Is Na+ a coagulation factor?

Thromb Haemost 2006; 95: 920–1 Blood coagulation is founded upon the regulated equilibrium of active and inactive states of trypsin-like proteolytic enzymes. Protein-based cofactors, Ca2+, and a phospholipid surface were woven together with proteolytic enzymes into a response to vascular damage. In addition to these coagulation factors, the most abundant alkali metal in plasma – Na+ – has emerged as an important effector of protease activity that played a key role shaping the evolution of clotting enzymes and proteases in general (1). Orthner and Kosow first identified Na+ activation in factor Xa (2) and thrombin (3). Steiner and Castellino discovered a drastic Na+ activation in activated protein C (4), but reported that Na+ had no effect on the interaction of this enzyme with the physiologic target factor VIIIa (5). A defined role for Na+ in coagulation proteases arose when the kinetic mechanism of Na+ activation of thrombin was found to be allosteric (6), the Na+ binding site of thrombin was crystallographically identified (7), and Na+ was shown to be a requirement for cleavage of fibrinogen, but not for activation of the anticoagulant protein C (8). Subsequent studies demonstrated that Na+ promotes thrombin cleavage of PAR1, PAR3 and PAR4 (9), thereby facilitating prothrombotic and signaling functions of the enzyme. The procoagulant role of Na+ was later reinforced by the groups of Leung, Fay and Walsh with the observation that Na+ promotes activation of factors V (10), VIII (11) and XI (12) by thrombin. Does Na+ have effects on other clotting factors similar to those observed in thrombin? One would expect similarities given common ancestral origin and similar Na+ binding environments. A necessary (yet not sufficient) structural determinant for Na+ binding to serine proteases was identified as the presence of Tyr or Phe at position 225 (13). A Pro residue at this position, as found in the majority of serine proteases, is sufficient to abrogate Na+ binding. Remarkably, all vitamin K dependent clotting proteases carryTyr or Phe at position 225, raising the possibility that the procoagulant role of Na+ in thrombin can be compounded in the progression of the coagulation cascade by similar effects on factors Xa, IXa and VIIa. In this issue of Thrombosis and Haemostasis, Gopalakrishna and Rezaie (see pages 936-41) (14) examine the effect of Na+ on the ability of factors IXa and VIIa to activate factor X in the intrinsic and extrinsic Xase complexes, respectively.The study follows up on the effect of Na+ on factor Xa in the prothrombinase complex (15) and completes the analysis of Na+-activated clotting factors in their physiologic interactions. The authors make an important observation: although factors IXa and VIIa possess structural prerequisites for Na+ binding (13), there is no effect of the cation on the activity of these proteases when assembled in their Xase complexes. Previous studies have shown that the activity of factor IXa toward small chromogenic substrates is en© 2006 Schattauer GmbH, Stuttgart