A
congenital dysfibrinogenemia,
fibrinogen(Nieuwegein), was discovered in a young man without any thromboembolic complications or
bleeding. A homozygous insertion of a single
nucleotide (C) in
codon Aalpha 453 (Pro) introduced a stop
codon at position 454, which resulted in the deletion of the carboxyl-terminal segment Aalpha 454-610. The ensuing unpaired
cysteine at Aalpha 442 generated
fibrinogen-
albumin complexes of different molecular weights. The molecular abnormalities of
fibrinogen(Nieuwegein) led to a delayed clotting and a
fibrin network with a low turbidity. Electron microscopy confirmed that thin
fibrin bundles were organized in a fine network. The use of
fibrinogen(Nieuwegein)-derived
fibrin (
fibrin(Nieuwegein)) in an in vitro angiogenesis model resulted in a strong reduction of tube formation. The ingrowth of human microvascular endothelial cells (hMVEC) was independent of alpha(v)beta(3), indicating that the reduced ingrowth is not due to the absence of the RGD-adhesion site at position Aalpha 572-574. Rather, the altered structure of
fibrin(Nieuwegein) is the cause, since partial normalization of the
fibrin network by lowering the pH during polymerization resulted in an increased tube formation. Whereas
factor XIIIa further decreased the ingrowth of hMVEC in
fibrin(Nieuwegein),
tissue transglutaminase (TG), which is released in areas of vessel injury, did not. This is in line with the absence of the cross-linking site for TG in the alpha-chains of
fibrinogen(Nieuwegein). In conclusion, this newly discovered
congenital dysfibrinogenemia has a delayed clotting time and leads to the formation of an altered
fibrin structure, which could not be cross-linked by TG and which is less supportive for ingrowth of endothelial cells.