Molecular basis for the fibrinogen structure and functions - Analysls of hereditary dysfibrinogens and their application to the study

Studies on two hereditary dysfibrinogens were conducted in collaboration with Dr.Michael W.Mosesson focusing on electron microscopic analyses.1)Fbg Niigata was found to have a unique BβAsn-160 to Ser substitution with an extra oligosaccharide N-linked to BβAsn-150.Although the double-stranded fibrin protofibrils are normally formed，their lateral association is impaired，most probably due to the extra oligosaccharide attached to the coiled-coil region。Indeed，enzymatic deglycosylation resulted in enhancement of fibrin monomer polymerization to a great extent。Scanning electron microscopic analyses of fibrin clots revealed an abnormal architecture，being composed of curvilinear fibrin fibers.After deglycosylation，the fibrin fibers became nearly normal，being straight and appropriately branched。The result together with biochemical and gene analysis data is now under the status of revision in BLOOD。Fibrinogen Marburg from Germany was found in a20-year-old woman who underwent a Caesarian section on her first delivery at the age of20.Severe bleeding and successive recurrent thrombo-embolic complications were characteristic。This molecule has a150-amino acid residue truncation of the Aα-chain，and is partly disulfide-bridged with serum albumin at AαCys-442。The Marburg fibrin clots are apparently fragile but totally resistant against plasmin Furthermore，factor XIIIa-crosslinking profiles analyzed by SDS-PAGE manifested severalα·β-heteromultimers，not observed in the normal sample。To be noted is that the Aα-chain-linked serum albumin was crosslinked to the g-chain of another fibrin molecules，creating disordered fibrin clots.Scanning electron microscopy showed compact fibrin gels consisting of extremely thin but highly branched fibrin fibers.These findings seem to account for recurrent postoperativethrombo-embolic complications。Part of these results appeared in BLOOD(91：3282-3288，1998)and the remainder is now in preparation for publication.

Studies on two hereditary dysfibrinogens were conducted in collaboration with Dr. Michael W. Mosesson focusing on electron microscopic analyses. 1) Fbg Niigata was found to have a unique Bβ Asn-160 to Ser substitution with an extra oligosaccharide N-linked to Bβ Asn-150.Although the double-stranded fibrin protofibrils are normally formed, their lateral association is impaired, most probably due to the extra oligosaccharide attached to the coiled-coil region. Indeed, enzymatic deglycosylation resulted in enhancement of fibrin monomer polymerization to a great extent. Scanning electron microscopic analyses of fibrin clots revealed an abnormal architecture, being composed of curvilinear fibrin fibers. After deglycosylation, the fibrin fibers became nearly normal, being straight and appropriately branched. The result together with biochemical and gene analysis data is now under the status of revision in BLOOD. Fibrinogen Marburg from Germany was found in a 20-year-old woman who underwent a Caesarian section on her first delivery at the age of 20.Severe bleeding and successive recurrent thrombo-embolic complications were characteristic. This molecule has a 150-amino acid residue truncation of the Aα-chain, and is partly disulfide-bridged with serum albumin at Aα Cys-442. The Marburg fibrin clots are apparently fragile but totally resistant against plasmin Furthermore, factor XIIIa-crosslinking profiles analyzed by SDS-PAGE manifested several α・β- heteromultimers, not observed in the normal sample. To be noted is that the Aα-chain-linked serum albumin was crosslinked to the g-chain of another fibrin molecules, creating disordered fibrin clots. Scanning electron microscopy showed compact fibrin gels consisting of extremely thin but highly branched fibrin fibers. These findings seem to account for recurrent postoperativethrombo-embolic complications. Part of these results appeared in BLOOD (91 : 3282-3288, 1998) and the remainder is now in preparation for publication.