Thrombocytopenia after aortic valve replacement with the Freedom Solo stentless bioprosthesis

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1 doi: /icvts Interctive CrdioVsculr nd Thorcic Surgery 7 (2008) Institutionl report - Vlves Thrombocytopeni fter ortic vlve replcement with the Freedom Solo stentless bioprosthesis, b Cn Yerebkn *, Alexnder Kminski, Bernd Westphl, Günther Kundt, Murt Ugurlucn, Gustv Steinhoff, Andres Liebold Deprtment of Crdic Surgery, Medicl Fculty, University of Rostock, Schillingllee 35, Rostock, Germny b Deprtment of Biometry nd Computer Sciences, Medicl Fculty, University of Rostock, Rostock, Germny Received 1 October 2007; received in revised form 16 April 2008; ccepted 22 April 2008 Abstrct Stentless bioprostheses hve been considered to chieve superior hemodynmics over stented bioprostheses for ortic vlve replcement with improved long-term performnce. We observed severe thrombocytopeni in ptients who received the Sorin Freedom Solo ortic stentless pericrdil bioprosthesis within the first dys fter implnttion. Absolute nd reltive pltelet counts within 2 weeks fter implnttion of either stentless (Sorin Freedom Solo) or stented (Sorin Mitroflow) bovine pericrdil bioprosthesis were compred in mtched-pirs nlysis in 40 ptients. Except the preopertive vlues, bsolute pltelet count ws higher t ll time points in the Mitroflow group. In the Mitroflow group, the men pltelet count modertely dropped to minimum of 60% of the initil vlue on POD 3 nd fully recovered by POD 8. In the Freedom Solo group, pltelet loss ws significntly more severe (minimum reltive vlue 25% on POD 4) with no recovery during follow-up (60% on POD 13). Eight ptients of the Freedom Solo group experienced criticl pltelet drop towrds -20% of their initil vlues, in five of them bsolute numbers decresed below 30,000yml. No bleeding complictions or other morbidity occurred. Attention should focus on the pltelet count fter implnttion of the Freedom Solo bioprosthesis, especilly in ptients who re supposed to receive pltelet inhibitors. However, the described phenomenon remins unexplined Published by Europen Assocition for Crdio-Thorcic Surgery. All rights reserved. Keywords: Aortic vlve, replcement; Hert vlve, stentless; Hert vlve, bioprosthesis; Blood cogultion 1. Introduction Stentless bioprosthesis for ortic vlve replcement (AVR) hve proven dvntges over stented vlves including better hemodynmic performnce w1x, improved left ventriculr remodeling w2x nd superior survivl w3x. The requirement for two suture lines for secure implnttion in the ortic root for stentless bioprosthesis nd consequently prolonged cross-clmp time hs led to the development of the Freedom Solo (FS) vlve which ws relesed by the Sorin compny in June For implnttion of this vlve in the suprnnulr position, only one continuous suture line is required w4x. FS vlve hd been used in our Deprtment since 2005 for AVR. After encourging initil experience with this type of stentless bioprosthesis regrding esy nd fst implnttion technique nd erly postopertive results, we encountered significnt decrese in pltelet count in severl cses within the erly postopertive dys. The im of this study ws to sttisticlly prove our clinicl observtion, tht reduction of pltelet count in ptients receiving FS vlve ws more severe thn in ptients who were implnted with stndrd stented bovine pericrdil bioprosthesis. *Corresponding uthor. Tel.: q ; fx:q E-mil ddress: cn.yerebkn@med.uni-rostock.de (C. Yerebkn) Published by Europen Assocition for Crdio-Thorcic Surgery 2. Mteril nd methods 2.1. Ptients Individul ptient consent ws not required becuse individul ptients were not identified in the study. Between Februry 2006 nd Februry 2007, 20 ptients (14 mles, 6 femles, men ge 70.3"7.5 yers, rnge: yers) requiring AVR received Freedom Solo vlves (Sorin Group, Sluggi, Itly). Implnttion of the FS vlve ws performed by only two experienced surgeons. These ptients were retrospectively mtched with 20 ptients (14 mles, 6 femles, men ge 71.7"5.2, rnge: 63 82) who were implnted with Mitroflow (MF) stented bioprosthesis (Sorin Group, Sluggi, Itly) between Jnury 2006 nd My The implnttion of the MF vlve ws performed by five different surgeons, including those who implnted the FS bioprosthesis. The implnttion of the MF bioprosthesis ws supervised by one of the surgeons who implnted the FS bioprostheses. There ws no difference in the strtegy of the opertion, except the technique of the implnttion s described below. The indictions for AVR were ortic stenosis or regurgittion. There were no emergency cses. Only one ptient in the FS group hd ortic vlve endocrditis who ws operted electively. All opertions were performed only t the

2 C. Yerebkn et l. / Interctive CrdioVsculr nd Thorcic Surgery 7 (2008) deprtment of crdic surgery of the University of Rostock. Bseline preopertive nd periopertive dt with comprison of both groups re shown in Tble Surgicl technique After the institution of generl nesthesi nd medin sternotomy, crdiopulmonry bypss with moderte hypothermi ( C) ws begun. Intermitted cold blood crdioplegi ws pplied vi coronry osti fter trnsverse ortotomy. Inspection of the vlve, leflet resection nd declcifiction of the nnulus followed. The FS vlve is mde of two sheets of bovine pericrdium which is fixed in glutrldehyde-bsed process. The prosthesis is treted for the elimintion nd neutrliztion of ldehyde residues nd stored in buffer solution without ldehydes. Therefore, ccording to the mnufcturer s recommendtion rinsing of the FS vlve is not required. FS vlve ws implnted with continuous suprnnulr suture line technique using three 4-0 prolene monofilment running sutures strting t the bse of ech sinus vlslv nd proceeding to the top of the commisures. Sutures were tied outside of the ort without reinforcement. Our implnttion technique ws consistent with the recommendtions of the vlve mnufcturer. After deiring of the left ventricle nd ort, cross-clmp ws relesed nd crdiopulmonry bypss cesstion followed. The surgicl procedure for MF vlve replcement differed from the bove described mnner only regrding vlve implnttion technique. MF vlve ws implnted to the nnulus using double needled interrupted brided pledgeted sutures to tke plce in the suprnnulr position. Tble 1 Preopertive bseline chrcteristics, opertive nd periopertive dt of ptients Chrcteristic MF group FS group P-vlue Number of ptients Age 71.7" " Mle 14 (70) 14 (70) 1.00 Aortic stenosis 20 (100) 15 (75) 0.030* Aortic regurgittion 6 (30) 14 (70) 0.017* CHD 14 (70) 13 (65) Arteril hypertension 16 (80) 12 (60) DM 9 (45) 4 (20) Renl insufficiency 3 (15) 4 (15) Hyperlipidemi 11 (55) 10 (50) PVD history 2 (10) Pulmonry hypertension 2 (10) 7 (35) AF 5 (25) 4 (20) Mitrl vlve disese 2 (10) 4 (20) Concomitnt procedures CABG 12 (60) 11 (55) MVR 2 (10) 3 (15) Opertive dt Cross-clmp (min) 91.8" " Perfusion (min) 133.7" " Postopertive ejection frction 47.7" " CHD, coronry hert disese; DM, dibetes mellitus; PVD, peripherl vsculr disese; AF, tril fibrilltion; CABG, coronry rtery bypss surgery; MVR, mitrl vlve replcementyreconstruction. Dt re presented s men vlue"s.d. for continues vribles, frequency nd percentge of ffected subjects within the group (in prenthesis) for ctegoricl fctors nd significnce probbility (P-vlue) for comprison FS vs. MF group. *P-0.05 FS vs. MF group Postopertive mngement All ptients received subcutneous weight dpted highmoleculr heprin until estblishment of orl nticogultion with phenprocoumon which ws initited on POD 2 or 3 nd dvised to be continued for 3 months. In cses of concomitnt coronry rtery bypss surgery (CABG), spirin ws continued on the first postopertive dy with 100 mg per dy following single intrvenous infusion of 500 mg six hours postopertively. According to surgeon s preference, spirin ws replced with clopidogrel in six ptients in the FS group fter the institution of orl nticogultion on POD 3. Heprin induced thrombocytopeni (HIT) ws investigted in ten (50%) of the ptients in the FS group becuse of the reduction in pltelet count using specil enzyme immuno ssy (GTI Dignostics, PF4 enhnced, Wisconsin, USA). In ll cses with suspicion of HIT, but two, Dnproid ws begun with the sme time of cesstion of heprin. In one cse in the MF group orl nticogultion ws postponed becuse of hemorrhoidl bleeding following hemorrhoidectomy. The summry of postopertive medicl mngement is presented in Tble Sttisticl nlysis All dt were stored nd nlyzed using the SPSS sttisticl pckge 14.0 (SPSS Inc. Chicgo, IL, USA). The cretion of groups ws estblished by mtching regrding ge nd sex. Descriptive sttistics were computed for vribles of interest. The sttistics computed included men nd stndrd devitions of continuous vribles, frequencies nd reltive frequencies of ctegoricl fctors. Testing for differences of continuous vribles between two study groups creted by therpy ws ccomplished by nlysis of covrince djusted for the covrite plvix. For binry vribles, comprisons were relized by using the Mntel Henszel test combining two seprte tbles creted by plvix. All P-vlues resulted from two-sided sttisticl tests in the sense tht sufficiently lrge deprtures from the null hypothesis in either direction will be judged significnt nd generlly PF0.05 ws considered to be sttisticlly significnt. For the 15 multiple comprisons of pltelet counts, Bonferroni correction ws mde to Tble 2 Postopertive mediction in both groups Postopertive mediction MF group FS group P-vlue Heprin 20 (100) 20 (100) Not computble Dnproid 0 8 (40) 0.030* Bet blockers 18 (90) 15 (75) Phenprocoumon 19 (95) 15 (75) ACE inhibitors 10 (50) 7 (35) CSE inhibitors 10 (50) 11 (55) Clcium ntgonists 6 (30) 6 (30) Loop diuretics 15 (75) 16 (80) Antibiotics (Fluorchinolons) 4 (20) 2 (10) ASS 13 (65) 10 (50) Clopidogrel 0 6 (30) 0.008* ACE, ngiotensin-converting-enzyme; CSE, cholesterol-synthetse-enzyme; ASA, cetylslicylic cid. Frequencies, percentges of ffected subjects (in prenthesis) within the groups nd significnce probbilities (P-vlues) for comprison FS vs. MF group re shown. *P-0.05 FS vs. MF group.

3 618 C. Yerebkn et l. / Interctive CrdioVsculr nd Thorcic Surgery 7 (2008) control experiment-wise type I error. Tht mens, we work with lower criticl significnce probbility nd in Tble 3 nd Fig. 1 differences would be significnt only if P-0.05y 15s For our dt, checking of pltelet counts for norml distribution by the Kolmogorov Smirnov test obviously results in no rejection of hypothesis of normlity (P)0.6 for every point in time). The uthors hd full ccess to the dt nd tke responsibility for its integrity. All of the uthors hve red nd greed to the rticle s written. 3. Results There ws no difference in most of group demogrphics, mediction nd periopertive dt (Tbles 1, 2). No significnt difference ws observed between the groups regrding the concomitnt procedures performed with AVR. No mortlity ws observed. In the MF group, the men pltelet count modertely dropped to minimum of 60% of the initil count on POD 3 with full recovery by POD 8. In the Freedom Solo group, pltelet loss ws significntly more severe (minimum reltive vlue of 25% on POD 4) showing no recovery during follow-up (60% on POD 13). In five ptients (25%) of the FS group, the pltelet count ws criticlly decresed below the vlue of 30,000yml, wheres in eight ptients the reltive number of pltelets ws reduced up to 20% of the preopertive vlue between 3 5 postopertive dys. The bsolute pltelet count ws not different in both groups preopertively but from the dy of the opertion it decresed more clerly in the FS group in comprison to the MF group. Except the initil vlues, bsolute pltelet count ws higher t ll time points in the MF group. In considertion of Bonferroni correction, the differences between the two groups were significnt t the 3rd, 5th, 6th nd 8th postopertive dy nd t the 1st, 2nd, 4th, 12th nd 13th postopertive dy, P-vlues were The chnge in pltelet count ws similr in the subgroup of ptients who received concomitnt CABG surgery with AVR. Fig. 1. Pltelet count in percentge difference from the preopertive vlue (considered s 100%) presented s men vlues nd stndrd error (*PF0.05y15s FS vs. MF group). No significnt bleeding or thrombembolic compliction occurred in either group. No mjor crdiovsculr event ws encountered in the erly postopertive period. HIT ws investigted in 10 ptients (50%) of the FS group using the enzyme immune ssy nd ws negtive in ll subjects. Red blood cell concentrtes were given in totl number of eight nd six pcks in the FS nd MF group, respectively, in the erly postopertive period. No fresh frozen plsm ws needed in the MF group, wheres one ptient in the FS group needed six pcks. There ws no significnt difference regrding blood product delivery between the groups. Tble 3 shows the bsolute pltelet number preopertively, t dy of opertion nd t 13 postopertive dys, nd Fig. 1 presents percentge differences of pltelet counts t the dy of opertion nd during the first 13 postopertive dys compred with the preopertive sitution in both groups. In considertion of Bonferroni correction t the 3rd, 5th, 6th nd t the 8th postopertive dy, these percentge decreses were significntly greter in the FS Tble 3 Postopertive bsolute pltelet count Pltelets FS group MF group P-vlue n Men S.D. 95% CI n Men S.D. 95% CI Preop w195.0, 246.9x w203.4, 256.7x Op dy w82.9, 138.3x w118.4, 159.8x Pod w87.3, 130.5x w123.6, 168.1x Pod w54.9, 94.3x w97.3, 148.7x Pod w30.0, 71.8x w89.6, 140.2x 0.001* 4. Pod w26.3, 93.3x w101.5, 94.9x Pod w33.7, 100.3x w118.3, 200.3x 0.001* 6. Pod w52.6, 138.9x w156.8, 229.8x 0.003* 7. Pod w81.8, 159.2x w125.4, 227.2x Pod w24.6, 147.2x w216.7, 348.7x 0.001* 9. Pod w72.7, 212.1x w163.3, 330.3x Pod Pod w39.3, 324.1x w146.9, 393.6x Pod w79.9, 159.8x w192.7, 307.6x Pod w70.4, 208.6x w224.0, 362.3x Absolute pltelet count in 10 yml during the postopertive period of 13 dys. Dt re presented s men vlue"stndrd devition (S.D.) with 95%-confidence intervl (95% CI) nd significnce probbility (P-vlue) for comprison FS vs. MF group. The significnce ws presented ccording to the Bonferroni correction s *P Bold typed P-vlues below 0.05 express the results without correction.

4 C. Yerebkn et l. / Interctive CrdioVsculr nd Thorcic Surgery 7 (2008) group in comprison to the MF group, nd t the 2nd, 4th, 12th nd 13th dys P-0.05 becuse of the smll number of subjects. The pek nd men grdients between the MF nd FS groups reveled no difference in the echocrdiogrphic control within the first postopertive week. Furthermore, there ws no difference in the body surfce re or in the size of the implnted vlve (Tble 4). 4. Discussion Stentless bioprostheses for AVR hve been considered superior regrding their hemodynmic properties, effect on the left ventriculr remodeling nd survivl w1 3x in comprison to stented prostheses. The FS vlve is mde of bovine pericrdium nd ws developed to overcome certin disdvntges of the prior stentless bioprostheses w5x. This vlve especilly needs single continuous suture line nd no rinsing before implnttion w4x. Since the first FS stentless bioprostheses were implnted in our Deprtment, we encountered severe reduction of pltelet count in severl ptients. After ssurnce of other fctors, such s HIT or other possible toxic gents on thrombocytes, we decided to systemticlly ddress this observtion. In mtched-pirs nlysis, we imed to show tht the pltelet count in the FS vlve group ws lower thn the MF vlve group in the erly postopertive period. Even when concomitnt procedures, such s CABG nd mitrl vlve replcement hve been performed the percentge of these ptients in both groups did not differ significntly. Furthermore, the higher incidence of ortic vlve regurgittion in the FS group my be ttributed tht the FS vlve hs preferbly chosen for ptients with sole ortic insufficiency nd with less ortic vlve nnulus clcifictions. In totl, 50% of ptients of the FS vlve group were investigted for suspected HIT. In the enzyme immunossy, no HIT ntibodies were detected in these ptients. Dnproid therpy ws instituted in eight (40%) ptients in the FS group before witing the lbortory evidence for HIT. The chnge of nticogultion hd no effect on the course of the pltelet count. To the uthor s knowledge, no report hs been published bout postopertive thrombocytopeni in ptients fter FS vlve implnttion yet. This is the first report of such n occurrence. Similr but not published observtions in other crdic surgicl centers occurred with the sme type of vlve (personl communictions). Currently, the reson for the occurrence of the thrombocytopeni is mbiguous. One possible reson my be trnsitory direct toxic effect on pltelets originting from Tble 4 Echocrdiogrphic nd vlve size relted dt MF group (ns17) FS group (ns17) P-vlue Pek grdient 21.3" " Men grdient 9.17" " BSA 1.85" " Vlve size 23.9" " Postopertive echocrdiogrphic dt presented s men vlue"s.d. nd significnce probbility (P-vlue) for comprison between the groups. the FS vlve. This hypothesis is corroborted by the cute decrese of the pltelet count immeditely fter AVR nd slow trend towrds recovery in the second postopertive week. A possible toxic effect on the pltelets cnnot be eliminted by rinsing of the vlve in similr mnner, such s glutrldehyde-fixed bioprostheses, which usully hve not been detoxificted, such s the FS vlve (not published observtion). The inclusion of clopidogrel in six subjects hppened fter the POD 3 without loding dose. The time point of severe reduction in pltelet count ws before the initition of clopidogrel. Given 75 mg dily without loding dose, this gent needs severl dys to exert ny effect on pltelet function. Moreover, we djusted our sttisticl nlysis regrding the difference of clopidogrel dministrtion between the groups. In comprison to other ptients, no correltion with the severity of pltelet reduction ws observed in ptients who received clopidogrel. A second considertion would be the mechnicl stress on pltelets which cnnot be disproved with our dt, but is either improbble considering superior hemodynmic properties of the FS vlve. Postopertive echocrdiogrphic dt did not indicte ny dysfunction of the FS vlve in our ptients. Although no dt re vilble of the ortic vlve nnulus size before implnttion, implnted vlve size did not differ significntly between the groups. In echocrdiogrphic nlysis fter AVR, the pek grdient nd the men grdients were 21.6"7.66 mmhg nd 10.8"4.13 mmhg, respectively. These results re comprble to other studies in the literture w5, 6x. Although no bleeding compliction hs occurred in ptients with severe thrombocytopeni, this compliction is still to be considered possible, especilly ptients who re treted with pltelet inhibitors with higher risk of bleeding. Therefore, close meshed monitoring of the pltelet count fter AVR with the FS vlve prosthesis is essentil. Further studies re needed to clrify the mechnisms nd consequences of pltelet reduction fter the implnttion of the FS bioprosthesis. A prospective, rndomized study is plnned in our Deprtment for the explntion of the thrombocytopeni ptients undergoing AVR with the FS stentless bioprosthesis. 5. Limittions of the study The prospective comprison of single AVR would hve eliminted ny possible group or procedure relted effect on the pltelet count. In ptients with thrombocytopeni, no further evlution, such s bone mrrow spirtes or pltelet smers, were vilble. The number of subjects is limited due to the frequency of the implnttion of the FS prosthesis in our deprtment. After our report, the experience of other deprtments with lrger smple of ptients should be wited to strengthen our conclusion. Moreover, we provide only up to three months follow-up of our ptients postopertively. After dischrge from our clinic no morbidity or mortlity ws reported from secondry helth cre institutions in this period. However, to dte no further follow-up of the pltelet count thn presented is vilble.

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