Immunologic Assessment of Patients Treated with Bovine Fibrin as a Hemostatic Agent

Abstract

SummaryTwenty-one cardiothoracic surgical patients have been treated with fibrin as a topical hemostatic/sealing agent, prepared from bovine fibrinogen clotted with bovine thrombin. Serum samples have been collected before treatment with fibrin and postoperatively between 1 and 9 days, 3 and 12 weeks, and 6 and 8 months. The titers of anti-bovine fibrinogen antibodies, measured by ELISA specific for immunoglobulins IgG or IgM, increased to maximal values after about 8 or 6 weeks, respectively. After 8 months, IgG titers were on average 20-fold lower than the mean maximal value, while IgM titers returned to the normal range. IgG was the predominant anti-bovine fibrinogen immunoglobulin as documented by ELISA, affinity chromatography and electrophoresis. Anti-bovine fibrinogen antibodies present in patients reacted readily with bovine fibrinogen, but did not cross-react with human fibrinogen as measured by ELISA or by immunoelectrophoresis. A significant amount of antibodies against bovine thrombin and factor V has been found, many cross-reacting with the human counterparts. No hemorrhagic or thrombotic complications, or clinically significant allergic reactions, occurred in any patient, in spite of antibody presence against some bovine and human coagulation factors. The treatment of patients with bovine fibrin, without induction of immunologic response against human fibrinogen, appeared to be an effective topical hemostatic/sealing measure.

Isolation and characterization of an antifactor V antibody causing activated protein C resistance from a patient with severe thrombotic manifestations

“…However, antibodies to factor V have frequently been found in individuals exposed to topical thrombin 36,37 or to bovine proteins (bovine thrombin or fibrin sealant) during major surgery. [38][39][40] The isolated antifactor V antibody found in our patient has some peculiarity. It is not able to induce prolongation of the clotting time (no neutralizing effect), and because the concentration of factor V found in the patient's plasma was normal, it does not appear to interfere with the clearance of factor V. These characteristics make the antibody presented herein different from other antifactor V antibodies, which are often associated with bleeding manifestations and are directed against the C2 domain of the cofactor.…”

Bovine Thrombin Safety Reporting: An Example of Study Design and Publication Bias

“…Three years later, Carroll et al confirmed these results in 21 fibrin-treated cardiothoracic patients. Using enzyme-linked immunosorbent assay, Carroll et al showed that all patients develop antibodies to bovine fibrinogen, thrombin, and factor V that peak at 2 mo [35]. However, the authors found [no] ''postoperative clinical signs or symptoms'' and no ''postoperative.bleeding complications'' [35].…”

Bovine Thrombin Induces an Acquired Coagulopathy in Sensitized Patients Undergoing Revision Spinal Surgery: A Report of Two Cases

“…1 Many of these products contain a variety of bovine clotting factors in addition to thrombin, particularly factor V, 2 all of which are immunogenic. [3][4][5][6][7][8][9] Cross-reactivity of antibovine clotting factor antibodies with the corresponding human factor has been reported, most commonly for factor V. 2-4,6,8 -11 Antibodies to bovine factor V often cross-react with human factor V, leading to an acquired factor V deficiency. This has been associated with excessive bleeding and even death in a subset of sensitized patients following reexposure to bovine thrombin.…”

“…Acquired coagulopathy associated with the use of bovine thrombin has been reported in patients after cardiac [2][3][4]6,8,9,12,15 and peripheral vascular surgery, 15,16 orthopedic trauma surgery, 9 and neurosurgery. 14,15,17 It has not been reported in spinal surgical patients.…”