Building an immune-mediated coagulopathy consensus: early recognition and evaluation to enhance post-surgical patient safety
© Ness et al; licensee BioMed Central Ltd. 2009
Received: 27 February 2009
Accepted: 22 May 2009
Published: 22 May 2009
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.
Recognizing Immune-Mediated Coagulopathy Associated with Bovine Thrombin
Reports of bleeding and non-bleeding IMC
Time from bovine thrombin exposure to clinical presentation of IMC
(n = 61)
Standard Dev (days)
95% CI (days)
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 . 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 , 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.
Evaluation and diagnosis
Number of patients presenting with either anti- Factor IIa (thrombin) inhibitor, anti-Factor V (FV) inhibitor, or both
N = 32
N = 32
N = 64
FIIa and FV
In the presence of elevated PT and aPTT, a plasma mixing study should be ordered along with other laboratory studies (i.e., D-dimer, fibrinogen). Ideally, these studies should be ordered as soon as prolonged PT and aPTT are observed and before intervention of any kind, including administration of blood products. The clotting time of a 1:1 mix of patient plasma with normal pooled plasma should be evaluated immediately and at 60 and 120 minutes after incubation at 37°C. If the mixing study fails to correct and the clotting time falls outside of the reference range, then an inhibitor such as an antibody to a coagulation factor should be suspected. It should be noted that a mixing study is relatively insensitive for the early detection of a factor V inhibitor due to potentially low antibody titer levels in the period immediately following antigen exposure. However, if the PT and aPTT continue to be prolonged in the absence of a negative mixing test, the PT and aPTT should be monitored daily in conjunction with repeated mixing studies in any actively bleeding patient.
If not already initiated, a hematology and/or blood bank consult as well as confirmatory testing should follow a positive result from the mixing study. Laboratory evaluation should include specific quantitative assays of factor V and factor V inhibitor, if available. Most laboratories can evaluate factor V levels, but specific factor V antibody assays are not readily available and must be specially performed. More than one factor may be inhibited, but the majority of bovine thrombin-associated IMC cases reported in the literature have been linked to the development of pathogenic factor V inhibitors [17, 19, 27, 31, 43]. Transfusion will confound more specific factor and inhibitor assays; therefore, before initiating therapy additional blood samples should be obtained for more specific, definitive testing. Necessary supportive care and treatment should not be delayed while awaiting results since factor assay results may not be available for several days.
Management of patients with an IMC
Management of patients with IMC may be challenging. While the following recommendations reflect the consensus reached by the panel, it is important to note that there is limited large-scale clinical evidence supporting these recommendations.
Reports of resource utilization in non-bleeding patients with IMC
Reports of resource utilization in bleeding patients with IMC
Once the patient has stopped bleeding, supportive care and follow-up should continue until antibodies resolve and PT/aPTT normalize. Further intervention may not be required once hemostasis is achieved and if no other surgical procedures are required. If the PT/aPTT is not resolving, a new mixing study and factor assays should be ordered. If the PT does not begin to normalize and the factor V level is not recovering and a risk of spontaneous hemorrhage remains, then immunosuppression with IVIG or steroids may be indicated. The risks of immunosuppression in the post-surgical patient should be carefully weighed. As with non-bleeding patients with IMC, post-hemorrhagic patients should be monitored until resolution of the inhibitor. In both asymptomatic and bleeding patients where bovine thrombin-associated IMC has been confirmed, patients should be counseled to avoid re-exposure to bovine thrombin due to the risk for an anamnestic (B-memory cell mediated) response. If further invasive procedures are planned, alternative topical hemostats should be considered.
IMC is an iatrogenic and preventable medical condition that continues to cause patient morbidity and mortality. The panel's goal was to develop the recommendations included in this brief communication as a means of helping clinicians recognize, diagnose, and manage patients with IMC. The diagnosis of IMC requires clinical awareness and early re-evaluation of patient history; serial PT/aPTT tests, mixing studies, and factor assays are essential for the definitive diagnosis of this condition. While supportive care is largely patient specific, a number of management options are available including replacement transfusion, platelets, plasmapheresis, and immunosuppression. IMC is an avoidable condition and alternatives to bovine thrombin should be considered in patients with a history of unexplained post-operative bleeding. Avoiding the use of bovine thrombin preparations altogether would likely reduce the risk of bovine thrombin-associated IMC, thus avoiding the morbidity and extensive hospital resource utilization that are associated with this difficult to diagnose and manage condition.
We thank Michaela Ryan, PhD for editorial assistance, supported by ZymoGenetics, Inc.
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