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.
D015055:1-Carboxyglutamic Acid / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000925:Anticoagulants / Q000502:physiology; D001011:Aorta / Q000166:cytology; D001777:Blood Coagulation / Q000187:drug effects*; D002417:Cattle; D002918:Chymotrypsin / Q000494:pharmacology; D004727:Endothelium / Q000187:drug effects; D005164:Factor IX / Q000037:antagonists & inhibitors; D005170:Factor X / Q000378:metabolism* / Q000502:physiology; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000302:isolation & purification* / Q000502:physiology; D011485:Protein Binding; D011516:Prothrombin / Q000037:antagonists & inhibitors; D011817:Rabbits; D013927:Thrombosis / Q000517:prevention & control
D000925:Anticoagulants; D010446:Peptide Fragments; D015055:1-Carboxyglutamic Acid; D011516:Prothrombin; D005164:Factor IX; D005170:Factor X; D002918:Chymotrypsin