PMID:
     6604220
Authors:
     Owen MC, Brennan SO, Lewis JH, Carrell RW.
Title:
     Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met 
     leads to Arg), a fatal bleeding disorder.
Journal:
     N Engl J Med. 1983 Sep 22;309(12):694-8.
Abstract:
     Our previous studies predicted a functional relationship between the plasma
     proteins alpha 1-antitrypsin and antithrombin III. To elucidate this relationship
     we investigated the plasma of a 14-year-old boy who had died from an episodic
     bleeding disorder. A variant alpha 1-antitrypsin was identified in which the
     methionine at position 358 had been replaced by an arginine. This had converted
     the alpha 1-antitrypsin from its normal function as an inhibitor of elastase to
     that of an inhibitor of thrombin. This finding indicates that the reactive center
     of alpha 1-antitrypsin is methionine 358, which acts as a bait for elastase, just
     as the normal reactive center of antithrombin III is arginine 393, which acts as 
     a bait for thrombin. The independence of the new thrombin inhibitor from heparin 
     control explains the bleeding disorder; it also indicates that heparin normally
     acts directly on antithrombin III, revealing its inherent inhibitory activity.
     The episodic nature of the bleeding was a consequence of the mutant protein's
     being an acute-phase reactant, the level of which increased several-fold after
     trauma.

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