Regulation of arterial thrombolysis by plasminogen activator inhibitor-1 in mice.
BACKGROUND
Platelet-rich arterial thrombi are resistant to lysis by plasminogen activators. However, the mechanisms underlying thrombolysis resistance are poorly defined. Plasminogen activator inhibitor-1 (PAI-1), which is present in plasma, platelets, and vascular endothelium, may be an important determinant of the resistance of arterial thrombi to lysis. However, in vitro studies examining the regulation of platelet-rich clot lysis by PAI-1 have yielded inconsistent results.


RESULTS
We developed a murine arterial injury model and applied it to wild-type (PAI-1 [+/+]) and PAI-1-deficient (PAI-1 [-/-]) animals. FeCl3 was used to induce carotid artery thrombosis. Thrombi consisted predominantly of dense platelet aggregates, consistent with the histology of thrombi in large-animal arterial injury models and human acute coronary syndromes. To examine the role of PAI-1 in regulating endogenous clearance of platelet-rich arterial thrombi, thrombi were induced in 22 PAI-1 (+/+) mice 14 PAI-1 (-/-) mice. Twenty-four hours later, the amount of residual thrombus was determined by histological analysis of multiple transverse sections of each artery. Residual thrombus was detected in 55 of 85 sections (64.7%) obtained from PAI-1 (+/+) mice compared with 19 of 56 sections (33.9%) from PAI-1 (-/-) mice (P=.009). Computer-assisted planimetry analysis revealed that mean thrombus cross-sectional area was 0.033+/-0.0271 mm2 in PAI-1 (+/+) mice versus 0.016+/-0.015 mm2 in PAI-1 (-/-) mice (P=.048).


CONCLUSIONS
PAI-1 is an important determinant of thrombolysis at sites of arterial injury. Application of this model to other genetically altered mice should prove useful for studying the molecular determinants of arterial thrombosis and thrombolysis.
Farrehi
P M
PM
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, USA.
Ozaki
C K
CK
Carmeliet
P
P
Fay
W P
WP
D000818:Animals; D015415:Biomarkers; D002341:Carotid Artery Thrombosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*
D015415:Biomarkers; D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1