Endothelial Plasminogen Activator Inhibitor-1 Blocks the Intrinsic Pathway of Coagulation, Inducing the Clearance and Degradation of Activated Factor XI
ISTH Academy. Puy C. Jul 10, 2019; 273906; OC 71.3
Cristina Puy
Cristina Puy
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OC 71.3

Endothelial Plasminogen Activator Inhibitor-1 Blocks the Intrinsic Pathway of Coagulation, Inducing the Clearance and Degradation of Activated Factor XI

C. Puy1, A. Ngo1, J. Pang1, R.S. Keshari2, D. Gailani3, A. Gruber1, F. Lupu2, O.J.T. McCarty1
1Oregon Health & Science University, Portland, United States, 2Oklahoma Medical Research Foundation, Oklahoma City, United States, 3Vanderbilt University School of Medicine, Nashville, United States

Main Topic: Coagulation and Anticoagulation
Category: Contact Pathway

Background: The activation of coagulation factor (F) XI by activated coagulation FXII (FXIIa) is a prothrombotic process. The endothelium is known to play an antithrombotic role by limiting thrombin generation and platelet activation. It is unknown whether the antithrombotic role of the endothelium includes sequestration of FXIa activity.
Aims: Determine the regulation of the intrinsic pathway of coagulation by endothelial cells.
Methods: To measure FXIa activity in the presence of human umbilical vein endothelial cells (ECs) we used a FXIa chromogenic assay. To detect and identify FXIa-ECs inhibitor complex we used western blot and mass spectrometry (MS) analysis. Immunofluorescence was used to measure FXIa binding to ECs and internalization. FXIa- plasminogen activator inhibitor-1 (PAI-1) complexes in baboons challenged with heat-inactivated Staphylococcus aureus (S. aureus) were detected by ELISA.
Results: ECs selectively block FXIa activity, while permitting kallikrein and FXIIa activity. FXIa formed a covalent bond with a potential inhibitor present on ECs. MS analysis revealed that FXIa forms a complex with PAI-1. Incubation of ECs with a blocking anti-PAI-1 antibody increased the cleavage of a chromogenic substrate by FXIa and the capacity of FXIa to promote fibrin formation in recalcified plasma. We observed that after incubation of FXIa with ECs, FXIa-PAI-1 complexes were detected 1) in the supernatant and 2) in ECs localized with early and late endosomes and lysosomes. When baboons were challenged with S.aureus, a significant increase in FXIa-PAI-1 complexes was detected in the circulation within the first 2-8 hours post-challenge.
Conclusions: PAI-1 forms a complex with FXIa on ECs blocking its procoagulant activity and inducing the clearance and degradation of FXIa. FXIa-PAI-1 complexes were detected in the circulation in a baboon model of S.aureus sepsis. While ECs support kallikrein and FXIIa activity, inhibition of FXIa by the endothelium may promote the clearance of thrombogenic FXIa from the circulation.

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