The protease factor Xla (fXIa) contributes to hemostasis by sustaining thrombin generation after initiation of blood coagulation. In addition to contributing to fibrin formation, fXIa promotes clot resistance to fibrinolysis in a process involving the proteinase TAFI. Several lines of evidence indicate fXIa contributes to pathologic coagulation. Elevated plasma levels of the fXIa precursor fXI are associated with increased risks for arterial and venous thrombosis in humans. We observed that fXI deficient mice are resistant to vascular occlusion in arterial injury models, indicating fXIa contributes to platelet rich thrombus formation. FXI binds to platelets in vitro, and is converted to fXIa by thrombin or factor XI la (fXlla). The importance of these interactions in vivo or in complex in vitro systems is not known, and the relative importance of thrombin and fXlla to fXI activation is not clear. FXI I deficiency does not cause a bleeding abnormality, indicating fXI is activated in vivo by other proteases. However, fXII deficient mice are resistant to arterial occlusion, raising the possibility that formation of a pathologic occlusive thrombus involves processes distinct from those involved in normal hemostasis.
In Aim 1 of this proposal, we will use mice with deficiencies of fXI, fXII, and TAFI to investigate the importance of these proteins in models of pathologic coagulation. Using a panel of novel recombinant fXI variants to reconstitute fXI deficient mice, we will determine the importance of fXI interactions with platelets, thrombin and fXlla to these models, and look for alternative functions for fXI and fXII unrelated to classical coagulation pathways.
In Aim 2, a murine fXI-dependent bleeding model will be used to determine if fXI interactions with platelets, thrombin and fXlla are required for hemostasis.
In Aim 3 we will use human and murine platelet rich plasma systems to examine the importance of fXI and fXII to thrombin generation and platelet activation in vitro, with the primary goal of determining if there are differences between the two species. These studies will allow us to compare the importance of fXI, fXII and TAFI to normal hemostasis and to pathologic coagulation, and will provide valuable information regarding the mechanism(s) for fXI activation in complex systems. Ultimately, the work may demonstrate that fXI and/or fXII contribute in a substantive way to blood vessel occlusion, and are therefore, legitimate targets for novel investigative therapies to treat or prevent vascular thromboembolism in humans. Relevance: Anticoagulant drugs have been very beneficial for treating abnormal blood clots in a variety of diseases, but have the disadvantage of leaving the patient prone to serious bleeding. We are looking for new targets in blood for anticoagulation therapy that will not be associated with high bleeding risk.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081326-04
Application #
7790577
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Link, Rebecca P
Project Start
2007-04-06
Project End
2011-12-31
Budget Start
2010-04-01
Budget End
2011-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$307,000
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Ivanov, Ivan; Matafonov, Anton; Sun, Mao-Fu et al. (2017) Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation. Blood 129:1527-1537
Ivanov, Ivan; Shakhawat, Ruhama; Sun, Mao-Fu et al. (2017) Nucleic acids as cofactors for factor XI and prekallikrein activation: Different roles for high-molecular-weight kininogen. Thromb Haemost 117:671-681
Ivanov, Ivan; Matafonov, Anton; Gailani, David (2017) Single-chain factor XII: a new form of activated factor XII. Curr Opin Hematol 24:411-418
Woodruff, R S; Ivanov, I; Verhamme, I M et al. (2017) Generation and characterization of aptamers targeting factor XIa. Thromb Res 156:134-141
Tillman, Benjamin; Gailani, David (2017) Inhibition of Factors XI and XII for Prevention of Thrombosis Induced by Artificial Surfaces. Semin Thromb Hemost :
Puy, Cristina; Tucker, Erik I; Ivanov, Ivan S et al. (2016) Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI. PLoS One 11:e0165172
Gailani, David; Gruber, Andras (2016) Factor XI as a Therapeutic Target. Arterioscler Thromb Vasc Biol 36:1316-22
Wheeler, Allison P; Gailani, David (2016) The Intrinsic Pathway of Coagulation as a Target for Antithrombotic Therapy. Hematol Oncol Clin North Am 30:1099-114
Shnerb Ganor, Reut; Harats, Dror; Schiby, Ginette et al. (2016) Factor XI Deficiency Protects Against Atherogenesis in Apolipoprotein E/Factor XI Double Knockout Mice. Arterioscler Thromb Vasc Biol 36:475-81
Bane Jr, Charles E; Ivanov, Ivan; Matafonov, Anton et al. (2016) Factor XI Deficiency Alters the Cytokine Response and Activation of Contact Proteases during Polymicrobial Sepsis in Mice. PLoS One 11:e0152968

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