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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 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 Citation Map 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. Related Collections Hemostasis, Thrombosis, and Vascular Biology Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AIVS4 + 1G>T mutation and an AGln328 truncation (fibrinogen Keokuk) Phil Lefebvre, Pauline T. Velasco, Amy Dear, Karim C. Lounes, Susan T. Lord, Stephen O. Brennan, David Green, and Laszlo Lorand From the Department of Cell and Molecular Biology and the Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL; the Molecular Pathology Laboratory, Canterbury Health Laboratories, Christchurch, New Zealand; and the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill. Two siblings with hypofibrinogenemia have lifelong trauma-related bleeding. Recently, the brother experienced recurrent thrombosis after cryoprecipitate infusions following surgery. The sister had 6 miscarriages. Plasma clots in each were resistant to compression and fibrinolysis and were soluble in 5 M urea. Examination by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (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 the mature fibrinogen A–chain residues 241-476 but not by antibodies to A219-348 or A349-406. DNA analysis revealed a heterozygous CAA TAA mutation at the codon for amino acid 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 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 GT TT 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 for 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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