Factor XI (FXI) and Factor XII (FXII) are the zymogens of plasma proteases (FXIa and FXIIa) that are components of the classic plasma contact activation system. While the proteins are considered coagulation proteases, FXI deficiency is associated with a relatively mild bleeding diathesis, and FXII deficiency does not cause abnormal bleeding. Despite their limited contributions to hemostasis, there is mounting evidence that FXI and FXII contribute substantively to thrombotic diseases. Both proteins are required for thrombosis in rodent, rabbit and primate models. Epidemiologic evidence indicates that FXI contributes to venous thrombosis, stroke, and perhaps myocardial infarction in humans. FXII is implicated in thrombosis triggered when blood is exposed to extracorporeal devices, such as during cardiopulmonary bypass. The beneficial effects of drugs such as heparin, warfarin and the newer direct oral anticoagulants come at a cost of increased bleeding, because they target plasma components required for hemostasis as well as thrombosis. It is anticipated that therapies targeting FXI and FXII would produce an antithrombotic effect without significantly compromising hemostasis. A phase 2 trial demonstrating that lowering the plasma FXI level effectively and safely prevents venous thrombosis in patients undergoing knee replacement surgery provides proof of concept for this premise. The goal of this proposal is to identify and understand mechanisms that recruit FXI and FXII into thrombotic and inflammatory processes. Central to this work is the hypothesis that FXI and FXII activation are promoted by blood exposure to certain types of polyanions or artificial surfaces.
In Aim 1 we will establish the mechanisms by which inorganic polyphosphate; DNA and RNA enhance activation of FXI, FXII, and the related contact protein prekallikrein (PK). This will be achieved using novel panels of recombinant proteins and antibodies in purified systems and in plasma. Structure-function relationships are poorly understood for the FXII molecule.
In Aim 2 we will study the structure of FXII to determine how it interacts with polyanions and artificial surfaces. Patients on ventricular assist devices (VADs) for advanced heart failure have a complex constellation of thrombotic and bleeding tendencies related to the device and to anticoagulation therapy. We will determine if VADs induce contact activation, and if targeting FXIIa or FXIa can attenuate this process. Finally, the contact system is known to contribute to inflammation. Previously, we showed that FXI deficiency increases survival in mice in sepsis models, by blunting the cytokine storm that occurs within the first few hours after infection.
In Aim 3 we will determine if this is related to effects on contact activation by studying FXI, FXII and PK deficient mice in a model of polymicrobial sepsis. We will also test plasma samples from patients with therapy-induced reduction in FXI to see it affects markers of inflammation. Through this work we hope to better understand mechanisms by which FXI and FXII contribute to thrombotic and inflammatory disease, to better inform efforts to develop novel antithrombotic therapies that do not compromise hemostasis.
The plasma protease Factor XI (FXI) serves a relatively minor role in normal blood coagulation, but makes significant contributions to thrombosis and inflammation. As such, it may be ideal target for anticoagulation therapy. The goal of this proposal is to understand the mechanisms by which FXI and the related proteins factor XII and prekallikrein, become activated in different pathologic conditions.
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| Tillman, Benjamin; Gailani, David (2018) Inhibition of Factors XI and XII for Prevention of Thrombosis Induced by Artificial Surfaces. Semin Thromb Hemost 44:60-69 |
| Gailani, D; Mohammed, B M; Cheng, Q (2018) Factor XI and pulmonary infections. Haemophilia 24:519-521 |
| Tillman, Benjamin F; Gruber, Andras; McCarty, Owen J T et al. (2018) Plasma contact factors as therapeutic targets. Blood Rev 32:433-448 |
| Mohammed, Bassem M; Ivanov, Ivan; Matafonov, Anton et al. (2018) Activity of Factor XII-Locarno. Res Pract Thromb Haemost 2:168-173 |
| Mohammed, Bassem M; Matafonov, Anton; Ivanov, Ivan et al. (2018) An update on factor XI structure and function. Thromb Res 161:94-105 |
| Ivanov, Ivan; Matafonov, Anton; Gailani, David (2017) Single-chain factor XII: a new form of activated factor XII. Curr Opin Hematol 24:411-418 |
| Ivanov, Ivan; Matafonov, Anton; Sun, Mao-Fu et al. (2017) Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation. Blood 129:1527-1537 |
| Ivanov, Ivan; Shakhawat, Ruhama; Sun, Mao-Fu et al. (2017) Nucleic acids as cofactors for factor XI and prekallikrein activation: Different roles for high-molecular-weight kininogen. Thromb Haemost 117:671-681 |
| Woodruff, R S; Ivanov, I; Verhamme, I M et al. (2017) Generation and characterization of aptamers targeting factor XIa. Thromb Res 156:134-141 |
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