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Prepublished online as a Blood First Edition Paper on March 27, 2003; DOI 10.1182/blood-2002-10-3150.
Submitted October 17, 2002
Accepted March 10, 2003
Fibrinogen gamma chain splice variant  ' alters fibrin formation and structure
Amy V Cooper, Kristina F Standeven, and Robert A S Ariens*
Academic Unit of Molecular Vascular Medicine, University of Leeds, Leeds, United Kingdom
* Corresponding author; email: r.a.s.ariens{at}leeds.ac.uk.
 A/' fibrinogen results from alternative splicing of mRNA. This variant, which constitutes approximately 8-15% of plasma fibrinogen, contains FXIII and thrombin binding sites. Our objective was to investigate whether A/' differs in fibrin formation and structure from the more common variant A/A. Both variants were separated and purified by anion-exchange chromatography. Fibrin formation and clot structure of the variants and unfractionated fibrinogen were investigated by turbidity and scanning electron microscopy (SEM). Thrombin cleavage of fibrinopeptides was analysed by HPLC. Turbidity analysis showed significantly altered polymerization rates and overall fibre thickness in A/' clots compared with A/A and unfractionated fibrinogen. This finding was consistent with a range of thrombin concentrations. HPLC demonstrated reduced rates of FpB release from A/' fibrinogen compared with A/A. Delayed FpB release was associated with delayed lateral aggregation of protofibrils and significant differences were found on SEM, with A/' clots consisting of smaller diameter fibers and increased numbers of branch-points compared with both A/A and unfractionated fibrinogen. These results demonstrate that the A/' splice variant of fibrinogen directly alters fibrin formation and structure, which may help to explain the increased thrombotic risk associated with this variant.
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