Protamine: heparin antagonist in cardiac and vascular surgery
Protamine (specifically protamine sulphate) is a basic polypeptide obtained from the sperm of salmon and other fish. It is the specific antidote to unfractionated heparin and is used in cardiac and vascular surgery as well as in emergency medicine to neutralise heparin activity rapidly.
For low molecular weight heparins (LMWH) protamine is also used as an antidote, although with reduced effectiveness. Protamine has no effect on the direct oral anticoagulants (dabigatran, factor Xa inhibitors); the specific antidotes there are idarucizumab for dabigatran and andexanet alfa for factor Xa inhibitors.
Mechanism of action
Protamine is a strongly positively charged peptide (about 30 % arginine residues). With the strongly negatively charged heparin it forms a stable, inactive complex. Heparin's binding to antithrombin III is broken and the inhibition of thrombin and factor Xa is reversed.
The effect appears within 5 minutes of intravenous administration. Protamine itself has a half life of about 7 minutes, which is why an additional dose may occasionally be required when heparin activity persists.
For LMWH the complex formation is less complete: only the anti IIa component is fully neutralised while anti Xa activity persists in part. Clinically the effect is nevertheless usually sufficient to control significant bleeding.
Indications
- Reversal of unfractionated heparin after cardiopulmonary bypass: standard application in cardiac surgery at the end of the procedure
- Emergency reversal of heparin induced bleeding: in internal medicine and intensive care
- Before invasive procedures during heparin therapy: when rapid reversal of anticoagulation is required
- Reversal of low molecular weight heparins: in clinically relevant bleeding, with limited effectiveness
- Galenical component: protamine is part of NPH insulin formulations to delay absorption
Dosing and administration
Reversal of unfractionated heparin: 1 mg of protamine sulphate neutralises about 100 IU of heparin. The exact dose depends on the time since the last heparin administration and on the ACT (activated clotting time).
Low molecular weight heparins: 1 mg protamine per 100 anti Xa units of LMWH neutralises about 60 % of the anti Xa activity.
Administration: slow intravenous injection over at least 10 minutes. Rapid injection can cause severe hypotension and bradycardia. Maximum 50 mg per single dose.
Monitoring: ACT or aPTT before and after administration, clinical assessment of bleeding. Recurrent bleeding may require a second dose.
Adverse effects
Common: hypotension and bradycardia, particularly with too rapid injection, flushing, nausea, vomiting.
Uncommon: allergic skin reactions, pruritus, bronchospasm, headache.
Rare and very rare: anaphylaxis, acute pulmonary oedema, thrombocytopenia, heparin rebound after several hours, particularly after cardiopulmonary bypass.
Risk groups for anaphylactoid reactions:
- Patients with diabetes mellitus injecting NPH insulin, who can form antibodies against protamine
- Vasectomised men with antibodies against sperm protein
- Fish allergy (theoretical, rarely clinically relevant)
- Previous protamine administration with allergic reaction
Interactions
- Heparin and LMWH: specific reversal as the indication
- Other anticoagulants (DOACs, vitamin K antagonists): protamine has no effect
- NPH insulin users: possible antibody formation against protamine, with risk of anaphylactic reaction during heparin reversal
Special considerations
Pregnancy and breastfeeding: use in pregnancy is acceptable for clear emergency indications. Data limited.
Allergies and risks: careful history before use. With previous reaction or risk groups, titrate carefully and have anaphylaxis treatment ready.
Heparin rebound: after cardiopulmonary bypass, an initially successful reversal may be followed by recurrent heparin like activity as heparin redistributes from tissue stores. Close postoperative monitoring is required.
Pharmacokinetics: protamine itself has a very short half life. Repeat dosing may be needed with longer acting heparin.
Galenical use: protamine is part of intermediate acting insulins (NPH insulins such as Insuman Basal, Protaphane). This use is separate from antidote use and belongs in diabetology.
Related substances
- Idarucizumab, specific antidote for dabigatran
- Dabigatran etexilate, oral direct thrombin inhibitor
- Clopidogrel, platelet aggregation inhibitor
- Thrombin, local haemostatic
Frequently asked questions
What is protamine used for?
Protamine is the specific antidote to heparin. In cardiac surgery it is used at the end of an operation on cardiopulmonary bypass to terminate anticoagulation. It is also used in life threatening bleeding under heparin therapy.
Does protamine work against DOACs?
No. Direct oral anticoagulants such as dabigatran and factor Xa inhibitors are not affected by protamine. Idarucizumab is the specific antidote for dabigatran and andexanet alfa is available for factor Xa inhibitors.
Why can protamine cause allergic reactions?
Protamine is a foreign protein. Patients exposed repeatedly to protamine (for example as a component of NPH insulin) can develop antibodies. On re exposure allergic or anaphylactoid reactions are possible. Taking a careful history before use is therefore important.
What is heparin rebound?
After successful reversal, heparin can be released back into the circulation from tissue stores, leading to delayed return of anticoagulation. The phenomenon is mainly observed after long procedures on cardiopulmonary bypass and requires close postoperative monitoring.
Sources
- EMA European Medicines Agency
- BfArM German Federal Institute for Drugs and Medical Devices
- AWMF guidelines haemostasis and cardiac surgery
- Gelbe Liste protamine sulphate monograph
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