Abstract Number: PB1039
Meeting: ISTH 2021 Congress
Background: Protamine sulfate (PS) is the only available option to reverse anticoagulant activity of unfractionated heparin (UFH), however it can cause cardiovascular and respiratory complications.
Aims: We explored toxicity of PS and its complexes with UFH in zebrafish and rodents. The involvement of nitric oxide (NO), cationicity of PS and hERG channels in above effects was investigated.
Methods: To study survival and hatching rates, heart rate (HR) and organ toxicity, zebrafish embryos were exposed to the full range of PS concentrations, UFH and L–NAME alone, or together with PS. hERG blockade by PS was measured using the automated patch clamp technique in human embryonic kidney 293 cells. Blood pressure, HR, perfusion of paw vessels, blood oxygen saturation, respiratory rate, and peak exhaled CO2 were registered over 60 minutes after drug administration to rats. Cardiac troponin concentration and heart tissue histopathology were evaluated in mice treated repeatedly for 35 days. All procedures involving animals were approved (No. 2/2018).
Results: We found concentration-dependent lethality, morphological defects, and bradycardia in zebrafish. We also observed hypotension, and cardiovascular and respiratory disturbances more pronounced with increasing dose of PS. We found no effect of PS on hERG channels, or signs of heart damage in mice. The hypotension in rats and bradycardia in zebrafish were partially attenuated by inhibitor of endothelial NO synthase – L–NAME (Figure 1AB). The disturbances in cardiovascular and respiratory parameters were reduced or delayed when cationic groups of PS were neutralized with UFH. Data were analyzed using GraphPadPrism8 with Kruskal-Wallis ANOVA with Dunn’s post-hoc test and shown as median with range.
Conclusions: Cardiorespiratory toxicity of PS seems to be charge-dependent and involves enhanced release of NO. PS administered at appropriate doses and ratios with UFH should not cause permanent damage of heart tissue, although careful monitoring of cardiorespiratory parameters is necessary.
NCN grant number 2016/23/N/NZ7/00442
To cite this abstract in AMA style:Miklosz J, Kalaska B, Podlasz P, Chmielewska-Krzesinska M, Zajaczkowski M, Kosinski A, Pawlak D, Mogielnicki A. The Role of Nitric Oxide and Cationic Groups in Cardiovascular and Respiratory Toxicity of Protamine Sulfate in Zebrafish and Rodent [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/the-role-of-nitric-oxide-and-cationic-groups-in-cardiovascular-and-respiratory-toxicity-of-protamine-sulfate-in-zebrafish-and-rodent/. Accessed August 16, 2022.
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