Immune Response Following Exposures to Topical Bovine Thrombin Does Not Impair Hemostasis

Topical bovine thrombin has been used for over 30 years as an adjunct to accelerate intraoperative hemostasis for minor oozing or bleeding. Antibody-mediated hemostatic abnormalities suggested in case reports and small uncontrolled case series have raised safety concerns about topical bovine thrombin preparations. However, in 2 randomized controlled trials (RCTs) comparing the only currently available topical bovine thrombin (Thrombin-JMI^®) with topical recombinant (Chapman WC et al, J Am Coll Surg 2007;205:256-265) or plasma-derived (Doria C et al, CMRO 2008;24:785-794) human thrombins, similar efficacy and safety profiles were established for all 3 preparations.

To characterize the primary and secondary immune responses following intraoperative exposure and potential re-exposure to topical bovine thrombin and explore any potential relationship to hemostatic abnormalities.

This prospective, observational cohort study enrolled 554 patients from 50 US sites who were scheduled to undergo surgery and had a previous surgical procedure ≤4 years earlier with probable intraoperative exposure to topical bovine thrombin. Cohorts were defined prospectively but assigned at the conclusion of the study period, based on the presence or absence of human anti-bovine thrombin antibodies (aBT) in preoperative (baseline) plasma samples and intraoperative exposure or non-exposure to THROMBIN-JMI^®. The primary study cohort included patients with aBT pre-surgery who received THROMBIN-JMI^® during the study surgery, whereas the primary reference cohort was comprised of patients with no aBT pre-surgery who did not receive THROMBIN-JMI^® during study surgery. The primary end point was the mean change from baseline in aPTT at 48 h post-surgery. Secondary analyses included explorations of the relationships between changes in aBT, human anti-bovine factor V/Va antibodies (aBV/Va), human anti-human thrombin antibodies (aHT), human anti-human factor V/Va antibodies (aHV/Va) and coagulation parameters at 48 h and 4 and 8 weeks after surgery as well as incidences of treatment emergent adverse events (TEAEs).

The adjusted mean change in aPTT values at 48 h post-surgery for the primary study cohort exceeded that for the primary reference cohort by 2.03 sec (1-sided 97.5% upper confidence bound [UCB] of 4.67 sec). The UCB exceeded the prespecified 4.5 sec non-inferiority margin (chosen as 15% of expected mean baseline aPTT of 30 sec). Hence, non-inferiority was not met. Of note, the observed baseline aPTT in this study population was higher than expected (32.38 sec) and non-inferiority would have been met had the non-inferiority margin been a relative margin a priori set at 15% of baseline aPTT. There were no significant differences in the mean aPTT change observed in all other cohort comparisons at 48 h post-surgery. Similarly, there was no significant prolongation of the aPTT at 4 and 8 weeks post-surgery in any of the cohort comparisons. Moreover, exposure to THROMBIN-JMI^® did not lead to any change in immunologic (aHT, aBT, aHV/Va, or aBV/Va) markers at 48 h post-surgery. Immunologic markers evident at 4 or 8 weeks post-surgery demonstrated no relationship to any changes in coagulation measures. There was no evidence of any effect of prior exposure to thrombin, current THROMBIN-JMI^® treatment, or presence of pre-surgery aBT on the incidence of TEAEs. Overall, these data indicate that in patients treated with THROMBIN-JMI^® the presence of pre-surgery aBT or aBV/Va does not lead to impaired hemostasis.

Primary or secondary immune responses to perioperative exposure/re-exposure to THROMBIN-JMI^® do not adversely affect hemostasis after surgery. These results confirm earlier conclusions from 2 RCTs comparing topical bovine thrombin and recombinant and plasma-derived human thrombins.

Paterson:King Pharmaceuticals, Inc.: Employment. Pixton:King Pharmaceuticals, Inc.: Employment. Proskin:King Pharmaceuticals, Inc.: Consultancy. Massaro:King Pharmaceuticals, Inc.: Consultancy. Morasch: W. L. Gore & Associates, Inc.: Honoraria, Research Funding; King Pharmaceuticals, Inc.: Consultancy. Fareed:King Pharmaceuticals, Inc.: Consultancy, Research Funding; Sanofi-Aventis: Consultancy; Polymedix: Consultancy; Mitsubishi Pharma: Research Funding. Ofosu:King Pharmaceuticals, Inc.: Consultancy. Cronstein:King Pharmaceuticals, Inc.: Consultancy, Research Funding; Cephalon: Consultancy; Cypress Bioscience, Inc: Consultancy; CanFite Biopharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Cellzome: Consultancy; Takeda Pharmaceuticals: Consultancy; Prometheus Laboratories: Consultancy; Regeneron (Westat, DSMB): Consultancy; Sepracor: Consultancy; Amgen: Consultancy; Endocyte: Consultancy; Protalex: Consultancy; Allos, Inc.: Consultancy; Combinatorx: Consultancy; Kyowa Hakka: Consultancy; Hoffman-LaRoche: Consultancy; Savient: Consultancy; Avidimer Therapeutics: Consultancy; NIH: Research Funding; Vilcek Foundation: Research Funding; OSI Pharmaceuticals: Research Funding; Vilcek Foundation: Membership on an entity's Board of Directors or advisory committees; Bagels, ice cream, snacks, etc: Membership on an entity's Board of Directors or advisory committees; Eli Lilly & Co.: Membership on an entity's Board of Directors or advisory committees; UCB: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; adenosine A2A receptor agonists to promote wound healing and use of A2A receptor antagonists to inhibit fibrosis.: Patents & Royalties; adenosine A1 receptor antagonists to treat osteoporosis and other diseases of bone.: Patents & Royalties; adenosine A1 and A2B Receptor antagonists to treat fatty liver: Patents & Royalties; adenosine A2A receptor agonists to prevent prosthesis loosening: Patents & Royalties; CanFite Biopharmaceuticals received for membership in Scientific Advisory Board.: Equity Ownership, Speakers Bureau.