Thursday, November 21, 2024
11/21/2024
ABSTRACT Tissue Factor Pathway Inhibitor (TFPI) is an anticoagulant protein with essential roles in hemostasis, thrombosis, and embryonic development. TFPI was originally identified as the primary inhibitor of TF-FVIIa, the catalytic complex that initiates blood coagulation. We recognized that the basic C-terminal region of TFPIα and the basic region of the FV B-domain have homology and sought to define how TFPIα may specifically interact with FV/FVa. In biochemical studies, we described an interaction between TFPIα and FVa that promotes inhibition of nascent prothrombinase (FXa-FVa). This occurs at a previously unrecognized regulatory step in the blood coagulation cascade when FV has been activated by FXa but before thrombin is generated. The physiological importance of the TFPI-FV interaction is demonstrated by the following: 1) Bleeding disorders are associated with FV variants that tightly bind TFPIα through this mechanism; 2) TFPIα has reduced ability to inhibit prothrombinase assembled with FV Leiden (FVL) and likely contributes to the thrombotic disease associated with this variant; and 3) Mice lacking TFPI activity have defects in cerebrovascular development that contribute to their embryonic lethality, and removing FV from the embryos completely rescues the brain pathology. We want to better understand how inhibition of prothrombinase by TFPIα impacts biological processes. The proposed studies are based on recently published and new preliminary findings to define extravascular locations where TFPIα interacts with FV and to probe how TFPI alters thrombotic disease, placental development, and responses to endothelial damage. Aim 1 builds on our finding that heparin releasable TFPIα originates from extracellular matrix (ECM) rather than the endothelial surface. Proposed studies will define specific TFPIα binding proteins in ECM, the impact of binding ECM on TFPIα inhibitory activity, and how TFPIα competes with growth factors for ECM binding. Aim 2 builds on our finding that TFPIα and its interaction with FV modulates placental development, which will be probed using three mouse models of TFPI deficiency. Aim 3 builds on our finding that platelet TFPIα modifies development of cardiac fibrosis following irradiation. Proposed studies will further define the role of platelet TFPIα vs. other forms of TFPI in this process. Together, the results of the proposed experiments will advance our understanding of how the TFPIα-FV interaction modulates the pathophysiology of coagulation and coagulation-mediated cellular signaling in important biological processes. They will potentially lead to new therapeutic approaches for thrombotic diseases and bleeding disorders.
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