Demonstration of enhanced endogenous fibrinolysis in thrombin activatable fibrinolysis inhibitor-deficient mice.
To investigate the importance of thrombin activatable fibrinolysis inhibitor (TAFI) in the stabilization of plasma clots, we have compared fibrinolysis in TAFI-deficient (KO) and wild-type (WT) littermate mice. TAFI-deficient mice were previously generated by targeted gene disruption. The level of TAFI activity generated in plasma from WT mice in the presence of added thrombin and thrombomodulin (activatable TAFI) is twice that of plasma from TAFI heterozygous mice (HET); no activatable TAFI is detected in TAFI KO plasma. In vitro, TAFI KO plasma clots lysed faster than WT plasma clots, and HET plasma clots lysed at an intermediate rate. The rate of clot lysis for KO mice is not changed in the presence of potato carboxypeptidase inhibitor, a specific inhibitor of TAFIa, whereas the WT and HET clot lysis rates are increased in the presence of potato carboxypeptidase inhibitor. C-terminal lysine residues are preserved on partially degraded clots from KO mice, but are absent from partially degraded WT clots. In vivo, in a batroxobin-induced pulmonary embolism model, KO mice displayed a lower retention of fibrin in the lungs than did WT mice. These results are the first demonstration of enhanced endogenous fibrinolysis in an in vivo model without the addition of exogenous thrombolytic.
Mao
Shi-Shan
SS
Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Holahan
Marie A
MA
Bailey
Carolyn
C
Wu
Guoxin
G
Colussi
Dennis
D
Carroll
Steven S
SS
Cook
Jacquelynn J
JJ
D000818:Animals; D012103:Batroxobin / Q000008:administration & dosage / Q000633:toxicity; D025901:Carboxypeptidase B2 / Q000097:blood / Q000172:deficiency*; D005342:Fibrinolysis / Q000187:drug effects / Q000235:genetics*; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010940:Plant Proteins / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011655:Pulmonary Embolism / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D011198:Solanum tuberosum / Q000737:chemistry; D013917:Thrombin / Q000494:pharmacology; D018180:Thrombomodulin / Q000378:metabolism
D006490:Hemostatics; D010940:Plant Proteins; D011480:Protease Inhibitors; D018180:Thrombomodulin; D025901:Carboxypeptidase B2; D012103:Batroxobin; D013917:Thrombin