AUTHOR=Schmaier Alvin H. 

TITLE=A Novel Antithrombotic Mechanism Mediated by the Receptors of the Kallikrein/Kinin and Renin–Angiotensin Systems

JOURNAL=Frontiers in Medicine

VOLUME=Volume 3 - 2016

YEAR=2016

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2016.00061

DOI=10.3389/fmed.2016.00061

ISSN=2296-858X

ABSTRACT=The contact activation (CAS) and kallikrein/kinin (KKS) systems regulate thrombosis risk two ways.  First, the CAS influences contact activation-induced factor XI activation and thrombin formation through the hemostatic cascade.  Second, prekallikrein and bradykinin of the KKS regulate expression of three vessel wall G-protein coupled receptors, the bradykinin B2 receptor (B2R), angiotensin receptor 2 (AT2R), and Mas to influence prostacyclin formation.  The degree of intravascular prostacyclin formation inversely regulates intravascular thrombosis risk.  A 1.5-2-fold increase in prostacyclin, as seen in PK deficiency, increases vessel wall Sirt1 and KLF4 to down-regulate vessel wall tissue factor which alone is sufficient to lengthen induced thrombosis times.  A 2-3-fold increase in prostacyclin, as seen the B2R deficient mouse, delays thrombosis and produces a selective platelet function defect of reduced GPVI activation and platelet spreading.  Regulation of CAS and KKS protein expression has a profound influence on thrombosis generating mechanisms in the intravascular compartment.