Re: ZGEN's CP against bovine thrombin
I guess that is why they paid for this, published in Patient Safety in Surgey (whatever that is) a few months back.
http://www.pssjournal.com/content/3/1/8
"Building an immune-mediated coagulopathy consensus: early recognition and evaluation to enhance post-surgical patient safety"
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Abstract
Topical hemostats, fibrin sealants, and surgical adhesives are regularly used in a variety of surgical procedures involving multiple disciplines. Generally, these adjuncts to surgical hemostasis are valuable means for improving wound visualization, reducing blood loss or adding tissue adherence; however, some of these agents are responsible for under-recognized adverse reactions and outcomes. Bovine thrombin, for example, is a topical hemostat with a long history of clinical application that is widely used alone or in combination with other hemostatic agents. Hematologists and coagulation experts are aware that these agents can lead to development of an immune-mediated coagulopathy (IMC). A paucity of data on the incidence of IMC contributes to under-recognition and leaves many surgeons unaware that this clinical entity, originating from normal immune responses to foreign antigen exposure, requires enhanced post-operative vigilance and judicious clinical judgment to achieve best outcomes.
Postoperative bleeding may result from issues such as loosened ties or clips or the occurrence of a coagulopathy due to hemodilution, vitamin K deficiency, disseminated intravascular coagulation (DIC) or post-transfusion, post-shock coagulopathic states. Other causes, such as liver disease, may be ruled out by a careful patient history and common pre-operative liver function tests. Less common are coagulopathies secondary to pathologic immune responses. Such coagulopathies include those that may result from inherent patient problems such as patients with an immune dysfunction related to systemic lupus erythrematosus (SLE) or lymphoma that can invoke antibodies against native coagulation factors. Medical interventions may also provoke antibody formation in the form of self-directed anti-coagulation factor antibodies, that result in problematic bleeding; it is these iatrogenic post-operative coagulopathies, including those associated with bovine thrombin exposure and its clinical context, that this panel was convened to address.
The RETACC panel's goal was to attain a logical consensus by reviewing the scientific evidence surrounding IMC and to make recommendations for the clinical recognition, diagnosis and evaluation, and clinical management of these complications. In light of the under-recognition and under-reporting of IMC, and given the associated morbidity, utilization of health care resources, and potential economic impact to hospitals, the panel engaged in a detailed review of peer-reviewed reports of bovine thrombin associated IMC. From that clinical knowledge base, recommendations were developed to guide clinicians in the recognition, diagnosis, and management of this challenging condition.
Findings
Recognizing Immune-Mediated Coagulopathy Associated with Bovine Thrombin
IMC is thought to be a relatively uncommon, under-recognized, and iatrogenic medical condition that can result from exposure to non-human coagulation proteins, such as porcine FVIII and bovine thrombin [1,2]. Beginning in 1989, coincident with the rising utilization of bovine thrombin preparations for topical surgical hemostasis, a number of case reports of post-surgical bovine thrombin associated IMC began to appear in the literature [3-35]. IMC occurring unexpectedly in post-surgical patients who were either exposed or re-exposed to bovine thrombin preparations have continued to be reported in nearly all surgical specialties, though cardiac, pediatric and orthopedic/neurosurgical case reports comprise the majority (Table 1). Interestingly, in the panel's literature review of 64 cases with known or presumed surgical exposure to topical bovine thrombin, there is a near equal representation of bleeding versus non-bleeding case presentations. Given that the majority of data on this condition is from case reports, the true incidence is unknown, but numerous reports have appeared in the literature since the year 2000 [3,6,7,11,17-19,22,24,25,27-29,31,36]. The true incidence of IMC associated with bovine thrombin remains unknown due to the lack of a clinical trial designed to answer that question. The result is a mixture of low awareness and confusion in the clinical community about the delayed onset of antibody formation and the challenges posed by masking due to coexistent coagulopathies (e.g., consumptive, dilutive, drug-induced, etc.).
Table 1. Reports of bleeding and non-bleeding IMC
This panel's extensive review found that IMC always has a delayed onset following surgical procedures where bovine thrombin was used; none of the 61 cases reviewed (where time from exposure to clinical presentation was recorded), presented with symptoms or laboratory abnormalities earlier than 5 days following exposure (Table 2). The mean time to clinical presentation or laboratory abnormality (whichever was earlier) was 32 days, highlighting the potential for significant delay in onset and the potential for out of hospital risk. The most common time to presentation reported was 8 days (mode), while the median time to presentation was 11 days. Earlier clinical presentation in the 7 to 14 day time frame has most often been attributed to secondary exposure, where a second surgical exposure to a bovine thrombin preparation acts as a type of immunologic booster for antibody development [37,38]. Typically, primary exposure involves a more delayed clinical presentation due to the need for de novo maturation of the plasma B-cell antibody response. This obligatory time frame, dictated by the cellular and humoral mechanisms necessary for antibody formation, can delay diagnosis or even conceal the occurrence of these events from the surgeons employing these agents. The panel subscribe that with a proper index of suspicion, the resulting delays in recognition and treatment are preventable as are the increased morbidity, mortality, increased length of hospitalization and increased utilization of blood products that accompany this acquired disorder.
Table 2. Time from bovine thrombin exposure to clinical presentation of IMC
The evidence indicates that bovine thrombin related IMC results from antibodies that develop in response to bovine thrombin exposure and its associated proteins such as bovine factor V [18,31,39-41]. Bovine thrombin preparations have been reported to have in addition to bovine thrombin, bovine factors V, IX, and X as well as non-specific, immunoreactive proteins presumed to be protein fragments [42]. These antibodies may cross-react with human coagulation proteins, significantly interfering with the normal clotting cascade. Clinical sequelae range from individuals with abnormal prothrombin time (PT), activated partial thromboplastin time (aPTT) and thrombin time (TT) who are asymptomatic and at risk for bleeding [18,25,28,29,31] to anaphylaxis [36], hemorrhage [19,27], or other critical adverse events [17,19,27,43,44]. Despite prolonged efforts to improve manufacturing methods and remove contaminating proteins [18,38,40,41,45], there is no clinical evidence that bovine thrombin antigenicity has been reduced.
Most severe bleeding episodes occur following repeated exposure to bovine thrombin [34,46] and although history and documented use are often the best indication of previous bovine thrombin exposure, charts or pharmacy records can be incomplete. Accordingly, due to the widespread use of bovine thrombin in many different types of surgery, prior exposure can be difficult to determine in some patients. Even if documentation of prior exposure is available, it is impossible to predict whether antibodies will form or clinical sequelae will result. However, when presented with a patient with difficult to explain coagulopathy, a history that includes previous bovine thrombin exposure or procedures where it was likely used should raise suspicion of the potential for IMC as an etiology.
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