End-linked homodimers in fibrinogen Osaka VI with a B beta-chain extensionlead to fragile clot structure

The authors have identified a la-residue carboxyl-terminal extension of Lys -Ser-Pro-Met-Arg-Arg-Phe-Leu-Leu-Phe-Cys-Met in a dysfibrinogen derived fro m a woman heterozygotic for this abnormality and associated with severe ble eding. This extension is due to a T-to-A mutation that creates AAG encoding Lys at the stop (TAG) codon, thus translating 36 base pairs in the noncodi ng region of the B beta gene. The extra Cys residues appear to be involved in 1 or 2 disulfide bonds between 2 adjacent abnormal fibrinogen molecules, forming a fibrinogen homodimer as indicated by sodium dodecyl sulfate-poly acrylamide gel electrophoresis. Indeed, about half of the fibrinogen molecu les exist as end-linked dimers oriented in parallel or with an angle, as ob served by transmission electron microscopy, These end-linked dimers may wel l alter the conformations of D and DD regions on fibrin assembly, leading t o increased fiber branching at their sites in the growing protofibrils. By scanning electron microscopy, the Osaka VI fibrin network appears to have a lacelike structure composed of highly branched, thinner fibers than the no rmal fibrin architecture. Such fibrin networks may be easily damaged to for m large pores when fluids are allowed to pass through the gels. The fragili ty of Osaka VI fibrin clots, further confirmed by permeation and compaction studies, may account for the massive bleeding observed in this patient. (C ) 2000 by The American Society of Hematology.