Abstract
Carbonic anhydrase (CA) inhibitors have a long history of safe clinical use as mild diuretics, in the treatment of glaucoma and for altitude sickness prevention. In this study, we aimed to determine if CA inhibition may be an alternative approach to control thrombosis. We utilized a high-resolution dynamic imaging approach to provide mechanistic evidence that CA inhibitors may be potent anti-procoagulant agents in vitro and effective anti-thrombotics in vivo. Acetazolamide and methazolamide, while sparing platelet secretion, attenuated intracellular chloride ion entry and suppressed the procoagulant response of activated platelets in vitro and thrombosis in vivo. The chemically similar N-methyl acetazolamide, which lacks CA inhibitory activity, did not affect platelet procoagulant response in vitro. Outputs from rotational thromboelastometry did not reflect changes in procoagulant activity and reveal the need for a suitable clinical test for procoagulant activity. Drugs specifically targeting procoagulant remodeling of activated platelets, by blockade of carbonic anhydrases, may provide a new way to control platelet-driven thrombosis without blocking essential platelet secretion responses.
Graphical Abstract
Acknowledgements
This study was supported by British Heart Foundation (BHF) project grant to AWP and EOA (PG/16/102/32647), a BHF Foundation grant to AWP (PG/15/96/31854) and a Wellcome Trust grant to AWP (RG/15/16/31758). This work was also supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund. Lastly, we are grateful for the support of EOA by the Libin Cardiovascular Institute of Alberta, Calgary, Canada.
Conflict-of-interest disclosure
The authors declare no competing financial interests or conflict of interest
Authorship contributions
EOA designed and performed experiments, analyzed data, contributed to the discussion, and wrote and revised the manuscript. CMW, JZ and RA performed experiments. ERS and IH contributed to the discussion and revised the manuscript. AWP designed research and co-wrote and revised the manuscript