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Evolutionary History of the Kallikrein-Kinin System and Factor XI

1University of Lodz, Department of General Biochemistry, Lodz, Poland, 2University of British Columbia, Vancouver, Canada, 3Vanderbilt University Medical Center, Dept. of Pathology, Microbiology and Immunology, Nashville, United States, 4Vanderbilt University Medical Center, Department of Pathology, Immunology and Microbiology, Nashville, United States, 5Oregon Health and Science University, Portland, United States, 6University of Nottingham, Nottingham, United Kingdom

Abstract Number: PB0255

Meeting: ISTH 2020 Congress

Theme: Coagulation and Natural Anticoagulants » Contact Pathway

Background: Whole genome sequences have facilitated reconstruction of the natural histories of complex processes, such as vertebrate blood coagulation (Figure).

Aims: To update and correct our prior work on the evolution of the kallikrein-kinin system (KKS) proteases prekallikrein and factor (FXII), and their connection to coagulation through factor XI (FXI).

Methods: Genomes of multiple species of fish, amphibians, reptiles, birds and mammals were surveyed with BLAST searches using human protein sequences for prekallikrein, FXII, and FXI.

Results: Prekallikrein is not found in common ray-finned or cartilaginous fish, but is present in the lobe-finned coelacanth (Latimeria) and lungfish (Protopterus). Lobe-finned fish are ancestral to terrestrial vertebrates (tetrapods: amphibians, reptiles, birds, and mammals). Prekallikrein is found in all tetrapods, except for diving mammals (cetaceans), where the gene has been lost. FXII was not identified in common fish or Latimeria, but was present in Protopterus, amphibians, reptiles and most mammals. It has been lost in birds and cetaceans. FXI arose either in a reptile-like proto-mammal or primitive egg-laying mammal (monotreme) by duplication of the prekallikrein gene.

Conclusions: Our analysis indicates prekallikrein and FXII appeared in lobed-finned aquatic ancestors of tetrapods. This suggests a functional KKS may have been present earlier than previously suspected. Interestingly, parts of the KKS are missing in some groups, suggesting the proteins can function independently of each other. For example, prekallikrein is present without FXII in birds and Latimeria, consistent with the observation that prekallikrein is activated by FXIIa-independent processes in humans. FXI is found only in mammals, explaining why KKS activation by contact activation induces clotting in plasma from mammals, but not other tetrapods. It also appeared earlier than previously suspected. The presence of FXI in cetaceans in the absence of prekallikrein and FXII supports the hypothesis that FXI can be activated independently of FXIIa and contact activation.


[Evolution of the vertebrate plasma coagulation and kallikrein-kinin systems]

To cite this abstract in AMA style:

Ponczek M, Kastrup C, Shamanaev A, Dickeson K, Mohammed BM, LaPlace AR, Sun M-, Cheng Q, Gruber A, Emsley J, Gailani D. Evolutionary History of the Kallikrein-Kinin System and Factor XI [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/evolutionary-history-of-the-kallikrein-kinin-system-and-factor-xi/. Accessed September 29, 2023.

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