The toxicology of heparin reversal with protamine: past, present and future

ABSTRACT

Introduction: Unfractionated heparin is a strongly anionic anticoagulant used extensively in medicine to prevent blood clotting. In the case of an emergency bleeding in response to heparin, the protamine sulfate is administered. Despite its extensive clinical use, protamine may produce life-threatening side effects such as systemic hypotension, catastrophic pulmonary vasoconstriction or allergic reactions. Recent studies have demonstrated new organ-specific complications of the heparin reversal with protamine.

Areas covered: Past and present knowledge of the mechanisms responsible for the toxicity of protamine and the most promising potential replacements of protamine in the different phases of development.

Expert opinion: Despite of the low therapeutic index, protamine is the only registered antidote of heparins. The toxicology of protamine depends on a complex interaction of the high molecular weight, a cationic peptide with the surfaces of the vasculature and blood cells. The mechanisms involve membrane receptors and ion channels targeted by different vasoactive compounds, such as nitric oxide, bradykinin or histamine. Unacceptable side effects of protamine have led to a search for new alternatives: UHRA, LMWP, and Dex40-GTMAC3 are in the preclinical stage; the two other agents (andexanet alfa and PER977) are already in the advanced clinical phases.

KEYWORDS:

• Antidote
• protamine
• safety
• toxicity
• heparin

Article highlights

• The history of protamine sulfate, the only option for heparin reversal, is 77 years old

• Heparin reversal by protamine can cause adverse effects, such as hypotension, bradycardia, anaphylactic reaction, and pulmonary hypertension, through direct or indirect, systemic or local mechanisms

• Some adverse effects of protamine manifest clinically, like hypotension, some do not, like liver or kidney tissue damage

• The development of many alternative antidotes for heparin was suspended because of unacceptable side effects

• In the absence of safer alternatives, protamine is currently a valuable agent for controlling bleeding after heparin treatment.

• Heparin/protamine may be replaced by new anticoagulant/antidote for cardiac surgery or other invasive cardiovascular procedures in the near future.

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Declaration of interest

The authors declare that they have received government financial sup-port, via a grant from the National Science Centre, Poland, DEC-2011/03/B/NZ7/00755. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.