(Circulation. 1999;99:299-304.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
The Contribution of Activated Factor XIII to Fibrinolytic Resistance in Experimental Pulmonary Embolism
From Harvard School of Public Health (G.L.R., A.K.H.), Harvard Medical School, and Massachusetts General Hospital (G.L.R.), Boston, Mass.
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—The resistance of thrombi to fibrinolysis induced by plasminogen activators remains a major impediment to the successful treatment of thrombotic diseases. This study examines the contribution of activated factor XIII (factor XIIIa) to fibrinolytic resistance in experimental pulmonary embolism.
Methods and Results—The fibrinolytic effects of specific
inhibitors of factor XIIIa–mediated fibrin-fibrin
cross-linking and 
2-antiplasmin–fibrin cross-linking were measured
in anesthetized ferrets with pulmonary emboli. Five
experimental groups were treated with heparin (100 U/kg) and/or tissue
plasminogen activator (TPA, 1 mg/kg) and the
percent (mean±SD) lysis of emboli was determined: (1) control, normal
factor XIIIa activity (14.1±4.8% lysis); (2) inhibited factor XIIIa
activity (42.7±7.4%); (3) normal factor XIIIa activity+TPA
(32.3±7.7%); (4) inhibited factor XIIIa activity+TPA (76.0±11.9%);
and (5) inhibited 2-antiplasmin–fibrin cross-linking+TPA
(54.7±3.9%). Inhibition of factor XIIIa activity increased
endogenous lysis markedly (group 1 versus 2;
P<0.0001), to a level comparable to that achieved with
TPA (group 2 versus 3; P<0.05). Among groups receiving
TPA, selective inhibition of factor XIII-mediated
2-antiplasmin–fibrin cross-linking enhanced lysis (group 3 versus
5; P<0.0005). Complete inhibition of factor XIIIa also
amplified lysis (group 3 versus 4; P<0.0001) and had
greater effects than inhibition of 2-antiplasmin
cross-linking alone (group 4 versus 5; P<0.0005). No
significant fibrinogen degradation occurred in any group.
Conclusions—Factor XIIIa–mediated fibrin-fibrin and
2-antiplasmin–fibrin cross-linking both caused experimental
pulmonary emboli to resist endogenous and
TPA-induced fibrinolysis. This suggests that factor
XIIIa may play a critical role in regulating
fibrinolysis in human thrombosis.
Key Words: embolism • fibrinolysis • plasminogen activators • thrombus
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