A non-circulating pool of factor XI associated with glycosaminoglycans in mice

Bassem M. Mohammed, Qiufang Cheng, Anton Matafonov, Ingrid M. Verhamme, Jonas Emsley, Keith R. McCrae, Owen McCarty, Andras Gruber, David Gailani

Research output: Contribution to journalArticle

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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 (GAGs). 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 GAGs on blood vessel endothelium and does not circulate in plasma.

Original languageEnglish (US)
JournalJournal of Thrombosis and Haemostasis
DOIs
StatePublished - Jan 1 2019

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Factor XI
Glycosaminoglycans
Blood Vessels
Prekallikrein
Heparin
Polyphosphates
Protamines
Endothelium
High Molecular Weight Kininogens
Kininogens
Papio
Vascular Endothelium
Malus

Keywords

  • factor XI
  • glycosaminoglycans
  • heparin
  • mice
  • protamine

ASJC Scopus subject areas

  • Hematology

Cite this

Mohammed, B. M., Cheng, Q., Matafonov, A., Verhamme, I. M., Emsley, J., McCrae, K. R., ... Gailani, D. (2019). A non-circulating pool of factor XI associated with glycosaminoglycans in mice. Journal of Thrombosis and Haemostasis. https://doi.org/10.1111/jth.14494

A non-circulating pool of factor XI associated with glycosaminoglycans in mice. / Mohammed, Bassem M.; Cheng, Qiufang; Matafonov, Anton; Verhamme, Ingrid M.; Emsley, Jonas; McCrae, Keith R.; McCarty, Owen; Gruber, Andras; Gailani, David.

In: Journal of Thrombosis and Haemostasis, 01.01.2019.

Research output: Contribution to journalArticle

Mohammed, Bassem M. ; Cheng, Qiufang ; Matafonov, Anton ; Verhamme, Ingrid M. ; Emsley, Jonas ; McCrae, Keith R. ; McCarty, Owen ; Gruber, Andras ; Gailani, David. / A non-circulating pool of factor XI associated with glycosaminoglycans in mice. In: Journal of Thrombosis and Haemostasis. 2019.
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