EFFECT OF HEPARIN ON THE ACTIVATION OF FACTOR-XI BY FIBRIN-BOUND THROMBIN

Fibrin-bound thrombin is protected from inactivation by antithrombin I II, while its coagulant potential is retained. In the presence of hepa rin, ternary complexes between thrombin, fibrin and heparin are formed . In these complexes the coagulant activity of thrombin is retained, w hereas the anticoagulant activity of fibrin-bound heparin is neutraliz ed. The limited effectiveness of heparin in the prevention of both ven ous thrombosis and coronary reocclusion is probably related to the pro tective effect of fibrin on the inactivation of thrombin by antithromb in III. Recently, it has been shown that factor XI can be activated by thrombin, resulting in the generation of additional thrombin via the intrinsic pathway. This additional thrombin is capable of stabilizing the clot by protecting it from fibrinolysis. We studied the effect of heparin on the activation of factor XI by fibrin-bound thrombin. First , we used fibrin monomers coupled to Sepharose to which thrombin and u nfractionated heparin (UFH) were bound. Factor XI activation by thromb in was the same in the presence of fibrin-Sepharose or control-Sepharo se. The addition of heparin (0.1 U/ml) resulted in a 91 and 15-fold en hancement in the presence of control-Sepharose and fibrin-Sepharose, r espectively. Next, we added complexes of heparin, thrombin and fibrin monomer to factor XII and XI double-deficient plasma in the presence o r absence of a reconstituting amount of factor XI. In the presence of factor XI, additional fibrin formation was observed indicating that fa ctor XI activation by thrombin in complex with fibrin and heparin can take place in plasma. We then studied the effect of other heparin-like anticoagulants on the thrombin-mediated factor XI activation. UFH enh anced thrombin-mediated factor XI activation 68-fold, LMWH (low molecu lar weight heparin, Fragmin) 12-fold, danaparoid (Orgaran) 3-fold, whi le the pentasaccharide ORG 31540 did not result in an enhancement. Bin ding studies of these anticoagulants to fibrin-Sepharose showed that L MWH bound with approximately the same affinity as UFH, while danaparoi d and the pentasaccharide did not bind to fibrin. We conclude that fib rin-bound thrombin is capable of factor XI activation. Furthermore, he parin bound in a complex with fibrin can act as a cofactor for this ac tivation. This factor XI activation capacity may play a role in the li mited effectiveness of heparin. Provided that thrombin-mediated factor XI activation plays an important role in vivo, danaparoid and especia lly the pentasaccharide may be better anticoagulants than UFH and LMWH .