The Structure and Biological Features of Fibrinogen and Fibrin

Authors

Michael W. Mosesson, Blood Center of WisconsinFollow
Kevin R. Siebenlist, Marquette UniversityFollow
David A. Meh, Blood Center of WisconsinFollow

Document Type

Article

Language

eng

Format of Original

20 p.

Publication Date

6-2001

Publisher

New York Academy of Sciences

Source Publication

Annals of the New York Academy of Sciences

Source ISSN

0077-8923

Original Item ID

doi: 10.1111/j.1749-6632.2001.tb03491.x

Abstract

Fibrinogen and fibrin play important, overlapping roles in blood clotting, fibrinolysis, cellular and matrix interactions, inflammation, wound healing, and neoplasia. These events are regulated to a large extent by fibrin formation itself and by complementary interactions between specific binding sites on fibrin(ogen) and extrinsic molecules including proenzymes, clotting factors, enzyme inhibitors, and cell receptors. Fibrinogen is comprised of two sets of three polypeptide chains termed Aα, Bβ, and γ, that are joined by disulfide bridging within the N-terminal E domain. The molecules are elongated 45-nm structures consisting of two outer D domains, each connected to a central E domain by a coiled-coil segment. These domains contain constitutive binding sites that participate in fibrinogen conversion to fibrin, fibrin assembly, crosslinking, and platelet interactions (e.g., thrombin substrate, Da, Db, γXL, D:D, αC, γA chain platelet receptor) as well as sites that are available after fibrinopeptide cleavage (e.g., E domain low affinity non-substrate thrombin binding site); or that become exposed as a consequence of the polymerization process (e.g., tPA-dependent plasminogen activation). A constitutive plasma factor XIII binding site and a high affinity non-substrate thrombin binding site are located on variant γ′ chains that comprise a minor proportion of the γ chain population. Initiation of fibrin assembly by thrombin-mediated cleavage of fibrinopeptide A from Aα chains exposes two E_A polymerization sites, and subsequent fibrinopeptide B cleavage exposes two E_B polymerization sites that can also interact with platelets, fibroblasts, and endothelial cells. Fibrin generation leads to end-to-middle intermolecular Da to E_A associations, resulting in linear double-stranded fibrils and equilaterally branched trimolecular fibril junctions. Side-to-side fibril convergence results in bilateral network branches and multistranded thick fiber cables. Concomitantly, factor XIII or thrombin-activated factor XIIIa introduce intermolecular covalent ε-(γ glutamyl)lysine bonds into these polymers, first creating γ dimers between properly aligned C-terminal γXL sites, which are positioned transversely between the two strands of each fibrin fibril. Later, crosslinks form mainly between complementary sites on γ chains (forming γ-polymers), and even more slowly among γ dimers to create higher order crosslinked γ trimers and tetramers, to complete the mature network structure.

Comments

Accepted version. Annals of the New York Academy of Sciences, Vol. 936 (June 2001): 11-30. DOI. © 2001 New York Academy of Sciences. Used with permission.

Recommended Citation

Mosesson, Michael W.; Siebenlist, Kevin R.; and Meh, David A., "The Structure and Biological Features of Fibrinogen and Fibrin" (2001). Biomedical Sciences Faculty Research and Publications. 48.
https://epublications.marquette.edu/biomedsci_fac/48