Latent antithrombin and its detection, formation and turnover in the circulation.
It is now apparent that the inactivated latent and cleaved conformers of antithrombin (AT) are of pathological significance. Using a single-run electrophoretic technique that allows the quantitative assessment of these conformers in 2 microL plasma, we show that near 3% of the total AT in the circulations of normal individuals is in latent conformation. Only trace amounts of cleaved AT were observed. The slow decline in AT activity on incubation of plasma at 37 degrees C was shown to be almost wholly due to a transition of native AT to its inactive latent form. Also initial studies in the rabbit indicate that the latent form, like the cleaved, has an identical circulatory half-life to that of native AT. We deduce that the steady concentration of latent AT in the circulation is due to the transition of some 10(12) molecules of AT per second balanced by an equivalent clearance of the latent form. Examples of clinical applications of the new technique include its use as a comprehensive single-step screen for genetic variants associated with AT deficiency, and notably the potential it provides to monitor the changes responsible for the loss of AT in the shock syndromes.
Mushunje
A
A
Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK.
Evans
G
G
Brennan
S O
SO
Carrell
R W
RW
Zhou
A
A
D000818:Animals; D000991:Antithrombins / Q000032:analysis* / Q000737:chemistry*; D001775:Blood Circulation; D002417:Cattle; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods*; D015951:Factor Xa / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011817:Rabbits; D015843:Serpins / Q000737:chemistry; D013696:Temperature; D013997:Time Factors; D014508:Urea / Q000494:pharmacology
D000991:Antithrombins; D015843:Serpins; D014508:Urea; D015951:Factor Xa