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.
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.
|Matafonov, Anton; Leung, Philberta Y; Gailani, Adam E et al. (2014) Factor XII inhibition reduces thrombus formation in a primate thrombosis model. Blood 123:1739-46|
|Bane Jr, Charles E; Gailani, David (2014) Factor XI as a target for antithrombotic therapy. Drug Discov Today 19:1454-8|
|Gailani, David; Geng, Yipeng; Verhamme, Ingrid et al. (2014) The mechanism underlying activation of factor IX by factor XIa. Thromb Res 133 Suppl 1:S48-51|
|Matafonov, A; Cheng, Q; Geng, Y et al. (2013) Evidence for factor IX-independent roles for factor XIa in blood coagulation. J Thromb Haemost 11:2118-27|
|Geng, Yipeng; Verhamme, Ingrid M; Smith, Stephen B et al. (2013) The dimeric structure of factor XI and zymogen activation. Blood 121:3962-9|
|Geng, Y; Verhamme, I M; Sun, M F et al. (2013) Analysis of the factorýýXI variant Arg184Gly suggests a structural basis for factorýýIX binding to factorýýXIa. J Thromb Haemost 11:1374-84|
|Luo, Deyan; Szaba, Frank M; Kummer, Lawrence W et al. (2012) Factor XI-deficient mice display reduced inflammation, coagulopathy, and bacterial growth during listeriosis. Infect Immun 80:91-9|
|Matafonov, Anton; Sarilla, Suryakala; Sun, Mao-fu et al. (2011) Activation of factor XI by products of prothrombin activation. Blood 118:437-45|
|Emsley, Jonas; McEwan, Paul A; Gailani, David (2010) Structure and function of factor XI. Blood 115:2569-77|
|Cheng, Qiufang; Tucker, Erik I; Pine, Meghann S et al. (2010) A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. Blood 116:3981-9|
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