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.
Highlights
Pentamidine isethionate (Figure 1) is an antimicrobial drug that is used parenterally or by inhalation for the treatment of African trypanosomiasis, babesiosis, and leishmaniasis
Plasma clotting assays including activated partial partial thromboplastin thromboplastintime time (APTT), PT, and thrombin time (TT) are routinely used to assess the potential effect of molecules on the coagulation process in an in vitro setting
The APTT assay typically measures the effect of molecules on the intrinsic pathway of coagulation which involves FXIIa, factor XIa (FXIa), and FIXa, in addition to the effect on the common coagulation pathway, on thrombin and factor Xa (FXa)
Summary
Pentamidine isethionate (Figure 1) is an antimicrobial drug that is used parenterally or by inhalation for the treatment of African trypanosomiasis, babesiosis, and leishmaniasis. Given its strong basic characteristics, pentamidine does not significantly cross the blood brain barrier, and it is only used for the early stage of African trypanosomiasis at which there is no central nervous system involvement [1,2,3]. It is used in the treatment of Pneumocystis jirovecii pneumonia which is a major opportunistic infection in immune compromised patients including patients with acquired immunodeficiency disease [4].
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