INHIBITION OF THROMBIN BY ANTITHROMBIN-III AND HEPARIN-COFACTOR-II IN-VIVO

The critical role of thrombin in the pathogenesis of venous and arteri al thrombosis, and the effectiveness of glycosaminoglycans as anti- th rombotic drugs are well known. Antithrombin III is a major inhibitor o f thrombin and augmentation of its inhibitory actions by heparin is th e basis for the clinical uses of heparin. Recent clinical and experime ntal studies have demonstrated that another glycosaminoglycan, dermata n sulfate, is an effective antithrombotic drug. Dermatan sulfate catal yses the inhibition of thrombin by heparin cofactor II. The concentrat ions of heparin cofactor II are higher in the plasmas of individuals w ith congenital antithrombin III deficiency and pregnant women than con trols. The role of heparin cofactor II as a physiologic thrombin inhib itor is unknown. Enzyme-linked immunosorbent assays were used to quant ify thrombin-heparin cofactor II and thrombin-antithrombin III endogen ous to the plasmas of adult antithrombin III-Hamilton deficient subjec ts, their siblings with normal antithrombin III levels, pregnant women at term and 3 to 5 days after delivery. Both thrombin-antithrombin an d thrombin-heparin cofactor II complexed with vitronectin were detecte d in all the plasmas. Significantly, the concentrations of thrombin-he parin cofactor II-vitronectin were higher in the plasmas of congenital antithrombin III deficient subjects and in pre- and post-delivery pla smas than those of normal subjects. In addition, the concentrations of thrombin-heparin cofactor II decreased 3 to 5 days after delivery, re flecting the disappearance of the catalytically active dermatan sulfat e elaborated by the placenta. Thus, heparin cofactor II normally inact ivates thrombin in vivo, with its role increasing in conditions associ ated with high levels of heparin cofactor II and/or dermatan sulfate.