Antithrombin inactivation by neutrophil elastase requires heparin.
In certain thrombotic states, large declines in the levels of functional circulating antithrombin occur, which may reflect the highly active nature of the endothelial surface in suppressing excessive amounts of activated coagulation enzymes. Alternatively, we have recently observed an unexpected and paradoxical in vitro functioning of heparin that could result in the inactivation of antithrombin in pathologic conditions. Specifically, antithrombin was rendered nonfunctional as an inhibitor of clotting enzymes as a result of a limited, heparin-dependent cleavage by neutrophil elastase. This inactivation occurred only in the presence of the active anticoagulant heparin fraction, which suggested that the heparin-antithrombin complex was the substrate for elastase attack. Interestingly, neutrophil elastase was found to bind tightly to heparin and heparin-like materials. Neutrophil elastase has been previously linked to nonspecific proteinolysis occurring in inflammatory thrombotic reactions. This affinity of both antithrombin and elastase for heparin suggests a novel mechanism of potential specificity. An important component of this hypothesis is the localization of the elastase/antithrombin reaction away from the high circulating levels of elastase inhibitors. The proposed inactivation of antithrombin on the vascular surface would likely occur only in pathologic states associated with neutrophil sequestration and activation. Nevertheless, this mechanism could lead to a localized reversal of the nonthrombogenic nature of the endothelium and potentially lead to significant reductions of functional antithrombin in certain disease states.
Jordan
R E
RE
Department of Physiology, Cutter Biological, Miles Inc., Berkeley, California.
Nelson
R M
RM
Kilpatrick
J
J
Newgren
J O
JO
Esmon
P C
PC
Fournel
M A
MA
D000991:Antithrombins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D006493:Heparin / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D009504:Neutrophils / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000378:metabolism*
D000991:Antithrombins; D006493:Heparin; D010196:Pancreatic Elastase