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Case Reports
, 309 (12), 694-8

Mutation of Antitrypsin to Antithrombin. Alpha 1-antitrypsin Pittsburgh (358 Met Leads to Arg), a Fatal Bleeding Disorder

Case Reports

Mutation of Antitrypsin to Antithrombin. Alpha 1-antitrypsin Pittsburgh (358 Met Leads to Arg), a Fatal Bleeding Disorder

M C Owen et al. N Engl J Med.

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 A variant alpha 1-antitrypsin was identified in which the methionine at position 358 had been replaced by an arginine.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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