Influence of Low Molecular Weight Heparin and Low Molecular Weight Dextran Sulfate on the Inhibition of Coagulation Factor XIa by Serpins

Abstract

SummaryWe investigated the influence of low molecular weight dextran sulfate (LMWdxs) and low molecular weight heparins (LMWH: dalteparin, enoxaparin and nadroparin) on the inhibition of FXIa by C1-inhibitor, α1-antitrypsin, α2-antiplasmin and antithrombin in a purified system and in plasma.The second order rate constant for inactivation of FXIa by C1-inhibitor, α1-antitrypsin, α2-antiplasmin, and antithrombin was 1.23, 0.056, 0.33 and 0.59 × 103 M–1 s–1, respectively.LMWdxs and LMWH dose-dependently increased the second order rate constant of the inactivation of FXIa by C1-inhibitor up to 39-fold. The second order rate constant of the inactivation of FXIa by anti-thrombin was increased up to 6-fold by LMWH, whereas LMWdxs had no effect. In plasma, FXIa was inactivated to about 50% by C1-inhibitor, while the other serpins contributed together to the remaining 50% of plasma’s inhibitory capacity towards FXIa. In the presence of LMWdxs or LMWH, FXIa was inactivated in plasma to more than 90% by C1-inhibitor. LMWH at maximal therapeutic plasma levels enhanced the contribution of antithrombin to the inactivation of FXIa in plasma up to 5-fold.In conclusion, we found that the tested low molecular weight glycosaminoglycans dalteparin, enoxaparin and nadroparin and LMWdxs stimulate inactivation of FXIa by C1-inhibitor in a system using purified proteins as well as in plasma. Furthermore, LMWH but not LMWdxs slightly enhanced FXIa inhibition by antithrombin.