title: Ca2+ switches the effect of PS-containing membranes on Factor Xa from activating to inhibiting: implications for initiation of blood coagulation.
abstract: Calcium (Ca2+) plays a pivotal role in cellular and organismal physiology. The Ca2+ ion has an intermediate protein-binding affinity and thus it can serve as an on/off switch in the regulation of different biochemical processes. The serum level of ionized Ca2+ is regulated with normal ionized Ca2+ being in the range 1.10-1.3 mM. Hypocalcaemia (free Ca2+<1.1 mM) in critically ill patients is commonly accompanied by haemostatic abnormalities, ranging from isolated thrombocytopenia to complex defects such as disseminated intravascular coagulation, commonly thought to be due to insufficient functioning of anticoagulation pathways. A small amount of fXa (Factor Xa) produced by Factor VIIa and exposed tissue factor is key to initiating blood coagulation by producing enough thrombin to induce the later stages of coagulation. fXa must bind to PS (phosphatidylserine)-containing membranes to produce thrombin at a physiologically significant rate. In the present study, we show that overall fXa activity on PS-containing membranes is sharply regulated by a 'Ca2+ switch' centred at 1.16 mM, below which fXa is active and above which fXa forms inactive dimers on PS-exposing membranes. Our data lead to a mathematical model that predicts the variation of fXa activity as a function of both Ca2+ and membrane concentrations. Because the critical Ca2+ concentration is at the lower end of the normal plasma ionized Ca2+ concentration range, we propose a new regulatory mechanism by which local Ca2+ concentration switches fXa from an intrinsically active form to a form requiring its cofactor [fVa (Factor Va)] to achieve significant activity.
authors.forename: Tilen
authors.initials: T
authors.lastname: Koklic
authors.affiliation: *Department of Biochemistry and Biophysics, CB#7260, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7260, U.S.A.
authors.forename: Rinku
authors.initials: R
authors.lastname: Majumder
authors.affiliation: *Department of Biochemistry and Biophysics, CB#7260, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7260, U.S.A.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Lentz
mesh_terms: D001777:Blood Coagulation / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D015951:Factor Xa / Q000378:metabolism*; D006801:Humans; D010718:Phosphatidylserines / Q000378:metabolism; D055503:Protein Multimerization; D053835:Unilamellar Liposomes
chemical_list: D010718:Phosphatidylserines; D053835:Unilamellar Liposomes; D015951:Factor Xa; D002118:Calcium