title: The toxicology of heparin reversal with protamine: past, present and future.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Department of Pharmacodynamics , Medical University of Bialystok , Bialystok , Poland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Sokolowska
authors.affiliation: a Department of Pharmacodynamics , Medical University of Bialystok , Bialystok , Poland.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Kalaska
authors.affiliation: a Department of Pharmacodynamics , Medical University of Bialystok , Bialystok , Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Miklosz
authors.affiliation: a Department of Pharmacodynamics , Medical University of Bialystok , Bialystok , Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Mogielnicki
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects; D000931:Antidotes / Q000009:adverse effects / Q000627:therapeutic use; D015195:Drug Design; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy; D006493:Heparin / Q000009:adverse effects*; D006494:Heparin Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D011479:Protamines / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D000931:Antidotes; D006494:Heparin Antagonists; D011479:Protamines; D006493:Heparin
keywords: Antidote; heparin; protamine; safety; toxicity