What Is the Biological and Clinical Relevance of Fibrin?

Abstract

As our knowledge of the structure and functions of fibrinogen and fibrin has increased tremendously, several key findings have given some people a superficial impression that the biological and clinical significance of these clotting proteins may be less than earlier thought. Most strikingly, studies of fibrinogen knockout mice demonstrated that many of these mice survive to weaning and beyond, suggesting that fibrin(ogen) may not be entirely necessary. Humans with afibrinogenemia also survive. Furthermore, in recent years, the major emphasis in the treatment of arterial thrombosis has been on inhibition of platelets, rather than fibrin. In contrast to the initially apparent conclusions from these results, it has become increasingly clear that fibrin is essential for hemostasis; is a key factor in thrombosis; and plays an important biological role in infection, inflammation, immunology, and wound healing. In addition, fibrinogen replacement therapy has become a preferred, major treatment for severe bleeding in trauma and surgery. Finally, fibrin is a unique biomaterial and is used as a sealant or glue, a matrix for cells, a scaffold for tissue engineering, and a carrier and/or a vector for targeted drug delivery.

Fig. 1

Schematic representation of the major steps of fibrin polymerization, beginning with a crystallographic image of fibrinogen (PDB Entry: 3GHG), a soluble plasma protein. Fibrinogen molecule has a rod-like shape and is composed of the lateral globular parts (two β- and two γ-nodules) and one central nodule linked with the lateral portions via two triple-helical coiled-coil connectors. Limited thrombin-catalyzed cleavage of four peptide bonds in fibrinogen leads to formation of monomeric fibrin with two C-terminal globules and a central N-terminal globule containing complementary intermolecular binding sites. Self-assembly of monomeric fibrin in a half-staggered manner forms two-stranded fibrin oligomers that elongate up to the length of a protofibril comprising 20 to 25 monomeric units. Protofibrils aggregate laterally and get packed into a fiber with a regular 22.5-nm periodic cross-striation due to the half-staggered molecular structure and regular protofibril arrangement. A detailed description of fibrin formation can be found in our review article.

Fig. 2

Scanning electron micrographs of in vitro clots. (A) Clot from platelet-poor plasma, which is an open branched network of fibrin fibers. (B) Clot from platelet-rich plasma, with platelet aggregates connected by fibrin fibers. (C) Whole blood clot, with fibrin, platelets, and red blood cells. Magnification bar = 20 µm.

Fig. 3

Scanning electron micrographs of in vivo thrombi. (A) Coronary artery thrombus, with dense mesh of fibrin and platelet aggregates. Magnification bar = 10 µm. (B) Pulmonary embolus, with dense mesh of fibrin, platelet aggregates, and red blood cells. Magnification bar = 10 µm.

Fig. 4

Formation of fibrin clots in vivo, their size, and location, as well as fine structure and properties are greatly influenced by several variable pathogenic factors shown in the upper part of the cartoon. The biological and clinical relevance of fibrin is determined by its implications in the vital interconnected patho (physiological) reactions and processes as well as by the use of fibrin polymers as a versatile biomaterial.