Cross-linked γ-chains in fibrin fibrils bridge transversely between strands: Yes

Abstract

In the course of this discussion I covered all significant arguments for or against the transverse cross-linking arrangement in fibrin. Experiments that employed fibrin as a template for disposing the D domains of fibrinogen, from Selmayr's experiments onward, showed unambiguously that the γ-chain arrangement in fibrin was transverse. Analyses of cross-linked fibrinogen fibrils, either by themselves or after assembly on a fibrin fragment E template, also showed that transverse cross-linking was the operative mechanism. In the other camp, interpretations of experiments by John Weisel's group favoring DD-long cross-linking depended vitally upon the electron microscopic appearance of acetic acid-dissociated molecular assemblies. Acidic conditions disrupt fibrin D:E contacts and inevitably result in unfolding to single-stranded fibrils whose γ-chains are de facto in DD-long alignment. Such experimental conditions do not reproduce the important intermolecular contacts that exist in a fibrin polymer, and they therefore are not useful for assessing the cross-linking arrangement in fibrin. Similarly, arguments for DD-long cross-linking based upon existing X-ray structures have little or no discriminatory power to locate the cross-linked γ-chains in fibrin. I consider these arguments to be non-contributory to the issue at hand. Based upon these several considerations, I conclude that transverse positioning accounts for most, if not all, γ-chain alignments in cross-linked fibrin fibrils. I further conclude that because transversely cross-linked γ-chains bridge between the strands of a fibril, their unique location in the polymer structure accounts for the limits on stretch that accompany maximal clot deformation, as well as the elastic recovery of a deformed cross-linked clot. © 2004 International Society on Thrombosis and Haemostasis.