Summary
Serpins are key actors of systems involving proteolytic reactions, such as the haemostatic
system, as they are irreversible suicide inhibitors of serine proteases. The structural
flexibility and physical properties of serpins that are required for their efficient
inhibitory mechanism also make them especially vulnerable to even minor factors that
induce conformational changes in the native form of these molecules, leading to a
number of inactive conformations, such as latent, cleaved or polymers. Increasing
numbers of conformational mutations affecting haemostatic serpins, mainly antithrombin,
the main endogenous anticoagulant, have been described. These mutations cause circulating
deficiencies of the molecules, in most cases due to intracellular retention, which
may be associated with a hyper-coagulable state. Indeed, conformational mutations
in antithrombin have been identified in patients with severe venous thrombosis,which
has led to the hypothesis that these disorders might be included in the group of conformational
diseases. Moreover,we have recently demonstrated that other factors,including both
drugs,such as the treatment with L-asparaginase,or environmental factors, such as
high temperatures or hyperlipidemia, may also have conformational consequences on
hepatic antithrombin,thus resulting in intracellular aggregation and plasma deficiency,
which may increase the risk of thrombosis. In this study,we review the causes of deficiency
of haemostatic serpins that may be explained by conformational mechanisms, and their
association with an increased risk of venous thrombosis.
Keywords
Antithrombin - SERPINs - venous thrombosis - liver
