Positive Heprin-Pltelet Fctor 4 Antibody Complex nd Crdic Surgicl Outcomes Dvid C. Kress, MD, Solomon Aronson, MD, Monic L. McDonld, MD, Mohmmd I. Mlik, MD, Ajit B. Divgi, MD, Alfred J. Tector, MD, Frncis X. Downey III, MD, Alfred J. Anderson, MS, Mi Stone, MS, RN, nd Cssndr Clncy, RN Deprtments of Thorcic nd Crdiovsculr Surgery, Lbortory Medicine, Internl Medicine, Section of Hemtology/Oncology; Qulity Mngement; nd Crdiovsculr Reserch, St. Luke s Medicl Center, Milwukee, Wisconsin; nd Deprtment of Anesthesiology, Duke University Medicl Center, Durhm, North Crolin Bckground. Given the lrge number of ptients undergoing crdic opertions nnully, it is importnt to identify popultions t high risk for dverse outcomes. This observtionl study ws conducted to determine the incidence of preopertive heprin-pltelet fctor 4 (HPF4) ntibodies nd to ssess the ssocited risk of postopertive dverse outcomes in nonselected crdic surgery ptient popultion. Methods. Between Mrch 2002 nd December 2004, 1114 (92%) of 1209 ptients undergoing crdic surgery with heprin were tested in n unselected mnner for HPF4 ntibodies. Min outcome mesures were HPF4 ntibody seropositivity nd ftl nd nonftl dverse clinicl outcomes fter crdic surgery. Results. Of those screened, 60 (5.4%) of 1114 hd positive HPF4 ntibodies preopertively. These ptients hd longer men postopertive length of sty (14.0 dys versus 9.8 dys, p 0.05), higher incidence of prolonged (>96 hours) mechnicl ventiltion (20.3% versus 9.2%, p 0.02), cute limb ischemi (5.1% versus 0.9%, p 0.03), renl complictions including dilysis (20.3% versus 10.5%, p 0.03), nd gstrointestinl complictions (15.3% versus 5.9%, p 0.01). Stepwise logistic regression nlysis showed positive HPF4 ntibody sttus to be n independent predictor for dverse outcome nd ws ssocited with higher risk for renl complictions, including dilysis (djusted odds rtio 2.2; 95% confidence intervl, 1.1 to 4.3), thn ws dibetes. Conclusions. In this lrge ptient series, the presence of HPF4 ntibodies before surgicl heprin dministrtion ws n independent nd cliniclly significnt risk fctor for postopertive dverse events fter crdic surgery. An optiml preopertive crdic surgery risk profile should include HPF4 ntibody sttus. (Ann Thorc Surg 2007;83:1737 43) 2007 by The Society of Thorcic Surgeons Accepted for publiction Dec 11, 2006. Address correspondence to Dr Kress, Midwest Hert Surgery Institute, Ltd, 2901 W. Kinnickinnic River Pkwy, Suite 511, Milwukee, WI 53215; e-mil: dkress2003@msn.com. Heprin-induced thrombocytopeni (HIT) is n immune-medited compliction of heprin dministrtion tht contrindictes further heprin exposure during crdic surgicl procedures. Overt heprininduced thrombocytopeni nd thrombosis (HITT) occurs in pproximtely 50% of HIT ptients, with devstting consequences such s limb ischemi requiring mputtion in 10% to 20%, myocrdil infrction (MI), stroke, pulmonry embolism, nd deth in 20% to 30% [1 4]. HIT occurs in 5% of orthopedic surgicl procedures, 3% of crdic opertions, 1% of vsculr opertions, nd in 1% of mediclly mnged ptients who receive heprin [3 6]. Antibodies ginst heprin-pltelet fctor 4 (HPF4) represent n importnt component in the overll dignosis of HIT [7]. A clinicl dignosis of HIT is often thought to be herlded by new onset thrombocytopeni in the presence of recent heprin dministrtion with or without HPF4 ntibodies [8]. HPF4 ntibodies my constitute n independent risk fctor. Before crdic opertions, 13% to 22% of ptients test positive for HPF4 ntibodies [9, 10], nd HPF4 ntibodies develop in s mny s 50% of ptients fter crdic opertions, which re distinguished by the need for lrge systemic doses of heprin for nticogultion [10 15]. The presence of HPF4 ntibodies hs been reported to predict dverse crdic events in some ptient popultions even in the bsence of thrombocytopeni [9, 11, 16]. Given the lrge number of ptients undergoing crdic opertions nnully, it is importnt to identify popultions tht re t high risk for dverse outcomes. It is not known whether ptients with HPF4 ntibodies before the procedure, even in the bsence of thrombocytopeni, my be t higher risk for certin dverse outcomes. To ddress this question, we conducted n observtionl study to determine the incidence of ptients with positive ssy for HPF4 ntibodies before opertion nd its reltionship to ftl nd nonftl events in nonse- Drs Kress nd Aronson disclose tht they hve finncil reltionship with The Medicines Compny. 2007 by The Society of Thorcic Surgeons 0003-4975/07/$32.00 Published by Elsevier Inc doi:10.1016/j.thorcsur.2006.12.011
1738 KRESS ET AL Ann Thorc Surg HEPARIN ANTIBODIES INCREASE SURGICAL RISK 2007;83:1737 43 lected crdic surgicl ptient popultion exposed to heprin for procedurl nticogultion. During 2.5-yer period, our study compred postopertive outcomes in preopertive HPF4 ntibody-positive nd HPF4 ntibody-negtive ptients undergoing coronry or vlve procedures with crdiopulmonry bypss (CPB) nd nticogulted with heprin. Ptient Popultion Ptients scheduled to undergo coronry rtery bypss grfting (CABG) lone or vlve procedures with or without CABG using CPB were evluted. This study ws bsed on dt obtined by crdiovsculr surgicl group tht routinely performs preopertive HPF4 ntibody screening nd pltelet counts for ll crdic surgicl ptients. All ptients studied hd similr intropertive mngement for surgicl nticogultion, which included bolus of porcine heprin (300 mg/kg) before CPB. The dose ws djusted to mintin n ctivted clotting time (ACT) of more thn 400 seconds. Ptients nd Methods Study Design This ws single-center retrospective nlysis derived from comprehensive dtbse bsed on the evlution nd observtion of crdic surgicl ptients during 2.5-yer period. This study ws reviewed by the Institutionl Review Bord on November 1, 2004 nd pproved on November 9, 2004. Informed consent ws wived. Dt collection included chrt reviews, ssessments of lbortory records, nd nlyses of outcomes nd other clinicl dt from the ongoing dtbse mintined by St. Luke s Medicl Center s n institutionl prticipnt in The Society of Thorcic Surgeons (STS) Ntionl Adult Crdic Surgery Dtbse nd Outcomes Progrm. The study included dt from 1209 consecutive ptients dmitted to single crdiovsculr surgicl service from Mrch 2002 through December 2004. Lbortory Dignostic Evlution The presence of HPF4 ntibodies ws determined by enzyme-linked immunosorbent ssy (ELISA) (GTI Inc, Wukesh, WI) [17]. Assy results were considered positive if n opticl density (OD) of more thn 0.4 ws observed. HPF4 ntibodies were tested t lest once during the index hospitliztion nd were identified s positive if t lest one test demonstrted n OD of more thn 0.4. Preopertive ntibody sttus ws defined from blood smples obtined before the surgicl procedure, on the dy of the procedure, or within the first 4 dys fter the procedure, bsed on the ssumption tht HPF4 ntibodies resulting from surgicl heprin exposure re typiclly not detectble until fter postopertive dy 4 [12, 18]. In some instnces, more thn one blood smple ws obtined from ptients beyond 4 dys fter the procedure in ccordnce with the treting physicin s discretion. Ptients with positive test result during this time period were identified s hving positive postopertive ntibody sttus. Ptients with positive ELISA results were dministered confirmtory heprin ntibody ggregtion (HAAG) functionl ssy [19]. HAAG results were considered positive if ggregtion exceeded 50%, indeterminte if Tble 1. Smple Definitions of Clinicl Terms Thrombocytopeni Septicemi Acute limb ischemi Renl filure requiring dilysis Prolonged ventiltion Renl filure GI complictions Reopertion for noncrdic problem A 50% drop in pltelet count from bseline, or n bsolute pltelet count of 100,000 10 9 /L. Septicemi (requires positive blood cultures) postopertively. Any compliction producing limb ischemi. This my include upper or lower limb ischemi. New requirement for dilysis postopertively. Pulmonry insufficiency requiring ventiltor. Including (but not limited to) cuses such s ARDS nd pulmonry edem nd/or ny ptient requiring mechnicl ventiltion 24 hours postopertively. Worsening renl filure resulting in one or more of the following: i. Increse of serum cretinine to 2.0 nd 2 most recent preopertive cretinine level. ii. A new requirement for dilysis postopertively. Postopertive occurrence of ny GI compliction including: i. GI bleeding requiring trnsfusion ii. Pncretitis with bnorml mylse/lipse requiring NG suction therpy iii. Cholecystitis requiring cholecystectomy or dringe iv. Mesenteric ischemi requiring explortion v. Other GI compliction Opertive reintervention ws required for other noncrdic resons. This includes procedures requiring return to the operting room such s trcheostomy, hemtom evcution, nd procedures tht ddress the sternum. This does not include procedures performed outside the OR such s GI lb for PEG tube, shunts for dilysis, etc. Bsed on definitions by the Society of Thorcic Surgeons. ARDS dult respirtory distress syndrome; GI gstrointestinl; NG nsogstric; OR operting room; PEG percutneous endoscopic gstrostomy.
Ann Thorc Surg KRESS ET AL 2007;83:1737 43 HEPARIN ANTIBODIES INCREASE SURGICAL RISK Tble 2. Preopertive Ptient Chrcteristics Chrcteristic HPF4 Ab Neg n 1054 (94.7%) All Surgery HPF4 Ab Pos n 59 (5.3%) p Vlue b Age (yers) 66.9 11.7 67.7 10.4 0.2 % mle 65.1 61.0 0.2 BMI (kg/m 2 ) 29.4 6.3 29.8 7.3 0.2 LVEF 0.502 0.134 0.485 0.136 0.2 Unstble ngin 81 (7.7) 6 (10.2) 0.2 Arrhythmi 180 (17.1) 18 (30.5) 0.02 VT/fibrilltion 38 (3.6) 6 (10.2) 0.05 Hert block 14 (1.3) 2 (3.4) 0.2 Atril fibrilltion 139 (13.2) 12 (20.3) 0.12 NYHA clssifiction 0.2 c I 173 (16.4) 7 (11.9) II 277 (26.3) 11 (18.6) III 452 (42.9) 31 (52.5) IV 152 (14.4) 10 (16.9) Mitrl insufficiency 146 (13.9) 15 (25.4) 0.03 Congestive hert filure 193 (18.3) 18 (30.5) 0.03 Prior CVA, n (%) 80 (7.6) 12 (20.3) 0.01 PVD 92 (8.7) 3 (5.1) 0.2 Prior on-pump procedure 119 (11.3) 7 (11.9) 0.2 Urgent/ slvge surgery 26 (2.5) 2 (3.4) 0.2 Chronic lung disese 23 (2.2) 3 (5.1) 0.06 Renl dysfunction 60 (5.7) 5 (8.5) 0.2 Renl dilysis 19 (1.8) 3 (5.1) 0.12 Dibetes 369 (35.0) 24 (40.7) 0.2 Ctegoric dt re presented s n (%); continuous dt s mens SD. b Student t test for continuous dt; Fischer exct test for ctegoric dt. c This vlue indictes there ws no sttisticl difference in the distribution between NYHA clsses. BMI body mss index; CVA cerebrovsculr ccident; HPF4 Ab heprin-pltelet fctor 4 ntibody; LVEF left ventriculr ejection frction; Neg negtive; NYHA clssifiction New York Hert Assocition functionl cpcity clssifiction for ptients with hert disese; Pos positive; PVD peripherl vsculr disese; SD stndrd devition; VT ventriculr tchycrdi. ggregtion ws between 26% nd 50%, nd negtive if pltelet ggregtion ws less thn 26%. Pltelet counts were ssessed preopertively t bseline nd postopertively. Bseline pltelet count ws determined up to 7 dys before surgery. Postopertive thrombocytopeni ws defined s 50% drop in pltelet count from bseline, or n bsolute pltelet count of less thn 100,000 10 9 /L from postopertive dy 4 to dy 8 or dischrge, whichever cme first. Clinicl Dignostic Evlution Ptient demogrphics, prior medicl history, preopertive medicl sttus, postopertive outcomes through hospitl dischrge, nd dischrge sttus were determined by ptient history, medicl exmintion, nd lbortory evlution. Results were recorded in the dtbse mintined by St. Luke s Medicl Center on n ongoing bsis for contribution to the ntionl STS dtbse. For the purposes of this study, dt from this ptient series were retrieved from this locl dtbse nd nlyzed. Ptient vribles vilble for nlysis included ll dt fields defined nd specified by STS [20]. Exmples of definitions re in Tble 1. Sttisticl Anlysis Demogrphics, ptient chrcteristics, nd postopertive outcomes were compred between ptients testing positive or negtive for HPF4 ntibodies using the Student t test or Wilcoxon rnk sum for continuous vribles nd the 2 test or Fischer exct test for ctegoric vribles. For these tests, two-tiled p 0.05 ws considered sttisticlly significnt. For stepwise logistic regression nlysis, vribles found to meet p 0.10 by univrite nlysis were entered into the logistic regression model nd p 0.08 ws used s sty criterion. This model ws used to determine whether positive preopertive HPF4 ntibody sttus ws independently ssocited with specific dverse outcome. All other preopertive comorbidities were included in the model. Adjusted odds rtios (OR) nd 95% confidence intervls (CI) were derived from the finl logistic model. Ptients with positive ELISA HPF4 ntibody test results were evluted for the presence of thrombocytopeni when possible. Ptients with positive preopertive HPF4 ntibodies nd thrombocytopeni were compred with ptients with positive preopertive HPF4 ntibodies without thrombocytopeni for dverse outcomes. Anlyses were con- Tble 3. All Postopertive Outcomes by Preopertive Heprin-Pltelet Fctor 4 Antibody Sttus Outcome HPF4 Ab Neg n 1054 (%) All Surgery HPF4 Ab Pos n 59 (%) p Vlue Mortlity to hospitl 42 (4.0) 3 (5.1) 0.2 dischrge Reopertion for bleeding 54 (5.1) 6 (10.2) 0.15 Reopertion for other 65 (6.2) 8 (13.6) 0.05 (noncrdic) resons Periopertive myocrdil 1 (0.09) 0 (0) 0.2 infrction Ventiltion 96 hours 97 (9.2) 12 (20.3) 0.02 Deep sternl wound 13 (1.2) 2 (3.4) 0.20 infection Septicemi 21 (2.0) 3 (5.1) 0.15 Cerebrovsculr ccident 37 (3.5) 4 (6.8) 0.2 Pulmonry insufficiency/ 192 (18.2) 16 (27.1) 0.12 prolonged ventiltion Acute limb ischemi 10 (0.9) 3 (5.1) 0.03 Renl complictions 111 (10.5) 12 (20.3) 0.03 including dilysis Gstrointestinl complictions 62 (5.9) 9 (15.3) 0.01 Fischer exct test for ctegoric dt. HPF4 Ab heprin-pltelet fctor 4 ntibody; Pos positive. 1739 Neg negtive;
1740 KRESS ET AL Ann Thorc Surg HEPARIN ANTIBODIES INCREASE SURGICAL RISK 2007;83:1737 43 Tble 4. Length of Hospitl Sty nd Ventiltion Time by Preopertive Heprin-Pltelet Fctor 4 Antibody Sttus (All Surgery Combined) HPF4 Ab Negtive n 1054 HPF4 Ab Positive n 59 p Vlue Preopertive LOS (dys) Men 2.2 2.5 0.2 Medin (rnge) 1.0 (0 26) 2.0 (0 10) 0.15 Postopertive LOS (dys) Men 9.8 14.0 0.05 Medin (rnge) 7.0 (0 180) 9.0 (3 97) 0.01 ICU LOS (hours) Men 101.2 188.8 0.08 Medin (rnge) 42.0 (0 2040) 48.0 (15 1797) 0.07 Ventiltion time (hours) Men 42.3 112.5 0.08 Medin (rnge) 7.0 (0 2007) 8.0 (2 1714) 0.07 Student t test for mens; Wilcoxon rnk sum for medins. HPF4 Ab heprin-pltelet fctor 4 ntibody; unit; LOS length of sty. ICU intensive cre ducted for ll ptients undergoing crdic surgery, which included CABG only (76%) or vlve surgery with or without CABG (24%). The dt were nlyzed using the SAS sttisticl softwre (SAS Institute Inc, Cry, NC). Results Heprin-Pltelet Fctor 4 Antibody Sttus Between Mrch 2002 nd December 2004, 1114 (92%) of 1209 consecutive ptients scheduled to undergo either CABG with CPB or crdic vlve opertions, with or without CABG with CPB, were tested in n unselected mnner for HPF4 ntibodies. Specificlly, 851 (91%) of 933 ptients scheduled for CABG-only procedures nd 263 (95%) of 276 ptients scheduled for vlve opertions with or without CABG were tested. Ptients not tested for HPF4 ntibodies were not included in this study. None of the ptients studied hd preopertive evidence of clinicl HIT. The first blood smple for evlution of HPF4 ntibodies ws obtined before or including the dy of surgery in 1098 (98.6%) of 1114 of the ptients. In 99.5% of ptients, the first blood smple ws obtined before nd including the dy of surgery or within the first 4 dys fter surgery. The first blood smples were obtined in some ptients within the first 4 dys fter the procedure rther thn before the procedure primrily becuse of urgent scheduling needs nd other time-limiting fctors unrelted to routine elective mngement. These results were considered to represent ntibody sttus before the procedure becuse HPF4 ntibody formtion fter crdic surgicl heprin exposure typiclly requires 4 dys [18]. One blood smple ws drwn for HPF4 ntibody testing in 933 ptients, nd two or more blood smples were drwn for 181 ptients. Sixty (5.4%) of 1114 ptients tested positive for HPF4 ntibodies preopertively, with 51 (85%) of 60 identified before nd including the dy of the opertion nd 9 identified within the first 4 dys postopertively. All 60 of these ptients who were identified s hving positive preopertive ntibody sttus hd negtive HAAG ssys. Bsed on the negtive HAAG results, nticogultion protocols, postopertive monitoring, nd mngement Tble 5. Postopertive Outcomes Adjusted Odds Rtios Comorbidity (Adjustment Vrible) Compliction Renl/Dilysis Ventiltor 96 h GI Acute Limb Ischemi HPF4 Ab Positive 2.2 (1.1 4.3) 1.9 (0.92 4.1) 2.9 (1.3 6.6) 4.9 (1.2 20.2) EF 0.35 2.1 (1.3 3.3) 1.7 (1.1 2.8) 2.0 (1.2 3.5) Age 80 yers 2.4 (1.5 4.2) 2.6 (1.4 4.7) 5.7 (1.5 21.4) Age 70 79 yers 1.6 (0.98 2.7) BMI 20 kg/m 2 2.9 (1.0 8.6) PVD 1.8 (1.0 3.3) 2.4 (1.3 4.4) 3.0 (1.5 6.0) 6.9 (1.5 31.4) Lst cretinine 2.0 2.4 (1.3 4.6) 3.4 (1.8 6.4) 8.9 (2.5 32.4) Urgent/slvge surgery 2.3 (0.91 5.9) 6.3 (2.7 14.9) 3.6 (1.3 10.2) 10.5 (1.9 56.9) Arrhythmi 2.0 (1.3 3.3) CVA 2.6 (1.5 4.7) 5.8 (1.5 22.4) CHF 1.6 (0.94 2.5) Dibetes 1.8 (1.1 3.1) Mitrl Insufficiency 1.7 (0.96 3.2) Residul 2 p vlue 0.50 0.45 0.50 0.45 Vrible did not meet p 0.08 for sty criterion; p 0.10 used for entry criterion. All vlues shown s odds rtios (95% confidence intervls). Stepwise logistic regression nlysis; djustment vribles re the comorbidities shown. BMI body mss index; CHF congestive hert filure; CVA cerebrovsculr ccident; EF ejection frction; GI gstrointestinl; HPF4 Ab heprin-pltelet fctor 4 ntibody; PVD peripherl vsculr disese.
Ann Thorc Surg KRESS ET AL 2007;83:1737 43 HEPARIN ANTIBODIES INCREASE SURGICAL RISK were not modified for these ptients. One of the 60 ptients hd strongly positive preopertive HPF4 ntibody ssy nd ws treted with lepirudin for surgicl nticogultion. This ptient ws excluded from the outcomes nlysis. An dditionl 13 ptients tested positive for HPF4 ntibodies fter the defined preopertive time period nd were chrcterized s postopertive seroconverters. Ptients who received HPF4 ntibody testing fter the first 4 dys postsurgery were universlly evluted becuse of suspicion of clinicl HIT. All postopertive seroconverters were found to hve postopertive thrombocytopeni, nd five were identified s hving positive HAAG nlysis. Ptient Chrcteristics Preopertive demogrphic dt nd medicl risk fctors for ptients undergoing ll subtypes of procedures combined re listed in Tble 2. Profiles were similr in ptients testing positive or negtive for preopertive HPF4 ntibodies, except for higher incidence of rrhythmi, mitrl insufficiency, congestive hert filure, nd prior cerebrovsculr ccident in the HPF4 ntibodypositive ptient group. No ptients who tested positive for HPF4 ntibodies hd preopertive thrombocytopeni. Among ll ptients evluted in this study, only 15 hd preopertive pltelet counts of less thn 100,000 10 9 /L, ll of whom tested negtive for HPF4 ntibodies. Postopertive Outcomes Postopertive outcomes were significntly different between ptients who tested HPF4 ntibody-positive preopertively versus those who tested ntibody-negtive (Tbles 3 nd 4). Men postopertive length of sty ws 4.2 dys longer (14.0 dys versus 9.8 dys, p 0.05) for ptients testing HPF4 ntibody-positive preopertively compred with ptients who were HPF4 ntibody-negtive. The incidence of prolonged ventiltion of 96 hours or more ws significntly greter for HPF4 ntibodypositive ptients (20.3% versus 9.2%, p 0.02) compred with HPF4 ntibody-negtive ptients. HPF4 ntibodypositive ptients were lso more likely to experience cute limb ischemi (5.1% versus 0.9%, p 0.03), postopertive renl filure including dilysis (20.3% versus 10.5%, p 0.03), nd gstrointestinl complictions (15.3% versus 5.9%, p 0.01) thn ntibody-negtive ptients. In the HPF4 ntibody-positive cohort with cute limb ischemi, no ptients hd n intrortic blloon pump nd none hd postopertive pressors for longer thn 24 hours, wheres in the HPF4 ntibody-negtive cohort with cute limb ischemi, 4 ptients hd n intrortic blloon pump postopertively, nd 2 were lso mintined on postopertive pressors for longer thn 24 hours. Ptient risk for dverse postopertive outcomes ws correlted with preopertive HPF4 ntibody sttus (Tble 5). Adjusted odds rtios obtined by stepwise logistic regression nlysis showed tht preopertive HPF4 ntibody-positive sttus ws ssocited with significnt risk for cute limb ischemi (OR, 4.9; 95% CI, 1.2 to 20.2), renl complictions including dilysis (OR, 2.2; 95% CI, 1.1 to 4.3) nd gstrointestinl complictions (OR, 2.9; 95% CI, 1.3 to 6.6). As predictor of risk, HPF4 ntibody sttus ws found to hve greter ssocition thn dibetes with renl dilysis. HPF4 ntibodies nd thrombocytopeni developed postopertively in subset of 13 ptients who hd higher rte of prolonged ventiltion (61.5% versus 28.3%) compred with the 59 ptients with preopertive HPF4 ntibodies. No difference ws noted in ny other postopertive outcome when the 13 ptients with postopertive onset of HIT were compred with the ptients who were HPF4 ntibody-positive preopertively. Heprin ws dministered intropertively to 725 ptients whose pltelet counts were determined t bseline nd t postopertive intervl between dys 4 nd 8. Thrombocytopeni within the first 4 dys fter surgery ws considered reflective of other cuses common to crdic opertions, but not relted to heprin dministrtion, becuse the development of thrombocytopeni fter crdic opertions resulting from heprin exposure typiclly requires 4 dys [18]. Among these 725 ptients, 52 hd positive preopertive HPF4 ntibodies, with postopertive thrombocytopeni developing in 23. No difference ws found in the incidence of ny dverse postopertive outcome for the 23 preopertive HPF4 ntibody-positive ptients with postopertive thrombocytopeni compred with the 29 preopertive HPF4 ntibody-positive ptients without postopertive thrombocytopeni. Overll, HIT developed in 36 ptients, s evidenced by preopertive HPF4 ntibodies nd postopertive thrombocytopeni in 23 or postopertive seroconversion nd thrombocytopeni in 13. In our series, postopertive HIT Tble 6. Summry of Preopertive nd Postopertive Serology nd Clinicl Sttus Preopertive n/n (%) Postopertive n/n (%) HPF4 Ab 60/1114 (5.4) b 13/164 (7.9) c HAAG 0/60 (0.0) 5/13 (38.5) d HIT 0/1114 (0.0) 36/725 (5.0) e HITT 0/1114 (0.0) 9/1114 (0.8) 1741 Postopertive dy 4 7. Postopertive informtion regrding seroconversion ws only obtined fter there ws clinicl suspicion of HIT. b Among the 60 ptients identified s hving positive preopertive ntibody sttus, one ptient hd strongly positive preopertive HPF4 ntibody ssy nd ws treted with lterntive nticogultion nd excluded from outcomes nlysis. c A totl of 164 ptients with thrombocytopeni nd negtive preopertive HPF4 were tested postopertively for HPF4 ntibodies; 13 were positive. d All 13 ptients who tested positively for postopertive HPF4 ntibodies were tested with HAAG functionl ssy, nd 5 were positive. e Postopertive pltelet count only obtined in 725 ptients. Numertor represents 23 ptients with preopertive seroconversion nd postopertive thrombocytopeni plus 13 ptients with postopertive seroconversion nd postopertive thrombocytopeni. Note: Selection bis influenced the probbility of positive result when ptients were tested postopertively for HPF4 ntibodies but the totl number of positive postopertive seroconverters is underrepresented by the totl number of ptients who were tested in the postopertive setting. HITT heprin-induced thrombocytopeni nd thrombosis; HPF4 Ab heprin-pltelet fctor 4 ntibody.
1742 KRESS ET AL Ann Thorc Surg HEPARIN ANTIBODIES INCREASE SURGICAL RISK 2007;83:1737 43 nd HITT developed in 9 ptients, s evidenced by exposure to heprin, thrombocytopeni, nd overt thrombosis (Tble 6). Comment A few reports hve been published on the incidence of ptients presenting with positive HPF4 ntibody sttus before surgicl procedures with follow-up outcomes nlysis. In 2005, Bennett-Guerrero nd collegues [9] reported tht 13% of 466 ptients presented for crdic opertions with positive HPF4 ntibody sttus, nd these nonconsecutive ptients hd incresed mortlity nd prolonged length of sty compred with HPF4 ntibody-negtive ptients. Buer nd collegues [13] reported the prevlence of preopertive HPF4 ntibodies ws 19% in 111 ptients presenting for crdic opertions, but they did not describe n ssocition with outcomes. We report outcomes for consecutive, unselected ptients fter crdic opertions (76% CABG only, 24% vlve procedures with or without CABG) from lrge single center using routine experience screening for HPF4 ntibodies. Our dt re consistent with the observtions mde by Bennett-Guerrero nd collegues [9], nd indicte tht morbidity is significntly ssocited with the presence of preopertive HPF4 ntibodies defined by commonly used clinicl screening criteri. This previously unrecognized reltionship between heprin ntibody formtion nd surgicl outcome clerly hs significnt impct on risk profiling. This observtion, now recognized in crdic surgicl popultion, my not be surprising. Evidence of the vlidity of our study cohort is derived from the observtion tht the incidence of HIT nd HITT is consistent with previously published reports of crdic surgicl ptients exposed to heprin intropertively [4]. In this study the respective incidence of HIT nd HITT ws 3.2% nd 0.8%. The first indiction tht HPF4 ntibodies independently ffect outcome beyond the risk for HIT ws reported by Mttioli nd collegues [7] in ptients with unstble ngin treted with unfrctionted heprin. The incidences of mjor dverse ischemic outcomes (MI, stroke, deth) in these ptients were lmost 50% greter in the group with HPF4 ntibodies compred with the group without HPF4 ntibodies. None of the ptients studied hd clinicl HIT. Their study differed from ours with respect to ptient popultion nd timing for HPF ntibody testing reltive to heprin exposure (ie, on dys 1 nd 40 fter the beginning of heprin therpy). Willims nd collegues [16] found n ssocition between HPF4 ntibody positivity nd 30-dy deth or MI (30% versus 11%) in smll subset of 218 ptients without thrombocytopeni nd treted with unfrctionted heprin. Positive HPF4 ntibody sttus ws strong independent predictor for 30-dy MI (22% versus 6%). Clitges nd collegues [21] reported tht 7% of 106 ptients scheduled to hve peripherl rteril reconstruction surgery hd preopertive HPF4 ntibodies, nd 21% hd positive ntibody ssy during their index hospitliztion. Ptients with positive HPF4 ntibodies were 2.6 times more likely to hve thrombotic event during their index hospitliztion compred with HPF4 ntibody-negtive ptients. No ptient with the ntibody nd thrombotic event hd clinicl HIT. Antibody conversion is not lwys ssocited with clinicl evidence of heprin-dependent pltelet ctivtion or thrombocytopeni. In our study, none of the ptients with preopertive HPF4 ntibodies hd positive HAAG ssy or preopertive thrombocytopeni. No difference in outcome ws found between those preopertive HPF4 ntibody-positive ptients who developed postopertive thrombocytopeni nd those who did not. The presence of positive preopertive HPF4 ntibody independently identified ptients t incresed risk for dverse renl, gstrointestinl, respirtory, nd ischemic limb outcomes. It is uncler whether the HPF4 ntibodies re custive or correltive for dverse outcomes, nd these reltionships wrrnt further mechnistic study. In ddition, positive preopertive HPF4 ntibody identified ptients who my develop HIT postopertively. In this series, HIT developed postopertively in 44% of ptients (23/52) who tested positive preopertively for HPF4 ntibodies in the bsence of preopertive thrombocytopeni. These dt provide evidence tht HPF4 ntibody sttus should be considered for optiml risk ssessment, prticulrly in tody s clinicl setting, becuse it is unusul for crdic surgicl ptients not to hve experienced one or more heprin exposures from prior crdic ctheteriztions. Our findings showed tht HPF4 ntibody sttus is s importnt or in some instnces more relevnt thn ge, left ventriculr ejection frction, dibetes, hypertension, or other commonly recognized preopertive predictors of postopertive outcomes. In ddition, positive preopertive HPF4 ntibody sttus is n independent predictor of ptients who will require dditionl hospitl nd intensive cre resources. This study hs severl limittions. It ws performed by retrospective nlysis, but the dt were collected prospectively in stndrdized nd comprehensive dtbse. Although this represents lrge reported series for preopertive HPF4 ntibody testing in n unselected surgicl popultion, our smple size ws underpowered for extensive subgroup nlyses such s re performed in lrger confirmtory trils. Not ll ptients hd lbortory evlution for HPF4 ntibodies or pltelets t the exct sme intervl during index hospitliztion, nd some HPF4 ntibody-positive test results were identified fter the dy of the procedure. We used cutoff of 4 dys fter the opertion to define preopertive positive ntibody sttus on the ssumption tht HPF4 ntibody formtion fter intropertive heprin exposure would tke longer thn 4 dys [18]. In these ptients, it ws not possible to precisely determine the dy of seroconversion. A binomil metric ws used to define positive versus negtive HPF4 ntibody sttus. The vlues used to define significnt OD with the ELISA method (GTI or Dig-
Ann Thorc Surg KRESS ET AL 2007;83:1737 43 HEPARIN ANTIBODIES INCREASE SURGICAL RISK nostic Stgo, Inc, Prsippny, NJ) re vrible, rnging between 0.4 nd 1.0, nd re typiclly bsed on studies of ptients with clinicl HIT [10, 14, 15, 22]. It is possible tht subthreshold vlues of ntibody titers could hve physiologic effects other thn overt HIT. We used vlue exceeding 0.4 OD with the GTI- ELISA, which is within commonly ccepted clinicl stndrds. Our results show reltionship between HPF4 ntibody positivity before crdic opertions nd certin dverse outcomes. This finding demonstrtes the significnce of preopertive HPF4 ntibodies on clinicl spectrum tht is seprte from their bility to precipitte HIT nd thrombosis. The presence of preopertive HPF4 ntibodies not ssocited with thrombocytopeni is n importnt, independent, nd predictive risk fctor for postopertive dverse outcome fter crdic opertion. Further study is needed to define the best wys to tret (eg, nticogulnt protocols, postopertive monitoring nd mngement) nd minimize risk for HPF4 ntibodypositive ptients undergoing crdic opertions. An optiml crdic surgicl risk index profile should consider HPF4 ntibody sttus. Ptients with positive HPF4 ntibody sttus should be closely monitored postopertively becuse their risk for dverse outcomes nd incresed resource utiliztion is high. Dignostic nd therpeutic methods to identify nd minimize the impct of HPF4 ntibodies during crdic opertions my be importnt for reducing risk in the overll crdic surgicl ptient popultion. We thnk Lnce Bldo, MD, Director of Medicl Affirs t The Medicines Compny, for his support in proofreding nd reviewing the drft mnuscript. Auror St. Luke s Medicl Center received funding support from The Medicines Compny. The Medicines Compny provided drft mnuscript review secondry to uthor pprovl. References 1. Wrkentin TE, Levine MN, Hirsh J, et l. 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