FXIa and platelet polyphosphate as therapeutic targets during human blood clotting on collagen/tissue factor surfaces under flow

Shu Zhu, Richard J. Travers, James H. Morrissey, Scott L. Diamond

Research output: Contribution to journalArticle

Abstract

Factor XIIa (FXIIa) and factor XIa (FXIa) contribute to thrombosis in animalmodels,whereas platelet-derived polyphosphate (polyP) may potentiate contact or thrombin-feedback pathways. The significance of thesemediators in human blood under thrombotic flow conditions on tissue factor (TF) -bearing surfaces remains inadequately resolved. Human blood (corn trypsin inhibitor treated [4mg/mL])was tested by microfluidic assay for clotting on collagen/TF at TFsurface concentration ([TF]wall) from∼0.1 to 2molecules per μm2.Anti- FXI antibodies (14E11 and O1A6) or polyP-binding protein (PPXbd) were used to block FXIIa-dependent FXI activation, FXIa-dependent factor IX (FIX) activation, or plateletderivedpolyP, respectively. Fibrin formationwassensitiveto14E11at0to0.1molecule sper μm2andsensitivetoO1A6at0to 0.2molecules per μm2.However,neitherantibodyreduced fibrin generation at ∼2 molecules per μm2 when the extrinsic pathway became dominant. Interestingly, PPXbd reduced fibrin generation at low [TF]wall (0.1 molecules per μm2) but not at zero or high [TF]wall, suggesting a role for polyP distinct from FXIIa activation and requiringlowextrinsicpathwayparticipation.Regardlessof [TF]wall,PPXbdenhancedfibrin sensitivity to tissue plasminogen activator and promoted clot retraction during fibrinolysis concomitant with an observed PPXbdmediated reduction of fibrin fiber diameter. This is the first detection of endogenous polyP function in human blood under thrombotic flow conditions. When triggered by low [TF]wall, thrombosis may be druggable by contact pathway inhibition, although thrombolytic susceptibility may benefit from polyP antagonism regardless of [TF]wall. (Blood. 2015;126(12):1494-1502).

Original languageEnglish (US)
Pages (from-to)1494-1502
Number of pages9
JournalBlood
Volume126
Issue number12
DOIs
StatePublished - Sep 17 2015

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'FXIa and platelet polyphosphate as therapeutic targets during human blood clotting on collagen/tissue factor surfaces under flow'. Together they form a unique fingerprint.

  • Cite this