A recombinant murine meizothrombin precursor, prothrombin R157A/R268A, inhibits thrombosis in a model of acute carotid artery injury.

Abstract:

:Mutations in human prothrombin that generate a stable form of meizothrombin or meizothrombin(desF1) cause dysprothrombinemia in both the homozygous and heterozygous state, suggesting that meizothrombin has dominant anticoagulant effects in vivo. The enzymatic characterization of recombinant mouse meizothrombin, meizothrombin(desF1), and thrombin indicates that all 3 enzymes have similar activity toward the chromogenic substrate S-2238, that meizothrombin and meizothrombin(desF1) have less than 10% of the fibrinogen-clotting activity of thrombin, and that meizothrombin is more active than thrombin or meizothrombin(desF1) for thrombomodulin-dependent protein C activation. Thus, activated mouse prothrombin R157A/R268A is similar to human meizothrombin in activity toward S-2238, fibrinogen, and protein C. The time to occlusion after FeCl(3)-induced carotid artery injury was delayed (11.8 +/- 3.6 minutes, n = 5) in Cf2(+/-) mice infused with prothrombin R157A/R268A compared with control mice infused with wild-type prothrombin (5.3 +/- 1.5 minutes, n = 3; P =.006). In this model, prothrombin R157A/R268A has anticoagulant activity that reflects its decreased fibrinogen-clotting activity and preserved protein C-activating activity and is consistent with dominant inhibition of fibrinogen clotting.

journal_name

Blood

journal_title

Blood

authors

Shim K,Zhu H,Westfield LA,Sadler JE

doi

10.1182/blood-2004-02-0478

subject

Has Abstract

pub_date

2004-07-15 00:00:00

pages

415-9

issue

2

eissn

0006-4971

issn

1528-0020

pii

2004-02-0478

journal_volume

104

pub_type

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