Abstract
The inhibition of activated human Factor X by human plasma protease inhibitors was investigated in both purified and plasma systems. In the former, antithrombin III, alpha 1-proteinase inhibitor, and alpha 2-macroglobulin, at normal plasma concentrations, markedly inhibited activated Factor X. Significant inhibition by alpha 2-antiplasmin, however, was only achieved when present at 40 times its plasma concentration. The relative rates of inhibition of activated Factor X coagulant activity in normal human plasma, antithrombin III-deficient plasma, and alpha 1-proteinase inhibitor-deficient plasma were 1.0, 0.63, and 0.75, respectively. From these relative rates of inhibition and their measured concentrations in the 3 plasmas, it was calculated that antithrombin III, alpha 1-proteinase inhibitor, and alpha 2-macroglobulin contribute 53, 35, and 12%, respectively, to the inhibition of activated Factor X in normal human plasma. Using 125I-labeled activated Factor X and a combination of sodium dodecyl sulfate disc gel electrophoresis and immunoadsorption, it was then demonstrated that antithrombin III accounted for 45-55%, alpha 1-proteinase inhibitor, 35-40%, and alpha 2-macroglobulin, 10-15% of the inhibition of the labeled protease in normal human plasma. The values obtained with the deficient plasmas are consistent with the distribution of activated Factor X-inhibitor complexes in normal human plasma. These data show by two independent techniques, one measuring coagulant activity and the other 125I-labeled activated Factor X-inhibitor complexes, that both antithrombin III and alpha 1-proteinase inhibitor are the major inhibitors of activated Factor X in normal human plasma.
Highlights
A2-antiplasmin,wasonlyachievedwhen present at 40 times its plasma concentration
Thqeuantities of lZ5I-Factor Xa-inhibitor complexes formed in NHP, alPI-deficient plasma, and AT 111-deficient plasma were measured directly by a combination of SDS-disc gel electrophoresis and immunoadsorption
The former was used to determine the amount of Factor Xa inhibited by a high molecular weight inhibitor, most probably a2M(11).The remaining Factor Xawas inhibited by AT I11 and alPI.Since these two inhibitor-Factor Xa complexes could not be separated by SDS-disc gel electrophoresis, an immunoadsorption technique was employed
Summary
A2-antiplasmin,,wasonlyachievedwhen present at 40 times its plasma concentration. Therelative rates of inhibition of activated Factor X coagulant activity in normal human plasma, antithrombin 111-deficient plasma, and al-proteinase inhibitor-deficient plasma were 1.0,0.63, and 0.75, respectively. With the deficient plasmasare consistent with the dis- ,in thepresent investigation these observations were tribution of activated Factor X-inhibitorcomplexes in further confirmed by data obtained by determination of the normal human plasma. These data show by two inde- rates of inhibition of humanFactorXa in NHP, AT IIIpendent techniques, one measuring coagulant activity deficient plasma, and a,PI-deficient plasma. These data show by two inde- rates of inhibition of humanFactorXa in NHP, AT IIIpendent techniques, one measuring coagulant activity deficient plasma, and a,PI-deficient plasma. and the othe1r 2‘I-labeled activated FactorX-inhibitor complexes, that both antithrombin I11 and al-protein-
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