The plasma protease factor XI is a key component of the intrinsic pathway of coagulation. Originally thought to be required for initiation of fibrin clot formation, an abundance of clinical and biochemical evidence now suggests that factor XI is required for consolidation and protection of the clot after initial fibrin formation. This is most important with severe bleeding or at sites with high fibrinolytic activity. Furthermore, recent studies in humans and mice suggest that factor XI may influence thrombotic disease processes. The molecular structure of factor XI differs substantially from those of other coagulation proteases. In contrast to the vitamin K-dependent proteins (prothrombin and factors VII, IX, and X), factor XI lacks a calcium binding Gla domain. and phospholipid has little influence on its activity. Properties of factor XI therefore, are not easily extrapolated from observations made on the vitamin K-dependent proteases. The goals of this proposal are to understand the mechanism by which factor XI attaches to platelets during normal hemostasis, to study its contribution to factor IX activation, and to determine the factors that regulate plasma factor XI levels. We have expressed recombinant factor XII molecules containing domain substitutions from the structurally related protein prekallikrein, as well as factor XI molecules with specific site-directed mutations. These have been used to identify binding sites on factor XI for factor IX, activated platelets, and heparin. We propose to use these, and additional recombinant proteins to study the mechanism by which factor XI interacts with high molecular weight kininogen and prothrombin while binding to platelets, and to study the mechanism by which factor IX is activated on the platelet surface. We have cloned the promoter regions for the factor XI and prekallikrein genes, and identified common polymorphisms that may influence function. We will identify areas of the promoters required for tissue specific expression, identify transcription factors involved in expression, and study the influences of polymorphisms on plasma factor XII levels. Finally, we have demonstrated that factor XI deficiency partially rescues protein C deficient mice from early death due to disseminated thrombosis. We will test the effect of factor XI deficiency on the phenotypes of mice with ApoE deficiency, and with PAl-1 over-expression. This work will substantially increase our understanding of a relatively poorly characterized part of the coagulation mechanism, and will provide a firmer knowledge base from which to assess the contribution of factor XI and the intrinsic pathway to thromboembolic disease.
| 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 |
| Mohammed, B M; Cheng, Q; Matafonov, A et al. (2018) Factor XI promotes hemostasis in factor IX-deficient mice. J Thromb Haemost 16:2044-2049 |
| 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 |
| 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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