Characterization of coagulation factor-platelet interactions: role of FXI

Project Details

Description

DESCRIPTION (provided by applicant): 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.
StatusFinished
Effective start/end date4/1/103/31/19

Funding

  • National Institutes of Health: $72,124.00
  • National Institutes of Health: $383,124.00
  • National Institutes of Health: $434,424.00
  • National Institutes of Health: $363,363.00
  • National Institutes of Health: $373,971.00
  • National Institutes of Health: $370,137.00
  • National Institutes of Health: $383,100.00
  • National Institutes of Health: $373,924.00

ASJC

  • Medicine(all)

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