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Contradictory to its effects on thrombin, C1-inhibitor reduces plasmin generation in the presence of thrombomodulin

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Abstract

C1-inhibitor (C1INH) was shown to enhance thrombin generation (TG) in the presence of thrombomodulin (TM) by reducing production of activated protein C. Because C1INH is known to inhibit fibrinolytic system proteases, the objective of this study was to evaluate the effect of moderate (3 IU/ml) and high (16 IU/ml) C1INH concentrations on TG and plasmin generation (PG) in the presence of TM. These concentrations were evaluated based on expected maximum plasma levels following C1INH replacement therapy and recently suggested supraphysiologic dosing. TG and PG were investigated in platelet poor plasmas obtained from 21 healthy donors. An assay designed to monitor the continuous generation of the 7-amino-4-methylcoumarin fluorescence from substrates specific to thrombin or plasmin was used to evaluate the impact of C1INH activity. To characterize the C1INH effects on TG and PG, the thrombin and plasmin concentration peaks and production rates were calculated. TM addition to donor plasma shifted the concentration dependence of C1INH on TG parameters from reduction to enhancement. Conversely, PG parameters were significantly reduced by 16 IU/ml in both the presence and absence of TM. Moderate C1INH concentration (3 IU/ml) reduced TG and PG in the absence of TM but did not significantly affect these parameters in the presence of TM. Finally, 3 IU/ml of C1INH reduced PG more so than TG in the absence of TM. The presented results suggest a mechanism by which C1INH could potentiate thrombosis by inhibition of fibrinolysis.

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Acknowledgements

All Experimental work was conducted under the FDA Research Involving Human Subjects Committee’s (RIHSC) approval, RIHSC protocol #03-120B.

Funding

This work was funded by the US FDA Office of Women’s Health. Dr. I. Tarandovskiy is grateful to the Oak Ridge Institute for Science and Education (ORISE) for fellowship.

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  1. Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation Research, Food and Drug Administration, 10903 New Hampshire Avenue, Building 52, Room 4109, Silver Spring, MD, 20993, USA

    Ivan D. Tarandovskiy, Ali A. Rajabi, Elena Karnaukhova & Paul W. Buehler

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  1. Ivan D. Tarandovskiy
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  3. Elena Karnaukhova
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Tarandovskiy, I.D., Rajabi, A.A., Karnaukhova, E. et al. Contradictory to its effects on thrombin, C1-inhibitor reduces plasmin generation in the presence of thrombomodulin. J Thromb Thrombolysis 48, 81–87 (2019). https://doi.org/10.1007/s11239-019-01869-y

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