Substrates, Cofactors, and Cellular Targets of Coagulation Factor XIa

Abstract

Coagulation factor XI (FXI) has increasingly been shown to play an integral role in several physiologic and pathological processes. FXI is among several zymogens within the blood coagulation cascade that are activated by proteolytic cleavage, with FXI converting to the active serine protease form (FXIa). The evolutionary origins of FXI trace back to duplication of the gene that transcribes plasma prekallikrein, a key factor in the plasma kallikrein–kinin system, before further genetic divergence led to FXI playing a unique role in blood coagulation. While FXIa is canonically known for activating the intrinsic pathway of coagulation by catalyzing the conversion of FIX into FIXa, it is promiscuous in nature and has been shown to contribute to thrombin generation independent of FIX. In addition to its role in the intrinsic pathway of coagulation, FXI also interacts with platelets, endothelial cells, and mediates the inflammatory response through activation of FXII and cleavage of high-molecular-weight kininogen to generate bradykinin. In this manuscript, we critically review the current body of knowledge surrounding how FXI navigates the interplay of hemostasis, inflammatory processes, and the immune response and highlight future avenues for research. As FXI continues to be clinically explored as a druggable therapeutic target, understanding how this coagulation factor fits into physiological and disease mechanisms becomes increasingly important.

Keywords

factor XIa - inflammation - coagulation - barrier function - platelets

Note

The figure included in this manuscript was created using BioRender.com.

Publication History

Article published online:
20 March 2023

• References

• 1 Di Cera E. Serine proteases. IUBMB Life 2009; 61 (05) 510-515
• 2 López-Otín C, Bond JS. Proteases: multifunctional enzymes in life and disease. J Biol Chem 2008; 283 (45) 30433-30437
• 3 Khan AR, James MN. Molecular mechanisms for the conversion of zymogens to active proteolytic enzymes. Protein Sci 1998; 7 (04) 815-836
• 4 Posma JJ, Posthuma JJ, Spronk HM. Coagulation and non-coagulation effects of thrombin. J Thromb Haemost 2016; 14 (10) 1908-1916
• 5 Di Cera E. Thrombin. Mol Aspects Med 2008; 29 (04) 203-254
• 6 Lakshmanan HHS, Estonilo A, Reitsma SE. et al. Revised model of the tissue factor pathway of thrombin generation: role of the feedback activation of FXI. J Thromb Haemost 2022; 20 (06) 1350-1363
• 7 Gailani D, Broze Jr GJ. Factor XI activation in a revised model of blood coagulation. Science 1991; 253 (5022): 909-912
• 8 Kravtsov DV, Matafonov A, Tucker EI. et al. Factor XI contributes to thrombin generation in the absence of factor XII. Blood 2009; 114 (02) 452-458
• 9 Gailani D, Geng Y, Verhamme I. et al. The mechanism underlying activation of factor IX by factor XIa. Thromb Res 2014; 133 (0 1, Suppl 1): S48-S51
• 10 Puy C, Rigg RA, McCarty OJT. The hemostatic role of factor XI. Thromb Res 2016; 141 (Suppl 2, Suppl 2): S8-S11
• 11 Doolittle RF. Step-by-step evolution of vertebrate blood coagulation. Cold Spring Harb Symp Quant Biol 2009; 74: 35-40
• 12 Ponczek MB, Gailani D, Doolittle RF. Evolution of the contact phase of vertebrate blood coagulation. J Thromb Haemost 2008; 6 (11) 1876-1883
• 13 Jiang Y, Doolittle RF. The evolution of vertebrate blood coagulation as viewed from a comparison of puffer fish and sea squirt genomes. Proc Natl Acad Sci U S A 2003; 100 (13) 7527-7532
• 14 Ponczek MB, Shamanaev A, LaPlace A. et al. The evolution of factor XI and the kallikrein-kinin system. Blood Adv 2020; 4 (24) 6135-6147
• 15 Papagrigoriou E, McEwan PA, Walsh PN, Emsley J. Crystal structure of the factor XI zymogen reveals a pathway for transactivation. Nat Struct Mol Biol 2006; 13 (06) 557-558
• 16 Emsley J, McEwan PA, Gailani D. Structure and function of factor XI. Blood 2010; 115 (13) 2569-2577
• 17 Mohammed BM, Matafonov A, Ivanov I. et al. An update on factor XI structure and function. Thromb Res 2018; 161: 94-105
• 18 Gailani D, Emsley J. Toward a better understanding of factor XI activation. J Thromb Haemost 2019; 17 (12) 2016-2018
• 19 Fujikawa K, Chung DW, Hendrickson LE, Davie EW. Amino acid sequence of human factor XI, a blood coagulation factor with four tandem repeats that are highly homologous with plasma prekallikrein. Biochemistry 1986; 25 (09) 2417-2424
• 20 McMullen BA, Fujikawa K, Davie EW. Location of the disulfide bonds in human coagulation factor XI: the presence of tandem apple domains. Biochemistry 1991; 30 (08) 2056-2060
• 21 Baglia FA, Walsh PN. A binding site for thrombin in the apple 1 domain of factor XI. J Biol Chem 1996; 271 (07) 3652-3658
• 22 Baglia FA, Jameson BA, Walsh PN. Identification and characterization of a binding site for factor XIIa in the Apple 4 domain of coagulation factor XI. J Biol Chem 1993; 268 (06) 3838-3844
• 23 Cheng Q, Tucker EI, Pine MS. et al. A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo . Blood 2010; 116 (19) 3981-3989
• 24 Zhao M, Abdel-Razek T, Sun MF, Gailani D. Characterization of a heparin binding site on the heavy chain of factor XI. J Biol Chem 1998; 273 (47) 31153-31159
• 25 Ho DH, Badellino K, Baglia FA, Walsh PN. A binding site for heparin in the apple 3 domain of factor XI. J Biol Chem 1998; 273 (26) 16382-16390
• 26 Yang L, Sun MF, Gailani D, Rezaie AR. Characterization of a heparin-binding site on the catalytic domain of factor XIa: mechanism of heparin acceleration of factor XIa inhibition by the serpins antithrombin and C1-inhibitor. Biochemistry 2009; 48 (07) 1517-1524
• 27 Choi SH, Smith SA, Morrissey JH. Polyphosphate is a cofactor for the activation of factor XI by thrombin. Blood 2011; 118 (26) 6963-6970
• 28 Geng Y, Verhamme IM, Smith SA. et al. Factor XI anion-binding sites are required for productive interactions with polyphosphate. J Thromb Haemost 2013; 11 (11) 2020-2028
• 29 Ivanov I, Shakhawat R, Sun MF. et al. Nucleic acids as cofactors for factor XI and prekallikrein activation: different roles for high-molecular-weight kininogen. Thromb Haemost 2017; 117 (04) 671-681
• 30 Geng Y, Verhamme IM, Smith SB. et al. The dimeric structure of factor XI and zymogen activation. Blood 2013; 121 (19) 3962-3969
• 31 Choi SH, Smith SA, Morrissey JH. Polyphosphate accelerates factor V activation by factor XIa. Thromb Haemost 2015; 113 (03) 599-604
• 32 Puy C, Tucker EI, Ivanov IS. et al. Platelet-derived short-chain polyphosphates enhance the inactivation of tissue factor pathway inhibitor by activated coagulation factor XI. PLoS One 2016; 11 (10) e0165172
• 33 Renné T, Sugiyama A, Gailani D, Jahnen-Dechent W, Walter U, Müller-Esterl W. Fine mapping of the H-kininogen binding site in plasma prekallikrein apple domain 2. Int Immunopharmacol 2002; 2 (13–14): 1867-1873
• 34 Renné T, Gailani D, Meijers JC, Müller-Esterl W. Characterization of the H-kininogen-binding site on factor XI: a comparison of factor XI and plasma prekallikrein. J Biol Chem 2002; 277 (07) 4892-4899
• 35 Bar Barroeta A, Marquart JA, Bakhtiari K, Meijer AB, Urbanus RT, Meijers JCM. Nanobodies against factor XI apple 3 domain inhibit binding of factor IX and reveal a novel binding site for high molecular weight kininogen. J Thromb Haemost 2022; 20 (11) 2538-2549
• 36 Moellmer SA, Puy C, McCarty OJT. HK is the apple of FXI's eye. J Thromb Haemost 2022; 20 (11) 2485-2487
• 37 Thompson RE, Mandle Jr R, Kaplan AP. Association of factor XI and high molecular weight kininogen in human plasma. J Clin Invest 1977; 60 (06) 1376-1380
• 38 Thompson RE, Mandle Jr R, Kaplan AP. Studies of binding of prekallikrein and Factor XI to high molecular weight kininogen and its light chain. Proc Natl Acad Sci U S A 1979; 76 (10) 4862-4866
• 39 Sinha D, Walsh PN. Binding of coagulation factor XIa to receptor on human platelets. Methods Enzymol 1992; 215: 361-369
• 40 Sinha D, Seaman FS, Walsh PN. Role of calcium ions and the heavy chain of factor XIa in the activation of human coagulation factor IX. Biochemistry 1987; 26 (13) 3768-3775
• 41 Ho DH, Baglia FA, Walsh PN. Factor XI binding to activated platelets is mediated by residues R(250), K(255), F(260), and Q(263) within the apple 3 domain. Biochemistry 2000; 39 (02) 316-323
• 42 Baglia FA, Gailani D, López JA, Walsh PN. Identification of a binding site for glycoprotein Ibalpha in the Apple 3 domain of factor XI. J Biol Chem 2004; 279 (44) 45470-45476
• 43 Morla S, Deguchi H, Zilberman-Rudenko J. et al. Skeletal muscle myosin promotes coagulation by binding factor XI via its A3 domain and enhancing thrombin-induced factor XI activation. J Biol Chem 2022; 298 (02) 101567
• 44 Matafonov A, Cheng Q, Geng Y. et al. Evidence for factor IX-independent roles for factor XIa in blood coagulation. J Thromb Haemost 2013; 11 (12) 2118-2127
• 45 Puy C, Tucker EI, Wong ZC. et al. Factor XII promotes blood coagulation independent of factor XI in the presence of long-chain polyphosphates. J Thromb Haemost 2013; 11 (07) 1341-1352
• 46 Whelihan MF, Orfeo T, Gissel MT, Mann KG. Coagulation procofactor activation by factor XIa. J Thromb Haemost 2010; 8 (07) 1532-1539
• 47 Puy C, Tucker EI, Matafonov A. et al. Activated factor XI increases the procoagulant activity of the extrinsic pathway by inactivating tissue factor pathway inhibitor. Blood 2015; 125 (09) 1488-1496
• 48 Muia J, Zhu J, Gupta G. et al. Allosteric activation of ADAMTS13 by von Willebrand factor. Proc Natl Acad Sci U S A 2014; 111 (52) 18584-18589
• 49 Zander CB, Cao W, Zheng XL. ADAMTS13 and von Willebrand factor interactions. Curr Opin Hematol 2015; 22 (05) 452-459
• 50 Garland KS, Reitsma SE, Shirai T. et al. Removal of the c-terminal domains of ADAMTS13 by activated coagulation factor XI induces platelet adhesion on endothelial cells under flow conditions. Front Med (Lausanne) 2017; 4: 232
• 51 Rosenthal RL, Dreskin OH, Rosenthal N. New hemophilia-like disease caused by deficiency of a third plasma thromboplastin factor. Proc Soc Exp Biol Med 1953; 82 (01) 171-174
• 52 Tillman BF, Gruber A, McCarty OJT, Gailani D. Plasma contact factors as therapeutic targets. Blood Rev 2018; 32 (06) 433-448
• 53 Seligsohn U. Factor XI deficiency in humans. J Thromb Haemost 2009; 7 (Suppl (Suppl. 01) 84-87
• 54 Gomez K, Bolton-Maggs P. Factor XI deficiency. Haemophilia 2008; 14 (06) 1183-1189
• 55 Pike GN, Cumming AM, Hay CR, Bolton-Maggs PH, Burthem J. Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency. Blood 2015; 126 (03) 397-405
• 56 Gidley GN, Holle LA, Burthem J, Bolton-Maggs PHB, Lin FC, Wolberg AS. Abnormal plasma clot formation and fibrinolysis reveal bleeding tendency in patients with partial factor XI deficiency. Blood Adv 2018; 2 (10) 1076-1088
• 57 Zucker M, Seligsohn U, Salomon O, Wolberg AS. Abnormal plasma clot structure and stability distinguish bleeding risk in patients with severe factor XI deficiency. J Thromb Haemost 2014; 12 (07) 1121-1130
• 58 Guéguen P, Galinat H, Blouch MT. et al. Biological determinants of bleeding in patients with heterozygous factor XI deficiency. Br J Haematol 2012; 156 (02) 245-251
• 59 Bolton-Maggs PH, Patterson DA, Wensley RT, Tuddenham EG. Definition of the bleeding tendency in factor XI-deficient kindreds--a clinical and laboratory study. Thromb Haemost 1995; 73 (02) 194-202
• 60 Gailani D. Factor XI as a target for preventing venous thromboembolism. J Thromb Haemost 2022; 20 (03) 550-555
• 61 Nopp S, Kraemmer D, Ay C. Factor XI inhibitors for prevention and treatment of venous thromboembolism: a review on the rationale and update on current evidence. Front Cardiovasc Med 2022; 9: 903029
• 62 DeLoughery EP, Olson SR, Puy C, McCarty OJT, Shatzel JJ. The safety and efficacy of novel agents targeting factors XI and XII in early phase human trials. Semin Thromb Hemost 2019; 45 (05) 502-508
• 63 Brass S. Cardiovascular biology. Platelets and proteases. Nature 2001; 413 (6851): 26-27
• 64 Schoenwaelder SM, Yuan Y, Josefsson EC. et al. Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function. Blood 2009; 114 (03) 663-666
• 65 Reddy EC, Rand ML. Procoagulant Phosphatidylserine-Exposing Platelets in vitro and in vivo . Front Cardiovasc Med 2020; 7: 15
• 66 Huang M, Rigby AC, Morelli X. et al. Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins. Nat Struct Biol 2003; 10 (09) 751-756
• 67 Walsh PN, Mills DC, Pareti FI. et al. Hereditary giant platelet syndrome. Absence of collagen-induced coagulant activity and deficiency of factor-XI binding to platelets. Br J Haematol 1975; 29 (04) 639-655
• 68 White-Adams TC, Berny MA, Tucker EI. et al. Identification of coagulation factor XI as a ligand for platelet apolipoprotein E receptor 2 (ApoER2). Arterioscler Thromb Vasc Biol 2009; 29 (10) 1602-1607
• 69 Baglia FA, Walsh PN. Prothrombin is a cofactor for the binding of factor XI to the platelet surface and for platelet-mediated factor XI activation by thrombin. Biochemistry 1998; 37 (08) 2271-2281 [Retracted in: Walsh PN. Biochemistry. 2007 Nov 6;46(44):12886–12887]
• 70 Yun TH, Baglia FA, Myles T. et al. Thrombin activation of factor XI on activated platelets requires the interaction of factor XI and platelet glycoprotein Ib alpha with thrombin anion-binding exosites I and II, respectively. J Biol Chem 2003; 278 (48) 48112-48119
• 71 Kossmann S, Lagrange J, Jäckel S. et al. Platelet-localized FXI promotes a vascular coagulation-inflammatory circuit in arterial hypertension. Sci Transl Med 2017; 9 (375) eaah4923
• 72 Döhrmann M, Makhoul S, Gross K. et al. CD36-fibrin interaction propagates FXI-dependent thrombin generation of human platelets. FASEB J 2020; 34 (07) 9337-9357
• 73 Verhoef JJ, Barendrecht AD, Nickel KF. et al. Polyphosphate nanoparticles on the platelet surface trigger contact system activation. Blood 2017; 129 (12) 1707-1717
• 74 Miller TN, Sinha D, Baird TR, Walsh PN. A catalytic domain exosite (Cys527-Cys542) in factor XIa mediates binding to a site on activated platelets. Biochemistry 2007; 46 (50) 14450-14460
• 75 Reitsma SE, Pang J, Raghunathan V. et al. Role of platelets in regulating activated coagulation factor XI activity. Am J Physiol Cell Physiol 2021; 320 (03) C365-C374
• 76 Rodrigues SF, Granger DN. Blood cells and endothelial barrier function. Tissue Barriers 2015; 3 (1–2): e978720
• 77 Yau JW, Teoh H, Verma S. Endothelial cell control of thrombosis. BMC Cardiovasc Disord 2015; 15: 130
• 78 van Hinsbergh VW. Endothelium--role in regulation of coagulation and inflammation. Semin Immunopathol 2012; 34 (01) 93-106
• 79 Long AT, Kenne E, Jung R, Fuchs TA, Renné T. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost 2016; 14 (03) 427-437
• 80 Pathak M, Kaira BG, Slater A, Emsley J. Cell receptor and cofactor interactions of the contact activation system and factor XI. Front Med (Lausanne) 2018; 5: 66
• 81 Berrettini M, Schleef RR, Heeb MJ, Hopmeier P, Griffin JH. Assembly and expression of an intrinsic factor IX activator complex on the surface of cultured human endothelial cells. J Biol Chem 1992; 267 (28) 19833-19839
• 82 Shariat-Madar Z, Mahdi F, Schmaier AH. Factor XI assembly and activation on human umbilical vein endothelial cells in culture. Thromb Haemost 2001; 85 (03) 544-551
• 83 Mohammed BM, Cheng Q, Matafonov A. et al. A non-circulating pool of factor XI associated with glycosaminoglycans in mice. J Thromb Haemost 2019; 17 (09) 1449-1460
• 84 Mahdi F, Shariat-Madar Z, Schmaier AH. The relative priority of prekallikrein and factors XI/XIa assembly on cultured endothelial cells. J Biol Chem 2003; 278 (45) 43983-43990
• 85 Baird TR, Walsh PN. The interaction of factor XIa with activated platelets but not endothelial cells promotes the activation of factor IX in the consolidation phase of blood coagulation. J Biol Chem 2002; 277 (41) 38462-38467
• 86 Baird TR, Walsh PN. Activated platelets but not endothelial cells participate in the initiation of the consolidation phase of blood coagulation. J Biol Chem 2002; 277 (32) 28498-28503
• 87 Puy C, Ngo ATP, Pang J. et al. Endothelial PAI-1 (plasminogen activator inhibitor-1) blocks the intrinsic pathway of coagulation, inducing the clearance and degradation of FXIa (activated factor XI). Arterioscler Thromb Vasc Biol 2019; 39 (07) 1390-1401
• 88 Ngo ATP, Jordan KR, Mueller PA. et al. Pharmacological targeting of coagulation factor XI mitigates the development of experimental atherosclerosis in low-density lipoprotein receptor-deficient mice. J Thromb Haemost 2021; 19 (04) 1001-1017
• 89 Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res 2016; 118 (09) 1392-1408
• 90 Schmaier AH. The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. J Thromb Haemost 2016; 14 (01) 28-39
• 91 Bryant JW, Shariat-Madar Z. Human plasma kallikrein-kinin system: physiological and biochemical parameters. Cardiovasc Hematol Agents Med Chem 2009; 7 (03) 234-250
• 92 Schmaier AH. The physiologic basis of assembly and activation of the plasma kallikrein/kinin system. Thromb Haemost 2004; 91 (01) 1-3
• 93 Silasi R, Keshari RS, Lupu C. et al. Inhibition of contact-mediated activation of factor XI protects baboons against S. aureus-induced organ damage and death. Blood Adv 2019; 3 (04) 658-669
• 94 Scott CF, Silver LD, Purdon AD, Colman RW. Cleavage of human high molecular weight kininogen by factor XIa in vitro. Effect on structure and function. J Biol Chem 1985; 260 (19) 10856-10863
• 95 Bane Jr CE, Ivanov I, Matafonov A. et al. Factor XI deficiency alters the cytokine response and activation of contact proteases during polymicrobial sepsis in mice. PLoS One 2016; 11 (04) e0152968
• 96 Rawish E, Sauter M, Sauter R, Nording H, Langer HF. Complement, inflammation and thrombosis. Br J Pharmacol 2021; 178 (14) 2892-2904
• 97 Ghebrehiwet B, Silverberg M, Kaplan AP. Activation of the classical pathway of complement by Hageman factor fragment. J Exp Med 1981; 153 (03) 665-676
• 98 Irmscher S, Döring N, Halder LD. et al. Kallikrein cleaves C3 and activates complement. J Innate Immun 2018; 10 (02) 94-105
• 99 Puy C, Pang J, Reitsma SE. et al. Cross-talk between the complement pathway and the contact activation system of coagulation: activated factor XI neutralizes complement factor H. J Immunol 2021; 206 (08) 1784-1792
• 100 Heal SL, Hardy LJ, Wilson CL. et al. Novel interaction of properdin and coagulation factor XI: Crosstalk between complement and coagulation. Res Pract Thromb Haemost 2022; 6 (04) e12715
• 101 Shi T, Giannakopoulos B, Iverson GM, Cockerill KA, Linnik MD, Krilis SA. Domain V of β2-glycoprotein I binds factor XI/XIa and is cleaved at Lys317-Thr318. J Biol Chem 2005; 280 (02) 907-912
• 102 Ge X, Yamaguchi Y, Zhao L. et al. Prochemerin cleavage by factor XIa links coagulation and inflammation. Blood 2018; 131 (03) 353-364
• 103 Shi T, Iverson GM, Qi JC. et al. Beta 2-Glycoprotein I binds factor XI and inhibits its activation by thrombin and factor XIIa: loss of inhibition by clipped beta 2-glycoprotein I. Proc Natl Acad Sci U S A 2004; 101 (11) 3939-3944
• 104 Horbach DA, van Oort E, Lisman T, Meijers JC, Derksen RH, de Groot PG. Beta2-glycoprotein I is proteolytically cleaved in vivo upon activation of fibrinolysis. Thromb Haemost 1999; 81 (01) 87-95
• 105 Itoh Y, Inuzuka K, Kohno I. et al. Highly increased plasma concentrations of the nicked form of beta(2) glycoprotein I in patients with leukemia and with lupus anticoagulant: measurement with a monoclonal antibody specific for a nicked form of domain V. J Biochem 2000; 128 (06) 1017-1024
• 106 Mattern A, Zellmann T, Beck-Sickinger AG. Processing, signaling, and physiological function of chemerin. IUBMB Life 2014; 66 (01) 19-26
• 107 Lorentz CU, Tucker EI, Verbout NG. et al. The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial. Blood 2021; 138 (22) 2173-2184
• 108 Pallares Robles A, Ten Cate V, Schulz A. et al. Association of FXI activity with thrombo-inflammation, extracellular matrix, lipid metabolism and apoptosis in venous thrombosis. Sci Rep 2022; 12 (01) 9761
• 109 Cao Y, Wang Y, Zhou Z. et al. Liver-heart cross-talk mediated by coagulation factor XI protects against heart failure. Science 2022; 377 (6613): 1399-1406