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Editorials

Fibrin glue

BMJ 1994; 308 doi: https://doi.org/10.1136/bmj.308.6934.933 (Published 09 April 1994) Cite this as: BMJ 1994;308:933

A mini review: Aprotinin in fibrin glue--a major concern!

A mini-review:

Aprotinin in fibrin glue--a major concern!

Jogenananda Pramanik 1, Tanu Pramanik 2, Lin Juntang3, and Guo Zhikun
4.

1 & 2. Allianze University College of Medical Sciences, Kepala
Batas, Pulau Penang, Malaysia
3. Jena University School of Medicine, Jena, Germany
4. Xinxiang Medical University, Xinxiang City, China
Corresponding author: Prof. Dr. Jogenananda pramanik MD

Fibrin glue consists of two main components: fibrinogen and thrombin.
Aprotinin is added to fibrin glue to delay the fibrinolytic action of
plasmin [1,2,3]. We applauded the insightful editorial of I.H.Atrah for
his concern about critical surgical emergency conditions where fibrin glue
often plays a crucial role.Here we discussed about our concern on
anaphylactic potential of aprotinin when used as additive to fibrin glue.
Aprotinin is an antifibrinolytic agent commonly used in fibrin glue. It
acts by inhibiting kallikrein and trypsin [4] while preserving platelet
function. It helps in hemostasis and therefore, very often used during
major surgical interventions to reduce the total quantity of blood
transfusion required otherwise.

Aprotinin is a bovine protein, composed of 58 amino acid residues
with a molecular weight of 6,512 Daltons. In the United States, aprotinin
has been approved by FDA for intravenous application only since 1993.
However, aprotinin-induced-hypersensitivity reactions raised serious
concerns since its clinical introduction.
Primary exposure to aprotinin is found to be quite safe. Reexposure to
aprotinin, however, carries a small, but significant risk of adverse
reactions which at times led to fatal consequences. So, aprotinin should
be considered as a potent allergen. The fact that more than 80% of
reactions occurred in patients with former exposures clearly indicates the
importance of this point.
It is recommended that while planning for aprotinin use, the history of
each patient should be thoroughly assessed for previous exposures to it.
The active region of the aprotinin molecule represents its immunogenic
epitope and is capable of inducing specific antibodies [5]. Allergic and
anaphylactic reactions are dose independent and require prior immunologic
sensitization with formation of specific IgE antibodies [6].
The incidence of specific serum-IgE is about 14% within the first three
months postexposure.[7] It has been assumed that IgG can trigger
hypersensitivity reactions by involving the complement system [8]. Cases
in which patients had experienced an adverse reaction in the presence of
high concentrations of antiaprotinin IgG antibodies support this theory
[9].
However, pseudo-allergic and anaphylactoid reactions are clinically
indistinguishable from allergy and anaphylaxis. They are triggered by
either a direct drug action on the effector cells or a drug induced
mediator release.
Former exposures by far represent the major risk factor for aprotinin-
induced hypersensitivity reactions and must therefore, be carefully
searched for in each individual's history, especially previous surgical
and medical treatments. Before reexposure, any patient with a documented
or possible former aprotinin exposure should be screened for aprotinin-
specific antibodies.

The absence of aprotinin-specific IgG indicates a low risk of a
hypersensitivity reaction due to its excellent negative predictive value
Hypersensitivity reaction to aprotinin is a rare event.
Patients with history of repeated intravenous exposure within three to six
months seem to be the highest risk group. Most cases reported can be
attributed to a transient immunologic sensitization.
Taking the patient's history with focus on recent potential aprotinin
exposures and screening tests for aprotinin-specific antibodies can
identify individuals at risk. Each patient's actual or possible past and
future aprotinin exposures should be taken into consideration before
aprotinin is considered.
Conclusion: Most commercially available fibrin sealants contain aprotinin
in doses of 1500 kallikrein inactivator units per milliliter. They are
used in many operative disciplines. An elevated risk of hypersensitivity
reactions exists at reexposure to aprotinin [10,11]
Though the incidence of allergic reactions to the aprotinin component of
fibrin tissue adhesives is reported to be about 0.5 per 100,000
applications [12], it is recommended that the physician in charge should
be prepared for life threatening consequences when aprotinin is used.

References:
1. Atrah HI. Fibrin glue. BMJ 1994;308:933.
2. Kram HB, Nathan RC, Mackabee JR, Klein SR, Shoemaker WC. Clinical use
of nonautologous fibrin glue. Am Surg 1988;54(9):570-3.
3. Thompson DF, Letassy NA, Thompson GD. Fibrin glue: a review of its
preparation, efficacy, and adverse effects as a topical hemostat. Drug
Intell Clin Pharm 1988; 22(12):946-52.
4. Kunitz M, Northrop JH. Isolation from beef pancreas of crystalline
trypsinogen, trypsin, a trypsin inhibitor, and an inhibitor-trypsin
compound. J Gen Physiol 1936;19:991-1007.
5. Siekmann J, Beckmann J, Mehlich A, et al. Immunological
characterization of natural and semisynthetic aprotinin variants. Biol
Chem Hoppe-Seyler 1989;370:677-81.
6. Ishizaka T, Ishizaka K. Activation of mast cells for mediator release
through IgE receptors. Prog Allergy 1984;34:188-235.
7. Scheule AM, Beierlein W, Wendel HP, Eckstein FS, Heinemann MK, Ziemer
G. Fibrin sealant, aprotinin, and immune response in children undergoing
operations for congenital heart disease. J Thorac Cardiovasc Surg
1998;115:883-9.
8. Colten HR. Immunology. Drawing a double-edged sword. Nature
1994;371:474-5.
9. Dietrich W, Sp?th P, Z?hlsdorf M, Dalichau H, Kirchhoff PG, Kuppe H,
Preiss DU, Mayer G. Anaphylactic reactions to aprotinin reexposure in
cardiac surgery: relation to antiaprotinin immunoglobulin G and E
antibodies. Anesthesiology 2001;95:64-71.
10. Scheule AM, Beierlein W, Lorenz H, Ziemer G. Repeated anaphylactic
reactions to aprotinin in fibrin sealant. Gastrointest Endosc. 1998
Jul;48(1):83-5.
11. Scheule AM, Beierlein W, Wendel HP, Eckstein FS, Heinemann MK, Ziemer
G. Fibrin sealant, aprotinin, and immune response in children undergoing
operations for congenital heart disease. J Thorac Cardiovasc Surg. 1998
Apr;115(4):883-9.
12. Beierlein W, Scheule AM, Antoniadis G, Braun C, Schosser R. An
immediate allergic skin reaction to aprotinin after reexposure to fibrin
sealant. Transfusion 2000;40:302-5.

Competing interests: No competing interests

28 October 2011
Jogenananda Pramanik
Head of Biochemistry & Genetics and Senior Associate Dean
Tanu Pramanik,Lecturer Pre-Medical Sciences; Dr.lin Juntang, Jena University School of Medicine,Germany; Prof. Guo Zhikun,Xinxiang Medical University,China.
Allianze University College of Medical Sciences, Waziria Medical Square,Kepala Batas-13200,Pulau Pen