The critical role of
thrombin in the pathogenesis of venous and arterial
thrombosis, and the effectiveness of
glycosaminoglycans as antithrombotic drugs are well known.
Antithrombin III is a major inhibitor of
thrombin and augmentation of its inhibitory actions by
heparin is the basis for the clinical uses of
heparin. Recent clinical and experimental studies have demonstrated that another
glycosaminoglycan,
dermatan sulfate, is an effective antithrombotic
drug.
Dermatan sulfate catalyses the inhibition of
thrombin by
heparin cofactor II. The concentrations of
heparin cofactor II are higher in the plasmas of individuals with
congenital antithrombin III deficiency and pregnant women than controls. The role of
heparin cofactor II as a physiologic
thrombin inhibitor is unknown.
Enzyme-linked
immunosorbent assays were used to quantify
thrombin-
heparin cofactor II and
thrombin-
antithrombin III endogenous to the plasmas of adult
antithrombin III-Hamilton deficient subjects, their siblings with normal
antithrombin III levels, pregnant women at term and 3 to 5 days after delivery. Both
thrombin-
antithrombin III and
thrombin-
heparin cofactor II complexed with
vitronectin were detected in all the plasmas. Significantly, the concentrations of
thrombin-
heparin cofactor II-
vitronectin were higher in the plasmas of congenital
antithrombin III deficient subjects and in pre- and post-delivery plasmas than those of normal subjects. In addition, the concentrations of
thrombin-
heparin cofactor II decreased 3 to 5 days after delivery, reflecting the disappearance of the catalytically active
dermatan sulfate elaborated by the placenta. Thus,
heparin cofactor II normally inactivates
thrombin in vivo, with its role increasing in conditions associated with high levels of
heparin cofactor II and/or
dermatan sulfate.