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A non‐circulating pool of factor XI associated with glycosaminoglycans in mice
Author(s) -
Mohammed Bassem M.,
Cheng Qiufang,
Matafonov Anton,
Verhamme Ingrid M.,
Emsley Jonas,
McCrae Keith R.,
McCarty Owen J. T.,
Gruber Andras,
Gailani David
Publication year - 2019
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14494
Subject(s) - prekallikrein , protamine sulfate , heparin , protamine , chemistry , high molecular weight kininogen , glycosaminoglycan , medicine , endocrinology , kininogen , factor xi , biochemistry , enzyme , biology , kallikrein , coagulation
Abstract Background The homologous plasma proteins prekallikrein and factor XI ( FXI ) circulate as complexes with high molecular weight kininogen. Although evidence supports an interaction between the prekallikrein ‐ kininogen complexes and vascular endothelium, there is conflicting information regarding FXI binding to endothelium. Objective To study the interaction between FXI and blood vessels in mice. Methods C57Bl/6 wild‐type or F11−/− mice in which variants of FXI were expressed by hydrodynamic tail vein injection, received intravenous infusions of saline, heparin, polyphosphates, protamine, or enzymes that digest glycosaminoglycans ( GAG s). Blood was collected after infusion and plasma was analyzed by western blot for FXI . Results and conclusions Plasma FXI increased 5‐ to 10‐fold in wild‐type mice after infusion of heparin, polyphosphates, protamine, or GAG ‐digesting enzymes, but not saline. Similar treatments resulted in a much smaller change in plasma FXI levels in rats, and infusions of large boluses of heparin did not change FXI levels appreciably in baboons or humans. The releasable FXI fraction was reconstituted in F11−/− mice by expressing murine FXI , but not human FXI . We identified a cluster of basic residues on the apple 4 domain of mouse FXI that is not present in other species. Replacing the basic residues with alanine prevented the interaction of mouse FXI with blood vessels, whereas introducing the basic residues into human FXI allowed it to bind to blood vessels. Most FXI in mice is noncovalently associated with GAG s on blood vessel endothelium and does not circulate in plasma.