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Gene targeting in hemostasis. Alpha2-antiplasmin
1Center for Molecular and Vascular Biology, University of Leuven, Campus, Gasthuisberg, O & N, Herestraat 49, B-3000 Leuven, Belgium. roger.lijnen@med.kuleuven.ac.be
Frontiers in Bioscience : a Journal and Virtual Library
|February 15, 2001
Summary
Alpha2-antiplasmin (AP) deficiency in mice enhances fibrinolysis without bleeding. This suggests AP primarily regulates circulating plasmin and intravascular fibrinolysis.
Area of Science:
- Biochemistry
- Physiology
- Genetics
Background:
- Alpha2-antiplasmin (AP) is the primary physiological inhibitor of plasmin in mammalian plasma.
- AP rapidly forms an inactive complex with plasmin, requiring active and lysine-binding sites on plasmin.
- AP deficiency in humans is linked to bleeding disorders, suggesting its critical role.
Purpose of the Study:
- To investigate the physiological role of alpha2-antiplasmin (AP) in vivo.
- To characterize the effects of AP deficiency on fibrinolysis and thrombosis in a murine model.
Main Methods:
- Gene targeting in embryonic stem cells to create AP-deficient mice via homologous recombination.
- Assessment of fibrinolytic capacity through pulmonary embolism lysis, kidney fibrin deposition, arterial thrombosis, and cerebral ischemia models.
- Evaluation of AP deficiency in a vascular injury restenosis model.
Main Results:
- Homozygous AP-deficient mice exhibited enhanced endogenous fibrinolytic capacity without overt bleeding.
- Reduced fibrin deposition, limited arterial thrombosis, and smaller infarct size were observed in AP-deficient mice.
- AP deficiency did not significantly impact smooth muscle cell migration or neointima formation in a restenosis model.
Conclusions:
- Alpha2-antiplasmin's main role in mice is regulating plasmin activity in circulating blood.
- AP is crucial for controlling intravascular fibrinolysis.
- AP deficiency enhances fibrinolysis but does not necessarily lead to spontaneous bleeding in mice.