Factor XIa (fXIa), the protease form of the plasma protein factor XI (fXI), contributes to thrombin generation by catalyzing activation of factor IX (fIX) and other coagulation proteins. FXI deficiency causes, at most, a modest bleeding disorder. Despite its limited role in hemostasis, epidemiologic data and animal studies indicate that fXI contributes to thrombosis. Targeting of fXIa may, therefore, be useful therapeutically, while having a small impact on hemostasis. FXI is structurally distinct from the vitamin K-dependent coagulation proteases involved in thrombin generation. The fXI gene arose from a duplication of the gene for prekallikrein (PK), the precursor of the protease ?-kallikrein. PK, factor XII (fXII) and high molecular weight kininogen form the kallikrein-kinin system (KKS), which generates proinflammatory peptides such as bradykinin. As homologs, PK and fXI are structurally similar, and fXI retains activities of its parent molecule PK. However, fXI has unique features that facilitate its interactions with hemostatic systems. Understanding these differences, and how they contribute to normal and pathologic coagulation, is the overarching goal of work funded by this award. Our prior work has identified binding sites for fIX, the platelet GP1b and ApoER2? receptors, and polyanions such as heparin and polyphosphate on fXI that are not found on PK. Also, fXI is a homodimeric molecule, while PK is a monomer. Interestingly, with the exception of fIX binding, none of the listed features are required for fXI function in static clotting assays such as the aPTT used in clinical practice. Here, we present evidence that these features support function in flowing blood.
In Aim 1 we will combine knowledge of fXI structure and our ability to generate recombinant fXI variants to address the hypothesis that the fXI dimer is a solution to the problem of interacting with a surface such as an activated platelet, while simultaneously binding to substrates such as fIX. Specifically, we propose that the two identical subunits of the fXI dimer serve different purposes. This will be investigated with novel heterodimers containing subunits with distinct functional features.
In Aim 2, we will investigate our recent observation that most fXI in the circulation is bound to vessel walls and does not circulate in blood. We will study the importance of fXI anion binding sites to this interaction, and the ability of prothrombotic substances such as polyphosphate and DNA to mobilize fXI from the non-circulating pool. Most plasma proteases are secreted in inactive single chain forms that undergo proteolysis to an active form. Recently, we observed that the KKS component fXII has activity in its single chain form that may trigger prothrombotic/proinflammatory process through activation of fXI and PK. We present evidence that fXI and PK also have activity in their single chain forms. These processes will be investigated in detail in Aim 3. We anticipate that results from the proposed studies will elucidate mechanisms by which fXI and the KKS contribute to coagulation and inflammation, and identify novel processes that can be exploited therapeutically.
The blood protein factor XI serves a relatively minor role in normal blood coagulation, but makes significant contributions to thrombosis. As such, it may be an ideal target for antithrombotic therapy. The goal of this proposal is to study the biochemistry of factor XI and the similar molecule prekallikrein, to better understand their roles in abnormal coagulation and inflammation.
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| 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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