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Ann Thorac Surg 2003;75:15-16
© 2003 The Society of Thoracic Surgeons
a Departments of Pathology and Molecular Medicine, and Medicine, McMaster University, Hamilton, Ontario, Canada
b Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada
* Address reprint requests to Dr Warkentin, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, General Site, 237 Barton St E, Hamilton, Ontario L8L 2X2, Canada.
Unfractionated heparin is usually obtained from one of two sources: porcine gut or bovine lung. Comparative studies performed in the 1970s of medical patients receiving pork or beef heparin found a much higher frequency of thrombocytopenia in patients who received the beef heparin preparation [1, 2]. However, these studies included all episodes of thrombocytopenia and did not focus on the important patient subgroup with late thrombocytopenia, beginning on or after day 5 of heparin, caused by heparin-dependent, platelet-activating antibodies. Indeed, this syndrome of immune heparin-induced thrombocytopenia (HIT) presents a paradox of anticoagulant-induced thrombosis, as patients with HIT are at high risk for developing venous or arterial thrombosis [3].
During the 1980s, four randomized trials [4–7] were performed that compared the frequency of immune HIT in patients receiving either pork and beef heparin for treatment of acute thrombosis. Although each study was fairly small, their combined results left little doubt that bovine lung heparin was more likely to cause immune HIT: 9 of 152 (5.9%) versus 0 of 154 (0%) patients (p = 0.0059) [8].
With time, unfractionated heparin derived from pork became preferred at many medical centers. However, some cardiac surgery units continue to use bovine lung heparin, for reasons that may include a possible lower risk of bleeding [9, 10]. But the issue of relative frequency of immune HIT between beef and pork heparin in cardiac surgical patients remained in question. The frequency of HIT after heart operation ranges from 0.75% to 3% [11, 12]. Although this variability probably reflects differences in use of postoperative heparin prophylaxis, it should be noted that even avoiding heparin completely after heart operation does not completely remove the risk of HIT: recent reports describe a syndrome of "delayed-onset HIT" characterized by onset of thrombocytopenia and thrombosis beginning 5 or more days after even a brief exposure to heparin [13, 14].
The target antigen of HIT is a multimolecular complex between heparin and platelet factor 4 (PF4), a protein found within platelet granules. However, only a subset of patients who form HIT antibodies will exhibit thrombocytopenia, probably because of differences in antibody class and titer, and circulating heparin and PF4 levels, among other patient-dependent factors [15, 16]. Nevertheless, differences in frequency of HIT antibody seroconversion between different heparin preparations can provide a surrogate marker for real differences in risk for HIT [3, 15]. For example, a large study of orthopedic surgical patients that found a higher seroconversion rate with (porcine) unfractionated heparin compared with (porcine-derived) low-molecular-weight heparin (7.8% versus 2.2%; p = 0.02) also found a correspondingly higher risk for immune HIT in the patients treated with unfractionated heparin (2.7% versus 0%; p = 0.0018) [3].
Given the availability for several years of sensitive, commercial PF4-dependent immunoassays to detect HIT antibodies, it is perhaps surprising that only one previous study has compared HIT antibody seroconversion rates in cardiac surgical patients receiving either pork or beef heparin [17]. These investigators found a similar frequency of HIT antibody formation between beef and pork heparin (34% versus 28%; p = 0.74). However, this study was relatively small (98 patients) and only tested blood samples obtained up until postoperative day 5, a time too early to detect the majority of HIT antibodies [18].
In this issue, Francis and colleagues [19] report their results of a randomized trial that compared the HIT antibody seroconversion rates between pork and beef heparin used to provide anticoagulation during cardiac operation. These investigators observed a significantly higher seroconversion rate with beef heparin, compared with pork heparin: 49.5% versus 35.2%; relative risk, 1.41 (95% confidence interval, 1.02 to 1.95; p = 0.037 by 
2 test). The seroconversion rate with beef heparin remained significantly higher when the analysis was restricted to the important subgroup of patients with late seroconversion: 46.8% versus 32.0%; relative risk, 1.46 (95% confidence interval, 1.03 to 2.08; p = 0.034). The reason for excluding from analysis the patients with early seroconversion is because their HIT antibody generation most likely was related to heparin received before cardiac operation.
Three strengths of this study are noteworthy. First, the study was fairly large (207 patients). Second, testing was performed using samples obtained up to postoperative day 7 (indeed, most seroconversion events occurred on postoperative days 6 and 7). Third, daily HIT antibody testing allowed the opportunity to determine those patients with very rapid seroconversion events that likely were related to heparin used before cardiac operation. Furthermore, postoperative use of porcine heparin (given to only 19.3% of the patients) did not influence the seroconversion rate. Although none of their patients exhibited clinical HIT, this is in keeping with other studies that have found the risk of immune HIT to be relatively low despite formation of HIT antibodies detectable by sensitive screening immunoassays [8, 15, 17].
A surprising finding was that the HIT antibody seroconversion rate was just as high in patients who underwent coronary artery bypass grafting off-pump as in patients who underwent cardiopulmonary bypass (41.5% versus 42.2%, respectively). This is disappointing, as it calls into question the theoretical, but unproven, benefit that avoiding intense platelet activation during cardiopulmonary bypass might reduce the risk of immunization against PF4–heparin complexes.
The serologic end points of this study have important epidemiologic implications. If this difference in seroconversion rates between use of porcine and bovine heparin in cardiac surgical patients observed by Francis and colleagues [19] is confirmed, it would provide a renewed impetus to remove beef lung heparin from the operating rooms. If the approximately one-third reduction in HIT antibody formation rate observed by Francis and coworkers [19] corresponds to a similar reduction in immune HIT after heart operation, whether that absolute risk declines from 0.75% to 0.5%, or from 3% to 2%, many hundreds of cases of immune HIT could be avoided each year.
References
This article has been cited by other articles:
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  R. Prondzinsky, A. Knupfer, H. Loppnow, F. Redling, D. W. Lehmann, I. Stabenow, R. Witthaut, S. Unverzagt, J. Radke, H.-R. Zerkowski, et al. Surgical trauma affects the proinflammatory status after cardiac surgery to a higher degree than cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., April 1, 2005; 129(4): 760 - 766. [Abstract] [Full Text] [PDF]
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