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The evolution of clot-promoting and amidolytic activities in mixtures of Hageman factor (factor XII) and ellagic acid

The enhancing effect of other proteins
  • Oscar D. Ratnoff
    Correspondence
    Reprint requests: Dr. Oscar D. Ratnoff, University Hospitals of Cleveland, Cleveland, Ohio 44106.
    Footnotes
    Affiliations
    From the Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A.

    From the University Hospitals of Cleveland, Cleveland, Ohio, U.S.A.
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  • Hidehiko Saito
    Affiliations
    From the Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A.

    From the University Hospitals of Cleveland, Cleveland, Ohio, U.S.A.
    Search for articles by this author
  • Author Footnotes
    1 Dr. Ratnoff is a Career Investigator of the American Heart Association.
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      Abstract

      Ellagic acid (4,4′,5,5′,6,6′-hexahydroxydiphenic acid 2,6,2′,6′-dilactone) can substitute for negatively charged surfaces as a stimulus to reactions of the intrinsic pathway. Incubation of solutions of 4 × 10−6M ellagic acid with purified HF (factor XII) induced clot-promoting and amidolytic activity. Clot-promoting activity tested on a substrate of HF-deficient plasma evolved much more rapidly than amidolytic activity. Clot-promoting activity generated in mixtures of HF and ellagic acid alone, but amidolytic activity was observed only if additional proteins such as albumin were also present. Treatment of purified HF with DFP or filtration of HF through columns of SBTI bound to agarose did not prevent its subsequent activation by ellagic acid. Solutions of SBTI, at high concentration, partly inhibited the generation of amidolytic activity, whereas popcorn inhibitor and a crude lgG fraction of anti-HF inhibited the amidolytic activity that had been generated in a mixture of HF and ellagic acid. Generation of clotting and amidolytic properties was accompanied by scission of HF within an internal disulfide loop and by cleavage of HF into fragments with approximate MWs of 50,000 and 30,000; cleavage was completely blocked by popcorn inhibitor and partially blocked by high concentrations of SBTI. These experiments demonstrate that ellagic acid can activate HF in a manner analogous to negatively charged solids such as glass or kaolin.

      Abbreviations:

      Hageman factor, or factor XII ((HF)), plasma thromboplastin antecedent, or factor XI ((PTA)), diisopropylfluorophosphate ((DFP)), soybean trypsin inhibitor ((SBTI)), H-d-prolyl-l-phenylalanyl-l-arginine p-nitroanilide dihydrochloride ((HPPAN)), p-nitroaniline ((p-NA)), high-molecular-weight ((HMW)), sodium dodecyl sulfate-polyacrylamide gel electrophoresis ((SDS-PAGE)), molecular weight ((MW))
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