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Polyphosphate, Zn 2+ and high molecular weight kininogen modulate individual reactions of the contact pathway of blood clotting
Author(s) -
Wang Yuqi,
Ivanov Ivan,
Smith Stephanie A.,
Gailani David,
Morrissey James H.
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.14612
Subject(s) - prekallikrein , high molecular weight kininogen , factor xii , kallikrein , polyphosphate , chemistry , kininogen , biochemistry , coagulation , enzyme , medicine , phosphate
Background Inorganic polyphosphate modulates the contact pathway of blood clotting, which is implicated in thrombosis and inflammation. Polyphosphate polymer lengths are highly variable, with shorter polymers (approximately 60‐100 phosphates) secreted from human platelets, and longer polymers (up to thousands of phosphates) in microbes. We previously reported that optimal triggering of clotting via the contact pathway requires very long polyphosphates, although the impact of shorter polyphosphate polymers on individual proteolytic reactions of the contact pathway was not interrogated. Objectives and methods We conducted in vitro measurements of enzyme kinetics to investigate the ability of varying polyphosphate sizes, together with high molecular weight kininogen and Zn 2+ , to mediate four individual proteolytic reactions of the contact pathway: factor XII autoactivation, factor XII activation by kallikrein, prekallikrein activation by factor XII a, and prekallikrein autoactivation. Results The individual contact pathway reactions were differentially dependent on polyphosphate length. Very long‐chain polyphosphate was required to support factor XII autoactivation, whereas platelet‐size polyphosphate significantly accelerated the activation of factor XII by kallikrein, and the activation of prekallikrein by factor XII a. Intriguingly, polyphosphate did not support prekallikrein autoactivation. We also report that high molecular weight kininogen was required only when kallikrein was the enzyme (ie, FXII activation by kallikrein), whereas Zn 2+ was required only when FXII was the substrate (ie, FXII activation by either kallikrein or FXII a). Activation of prekallikrein by FXII a required neither Zn 2+ nor high molecular weight kininogen. Conclusions Platelet polyphosphate and Zn 2+ can promote subsets of the reactions of the contact pathway, with implications for a variety of disease states.