Summary
Although known to play a critical role in thrombosis, the precise role of factor XIII
in other processes like wound healing and gestation remains to be elucidated. Because
a specific, potent inhibitor could help define the function of factor XIII in these
processes, or determine the potential benefits of factor XIII suppression in thrombotic
disease, we have derived and characterized a monoclonal antibody inhibitor of factor
XIII activation. This immunoinhibitor, 9C11, reacts specifically with both plasma
and platelet forms of factor XIII. When added to human plasma, either as whole immunoglobulin
or as Fab fragments, 9C11 completely prevented thrombin-activated factor XIII activity
with small molecular weight substrates like 14C-putrescine. In addition, when clotted with plasma, 9C11 ablated the gamma chain
crosslinking of fibrin catalyzed by factor XIII and markedly accelerated the fibrinolysis
of plasma clots by urokinase. Studies of the mechanism of action showed that 9C11
inhibited the cleavage and activation of factor XIII by thrombin, but did not affect
the catalytic function of previously activated factor XIII. Although it inhibited
thrombin activation, experiments indicated that it bound comparably to both factor
XIII zymogen and the thrombin-cleaved zymogen, and did not bind to the thrombin cleavage
site of the molecule. Taken together these experiments indicated that 9C11 acted as
an inhibitor of the thrombin cleavage and activation of the factor XIII A-subunit.
Its potency and specificity make it a useful agent for studying thrombin-activatable
factor XIII function in biological systems.
