Heparin antidote – protamine sulphate

Heparin antidote – protamine sulphate

Abstract: Heparin antidote is protamine sulphate. It is used when quick reversal of the action of heparin is needed as in case of bleeding or after an open heart surgery. Low molecular weight protamine is under development.

Protamine sulphate is a polypeptide, originally derived from salmon sperm, which binds to unfractionated heparin and neutralizes its effect. Hence protamine sulphate has been widely used to reverse the anticoagulant effects of heparin, especially after open heart surgery.¹ It is also the treatment of choice in case of significant bleeding with heparin therapy.

Anaphylactic reactions to protamine sulphate

It is well known that protamine sulphate can sometimes cause anaphylactic reactions when administered after open heart surgery for reversal of total body heparinization. After a systematic review of literature on this aspect, Nybo M and colleagues concluded that it is quite rare and the occurrence has been documented as 0.69% in prospective studies and 0.19% in retrospective studies.²

Paradoxical increase in bleeding with protamine sulphate

Protamine sulphate can sometimes paradoxically increase the bleeding, especially after open heart surgery.McLaughlin KE et al have reviewed this aspect and noted that high doses of protamine can cause increased bleeding and impaired platelet function.³ But this effect is not seen if the protamine heparin ratio is less than 2.6:1. It may be noted that in most cases, only half neutralization of heparin is applied, so the chance of this occurrence should be extremely low.

Effect of protamine sulphate on the effects of low molecular weight heparins

It is generally considered that protamine sulphate is not a good antidote for bleeding with low molecular weight heparins as it cannot completely neutralize the anti factor Xa activity of low molecular weight heparins. But a study by Van Ryn-McKenna in rabbits showed that protamine neutralized blood loss with both low molecular weight and conventional heparin, though the ex vivo anti factor Xa activity and anti thrombin activity could not be fully neutralized.⁴ Warkentin TE and colleagues in a review has mentioned that protamine sulphate neutralizes only about sixty percent of the anti factor Xa activity of low molecular weight heparins.⁵

Low molecular weight protamine

In order to reduce the potentially serious adverse effects associated with the use of protamine sulphate, He H and associates have developed low molecular weight protamine by enzymatic digestion of protamine.⁶ In experimental studies they have shown that low molecular weight protamine sulphate can neutralize the anticoagulant functions of heparin as well as low molecular weight heparin. Low molecular weight protamine has lower antigenicity which could mean lower potential for allergic reactions.

References

1. 1. Dunning J, Versteegh M, Fabbri A, Pavie A, Kolh P, Lockowandt U, Nashef SA; EACTS Audit and Guidelines Committee. Guideline on antiplatelet and anticoagulation management in cardiac surgery. Eur J Cardiothorac Surg. 2008 Jul;34(1):73-92.
   2. Nybo M, Madsen JS. Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol. 2008 Aug;103(2):192-6.
   3. McLaughlin KE, Dunning J. In patients post cardiac surgery do high doses of protamine cause increased bleeding? Interact Cardiovasc Thorac Surg. 2003 Dec;2(4):424-6.
   4. Van Ryn-McKenna J, Cai L, Ofosu FA, Hirsh J, Buchanan MR. Neutralization of enoxaparin-induced bleeding by protamine sulfate. Thromb Haemost. 1990 Apr 12;63(2):271-4.
   5. Warkentin TE, Crowther MA. Reversing anticoagulants both old and new. Can J Anaesth. 2002 Jun-Jul;49(6):S11-25.
   6. He H, Ye J, Liu E, Liang Q, Liu Q, Yang VC. Low molecular weight protamine (LMWP): A nontoxic protamine substitute and an effective cell-penetrating peptide. J Control Release. 2014 Nov 10;193C:63-73.