PROTHROMBIN GREENVILLE, ARG(517)-]GLN, IDENTIFIED IN AN INDIVIDUAL HETEROZYGOUS FOR DYSPROTHROMBINEMIA

A 64-year-old white male was referred for evaluation of prolonged prot hrombin time (PT) and activated partial thromboplastin time (aPTT) obt ained before elective surgery with initial PT and PTT results of 14.9 and 38.4 seconds, respectively, which corrected to normal in 1:1 mixes with normal plasma, Functional prothrombin assay indicated a level of 51% with thromboplastin as an activator. The prothrombin antigen was 102%. This discordance in the functional and immunologic prothrombin l evels was evidence for dysprothrombinemia. Western blotting showed tha t thrombin was formed at a normal rate in diluted plasma consistent wi th a mutation within the thrombin portion of prothrombin. DNA was isol ated from leukocytes and the thrombin exons were For exon 13, eight cl ones were sequenced with four clones showing a point mutation in the c odon for Arg((517), which would result in substitution by Gin. Arg(517 ) is part of the Arg-Gly Asp(RGD) sequence in thrombin and contributes to an ion cluster with aspartic acid residues 552 and 554. Mutation a t this residue most probably distorts the structure of the Naf binding site in thrombin. This is the first report indicating the critical ro le of Arg(517) in the normal physiological interaction of thrombin wit h fibrinogen. This dysprothrombin is designated Prothrombin Greenville . (C) 1998 by The American Society of Hematology.