Limiting prothrombin activation to meizothrombin is compatible with survival but significantly alters hemostasis in mice

摘要: Thrombin-mediated proteolysis is central to hemostatic function but also plays a prominent role in multiple disease processes. The proteolytic conversion of fII α-thrombin (fIIa) by the prothrombinase complex occurs through 2 parallel pathways: (1) inactive intermediate, prethrombin; or (2) proteolytically active meizothrombin (fIIa(MZ)). FIIa(MZ) has distinct catalytic properties relative fIIa, including diminished fibrinogen cleavage and increased protein C activation. Thus, activation may differentially influence hemostasis depending on pathway To determine vivo physiologic pathologic consequences restricting thrombin generation fIIa(MZ), mutations were introduced into endogenous gene, resulting expression prothrombin carrying 3 amino acid substitutions (R157A, R268A, K281A) limit events yield only fIIa(MZ) Homozygous fII(MZ) mice are viable, express levels comparable with fII(WT) mice, have reproductive success. Although vitro studies revealed delayed enzyme activity, platelet aggregation similar Consistent prior analyses human significant prolongation clotting times was observed for plasma. Adult animals displayed significantly compromised tail bleeding assays, did not demonstrate overt bleeding. More notably, had phenotypic advantages over animals: protection from occlusive thrombosis after arterial injury markedly metastatic potential setting experimental tumor metastasis lung. these novel will provide valuable tool assess both fIIa vivo.