Modifiers of fibrin(ogen) and association with disease. Clot formation, structure, and stability are influenced by conditions present during fibrin generation. Abnormal clot formation is observed in several diseases.

Modifiers of fibrin(ogen) and association with disease

Kattula S, Byrnes JR, Wolberg AS. Fibrinogen and Fibrin in Hemostasis Thrombosis. Arterioscler Thromb Vasc Biol. 2017;37:e13-e21.

FXIIIa cross-linking during fibrin formation. Fibrinogen is a hexamer composed of 2 Aα- (purple), 2 Bβ- (blue), and 2 γ-chains (green). During coagulation, thrombin cleaves N-terminal fibrinopeptides from the Aα- and Bβ-chains, producing fibrin monomers which polymerize into protofibrils and subsequently, fibers. FXIIIa increases clot stability by introducing ε-N-(γ-glutamyl)-lysyl cross-links between residues in the γ- and α-chains of fibrin monomers within individual fibers. FXIIIa first introduces cross-links between γ-chains (forming γ-γ dimers) and subsequently between γ- and α-chains (forming high-molecular-weight species [γ-multimers, α-polymers, and αγ-hybrids]).

FXIIIa cross-linking during fibrin formation

Byrnes JR, Wolberg AS. Newly-Recognized Roles of Factor XIII in Thrombosis. Semin Thromb Hemost. 2016;42(04):445-454.

Venous thrombi contain regions of high red blood cell (RBC) and fibrin content. Left) Gross image of a segment of human venous thrombus (pulmonary embolus) collected at autopsy at UNC Hospitals. Note the presence of darker (RBC rich) regions. Image courtesy of Vincent J. Moylan, Jr, MS, PA(ASCP), UNC at Chapel Hill, School of Medicine. Right) Transmission electron micrograph of a pulmonary embolus showing the ‘brick-and-mortar’ organization of RBCs and fibrin within the thrombus.

Venous thrombi contain regions of high RBC and fibrin content

Walton BL, Byrnes JR, Wolberg AS. Fibrinogen, red blood cells, and factor XIII in venous thrombosis. J Thromb Haemost. 2015;13(Suppl. 1):S208-S215.

Interplay between abnormalities in blood components, the vasculature, and blood flow contribute to the development of arterial thrombosis. Arterial thrombosis involves the formation of platelet-rich “white clots” that form after rupture of atherosclerotic plaques and exposure of procoagulant material such as lipid-rich macrophages (foam cells), collagen, tissue factor, and/or endothelial breach, in a high shear environment. TM = thrombomodulin; II = prothrombin; IIa = thrombin; Fgn = fibrinogen; TF = tissue factor.
Arterial thrombosis. Abbreviations: TM, thrombomodulin; II, prothrombin; IIa, thrombin; Fgn, fibrinogen; TF, tissue factorWolberg AS, Aleman MM, Leiderman K, Machlus KR. Procoagulant activity in hemostasis and thrombosis: Virchow’s triad revisited. Anesth Analg. 2012;114(2):275-285.
Tissue factor-initiated coagulation

Schematic of cell-mediated procoagulant activities leading to fibrin clot formation

Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev. 2007;21(3):131-142

Distribution of fibrin fibers above a cell surface using Laser Scanning Confocal Microscopy and Transmission Electron Microscopy
Distribution of fibrin fibers above a cell surface using Laser Scanning Confocal Microscopy and Transmission Electron Microscopy
Normal and Hemophilic Clots

Confocal micrographs of normal vs. hemophilic clots

Gray LD, Hussey MA, Larson BM, et al. Recombinant factor VIIa analog NN1731 (V158D/E296V/M298Q-FVIIa) enhances fibrin formation, structure and stability in lipidated hemophilic plasma. Thromb Res. 2011;128(6):570-576.

Networks formed under flow and stasis

Scanning electron micrographs of networks formed under flow (left) and stasis (right)

Campbell RA, Aleman MM, Gray LD, et al. Flow profoundly influences fibrin network structure: implications for fibrin formation and clot stability in haemostasis. Thromb Haemost. 2010;104(6):1281-1284.