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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL081326-05A1
Application #
8237528
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Link, Rebecca P
Project Start
2005-07-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$403,200
Indirect Cost
$131,600
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Zilberman-Rudenko, Jevgenia; Itakura, Asako; Wiesenekker, Chantal P et al. (2016) Coagulation Factor XI Promotes Distal Platelet Activation and Single Platelet Consumption in the Bloodstream Under Shear Flow. Arterioscler Thromb Vasc Biol 36:510-7
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
Wheeler, Allison P; Gailani, David (2016) Why factor XI deficiency is a clinical concern. Expert Rev Hematol 9:629-37
Kokoye, Yasin; Ivanov, Ivan; Cheng, Qiufang et al. (2016) A comparison of the effects of factor XII deficiency and prekallikrein deficiency on thrombus formation. Thromb Res 140:118-24
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
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
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
Al-Horani, Rami A; Gailani, David; Desai, Umesh R (2015) Allosteric inhibition of factor XIa. Sulfated non-saccharide glycosaminoglycan mimetics as promising anticoagulants. Thromb Res 136:379-87
Sparkenbaugh, Erica M; Chantrathammachart, Pichika; Wang, Shaobin et al. (2015) Excess of heme induces tissue factor-dependent activation of coagulation in mice. Haematologica 100:308-14

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