Abstract
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 α2-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 α2- 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 α2-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 α2-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 α2-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.
Original language | English (US) |
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Pages (from-to) | 299-304 |
Number of pages | 6 |
Journal | Circulation |
Volume | 99 |
Issue number | 2 |
DOIs | |
State | Published - Jan 19 1999 |
Externally published | Yes |
Keywords
- Embolism
- Fibrinolysis
- Plasminogen activators
- Thrombus
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)