schulz). address: Ludovici@gmx.de (L. Hilker) Published by European Association for Cardio-Thoracic Surgery 2. Material and methods 2.1. Patients During the period of investigation 406 patients underwent biological aortic valve surgery. For further retrospective comparison data of 137 PM-patients (90 males, 47 females; mean age 71.1"6.4 years) and 148 SOLO-patients (67 males, 81 females; mean age 73.9"6.4 years), who were operated on between February 2005 and August 2006, were included (Table 1). The main diagnosis in these patients was aortic valve disease (122 with pure aortic stenosis, 148 with mixed aortic valve disease, 15 with aortic regurgitation andyor endocarditis); 157 (55.1%) of them had concomitant coronary artery disease, 5 (1.8%) had additional mitral valve pathology and one patient had tricuspid valve pathology. In 11 patients an additional epicardial radiofrequency ablation of the right atrium was performed, in 11 cases the dilated ascending aorta was either plicated (ns10) or replaced (ns1). In five cases a persistent foramen ovale or an atrial septal defect was closed by direct suture. Five simultaneous thromboendarterectomies of a carotid artery were performed. Fifteen cases were emergencies, 22 cases were reoperations. One hundred and one patients underwent isolated AVR Implantation technique In all patients a complete median sternotomy was performed followed by the cannulation of the ascending aorta

2 L. Hilker et al. / Interactive CardioVascular and Thoracic Surgery 8 (2009) Table 1 Patient characteristics, patients treated between February 2005 and August 2006 with SOLO or PM. postoperative day. The blood samples were analyzed in an authorized hematological laboratory. SOLO PM 2.5. Data analysis n (myf) 148 (67y81) 137 (90y47) Age 73.9" "6.4 Weight 79.3" "16.2 Body surface 1.87" "0.21 Restricted LVF 26 (18%) 56 (41%) Endocarditis 2 7 Concomitant procedures 86 (58%) 74 (54%) Prosthesis size (mean) Ischemia (min) 89.9" "26.5 OP-time (min) 191" "49.4 Emergency 5 (3.4%) 10 (7.3%) Reoperation 7 (4.7%) 15 (10.9%) LVF, left ventricular function. and the right atrium for standard normothermic extracorporeal circulation with cardioplegic arrest induced by warm blood cardioplegia (Calafiore) and repeated every 10 to 15 min. If necessary, any concomitant procedures were performed. Then, after transverse incision of the aorta, the mostly degenerated aortic valve was excised. The annulus size was measured using specific obturators. The choice of prosthesis used was only influenced by the surgeon s individual decision. The size of the stentless prosthesis was chosen according to the size of the sinotubular junction, the size of the other prostheses depended on the diameter of the annulus. SOLO was implanted as stentless prosthesis completely supra annular with a 4-0 Prolene running suture interrupted at each commissure in routine fashion. A special detoxification technique (glutaraldehyde fixation, treatment with homocysteic acid) eliminated the need for rinsing before implantation as recommended by the SORIN company. The stented prostheses (PM) were implanted intra-annular with standard 3-0 Ethibond single pledgeted mattress sutures. The aortotomy was closed with a 4-0 Prolene suture in two layers. If necessary, the proximal anastomoses of aortocoronary bypasses were performed. Cardiopulmonary bypass was then discontinued and the chest closed in routine fashion. Demographic data and platelet levels are presented as mean"s.d. Statistical analysis was performed using Wilcoxon Mann Whitney rank sum test (Software from SAS Institute Inc., Cary, NC, USA). A P-value was considered to be statistically significant. 3. Results Fig. 1 shows the postoperative course of the mean platelet levels for all patients receiving a SOLO- or PM-prostheses between February 2005 and August No significant level differences were detected neither preoperatively nor directly postoperative. The commonly observed first decrease down to the half of the initial level (due to dilution and ECC technique) was seen for every prosthetic intervention. A slight regeneration of the platelet counts occurred on the first postoperative day, with higher incidence in the PM-group. On day two, a second decrease occurred and from here on significant differences between the platelet courses were observed. In patients with SOLO-prostheses, the second decrease was more intensive and lasted up to the third day. 71.9% of the SOLO-patients reached platelet levels below 100 Gptyl. After day three in most cases a slow secondary regeneration of platelet counts was found. A slight second decrease with minimum on day two was observed among the majority of patients with PM-prostheses. Only 36.6% of the PM-patients reached platelet levels below 100 Gptyl between day two and day five. After that a continuous increase was observed Subgroup comparison Following the primary observations, the analyses continued by investigating and comparing subgroups of the numerous patients with SOLO- and PM- aortic valve replacement (AVR) in order to achieve a better description of this 2.3. Postoperative management If there was no bleeding six hours postoperative, all patients were treated with intravenous heparin (PTT 600). After the second postoperative day we began an anticoagulation regime with Marcumar (INR ) for three months to prevent early valve thrombosis. Heparin treatment was finished when the aimed INR was reached. Furthermore, patients with concomitant coronary heart disease were treated with 100 g Acetylsalicylic acid per day. Before discharge a transthoracic echocardiography was performed Data assessment Platelet levels were measured preoperatively, directly after the operation and daily from the first to the fifth Fig. 1. SOLO- and PM-platelet courses (Gptyl), patients treated between February 2005 and August 2006.

3 72 L. Hilker et al. / Interactive CardioVascular and Thoracic Surgery 8 (2009) phenomenon (data relating to period between February 2005 and August 2006, Table 2) Comparison of patients with only AVR after exclusion of additional factors To get more comparable subgroups in the following all patients with any concomitant procedures (inclusive radiofrequency ablation), preoperative treatment with Acetylsalicylic acid, preoperative platelet levels below 100 Gpty l, reoperations, endocarditis, early postoperative bleeding with the need of reoperation or platelet substitution and postoperative diagnosis of HIT were excluded to eliminate effects potentially influencing the postoperative platelet course. In none of these patients postoperative echocardiography detected a paravalvular leakage. The data of these subgroups were analyzed using Wilcoxon Mann Whitney rank sum test. There are significant differences in the recovery of the platelet counts between these SOLO- and the PM-subgroups beginning on the third postoperative day (Table 3) Influence of patient s age on the SOLO platelet course To investigate the influence of patient s age on the SOLO platelet course, these patients were divided into two subgroups; one group of the patients younger than the over all mean age (73.9 years; subgroup mean age 68.3 years) and another group of the older patients (subgroup mean age 78.1 years). No significant differences were detectable (Table 4). Table 2 Patient characteristics, patients treated between February 2005 and August 2006 with SOLO or PM without concomitant procedures SOLO n (myf) 41 (18y23) 37 (20y17) Age 73.7" "7.6 Weight 78.2" "15.5 Body surface 1.85" "0.21 Restricted LVF 8 (19.5%) 7 (18.9%) Endocarditis 0 0 Concomitant procedures 0 0 Prosthesis size (mean) Ischemia (min) 66.7" "10.73 OP-time (min) 148.6" "22.8 Emergency 2 (4.9%) 0 Reoperation 0 0 PM 3.4. Influence of extracorporeal circulation (ECC) time on the SOLO platelet course To investigate the influence of ECC time on the SOLO platelet course two subgroups were created; one group of patients with ECC time )114 min (mean min) and another group of patients with ECC time -115 min (mean 89.7 min). The overall mean ECC time was 114.6"35 min. No significant differences between these groups were observed after day one (Table 5). 4. Discussion The data analyzed in this study reveal undefined differences in postoperative platelet count recovery, depending on the used aortic valve prosthesis. Furthermore, they refer to differences of platelet counts in the follow-up. The causes for this phenomenon are unclear. A slower recovery of platelet counts in the SOLO-group was seen for all used valve sizes and not related to the duration of bypass time nor with patient s age. Postoperatively, all patients received the similar anticoagulation protocol, including the use of intravenous heparin, which may similarly affect platelets. Microhemodynamic effects of the prosthesis structure or depending on the implantation technique andyor specific chemical preparations of biological prosthesis tissue could act as a trigger for the described phenomenon. It seems to be possible that transient unspecific activation of platelets result in diffuse consumption and lower platelet levels. In 2006 the group of Le Guyader in Limoges observed platelet activation after aortic valve replacement with two kinds of mechanical valves (Omnicarbon, St Jude Medical Regent) and three kinds of bioprostheses (St Jude Medical Epic, Sorin Mitroflow, Carpentier Edwards Perimount) in 33 Table 4 Platelet counts for SOLO patients treated between February 2005 and August 2006, depending on patient s age Day Platelets )73 years, Gptyl Platelets -74 years, Gptyl P (ns83) (ns64) 0 225" "69.3 n.s. OP 105" "43.8 n.s " "45.7 n.s " "37.1 n.s. 3 94" "38.9 n.s " "45.4 n.s " "53.1 n.s. Table 3 Mean platelet counts for SOLO and PM, patients without concomitant procedures treated between February 2005 and August Furthermore, the platelet levels before discharge (d) are to be seen Day Platelets SOLO, Gptyl Platelets PM, Gptyl P 0 240" "55.3 n.s. OP 120" "31.9 n.s " "35.8 n.s "46 124" " " " " "53 178" d 195" " Table 5 Platelet counts for SOLO patients treated between February 2005 and August 2006, depending on ECC time Day ECC )114 min ECC -115 min P Platelets, Gptyl Platelets, Gptyl (ns73) (ns75) 0 217" "63.9 n.s. OP 95" " "41 128" " "47 n.s. 3 88" "44.8 n.s. 4 93" "52.6 n.s " "53.1 n.s.

4 L. Hilker et al. / Interactive CardioVascular and Thoracic Surgery 8 (2009) patients assessing platelet P-selectin expression, plateletleukocyte conjugate formation and platelet micro particles. At the eighth day after implantation they found platelet activation of bioprostheses and bileaflet mechanical valves. Two months after surgery in these cases platelet activation had returned to the basic level observed prior to surgery in the bileaflet valve group, whereas it was still increased in the bioprosthesis group w2x. In 1997, Lehner et al. investigated the biocompatibility of commercially available bioprostheses either pre-treated or not with autologous endothelial cells in a model of adult baboons. After 40 days no endothelial cells were detectable on the leaflets surface of the non-endothelialized prostheses. Fibrin deposits and platelet aggregates were observed on the bioprostheses surface, but not on the pre-treated valves w3x. In conclusion, slower postoperative recovery of platelet levels in some kinds of aortic valve prostheses could be a sign of higher platelet activation. Platelet activation has been correlated with thromboembolic complications in previous reports w4 6x. In 2005, Grubitzsch et al. reported one case of reoperation for suspected valve thrombosis after AVR with SOLO w7x. In our clientele one patient of the SOLO-group underwent reoperation for suspected valve thrombosis. In this case we found a blockaded non-coronary cusp due to thrombus formation partly occluding the valve. Beholz et al. described this phenomenon in patients after AVR with implantation of another kind of stentless aortic valve prosthesis (Pericarbon Freedom) as a result from immobilization and subsequent partial valve thrombosis of the non-coronary cusp in case of implantation technique with nonsymmetric sinuses of Valsalva w8x. However, in all patients treated in our clinic with biological AVR there were no obvious bleeding- or thromboembolia related differences influencing the clinical outcome between the prostheses groups. Nevertheless, we investigate patients in a follow-up to observe the occurrence of such possible complications. In conclusion, the present paper describes a phenomenon of significant differences in the recovery of patient s platelet counts after biological aortic valve replacement with different kinds of prostheses. The causes for and the clinical implications of this phenomenon are not yet assessed. To investigate platelet activation, platelet levels and clinical outcome after AVR with different biological prostheses a prospective study should be arranged. w1x Beholz S, Liu J, Dushe S, Konertz WF. The Freedom Solo Valve: superior hemodynamic results with a new stentless pericardial valve in aortic valve replacement. J Heart Valve Dis 2007, Jan;16: w2x Le Guyader A, Watanabe R, Berbe J, Boumediene A, Cogne M, Laskar M. Platelet activation after aortic prosthetic valve surgery. Interact CardioVasc Surg 2006;5: w3x Lehner G, Fischlein T, Baretton G, Murphy JG, Reichart B. Endothelialized biological heart valve prostheses in the non-human primate model. Eur J Cardiothorac Surg 1997;11: w4x Geiser T, Sturzenegger M, Genewein U, Haberli A, Beer JH. Mechanisms of cerebrovascular events as assessed by procoagulant activity, cerebral micro emboli, and platelet micro particles in patients with prosthetic heart valves. Stroke 1998;29: w5x Nieuwland R, Berckmans RJ, Rotteveel-Eijkan RC, Maquelin KN, Roozendaal KJ, Jansen PG, Ten Have K, Eijsman L, Hack CE, Sturk A. Cellderived micro particles generated in patients during cardiopulmonary bypass are highly procoagulant. Circulation 1997;96: w6x Cohen Z, Gonzales RF, Davis-Gorman GF, Copeland JG, Mc Donagh PF. Thrombin activity and platelet micro particle formation are increased in type 2 diabetic platelets: a potential correlation with caspase activation. Thromb Res 2002;107: w7x Grubitzsch H, Linneweber J, Kossagk C, Sanli E, Beholz S, Konertz WF. Aortic valve replacement with new-generation stentless pericardial valves: short-term clinical and hemodynamic results. J Heart Valve Dis Sep;14: w8x Beholz S, Konertz WF. Avoiding early partial valve thrombosis of the Pericarbon Freedom stentless valve. J Heart Valve Dis 2007 Jan;16: ecomment: Lower postoperative platelet levels after aortic valve replacement with Freedom Solo prostheses: are there clinical repercussions? Authors: Alessandro Piccardo, Service de Chirurgie Cardiaque, CHU Amiens, Av. Laennec, Amiens, France; Thierry Caus doi: /icvts a We have read with great interest your study concerning platelet levels after aortic valve replacement with two pericardial prostheses and we congratulate you for this attentive investigation w1x. Despite similar preoperative clinical data and postoperative anticoagulation protocol, your results demonstrate a significant lower postoperative platelet level (-100 Gpt/l) after Freedom Solo implantation. Thrombocytopenia after Freedom Solo implantation was recently reported by Yerebakan and colleagues w2x. However, your study has the merit to perform the analysis in a large cohort of patients. Unfortunately, as this is the crux of the matter, you concluded that data presented in the study are insufficient to evaluate the clinical repercussions of these findings. Since Yerebakan et al. w2x reported this phenomenon, we analyzed the incidence of thrombocytopenia and its clinical repercussions at our Institution. Among 474 patients who had undergone biological aortic valve replacement between August 2006 and July 2008, we reviewed the postoperative platelet levels of 138 consecutive patients who had undergone isolated aortic valve replacement with pericardial prostheses. Despite similar preoperative clinical data, postoperative anticoagulation protocol, preoperative platelet levels and postoperative AntiPF4 positive rates, we found significant lower postoperative platelet levels after Freedom Solo implantation. We focused on your analysis of patients who underwent isolated aortic valve replacement and we noted that you excluded from your study patients with early postoperative bleeding requiring re-exploration or platelet substitution. Our question is: why? Could you exclude that the postoperative bleeding and the platelet substitution was not correlated with a lower platelet count? It would be interesting to analyze if the incidence was similar in the groups and if it was correlated to a severe postoperative thrombocytopenia. We included such patients in our analysis and we did not find any significant clinical difference regarding postoperative thrombo and hemorrhagic complications. According to our preliminary results, patients experience significant lower postoperative platelet levels after Freedom Solo implantation but it seems to be without any clinical repercussions. w1x Hilker L, Wodny M, Ginesta M, Wollert HG, Eckel L. Differences in the recovery of platelet counts after biological aortic valve replacement. Interact CardioVasc Thorac Surg 2009;8: w2x Yerebakan C, Kaminski A, Westphal B, Kundt G, Ugurlucan M, Steinhoff G, Liebold A. Thrombocytopenia after aortic valve replacement with the Freedom Solo stentless bioprosthesis. Interact CardioVasc Thorac Surg 2008;7: ecomment: Freedom Solo stentless aortic bioprosthesis and postoperative thrombocytopenia interpretation of available data and clinical consequences for surgeons Authors: Can Yerebakan, Department of Cardiac Surgery, University of Rostock, Schillingallee 35, Rostock, Germany; Bernd Westphal, Gustav Steinhoff, Andreas Liebold

5 74 L. Hilker et al. / Interactive CardioVascular and Thoracic Surgery 8 (2009) doi: /icvts b We read the paper by Hilker and colleagues on their analysis of postoperative platelet counts after aortic valve replacement with two different types of pericardial bioprostheses with great interest w1x. The authors were able to confirm our data by showing a significant reduction and a slower recovery of platelet counts during the first postoperative week after implantation of the Freedom Solo stentless bioprosthesis within a larger cohort of patients w2x. The origin of this phenomenon is still unknown and it has been observed in many centers around Europe without consequent publication until the year We do think there are some points that should be emphasized. In our series, we observed a reduction in the platelet count down to 20% of the initial value in eight of the patients in the Freedom Solo group (ns20), whereby five of these patients had platelet count drops to levels under 30,000/ml. Did the authors observe any patient within their group with similarly severe thrombocytopenia? Did any patient receive platelet concentrates and were there differences in blood product delivery between the groups? As our patients were subjected to a more severe decrease, it would be helpful to know which postoperative medications your patients received. Especially with respect to cases of coronary artery bypass surgery, did you administer a loading dose of aspirin in the early postoperative period, in some patients clopidogrel as an alternative to aspirin or dual platelet inhibition? In how many patients did you perform a heparin-induced thrombocytopenia (HIT) investigation and did you change your anticoagulation regime by switching to alternative agents for anticoagulation in cases when HIT was suspected? Did you perform platelet counts in all patients every day during the first five days? Why are there no values presented past the fifth postoperative day? We think that in order to achieve a sound interpretation of the limited available data, detailed inter-institutional comparison of information is inevitable. Taken together, our results and those of Hilker et al. as well as several personal communications from users of the Freedom Solo valve there is an unpredictable risk of severe thrombocytopenia in the postoperative course. The valve should therefore only very cautiously be implanted in patients who would need a dual platelet inhibition. To ensure ultimate safety for our patients the underlying mechanism and the clinical consequences of this phenomenon should further be investigated. w1x Hilker L, Wodny M, Ginesta M, Wollert HG, Eckel L. Differences in the recovery of platelet counts after biological aortic valve replacement. Interact CardioVasc Thorac Surg 2009;8: w2x Yerebakan C, Kaminski A, Westphal B, Kundt G, Ugurlucan M, Steinhoff G, Liebold A. Thrombocytopenia after aortic valve replacement with the Freedom Solo stentless bioprosthesis. Interact CardioVasc Thorac Surg 2008;7: