Published Online
on April 21, 2003

A more recent version of this article appeared on May 13, 2003

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Submitted on November 27, 2002
Revised on February 12, 2003
Accepted on February 18, 2003

Functional Analysis of the Fibrinogen A Thr312Ala Polymorphism. Effects on Fibrin Structure and Function

Kristina F. Standeven MSc, Peter J. Grant MD, FRCP^*, Angela M. Carter PhD, Thomas Scheiner MSc, John W. Weisel PhD, and Robert A.S. Ariëns PhD

From the Academic Unit of Molecular Vascular Medicine (K.F.S., P.J.G., A.M.C., R.A.S.A.), Research School of Medicine, University of Leeds, Leeds General Infirmary, Leeds, UK, and Department of Cell and Developmental Biology (T.S., J.W.W.), University of Pennsylvania School of Medicine, Philadelphia, Pa.

^* To whom correspondence should be addressed. E-mail: P.J.Grant{at}leeds.ac.uk.

Background--The fibrinogen A Thr312Ala polymorphism occurs within the C domain of fibrinogen, which is important for lateral aggregation and factor XIII-induced cross-linking of fibrin fibers. We have previously shown an association of Ala312 fibrinogen with poststroke mortality in subjects with atrial fibrillation and with pulmonary embolism in subjects with venous thrombosis.

Methods and Results--We studied the properties of clots formed from purified Ala312 and Thr312 fibrinogen and found that Ala312 fibrinogen produces stiffer clots, associated with increased chain cross-linking, as demonstrated by SDS-Page. On electron microscopy analysis, we found larger fiber diameters in the Ala312 clots and observed a lower number of fibers per square micrometer. The number of branch points per square micrometer was similar between genotypes.

Conclusions--Our study shows that Ala312 influences clot structure and properties by increased factor XIII cross-linking and formation of thicker fibrin fibers. These findings may provide a mechanism by which Ala312 fibrinogen could predispose to clot embolization.

Key words: fibrinogen • fibrin • thrombosis

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