Factor (f) XI, the zymogen of the coagulation protease fXIa, serves a limited role in normal blood clotting (hemostasis), as fXI deficiency is associated with a relatively mild bleeding tendency. Despite this, work in baboons, rabbits, and mice, supported by human population data, strongly indicate that fXI makes important contributions to pathologic coagulation (thromboembolism). In classic coagulation models, fXI is converted to fXIa by activated fXII (fXIIa) in a process called contact activation, which also requires the proteins prekallikrein (PK) and high molecular weight kininogen (HK). The relevance of contact activation to hemostasis has been questioned, justifiably, as patients lacking fXII, PK or HK do not bleed abnormally. Based on this, in newer models of hemostasis fXI is activated through mechanisms distinct from contact activation. However, mice lacking fXII, similar to those lacking fXI, are resistant to thrombosis, suggesting contact activation (or a process similar to it) contributes to pathologic coagulation. While available epidemiologic data are conflicted regarding the importance of contact activation to thrombosis in humans, we noted that fXII contributes to fibrin formation and platelet aggregation in human blood in an ex vivo flow model. We hypothesize that fXII working through contact activation or a related process contributes to pathologic thrombus formation and stability in mice and primates, and that inhibiting this process can produce an anti-thrombotic effect.
In Aim 1 of this proposal we will address the hypothesis that fXI must interact with platelets to contribute to thrombus formation by using transfection techniques that allow proteins to be transiently expressed in vivo. We will also investigate the possibility that fXIa can contribute to coagulation by processes distinct from those related to its classic function of activating factor IX. Studies in Aim 2 will investigate the interaction of fXI with fXIIa using chimeric and mutant recombinant proteins, conventional clotting assays, and whole blood flow models. We will also examine the importance of the fXI-HK interaction and the impact of PK deficiency on thrombus formation in mice. Previously we have shown that fXI deficiency confers a survival advantage in mice in models of bacterial infection.
In Aim 3 we will compare the effects of fXI deficiency on survival, disseminated intravascular coagulation, and inflammation to those of deficiencies of fXII, HK, and PK in a model of polymicrobial sepsis in mice. We have demonstrated that inhibiting fXI with an antibody has a dramatic effect on the growth of platelet-rich thrombi in a baboon vascular graft thrombosis model.
In Aim 4, we will compare the effects of fXI and fXII inhibition in this model to determine if fXII plays an important role in the growth of pathologic thrombi in primates. Results from these studies will give us a stronger understanding of the mechanisms involved in activation of fXI in pathologic coagulation, and may identify novel targets or pathways that could be targeted with novel therapeutic strategies to treat or prevent thromboembolic disease.

Public Health Relevance

Factor XI is a plasma protein that serves a limited role in normal blood coagulation, but appears to make disproportionately greater contributions to thrombosis. We are investigating the mechanisms by which factor XI and related plasma proteins affect thrombotic disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hemostasis and Thrombosis Study Section (HT)
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Link, Rebecca P
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Vanderbilt University Medical Center
Schools of Medicine
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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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