Elevated coagulation factor XI (FXI) level is an independent risk factor for deep vein thrombosis, ischemic stroke, and myocardial infarction. Inherited FXI-deficiency causes mild bleeding tendency, yet it has also been found to be protective against ischemic stroke. FXI has been shown to play a critical role in the formation of experimental thrombi, as evidenced by the fact that genetic deletion or pharmacological inhibition of FXI prevents vascular occlusions in animal thrombosis models. While these findings implicate an important role for FXI in thrombosis, and a possible role in hemostasis, they do not suggest molecular mechanisms by which FXI differentially contributes to (patho)physiological coagulation. Blood platelets are the essential cellular components of primary hemostasis. FXI has been shown to bind specifically to the platelet surface via the platelet glycoprotein (GP) Ib-IX-V complex;however, the functional significance of this interaction is unclear. Moreover, it is unknown whether shear forces due to blood flow play a role in regulating FXI-platelet binding. It has been suggested that GPIb orchestrates the activation of FXI through the protease thrombin;however, there is considerable controversy surrounding this hypothesis. Moreover, while thrombin, activated FXI (FXIa), or activated factor XII (FXIIa), has been shown to activate FXI in purified systems in vitro, the relative importance of these FXI activators on the platelet surface ex vivo or in vivo has not been established. The objectives of our proposed studies are to elucidate the mechanisms of FXI-platelet interactions and to provide further insight into the physiological role of FXI in normal hemostasis and pathologic coagulation. We hypothesize that FXI-platelet interactions promote clot formation under shear flow conditions. We have identified FXI as a ligand for the platelet apolipoprotein E receptor 2 (ApoER2). We hypothesize that ApoER2 plays a critical role in mediating FXI-platelet binding and in initiating coagulation under flow. These hypotheses will be tested through the following specific aims:
Aim 1 : Determine the molecular mechanisms and consequences of platelet-FXI interactions.
Aim 2 : Determine the role of FXI-platelet binding in ex vivo thrombus formation.
Aim 3 : Determine the role of FXI-platelet binding in thrombus formation in vivo. We are committed to the design and development of novel antithrombotic FXI inhibitors. We believe that therapeutic inhibition of the FXI axis is a promising therapeutic strategy to combat pathological thrombus formation, in light of the strong antithrombotic efficacy and mild bleeding diathesis associated with FXI deficiency. The ultimate goal of this line of research is to establish valuable mechanistic information concerning FXI-platelet interactions and to provide further insight into the physiological role of FXI in normal hemostasis and pathologic coagulation.
Cardiovascular disease and stroke remain major health concerns in the adult population in the United States. To combat these diseases, an ideal antithrombotic agent would selectively target an event crucial for thrombus formation without affecting hemostasis. We propose that elucidation of the role that FXI plays in clot formation may provide the basis for the pharmaceutical development of such a novel class of FXI-targeted anti-thrombotics.
|Baker-Groberg, S M; Lattimore, S; Recht, M et al. (2016) Assessment of neonatal platelet adhesion, activation, and aggregation. J Thromb Haemost 14:815-27|
|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|
|Rigg, Rachel A; Healy, Laura D; Nowak, Marie S et al. (2016) Heat shock protein 70 regulates platelet integrin activation, granule secretion and aggregation. Am J Physiol Cell Physiol 310:C568-75|
|Rigg, Rachel A; Aslan, Joseph E; Healy, Laura D et al. (2016) Oral administration of Bruton's tyrosine kinase inhibitors impairs GPVI-mediated platelet function. Am J Physiol Cell Physiol 310:C373-80|
|Deguchi, Hiroshi; Sinha, Ranjeet K; Marchese, Patrizia et al. (2016) Prothrombotic skeletal muscle myosin directly enhances prothrombin activation by binding factors Xa and Va. Blood :|
|Healy, Laura D; Puy, Cristina; Itakura, Asako et al. (2016) Colocalization of neutrophils, extracellular DNA and coagulation factors during NETosis: Development and utility of an immunofluorescence-based microscopy platform. J Immunol Methods 435:77-84|
|Mattheij, Nadine J A; Swieringa, Frauke; Mastenbroek, Tom G et al. (2016) Coated platelets function in platelet-dependent fibrin formation via integrin Î±IIbÎ²3 and transglutaminase factor XIII. Haematologica 101:427-36|
|Sylman, Joanna L; Daalkhaijav, Uranbileg; Zhang, Ying et al. (2016) Differential Roles for the Coagulation Factors XI and XII in Regulating the Physical Biology of Fibrin. Ann Biomed Eng :|
|Gailani, David; Gruber, Andras (2016) Factor XI as a Therapeutic Target. Arterioscler Thromb Vasc Biol 36:1316-22|
|Mitrugno, Annachiara; Tormoen, Garth W; Kuhn, Peter et al. (2016) The prothrombotic activity of cancer cells in the circulation. Blood Rev 30:11-9|
Showing the most recent 10 out of 57 publications