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Semin Thromb Hemost
DOI: 10.1055/s-0043-1764469
Review Article

Substrates, Cofactors, and Cellular Targets of Coagulation Factor XIa

André L. Lira
1   Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
,
Tia C.L. Kohs
1   Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
,
Samantha A. Moellmer
1   Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
,
Joseph J. Shatzel
1   Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
2   Divison of Hematology and Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, Oregon
,
Owen J.T. McCarty
1   Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
2   Divison of Hematology and Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, Oregon
,
Cristina Puy
1   Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
2   Divison of Hematology and Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, Oregon
› Author Affiliations Funding This work was supported by grants from the National Institute of Health (R01HL151367 to J.J.S. and R01HL101972, R01GM116184, and R01HL151367 to O.J.T.M.).
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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

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