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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Link, Rebecca P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
Engineering (All Types)
Schools of Medicine
United States
Zip Code
Verbout, Norah G; Yu, Xiaolin; Healy, Laura D et al. (2015) Thrombin mutant W215A/E217A treatment improves neurological outcome and attenuates central nervous system damage in experimental autoimmune encephalomyelitis. Metab Brain Dis 30:57-65
Phillips, Kevin G; Baker-Groberg, Sandra M; McCarty, Owen J T (2014) Quantitative optical microscopy: measurement of cellular biophysical features with a standard optical microscope. J Vis Exp :
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
Haley, Kristina M; Recht, Michael; McCarty, Owen J T (2014) Neonatal platelets: mediators of primary hemostasis in the developing hemostatic system. Pediatr Res 76:230-7
Baker-Groberg, Sandra M; Cianchetti, Flor A; Phillips, Kevin G et al. (2014) Development of a method to quantify platelet adhesion and aggregation under static conditions. Cell Mol Bioeng 7:285-290
Jones, Casey M; Baker-Groberg, Sandra M; Cianchetti, Flor A et al. (2014) Measurement science in the circulatory system. Cell Mol Bioeng 7:1-14
Baker-Groberg, Sandra M; Phillips, Kevin G; McCarty, Owen J T (2013) Quantification of volume, mass, and density of thrombus formation using brightfield and differential interference contrast microscopy. J Biomed Opt 18:16014
Tormoen, Garth W; Khader, Ayesha; Gruber, Andras et al. (2013) Physiological levels of blood coagulation factors IX and X control coagulation kinetics in an in vitro model of circulating tissue factor. Phys Biol 10:036003
Aslan, Joseph E; Itakura, Asako; Haley, Kristina M et al. (2013) p21 activated kinase signaling coordinates glycoprotein receptor VI-mediated platelet aggregation, lamellipodia formation, and aggregate stability under shear. Arterioscler Thromb Vasc Biol 33:1544-51
Aslan, Joseph E; Baker, Sandra M; Loren, Cassandra P et al. (2013) The PAK system links Rho GTPase signaling to thrombin-mediated platelet activation. Am J Physiol Cell Physiol 305:C519-28

Showing the most recent 10 out of 28 publications