Anticoagulant and antithrombotic properties of a gamma-carboxyglutamic acid-rich peptide derived from the light chain of blood coagulation factor X.

In this report, we describe the anticoagulant and antithrombotic properties of a peptide (residues 1-44) derived from the amino-terminus of the bovine Factor X light chain by limited proteolysis with chymotrypsin, and subsequently purified by QAE-Sephadex chromatography. The effect of Factor X gla-peptide on the activation of human 3H-Factors IX and X was studied using radiometric assays and purified coagulation factors. Factor VIIa-tissue factor catalyzed activation of Factors IX and X was half-maximally inhibited by Factor X gla-peptide at concentrations of 0.8 microM and 0.2 microM, respectively. Factor IXa-VIII catalyzed Factor X activation was half-maximally inhibited at a gla-peptide concentration of 0.5 microM. In addition, thrombin formation by platelets incubated with Factor Xa and prothrombin could be similarly blocked by gla-peptide. Studies with bovine aortic endothelial cells indicated that the Factor X gla-peptide blocked in parallel Factor X binding and activation on the cell surface. Decarboxylation of the peptide by acid heat treatment destroyed its anticoagulant activity. The in vivo anticoagulant potential of native gla-peptide was demonstrated by a rapid prolongation of the PT and APTT following intravenous infusion into a rabbit. In addition, gla-peptide prevented thrombus formation in response to Factors IXa and Xa, but not thrombin, in a Wessler venous stasis model.