From the Departments of Internal Medicine (P.M.F., W.P.F.) and Surgery
(C.K.O.), University of Michigan Medical School, Ann Arbor; the Ann Arbor
Veterans Affairs Hospital (W.P.F.); and the Center for Molecular and Vascular
Biology (P.C.), University of Leuven (Belgium).
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.
Methods and 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±0.027
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.
© 1998 American Heart Association, Inc.
Basic Science Reports
Regulation of Arterial Thrombolysis by Plasminogen Activator Inhibitor-1 in Mice
Key Words: thrombosis • thrombolysis • carotid arteries • plasminogen activators
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