Title
Aberrant fibrin formation and cross-linking of fibrinogen Nieuwegein, a variant with a shortened Aα-chain, alters endothelial capillary tube formation
Author
Collen, A.
Maas, A.
Kooistra, T.
Lupu, F.
Grimbergen, J.
Haas, F.J.L.M.
Biesma, D.H.
Koolwijk, P.
Koopman, J.
van Hinsbergh, V.W.M.
Gaubius instituut TNO
Publication year
2001
Abstract
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 Aα 453 (Pro) introduced a stop codon at position 454, which resulted in the deletion of the Carboxyl-terminal segment Aα 454-610. The ensuing unpaired cysteine at Aα 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 αvβ3, indicating that the reduced ingrowth is not due to the absence of the RGD-adhesion site at position Aα 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 α-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 crosslinked by TG and which is less supportive for ingrowth of endothelial cells. © 2001 by The American Society of Hematology.
Subject
Adult
Afibrinogenemia
Biopolymers
Capillaries
Cells, Cultured
Codon, Terminator
Endothelium, Vascular
Exons
Fibrin
Fibrinogens, Abnormal
Humans
Male
Microscopy, Electron
Molecular Weight
Mutagenesis, Insertional
Neovascularization, Physiologic
Oligopeptides
Partial Thromboplastin Time
Receptors, Vitronectin
Sequence Deletion
Structure-Activity Relationship
Transglutaminases
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DOI
https://doi.org/10.1182/blood.v97.4.973
TNO identifier
235975
ISSN
0006-4971
Source
Blood, 97 (4), 973-980
Document type
article