INFLUENCE OF LOW-MOLECULAR-WEIGHT HEPARIN AND LOW-MOLECULAR-WEIGHT DEXTRAN SULFATE ON THE INHIBITION OF COAGULATION-FACTOR XIA BY SERPINS

We investigated the influence of low molecular weight dextran sulfate (LMWdxs) and low molecular weight heparins (LMWH: dalteparin, enoxapar in and nadroparin) on the inhibition of FXIa by C1-inhibitor. alpha(1) -antitrypsin, alpha(2)-antiplasmin and antithrombin in a. purified sys tem and in plasma. The second order rate constant for inactivation of FXIa by C1-inhibitor, alpha(1)-antitrypsin, alpha(2)-antiplasmin. and antithrombin was 1.23. 0.056, 0.33 and 0.59 x 10(3) M-1 s(-1), respect ively. LMWdxs and LMWH dose-dependently increased the second order rat e 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-thr ombin 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 ant ithrombin to the inactivation of FXIa. in plasma up to 5-fold. In conc lusion, we found that the tested lon molecular weight glycosaminoglyca ns dalteparin. enoxaparin and nadroparin and LMWdxs stimulate inactiva tion of FXIa by C1-inhibitor in a system using purified proteins as we ll as in plasma. Furthermore, LMWH but not LMWdxs slightly enhanced FX Ia inhibition by antithrombin.