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(Circulation. 2000;102:1151.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Catalytic Life of Activated Factor XIII in Thrombi

Implications for Fibrinolytic Resistance and Thrombus Aging

Brian R. Robinson, MD; Aiilyan K. Houng, BS; Guy L. Reed, MD

From the Harvard School of Public Health (B.R.R., A.K.H., G.L.R.), Harvard Medical School and Massachusetts General Hospital (G.L.R.), Boston.

Correspondence to Guy L. Reed, MD, Cardiovascular Biology Laboratory, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115. E-mail reed{at}cvlab.harvard.edu

Background—Because the increased fibrinolytic resistance of older thrombi may be caused by the continuous cross-linking action of fibrin-bound activated factor XIII (FXIIIa), we examined the persistence of FXIIIa catalytic activity in clots of various ages.

Methods and Results—The time-related changes in FXIIIa activity in clots was measured with (1) ₂-antiplasmin (₂AP), a physiological glutamine substrate; (2) ₂AP_13–24, a peptide; and (3) pentylamine, a nonspecific lysine substrate. The cross-linking of ₂AP, ₂AP_13–24, and pentylamine into fibrin by clot-bound FXIIIa declined rapidly with half-lives of 19, 21, and 26 minutes, respectively. Mutational studies showed that glutamine 14 (but not glutamine 3 or 16) and valine 17 of ₂AP_13–24 were required for efficient cross-linking to fibrin. The loss of activity was not due primarily to FXIIIa proteolysis and was partially restored by reducing agents, suggesting that oxidation contributes to the loss of the enzyme’s activity in clots. In vivo, the ability of thrombus-bound FXIIIa to cross-link an infused ₂AP_13–24 peptide into existing pulmonary emboli also declined significantly over time.

Conclusions—FXIIIa cross-links ₂AP and an ₂AP peptide, in a sequence-specific manner, into formed clots with a catalytic half-life of 20 minutes. This indicates that FXIIIa activity is a hallmark of new thrombi and that the antifibrinolytic cross-linking effects of FXIIIa are achieved more rapidly in thrombi than previously believed.

Key Words: embolism • fibrinolysis • thrombus

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