The regulation of the delicate balance between the procoagulant and
anticoagulant mechanisms is of extreme importance for survival. The procoagulant enzymatic complexes (i.e.
prothrombinase,
intrinsic tenase and extrinsic
tenase) are similar in structure and composed of an
enzyme, a cofactor, and the substrate associated on a cell surface in the presence of divalent
metal ions.
Factor Va and
factor VIIIa, which are very similar in structure and function, are required for
prothrombinase and
intrinsic tenase activities respectively because both cofactors express a dual function in their respective complexes, acting as an
enzyme receptor and catalytic effector on the cell surface. The cofactors derive from inactive plasma precursors by regulatory proteolytic events, which involve
alpha-thrombin. In general
bleeding tendencies are usually associated with defects in the activation of one of the
zymogens or the cofactors of the procoagulant complexes. a-
Thrombin, participates in its own down-regulation by binding to the endothelial cell receptor
thrombomodulin, and initiating the
protein C pathway, which in turn leads to the formation of activated
protein C (APC). APC is required for efficient neutralization of
factor Va cofactor activity which results in the inactivation of the
prothrombin-activating complex. This inactivation can only occur in the presence of the appropriate membrane surface. APC down-regulates the
prothrombinase complex by cleaving specific
peptide bonds on the heavy chain of
factor Va which results in the dissociation of the A2 domain of
factor Va from the rest of the molecule. Irregularities in the mechanism of inactivation of
factor Va by APC, are associated with thrombotic risk, presumably due to sustained
prothrombin activation.