Activation of factor XI by products of prothrombin activation

Anton Matafonov, Suryakala Sarilla, Mao Fu Sun, John P. Sheehan, Vladimir Yurievich Serebrov, Ingrid M. Verhamme, David Gailani

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

The prothrombinase complex converts prothrombin to α-thrombin through the intermediate meizothrombin (Mz-IIa). Both α-thrombin and Mz-IIa catalyze factor (F) XI activation to FXIa, which sustains α-thrombin production through activation of FIX. The interaction with FXI is thought to involve thrombin anion binding exosite (ABE) I. α-Thrombin can undergo additional proteolysis to β-thrombin and γ-thrombin, neither of which have an intact ABE I. In a purified protein system, FXI is activated by β-thrombin or γ-thrombin, and by α-thrombin in the presence of the ABE I-blocking peptide hirugen, indicating that a fully formed ABE I is not absolutely required for FXI activation. In a FXI-dependent plasma thrombin generation assay, β-thrombin, γ-thrombin, and α-thrombins with mutations in ABE I are approximately 2-fold more potent initiators of thrombin generation than α-thrombin or Mz-IIa, possibly because fibrinogen, which binds to ABE I, competes poorly with FXI for forms of thrombin lacking ABE I. In addition, FXIa can activate factor FXII, which could contribute to thrombin generation through FXIIa-mediated FXI activation. The data indicate that forms of thrombin other than α-thrombin contribute directly to feedback activation of FXI in plasma and suggest that FXIa may provide a link between tissue factor-initiated coagulation and the proteases of the contact system.

Original languageEnglish
Pages (from-to)437-445
Number of pages9
JournalBlood
Volume118
Issue number2
DOIs
Publication statusPublished - 14 Jul 2011
Externally publishedYes

Fingerprint

Factor XI
Prothrombin
Thrombin
Byproducts
Chemical activation
Anions

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Matafonov, A., Sarilla, S., Sun, M. F., Sheehan, J. P., Serebrov, V. Y., Verhamme, I. M., & Gailani, D. (2011). Activation of factor XI by products of prothrombin activation. Blood, 118(2), 437-445. https://doi.org/10.1182/blood-2010-10-312983

Activation of factor XI by products of prothrombin activation. / Matafonov, Anton; Sarilla, Suryakala; Sun, Mao Fu; Sheehan, John P.; Serebrov, Vladimir Yurievich; Verhamme, Ingrid M.; Gailani, David.

In: Blood, Vol. 118, No. 2, 14.07.2011, p. 437-445.

Research output: Contribution to journalArticle

Matafonov, A, Sarilla, S, Sun, MF, Sheehan, JP, Serebrov, VY, Verhamme, IM & Gailani, D 2011, 'Activation of factor XI by products of prothrombin activation', Blood, vol. 118, no. 2, pp. 437-445. https://doi.org/10.1182/blood-2010-10-312983
Matafonov A, Sarilla S, Sun MF, Sheehan JP, Serebrov VY, Verhamme IM et al. Activation of factor XI by products of prothrombin activation. Blood. 2011 Jul 14;118(2):437-445. https://doi.org/10.1182/blood-2010-10-312983
Matafonov, Anton ; Sarilla, Suryakala ; Sun, Mao Fu ; Sheehan, John P. ; Serebrov, Vladimir Yurievich ; Verhamme, Ingrid M. ; Gailani, David. / Activation of factor XI by products of prothrombin activation. In: Blood. 2011 ; Vol. 118, No. 2. pp. 437-445.
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