Strongly alkaline polycationic molecule used to neutralize the anticoagulant effect of heparin or to slow the absorption of insulin. It is purified commercially from salmon milt.
2,9% to 26,6% of insulin diabetic patients with NPH insulin or PZ insulin have reactions to intravenously administered protamine versus 0,76% to 0,4% of non diabetic patients.
Pulmonary vasoconstriction: 1,2%
Risk factors
Single-dose intravenous protamine results in protamine specific IgE or IgG antibody production in 28% of patients. Seroconversion is associated with male gender and insulin-dependent mellitus; these patients may be at increased risk on subsequent exposure.
Insulin dependent diabetic patients treated with NPH or PZI: the presence of IgE to protamine leads to a relative risk of 95 if protamine is used; the presence of IgG to protamine leads to a relative risk of 38.
In patients with no prior exposure to SC protamine insulin preparations, the presence of IgG to protamine leads to a relative risk of 25.
Previous protamine exposure.
Vasectomy and fish allergy are not risk factors.
Clinical manifestations.
Anaphylactic shock.
Systemic hypotension +/- pulmonary vasoconstriction.
Urticaria, rash.
Diagnostic methods
Cutaneous testing (controversial).
Intradermal skin-tests with 1 µg/ ml and 10 µg/ ml protamine give false positive results.
Skin-prick tests positive at 10 mg/ ml in one patient with NPH insulin allergy.
Protamine specific antibody assays.
Solid phase immunoassay (IgE, IgG).
ELISA (IgE, IgG): false positive results.
RAST (IgE, IgG).
IgE or IgG-mediated hypersensitivity (with or without complement activation unrelated to rate of administration).
Complement activation (by heparin-protamine complexes or by interaction with protamine-antiprotamine IgG antibody complexes leading to generation of C3a, C4a, C5a).
Direct non-immunological histamine release.
Inhibition of serum carboxypeptidase.
Potentiation of IgE-mediated histamine release.
Augmentation in thromboxane A2 and 6 ketoprotaglandin F1 alpha, causing pulmonary arterial pressure elevation.
Use of ancrod or hirudin instead of heparin.
Use of hexadimethrine in place of protamine.
Use of adjuncts to promote hemostasis (antifibrinolytics, aprotinin).
Premedication with antihistamines and steroids reduces the severity of an allergic reaction (controversial)


  1. Nyhan D.P, Shampaine E.L, Hirshman C.A, Hamilton R.G, Frank S.M, Baumgartner W.A, Adkinson N.F Jr, "Single doses of intravenous protamine result in the formation of protamine-specific IgE and IgG antibodies", J. Allergy. Clin. Immunol., 1996; 97 (4): 991-7
  2. Horrow J.C, Pharo G.H, Levit L.S, Freeland C, "Neither skin-tests nor serum enzyme-linked immunosorbent assay tests provide specificity for protamine allergy", Anesth. Analg., 1996; 82 (2): 386-9
  3. Dykewicz M.S, Kim H.W, Orfan N, Yoo T.J, Lieberman P, "Immunologic analysis of anaphylaxis to protamine component in neutral protamine Hagedorn human insulin", J. Allergy Clin. Immunol., 1994; 93 (1.1): 117-25
  4. Weiss M.E, Adkinson N.F Jr, "Allergy to protamine", Clin. Rev. Allergy, 1991; 9 (3-4): 339–55
  5. Vincent G.M, Janowski M, Menlove R, "Protamine allergy reactions during cardiac catheterization and cardiac surgery: risk in patients taking protamine-insulin preparations", Cathet. Cardiovasc. Diagn., 1991; 23 (3): 164-8

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.