Abstract
The contact pathway of the plasma clotting cascade is dispensable for normal hemostasis, but contributes to thrombosis and serves as a bridge between inflammation and coagulation. This pathway is triggered upon exposure of plasma to certain anionic polymers and artificial surfaces. Recently, extracellular nucleic acids and inorganic polyphosphate (polyP) have been implicated as being important (patho)physiologically relevant activators of this pathway. However, mechanistic details regarding how nucleic acids or polyP modulate the individual reactions of the contact pathway have been lacking. In this study, we investigate the ability of RNA homopolymers and polyP to bind the primary constituents of the contact pathway: factor XIa, factor XIIa, and plasma kallikrein, in the presence and absence of high molecular weight kininogen (HK), an important cofactor in this pathway. We examine seven proteolytic activation reactions within the contact pathway and report that polyP greatly enhances the rate of all seven, while RNA is effective in supporting only a subset of these reactions. HK both enhances and suppresses these proteolytic activation reactions, depending on the specific reaction evaluated. Overall, we find that polyP is a potent mediator of contact pathway activation reactions in general, that RNA secondary structure may be important to its procoagulant activity, and that nucleic acids versus polyP may differentially modulate specific enzyme activation events within the contact pathway.
Highlights
The contact pathway of blood clotting is initiated when plasma is exposed to anionic surfaces and substances such as glass and clay [1, 2]
Animal models of arterial thrombosis have indicated a protective effect of factor XII (FXII) deficiency [7, 9, 10]; FXII contributes to thrombus stability on atherosclerotic plaques [11]; and several studies have reported a correlation between myocardial infarction and elevated plasma levels of contact pathway proteins [12,13,14]
Binding of plasma prekallikrein (PPK) and FXI to certain anionic surfaces is greatly enhanced by high molecular weight kininogen (HK) [27, 28], and HK is required in stoichiometric amounts for maximal enzymatic activity in vitro [28]
Summary
The contact pathway of blood clotting is initiated when plasma is exposed to anionic surfaces and substances such as glass and clay [1, 2]. This pathway is initiated when zymogen factor FXII undergoes autoactivation and/or allosteric activation upon interaction with certain anionic surfaces or polymers [1, 2]. Binding of PPK and FXI to certain anionic surfaces is greatly enhanced by HK [27, 28], and HK is required in stoichiometric amounts for maximal enzymatic activity in vitro [28]
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