Aberrant fibrin formation and cross-linking of fibrinogen Nieuwegein, a variant with a shortened A alpha-chain, alters endothelial capillary tube formation

A congenital dysfibrinogenemia, fibrinogen(Nieuwegein), was discovered in a young man without any thromboembolic complications or bleeding. A homozygo us insertion of a single nucleotide (C) in codon A alpha 453 (Pro) introduc ed a stop codon at position 454, which resulted in the deletion of the carb oxyl-terminal segment A alpha 454-610, The ensuing unpaired cysteine at A a lpha 442 generated fibrinogen-albumin complexes of different molecular weig hts, The molecular abnormalities of fibrinogen(Nieuwegein) led to a delayed clotting and a fibrin network with a low turbidity, Electron microscopy co nfirmed that thin fibrin bundles were organized in a fine network. The use of fibrinogen(Nieuwegein)-derived fibrin (fibrin(Nieuwegein)) in an in vitr o angiogenesis model resulted in a strong reduction of tube formation. The ingrowth of human microvascular endothelial cells (hMVEC) was independent o f alpha (v)beta (3), indicating that the reduced ingrowth is not due to the absence of the RGD-adhesion site at position A alpha 572-574, Rather, the altered structure of fibrin(Nieuwegein) is the cause, since partial normali zation of the fibrin network by lowering the pH during polymerization resul ted 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 or-chains of fibrinogen (Nieuwegein). In conclusion, this newly discovered congenital dysfibrinogen emia has a delayed clotting time and leads to the formation of an altered f ibrin structure, which could not be crosslinked by TG and which is less sup portive for ingrowth of endothelial cells. (C) 2001 by The American Society of Hematology.