PB1404 - Comparison of Cardiovascular and Respiratory Toxicity of Heparin Antidotes: Protamine Sulfate, PER977 and Heparin-Binding Copolymer (HBC)

Background: Major or life-threatening heparin-associated bleeding should be treated with a well-tolerated antidote. Protamine, the only approved antidote, is associated with harmful side effects; PER977 and HBC are antidotes in development. The cardiovascular and respiratory toxicity of these heparin neutralizers has not been directly compared.

Aims: Here, we present the first direct comparison of the effect of heparin antidotes on different parameters of cardiovascular and respiratory systems, including insight into their molecular mechanisms.

Methods: Blood pressure, heart rate, perfusion of paw vessels, blood oxygen saturation, respiratory rate, and peak exhaled CO2 were registered over 20 minutes after infusion of either protamine, PER977 or HBC to rats. After this time, the concentration of terminal complement complex C5b-9 in plasma and 6-keto-prostaglandin F1α, thromboxane B2, angiotensin 1-7 and II, endothelial and inducible nitric oxide (NO) synthase in serum were evaluated. Furthermore, vascular permeability in mouse heart, liver, kidney and lung was measured using the Evans blue. All procedures were approved by Local Ethical Committee on Animal Testing (Permit Number 60/2018).

Results: HBC with dose escalation most significantly reduced blood pressure and increased perfusion of paw vessels, which was accompanied by complement system activation and secretion of NO and angiotensin 1-7. We observed the respiratory disturbances and increased angiotensin II and thromboxane B2 production after protamine and HBC infusion. Protamine-induced hypotension and vasodilatation were accompanied by the release of prostacyclin metabolite and angiotensin 1-7 (Figure 1A-G). Both compounds elevated vascular permeability in major mouse organs (Figure 1H). PER977 slightly changed cardiorespiratory parameters, what may have been related to prostacyclin release. The data were analyzed using GraphPadPrism8.

Conclusion(s): All antidotes at the high dose were found to change cardiovascular and respiratory parameters through distinct mechanisms of action. PER977 seems to be the safest heparin neutralizer.

Funding: Medical University of Bialystok, project number B.SUB.23.388.