Forty years of clinical aprotinin use: A review of 124 hypersensitivity reactions

Beierlein W, Scheule AM, Dietrich W, Ziemer G. Ann Thorac Surg 79: 741-748, 2005.

Reviewer: Mark A. Chaney, MD
University of Chicago
Chicago, IL

Abstract: Since its clinical introduction, the anaphylactic potential of aprotinin has been a major concern. These investigators conducted a medline search (1963 to 2003) aimed at publications presenting reports of aprotinin-induced adverse reactions in order to characterize risk. The search was supplemented by a review of the literature cited in these publications. During this time period, 124 cases of aprotinin-induced anaphylaxis were identified in 61 publications. Eleven patients died. Reported symptoms of hypersensitivity were cardiovascular (36%), cutaneous (27%), respiratory (17%), abdominal (8%), vegetative (6%), and neurologic (5%). In twelve patients, symptoms were not described. Dichotomic characteristics (present-absent) and numeric data available from each publication was collected, as well as reported symptomatology and results of prophylactic and diagnostic measures. Additionally, five patients who suffered from anaphylaxis were reexamined, employing serologic tests and histamine release tests. The investigators conclude that hypersensitivity reaction to aprotinin is a rare event and the risk in the subgroup of reexposed patients in approximately 2.8%. Most cases reported are attributed to transient immunologic sensitization and patients with repeated intravenous exposure within three to six months seem to be the highest risk group. Taking the patient's history, with focus on recent potential aprotinin exposures, and utilizing screening tests for aprotinin-specific antibodies can help identify individuals at highest risk.

Comments: Aprotinin (in clinical use since 1959), by inhibiting fibrinolysis and preserving platelet function, reduces blood loss and transfusion requirements in cardiac surgery. It is a bovine protein which can induce hypersensitivity reactions, and its anaphylactic potential has remained a concern since its clinical introduction. Primary exposure is quite safe. Millions of doses have been administered over four decades with very few reported hypersensitivity reactions. Reexposure to aprotinin, however, carries a small yet significant risk of adverse reaction. The risk in this subgroup of reexposed patients appears to be slightly less than 3%. Furthermore, aprotinin-induced hypersensitivity reactions usually lead to severe complications. More than half of such reactions are life-threatening and approximately 10% are fatal. Aprotinin may initiate pathophysiologic changes via a number of mechanisms. Allergic and anaphylactic reactions are dose independent and require prior immunologic sensitization with formation of specific IgE antibodies. Regarding aprotinin, the incidence of specific serum-IgE is about 15% within the first three months postexposure (same time frame in which the majority of adverse reactions have been observed). Aprotinin may also trigger hypersensitivity reactions via IgG and the complement system. Lastly, aprotinin may cause pseudoallergic or anaphylactoid reactions via direct drug action on effecter cells or a drug-induced mediator release (clinically indistinguishable from allergy and anaphylaxis), which does not require sensitization from a previous exposure.

These investigators found that most of the recent reactions occurred in cardiac surgery at reexposures within three to six months. They also identified certain clinical features that appear to be associated with an elevated risk for adverse reaction. These include former exposure (80% of reactions occur in setting of reexposure), type of surgery (most during cardiac surgery), recent exposure (95% of reexposure reactions with 36 months), and application mode (92% during intravenous route). Clearly, time-dependency exists (risk increases with recent exposure), and these investigators speculate that aprotinin sensitization vanishes gradually over time. Long-term repeated measurements of aprotinin-specific antibodies support this interpretation.

In summary, aprotinin is a potent allergen, with aprotinin-specific serum-IgG detectable in about half of patients having received only one exposure. Aprotinin may cause detrimental changes via IgE, IgG , or pseudoallergic/anaphylactoid reactions. Former exposure by far represents the major risk factor for hypersensitivity reactions (with three to six months the highest risk group), and before reexposure, testing for aprotinin-specific antibodies should be considered. The absence of aprotinin -specific IgG indicates a low risk of hypersensitivity reaction due to its excellent negative predictive value. Prophylactic medications (histamine antagonists, corticosteroids) should also be considered. While prophylactic medications may not be effective in preventing hypersensitivity, they may beneficially affect outcome if hypersensitivity occurs. As with any administered medication, a thorough risk:benefit analysis should be contemplated prior to delivery. Each patient's actual or possible past and future aprotinin exposure should be taken into consideration.

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