Ofosu Frederick A, Crean Sheila, Reynolds Matthew W
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Clin Ther. 2009 Apr;31(4):679-91. doi: 10.1016/j.clinthera.2009.04.021.
Topical bovine thrombin has been used to accelerate attainment of hemostasis in the surgical setting for >60 years, and its immunogenicity has been widely reported. Although the development of antibodies is inherent in the introduction of any non-self-therapeutic protein such as bovine-sourced thrombin, there are questions about the relationship between the presence of antibodies to constituents of the therapeutic protein preparation and the occurrence of clinically relevant adverse events (AEs).
This review examines the proposed mechanisms for the immunogenicity of topical bovine thrombin preparations and summarizes available evidence from randomized clinical trials, observational studies, and case reports to explore possible relationships between the reported immunogenicity of topical bovine thrombin and the occurrence of AEs.
A search of MEDLINE (1966-August 2008) for studies published in English was conducted using the Medical Subject Heading terms surgery, antibodies, and hemorrhage, as well as equivalent key words for bovine, adverse events, and thrombin. For inclusion in the review, studies had to report clinical or laboratory safety data for patients exposed to topical bovine thrombin during surgery.
The evidence suggests that patients with repeated perioperative exposure to topical bovine thrombin have a 3- to 10-fold greater risk for development of antibodies to topical bovine thrombin than do patients with no history of surgery-related exposure to this agent. Early case reports associated the development of anti-bovine protein antibodies with bleeding and/or thrombotic complications. However, in one prospective, randomized controlled trial comparing topical bovine thrombin with topical recombinant human thrombin, 99.5% of patients in each treatment arm developed postoperative AEs. In an-other, 54% and 55% of patients in the respective treatment arms developed postoperative AEs. In a prospective, randomized controlled trial that compared topical bovine thrombin and plasma-derived human thrombin, 95.5% of patients in each treatment arm developed postoperative AEs.
Repeated perioperative exposure to topical bovine thrombin may increase both the prevalence and titers of antibodies to >or=1 protein contained in nonhomogeneous topical bovine thrombin preparations. However, the evidence reviewed does not support a definitive association between preoperative or postoperative generation of anti-bovine protein antibodies and an increased risk of AEs in surgical patients treated with topical bovine thrombin.
外用牛凝血酶已用于外科手术中加速止血超过60年，其免疫原性已被广泛报道。尽管引入任何非自身治疗性蛋白质（如牛源凝血酶）时都会产生抗体，但关于治疗性蛋白质制剂成分抗体的存在与临床相关不良事件（AE）发生之间的关系仍存在疑问。
本综述探讨了外用牛凝血酶制剂免疫原性的潜在机制，并总结了随机临床试验、观察性研究和病例报告中的现有证据，以探讨外用牛凝血酶报告的免疫原性与AE发生之间的可能关系。
使用医学主题词“手术”“抗体”和“出血”，以及牛、不良事件和凝血酶的等效关键词，对MEDLINE（1966年至2008年8月）中发表的英文研究进行检索。纳入本综述的研究必须报告手术期间接触外用牛凝血酶患者的临床或实验室安全数据。
证据表明，围手术期反复接触外用牛凝血酶的患者产生外用牛凝血酶抗体的风险比无手术相关接触史的患者高3至10倍。早期病例报告将抗牛蛋白抗体的产生与出血和/或血栓形成并发症相关联。然而，在一项比较外用牛凝血酶与外用重组人凝血酶的前瞻性随机对照试验中，每个治疗组99.5%的患者出现术后AE。在另一项试验中，各自治疗组中54%和55%的患者出现术后AE。在一项比较外用牛凝血酶和血浆源性人凝血酶的前瞻性随机对照试验中，每个治疗组95.5%的患者出现术后AE。
围手术期反复接触外用牛凝血酶可能会增加非均质外用牛凝血酶制剂中≥1种蛋白质抗体的发生率和滴度。然而，所审查的证据不支持术前或术后产生抗牛蛋白抗体与外用牛凝血酶治疗的手术患者AE风险增加之间存在明确关联。
