Adverse Reactions to Protamine: A Study Based on the FAERS Database and Bibliometric Analysis

Background: Protamine, the only antidote for unfractionated heparin, is crucial in cardiac and vascular surgery, but carries a significant risk of adverse drug events (ADEs). However, a comprehensive real-world safety profile is lacking. This study aimed to evaluate protamine-associated ADEs through data mining of the FDA Adverse Event Reporting System (FAERS) and bibliometric analysis. Methods: The FAERS database from Q1 2004 to Q4 2024 contained adverse event reports including protamine as the main suspect. Four algorithms—ROR, PRR, BCPNN, and MGPS—were used to investigate disproportionality to find relevant signals. A Web of Science Core Collection (WoSCC) bibliometric study identified research patterns. Results: Analysis of 512 protamine adverse event reports revealed 58 significant signals impacting 12 System Organ Classes(SOCs). Cardiac disorders constituted the most prevalent category, followed by investigations and vascular disorders. Confirmed risks encompassed recognized reactions including hypotension, pulmonary hypertension, bronchospasm, and anaphylaxis. Unexpected signals comprised resuscitation, heparin-induced thrombocytopenia, unresponsive to stimuli and product quality issues. Bibliometric analysis indicated a focused research emphasis on immune-related adverse events linked to nph insulin and adverse events associated with heparin. Conclusion: This research confirms known risks and identifies novel safety signals for protamine, underscoring the need for improved risk stratification, individualized dosing, and development of safer reversal agents.