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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2571-2576. Prepublished online as a Blood First Edition Paper on November 13, 2003; DOI 10.1182/blood-2003-07-2316. This Article Full Text (PDF) All Versions of this Article: 2003-07-2316v1 103/7/2571    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lefebvre, P. Articles by Lorand, L. Search for Related Content PubMed PubMed Citation Articles by Lefebvre, P. Articles by Lorand, L. Social Bookmarking                   What's this? Submitted July 11, 2003 Accepted October 28, 2003 Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AIVS4+1 G>T mutation and an AGln328 truncation (Fibrinogen Keokuk) Phil Lefebvre, Pauline T Velasco, Amy Dear, Karim C Lounes, Susan T Lord, Stephan O Brennan, David Green*, and Laszlo Lorand Department of Cell and Molecular Biology, Northwestern University, Chicago, IL, USA Department of Medicine, Northwestern University, Chicago, IL, USA Molecular Pathology Laboratory, Canterbury Health Laboratories, Christchurch, New Zealand Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA * Corresponding author; email: d-green{at}northwestern.edu. Two hypofibrinogenemic siblings have lifelong trauma-related bleeding. Recently, the brother suffered recurrent thrombosis after cryoprecipitate infusions post-surgery; the sister has suffered six miscarriages. Their plasma clots were resistant to compression and fibrinolysis, and soluble in 5M urea. Examination by SDS-PAGE revealed only the presence of crosslinked - fibrin chain dimers without high polymers of n. Fibrin clots contained an abnormal 35 kDa constituent recognized by an antibody to fibrinogen A chain residues 241-476 but not by antibodies to A291-348 or A349-406. DNA analysis revealed a heterozygous CAATAA mutation at codon 328 of the A gene in these siblings and 2 asymptomatic family members. The Gln328stop mutation (Fibrinogen Keokuk) predicted a 46% truncation and the production of a 35 kDa A chain. Analysis of purified fibrinogen revealed expression of the abnormal A chain in the 4 family members, but found no normal fibrinogen in the 2 hypofibrinogenemic patients. This paradox was resolved when they, and their asymptomatic mother, were found to be heterozygous for a second A mutation, a GTTT splice site mutation in intron 4 (IVS4+1 G>T). However, compound heterozygosity for both mutations was required for the expression of severe hypodysfibrinogenemia and clinical symptoms. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Uitte de Willige, K. F. Standeven, H. Philippou, and R. A. S. Ariens The pleiotropic role of the fibrinogen {gamma}' chain in hemostasis Blood, November 5, 2009; 114(19): 3994 - 4001. [Abstract] [Full Text] [PDF] S. O. Brennan, R. L. Davis, R. Lowen, and A. Ruskova Deletion of five residues from the coiled coil of fibrinogen (B{beta} Asn167_Glu171del) associated with bleeding and hypodysfibrinogenemia Haematologica, April 1, 2009; 94(4): 585 - 588. [Abstract] [Full Text] [PDF] L. Lorand Crosslinks in blood: transglutaminase and beyond FASEB J, June 1, 2007; 21(8): 1627 - 1632. [Full Text] [PDF] R. Park, H.-J. Doh, S.-S. A. An, J.-R. Choi, K.-H. Chung, and K.-S. Song A novel fibrinogen variant (fibrinogen Seoul II; A{alpha}Gln328Pro) characterized by impaired fibrin {alpha}-chain cross-linking Blood, September 15, 2006; 108(6): 1919 - 1924. [Abstract] [Full Text] [PDF] K. S. Song, N. J. Park, J. R. Choi, H. J. Doh, and K. H. Chung Fibrinogen Seoul (FGG Ala341Asp): A Novel Mutation Associated With Hypodysfibrinogenemia Clinical and Applied Thrombosis/Hemostasis, July 1, 2006; 12(3): 338 - 343. [Abstract] [PDF]

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