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Blood, 15 February 2001, Vol. 97, No. 4, pp. 973-980
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Aberrant fibrin formation and cross-linking of fibrinogen
Nieuwegein, a variant with a shortened A -chain, alters
endothelial capillary tube formation
Annemie Collen,
Annemarie Maas,
Teake Kooistra,
Florea Lupu,
Jos Grimbergen,
Fred J. L. M. Haas,
Douwe H. Biesma,
Pieter Koolwijk,
Jaap Koopman, and
Victor W. M. van Hinsbergh
A congenital dysfibrinogenemia,
fibrinogenNieuwegein, was discovered in a young man
without any thromboembolic complications or bleeding. A homozygous
insertion of a single nucleotide (C) in codon A 453 (Pro) introduced
a stop codon at position 454, which resulted in the deletion of the
carboxyl-terminal segment A 454-610. The ensuing unpaired cysteine
at A 442 generated fibrinogen-albumin complexes of different
molecular weights. The molecular abnormalities of
fibrinogenNieuwegein 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
fibrinogenNieuwegein-derived fibrin
(fibrinNieuwegein) 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
v 3, indicating that the reduced ingrowth
is not due to the absence of the RGD-adhesion site at position A
572-574. Rather, the altered structure of fibrinNieuwegein 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 fibrinNieuwegein, 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 -chains of
fibrinogenNieuwegein. 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.
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