TY - JOUR
T1 - FXIa and platelet polyphosphate as therapeutic targets during human blood clotting on collagen/tissue factor surfaces under flow
AU - Zhu, Shu
AU - Travers, Richard J.
AU - Morrissey, James H.
AU - Diamond, Scott L.
N1 - Publisher Copyright:
© 2015 by The American Society of Hematology.
PY - 2015/9/17
Y1 - 2015/9/17
N2 - 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).
AB - 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).
UR - http://www.scopus.com/inward/record.url?scp=84942865527&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84942865527&partnerID=8YFLogxK
U2 - 10.1182/blood-2015-04-641472
DO - 10.1182/blood-2015-04-641472
M3 - Article
C2 - 26136249
AN - SCOPUS:84942865527
SN - 0006-4971
VL - 126
SP - 1494
EP - 1502
JO - Blood
JF - Blood
IS - 12
ER -