Title

The in vitro Effects of Pentamidine Isethionate on Coagulation and Fibrinolysis

Funding Source

Health Resources and Services Administration, U.S. Department of Health and Human Services

Grant Number

P20 GM103424-17,SC3GM131986, 2G12MD007595, D34HP00006

Department

College of Pharmacy

Document Type

Article

Publication Date

6-6-2019

Abstract

Pentamidine is bis-oxybenzamidine-based antiprotozoal drug. The parenteral use of pentamidine appears to affect the processes of blood coagulation and/or fibrinolysis resulting in rare but potentially life-threatening blood clot formation. Pentamidine was also found to cause disseminated intravascular coagulation syndrome. To investigate the potential underlying molecular mechanism(s) of pentamidine’s effects on coagulation and fibrinolysis, we studied its effects on clotting times in normal and deficient human plasmas. Using normal plasma, pentamidine isethionate doubled the activated partial thromboplastin time at 27.5 µM, doubled the prothrombin time at 45.7 µM, and weakly doubled the thrombin time at 158.17 µM. Using plasmas deficient of factors VIIa, IXa, XIa, or XIIa, the concentrations to double the activated partial thromboplastin time were similar to that obtained using normal plasma. Pentamidine also inhibited plasmin-mediated clot lysis with half-maximal inhibitory concentration (IC50) value of ~3.6 µM. Chromogenic substrate hydrolysis assays indicated that pentamidine inhibits factor Xa and plasmin with IC50 values of 10.4 µM and 8.4 µM, respectively. Interestingly, it did not significantly inhibit thrombin, factor XIa, factor XIIIa, neutrophil elastase, or chymotrypsin at the highest concentrations tested. Michaelis-Menten kinetics and molecular modeling studies revealed that pentamidine inhibits factor Xa and plasmin in a competitive fashion. Overall, this study provides quantitative mechanistic insights into the in vitro effects of pentamidine isethionate on coagulation and fibrinolysis via the disruption of the proteolytic activity of factor Xa and plasmin.

Comments

DOI: 10.3390/molecules24112146

PubMed ID: 31174390

Funding text

Funding: Research reported was supported by NIGMS/NIH under award number SC3GM131986 to R.A.A.H. It was also supported by IDeA program from NIGMS/NIH under grant number P20 GM103424-17 to R.A.A.H. Also, D.C. is supported by the Health Resources and Services Administration of the U.S. Department of Health and Human Services under grant number D34HP00006. M.M. is supported by NIMHD/NIH under award number 2G12MD007595. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding institutions.

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