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Ann Thorac Surg 2003;75:17-22
© 2003 The Society of Thoracic Surgeons
a Center for Hemostasis and Thrombosis, Orlando, Florida, USA
b Department of Thoracic Cardiovascular Surgery, Florida Hospital, Orlando, Florida, USA
* Address reprint requests to Dr Francis, Florida Hospital, Center For Hemostasis and Thrombosis, Florida Hospital Cancer Institute, 2501 N. Orange Ave, Suite 786, Orlando, FL 32804, USA
e-mail: john.francis{at}flhosp.org
Presented at the Poster Session of the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2002.
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Abstract |
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 Top Abstract IntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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METHODS: Two hundred seven patients (108 porcine, 99 bovine) completed the study. Heparin given pre- or postoperatively was always porcine. Platelet counts and heparin-PF4 antibody tests (enzyme-linked immunosorbent assays) were performed preoperatively and daily until postoperative day 7 or discharge if earlier.
RESULTS: The overall incidence of heparin-PF4 antibody formation was 42%. Six patients (2.9%) were positive preoperatively, of which, 1 developed clinical HIT. When these were excluded, seroconversion rates were 44 of 99 (44.4%) and 33 of 108 (30.6%) for bovine and porcine heparin, respectively (p = 0.041). Among patients who produced antibodies, most (90% bovine, 85% porcine) seroconverted after postoperative day 2. There were no differences in postoperative platelet counts; only 1 patient developed thrombosis associated with seroconversion, but without developing thrombocytopenia. The seroconversion rates for patients having cardiopulmonary bypass or off-pump surgery were not significantly different.
CONCLUSIONS: This study confirms the high frequency of heparin-PF4 antibodies after coronary artery bypass grafting and demonstrates a significantly higher incidence after bovine heparin. However, because some patients may seroconvert after discharge, our study may underestimate the true incidence.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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A potential complication of therapy is the development of heparin-induced thrombocytopenia (HIT), which can be classified into two types [2]. Type I (nonimmune-mediated) HIT is characterized by a decrease in platelet count 1 to 3 days after heparin that normalizes spontaneously and is not associated with thrombosis. Type II (immune-mediated) HIT typically presents with thrombocytopenia 5 to 10 days after heparin exposure, although in patients with preexisting antibody, the onset may be more rapid [3]. The thrombocytopenia may paradoxically be associated with arterial or venous thrombosis, and can be severe and life threatening [4]. Treatment consists of immediate withdrawal of heparin and systemic anticoagulation with a nonheparin anticoagulant [5, 6]. On specific laboratory testing, these patients have an antibody to the complex between heparin and platelet factor 4 (PF4) [7], a protein released from platelet 
granules during platelet activation. Binding of the resultant antigen-antibody complexes to platelet membrane Fc
RII receptors induces further activation and aggregation of platelets and formation of procoagulant microparticles [8]. These events, and probably similar ones on the vascular endothelium, are thought to be responsible for the thrombotic diathesis [8].
Estimates of the frequency of HIT vary, although a significant determining factor may be the type and source of heparin. Typically, UFH is associated with a higher frequency of HIT (1% to 3%) than low-molecular weight heparin (LMWH; 0.1% to 0.5%) [9]. However, once an antibody to UFH has formed, it invariably cross-reacts with LMWH [10]. Commercial heparin is derived from either bovine lung or porcine intestinal mucosa, and HIT may be more common with the bovine product. Initial reports suggested an incidence of heparin-associated thrombocytopenia of 10% to 24% for bovine heparin, compared with 1% to 7% for porcine heparin [10–12], although not all studies agree [13]. Pooled analysis of subsequent studies suggested an incidence of 2.9% and 1.1% for bovine for porcine heparin, respectively [10, 14]. However, comparing published studies is complicated by different definitions for thrombocytopenia, laboratory tests with widely varying sensitivity for heparin-PF4 antibodies, or the lack of antibody testing.
Most published data are derived from deep vein thrombosis (DVT) treatment, and no studies have directly compared bovine and porcine heparin during cardiovascular surgery where the doses and duration of therapy are significantly different. Because bovine heparin is widely used in cardiovascular surgery, we conducted a prospective, randomized comparison of the effects of bovine and porcine heparins on heparin-PF4 antibody formation and HIT in this setting.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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Patients were randomized by the investigational pharmacist to receive either bovine or porcine heparin. Bovine heparin was a product of Upjohn (Pharmacia, Kalamazoo, MI). Porcine heparin was either from Elkins-Sinn, Inc. (Wyeth-Ayerst, St. Davids, PA) or from American Pharmaceutical Partners (Los Angeles, CA). Investigational heparin was derived from lots in use in the hospital, which were not controlled for study purposes. Surgeons, other caregivers, and laboratory staff were blinded to heparin type during surgery. All study heparin was provided by the investigational pharmacist in unmarked syringes and used exclusively for anticoagulation in the operating room. Heparin (300 U/kg) was administered before bypass, and additional heparin was given to maintain the activated clotting time above 480 seconds. Anticoagulation was reversed by protamine at the end of bypass. UFH used preoperatively (eg, in the catheterization laboratory) or postoperatively (eg, for atrial fibrillation) was always porcine.
Each patient received a heparin-coated Swan Ganz catheter and a radial artery line, which was routinely flushed with saline. Anesthesia was induced by fentanyl, midazolam, and inhalation agents as required. Standard CPB techniques were used (in the on-pump series) using COBE Duo oxygenators (Lakewood, CO) with open circuit, roller pump, and tubing packs. Moderate systemic hypothermia, hemodilution, and blood and crystalloid cardioplegia were used. No attempt was made to control for perfusion time (CPB group), or number of grafts, or single versus side clamping of the aorta (CPB and OPCAB groups), although these were noted.
Blood samples
Blood (10 mL) was collected into EDTA and 3.2% (wt/vol) trisodium citrate. Samples were collected preoperatively and on each postoperative day for 7 days or until discharge (whichever was sooner). The preoperative blood sample was drawn in the preoperative holding area shortly before the patient was transferred to the operating room.
CBC and platelet count was performed by electronic counting (Coulter MD16; Beckman-Coulter, Miami, FL). The detection of PF4-dependent HIT antibodies was determined by a commercially available enzyme-linked immunoassay (GTI-PF4 ELISA; GTI Inc., Brookfield, WI), in which a positive result was indicated by an optical density (OD) 
0.4. This assay detects antibodies to imminoglobulin (Ig)G, IgM, and IgA subclasses.
Statistical analysis
Summary statistics, 
2 analysis, and differences between groups were performed using SigmaStat (SPSS Inc., Chicago, IL). Statistical significance was assumed when p was less than 0.05.
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Results |
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Heparin-PF4 antibody formation
Overall, 87 of 207 (42.0%) patients developed heparin-PF4 antibodies. The incidence of seroconversion among patients undergoing OPCAB was 17 of 41 (41.5%), which was not significantly different from those having CPB (70/166, 42.2%; p > 0.05; Table 1). The data were therefore pooled for subsequent analysis.
The overall incidence of heparin-PF4 antibody positivity was 49 of 99 (49.5%) and 39 of 108 (36.1%) for bovine and porcine groups, respectively (p = 0.052). Six patients (4 in the bovine group and 2 given porcine heparin) tested positive preoperatively. Because these antibodies were presumably due to previous (porcine) heparin therapy, they were excluded from subsequent analysis. An additional 4 patients (1 in the bovine group, 3 in the porcine group) had developed antibodies by the second postoperative day (Fig 1). These patients were also excluded because it was questionable whether such early seroconversion could be attributed to heparin received during surgery. When these 10 individuals were excluded, 44 of 99 (44.4%) patients receiving bovine heparin were antibody positive, compared with 33 of 108 (30.6%) in the porcine group (p = 0.041).
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The mean OD in the ELISA assay for patients reported as heparin-PF4 antibody positive (OD 0.04) was not significantly different between the bovine (1.18 ± 0.74) and porcine (1.10 ± 0.81) groups. There was no significant difference between bovine and porcine heparin in the proportions of patients having strongly positive (OD > 1.0; 41% vs 37%), or borderline (OD 0.30 to 0.39; 13% vs 11%) values, respectively.
Thrombocytopenia
There was no difference in postoperative platelet counts between patients who developed a heparin-PF4 antibody and those that did not (Fig 2a),
or between those randomized to bovine or porcine heparin (Fig 2b). The postoperative day at which the platelet count nadir occurred was not significantly different for bovine- and porcine heparin-treated patients (2.4 ± 0.9 vs 2.3 ± 0.8 days, respectively). The magnitude of the platelet nadir (percent of baseline) was similar for patients receiving bovine (62.1% ± 15.9%) and porcine (61.6% ± 15.7%) heparin (p > 0.05) and for those who developed (60.9% ± 18.0%) or did not develop (62.5% ± 13.8%) an antibody (p > 0.05). However, antibody-positive patients were more likely to develop marked (> 60%) falls in platelet count (12.6 vs 3.4%; p = 0.02). The use of bovine or porcine heparin per se (without regard for antibody formation) did not affect the proportions of patients having more pronounced early postoperative falls in platelet count.
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Effect of preoperative antibody formation
As noted above, 6 patients were heparin-PF4 antibody positive before surgery. Because of the short time between drawing the preoperative sample and testing, it was not possible to use a nonheparin alternative for CABG. These individuals were followed closely during the postoperative period, and steps were taken to ensure that no additional heparin was used. Four of these patients had completely uneventful postoperative courses.
One patient, with a recent history of cardiac catheterization, developed early postoperative generalized ST changes in a 12-lead electrocardiogram (ECG), suggesting early graft closure. However, trans-esophageal echocardiogram suggested that all grafts were patent. Nevertheless, the patient was anticoagulated with danaparoid for 5 days starting on postoperative day 2. Her platelet count fell to 48% of baseline on day 3, but otherwise, she did well and was discharged 9 days after surgery.
The final patient, a 73-year-old female with a recent history of cardiac catheterization and percutaneous transluminal coronary angioplasty, was transferred to our hospital on a heparin drip before repeat cardiac catheterization. Before undergoing a two-vessel bypass, she suffered acute anaphylactic shock that was considered secondary to preoperative antibiotic therapy. She was emergently placed on full CPB, and the anaphylactic syndrome was reversed before this completion. On the third postoperative day, perfusion lung scan revealed a moderate-sized perfusion abnormality and possible pulmonary embolus. Her platelet count was 72 x 103/µL and continued to fall to a nadir of 52 x 103/µL on day 4, when the diagnosis of HIT was made. She was started on Argatroban with prompt recovery of the platelet count and discharged 9 days after surgery.
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Comment |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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It is a potential weakness of our study that a significant number (19%) of patients received additional heparin in the postoperative period. This was always of the porcine type. As previously reported, however, this did not significantly increase the frequency of antibody formation [16], at least within the period of the present study.
The incidence of antibody formation in patients having OPCAB was indistinguishable from those having CPB. Although OPCAB patients generally received less heparin, this suggests that platelet activation, which is presumably greater during CPB, is not a factor in seroconversion. However, the postoperative fall in platelet counts in the OPCAB group was greater than expected [18]. This suggests that significant platelet activation still occurred in these individuals, which may account for their high seroconversion rate. Nevertheless, none of the OPCAB patients required any intraor postoperative platelet transfusions, compared with 14% of the CABG group.
Our data indicate that seroconversion was more frequent among patients randomized to bovine heparin. Several subjects developed an antibody early (1 to 2 days) after surgery, and 6 were positive preoperatively. Most had received heparin preoperatively, and it was not possible to control for preoperative heparin use, which in any case, was always of the porcine type. Because we could not exclude the possibility that early antibody formation was due to preoperative heparin exposure, we analyzed only those patients who seroconverted after the second postoperative day. Thus, the incidence of antibody formation was significantly higher in the bovine group (44% vs 31%; p = 0.041), which conflicts with a report published while our study was underway [19]. These investigators conducted a prospective, randomized trial of bovine and porcine heparins in 98 patients undergoing CPB and, using an immunoassay for heparin-PF4 antibodies, found no significant difference in the incidence of antibody formation (35% and 29%, respectively). This discrepancy is probably due mainly to the difference in sample size, with the present study having more than twice as many patients. In addition, Konkle and associates tested their patients at only one postoperative time point (5 days) [19]. This would have underestimated the seroconversion rate, because we noted a significant number of patients developing antibodies on the sixth and seventh postoperative day. Indeed, we found that the difference between antibody formation to bovine and porcine heparin was particularly evident at day 6. Finally, their study was not designed to detect patients who seroconverted early, probably due to preoperative heparin, and they, therefore, did not exclude these, or patients who were preoperatively positive, from their analysis.
The finding that a significant number of patients have a heparin-PF4 antibody even before they undergo cardiovascular surgery and heparin exposure is worrying, but not entirely surprising. In fact, our figure of 2.9% is much lower than the 19% reported by others [20]. This difference may be due partly to patient selection, as we used only first-time CABG patients, as well as differences in assay sensitivity. A more recent study, using another commercially available immunoassay, found preoperative antibodies in 4.1% of patients [19], a figure closer to ours, considering that this study was not limited to first-time CABG.
In the present study, 4 of the 6 patients who were antibody positive preoperatively suffered no apparent ill effects from repeat exposure to heparin. One (randomized to bovine heparin) exhibited early postoperative ECG changes that were consistent with occluded grafts, although trans-esophageal echocardiogram suggested that all grafts were patent and there was no evidence of thrombosis. The final patient (bovine heparin group) had a secondary fall in platelet count, together with a DVT and possible pulmonary embolus, symptoms compatible with clinical HIT. She was treated with a thrombin inhibitor with prompt resolution of thrombocytopenia. This suggests that patients with preexisting heparin-PF4 antibodies may be at increased risk of developing clinical HIT, and raises the question of whether patients undergoing cardiovascular surgery should undergo preoperative antibody screening. Extrapolating our findings to the number of open-heart surgery cases performed annually at our institution (2,500) suggests that doing so would detect about 70 antibody-positive cases, and if heparin was subsequently avoided, would prevent approximately 12 cases of clinical HIT. Two issues currently preclude implementation of this strategy. First, although there is some experience with nonheparin anticoagulants in CPB [21], they have not been widely utilized. Such agents are in clinical trials for OPCAB and appear promising, particularly for the antibody-positive patient requiring urgent CABG [22]. Otherwise, few operative alternatives are available, although increasing use of nonheparin anticoagulants in the catheterization laboratory may reduce the scale of the problem [23]. Second, until the laboratory tests for heparin-PF4 antibodies are more widely available and are better able to predict the development of clinical HIT, it is difficult to advocate wholesale preoperative antibody screening before cardiovascular intervention.
Our study utilized a commercially available immunoassay with an OD endpoint. Results greater than 0.4 are considered positive, whereas higher values presumably reflect increasing antibody titer. Although virtually all antibody-positive patients remained asymptomatic, the apparent antibody titer (assessed by the OD) was indistinguishable from hospital patients diagnosed with clinical HIT (data not shown). Furthermore, despite the increased frequency of seroconversion among patients treated with bovine heparin, the antibody titers and the proportion of patients having high-titer antibodies in the two groups were comparable.
As previously observed [20], the presence or absence of a heparin-PF4 antibody did not influence the magnitude of the typical post-CABG platelet nadir. The incidence of thrombocytopenia was the same for both heparin groups, which conflicts with reports that this is more common with the bovine form [11–14]. Overall, however, significantly more of the antibody-positive patients suffered a marked (> 60%) fall in platelet count (12.6%) compared with those who did not seroconvert (3.4%).
Only 2 patients in our study developed possible HIT associated with thrombosis. One had a positive antibody test preoperatively. The other had a larger than typical early postoperative fall in platelet count and developed a DVT. It should be noted, however, that we performed antibody tests daily, and when positive, made every effort to prevent further heparin exposure. This high level of surveillance likely prevented several patients from receiving additional heparin postoperatively, and may have contributed to a relative paucity of clinical HIT despite frequent seroconversion.
In summary, we have confirmed the high frequency of heparin-PF4 antibody formation in patients undergoing open-heart surgery. Our data suggest that this may be a function of the relatively high heparin doses and the type of surgery rather than the use of CPB. Bovine heparin was associated with a higher rate of heparin-PF4 antibody formation, suggesting that this might be associated with a higher risk of HIT than porcine heparin. However, the relatively low risk for developing HIT in cardiac surgery patients, despite seroconversion, means that a much larger study would be required to test this hypothesis. The presence of a preexisting antibody, however, may be a risk factor for the development of postoperative HIT, and this issue deserves further study. Furthermore, because of the high incidence of antibody formation and the potential for late-onset HIT [24, 25], we recommend that patients readmitted after CABG with symptoms of thrombosis receive an alternative (nonheparin) anticoagulant before the results of antibody testing becoming available.
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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