Fibrinogen (factor I) is a glycoprotein complex that circulates in the blood of vertebrates. During tissue and vascular injury it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clot. Fibrin clots function primarily to occlude blood vessels to stop bleeding. Fibrin also binds and reduces the activity of thrombin.

This activity, sometimes referred to as antithrombin I, limits clotting. Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby promotes revascularization and wound healing.[1]

Reduced and/or dysfunctional fibrinogens occur in various congenital and acquired human fibrinogen-related disorders. These disorders represent a group of rare conditions in which individuals may present with severe episodes of pathological bleeding and thrombosis; these conditions are treated by supplementing blood fibrinogen levels and inhibiting blood clotting, respectively. These disorders may also be the cause of certain liver and kidney diseases.

Fibrinogen is a “positive” acute-phase protein, i.e. its blood levels rise in response to systemic inflammation, tissue injury, and certain other events. It is also elevated in various cancers. Elevated levels of fibrinogen in inflammation as well as cancer and other conditions have been suggested to be the cause of thrombosis and vascular injury that accompanies these conditions.

Fibrinogen In Blood Clotting

During blood clotting, thrombin attacks the N-terminus of the Aα and Bβ chains in fibrinogen to form individual fibrin strands plus two small polypeptides, fibrinopeptides A and B derived from these respective chains. The individual fibrin strands then polymerize and are crosslinked with other fibrin stands by blood factor XIIIa to form an extensive interconnected fibrin network that is the basis for the formation of a mature fibrin clot.

In addition to forming fibrin, fibrinogen also promotes blood clotting by forming bridges between, and activating, blood platelets through binding to their GpIIb/IIIa surface membrane fibrinogen receptor.

Fibrin participates in limiting blood clot formation and degraging formed blood clots by at least two important mechanisms. First, it possesses three low affinity binding sites (two in fibrin’s E domain; one in its D domain) for thrombin; this binding sequesters thrombin from attacking fibrinogen.

[caption id=“attachment_102072” align=“aligncenter” width=“700”]Fibrinogen to fibrin coagulation Blood soluble fibrinogens turn to insoluble fibrins to facilitate blood clotting.

  1. FpAs are cut off by thrombin. New N-terminals link to γA chains of D domains and protofibrils begin to form.
  2. FpBs are cut off by thrombin a bit later. New N-terminals link to Bβ chains of D domains. αCs previously bound by FpBs are also released. αCs allow for bi- and equilateral branching.
  3. XIIIa cross-links fibrins (dark blue lines). C-terminal γA-γA- and Aα-Aα-cross-links form. Cyan: Aα chains Red: Bβ chains Pink: γA chains FpA: fibrinopeptides A FpB: fibrinopeptides B αC: Aα chain C-terminal domain D: D domain E: E domain IIa: thrombin XIIIa: factor XIIIa (activated form) Bi: bilateral branching Eq: equilateral branching
    Credit: adapted from figure 3.1, (2018) Cardiovascular thrombus, Academic Press, pp. 31–43 ISBN: 9780128126165.[/caption]

Second, fibrin’s Aα chain accelerates by at least 100-fold the mount of plasmin activated by tissue plasminogen activator; plasmin breaks-down blood clots. Plasmin’s attack on fibrin releases D-dimers (also termed DD dimers). The detection of these dimers in blood is used as a clinical test for fibrinolysis.


Fibrinogen is made and secreted into the blood primarily by liver hepatocyte cells. Endothelium cells are also reported to make small amounts of fibrinogen but this fibrinogen has not been fully characterized; blood platelets and their precursors, bone marrow megakaryocytes, while once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein.

The final secreted, hepatocyte-derived glycoprotein is composed of two trimers with each trimer composed of three different polypeptide chains, the fibrinogen alpha chain (also termed the Aα or α chain) encoded by the FGA gene, the fibrinogen beta chain (also termed the Bβ or β chain) encoded by the FGB gene, and the fibrinogen gamma chain (also termed the γ chain) encoded by the FGG gene. All three genes are located on the long or “p” arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively).

[caption id=“attachment_102073” align=“aligncenter” width=“700”]Two relatively common human fibrinogen variants Two relatively common human fibrinogen variants that form via alternative splicing.
Top: γA/γ' is a hexamer of γ', γA, 2 Aαs and 2 Bβs. γ' is rarer than γA. γ' has an extended C-terminal. Even rarer γ'/γ' combination can exist. Bottom: rare fibrinogen-420 has a mass of 420 kDa. The C-terminals of its γ-chains are extended (αEC).
Cyan: Aα or extended α chains Red: Bβ chains Pink: γA or γ' chains Green (Ca2+): calcium ions
Orange: carbohydrates bound covalently to C-terminal domains of Bβ chains FpA: fibrinopeptides A FpB: fibrinopeptides B αC: Aα chain C-terminal domain D: D domain E: E domain
Credit: (picture adapted from figure 3.4): (2018) Cardiovascular thrombus, Academic Press, pp. 31–43 ISBN: 9780128126165.[/caption]

Alternate splicing of the FGA gene produces a minor expanded isoform of Aα termed AαE which replaces Aα in 1–3% of circulating fibrinogen; alternate splicing of FGG produces a minor isoform of γ termed γ' which replaces γ in 8–10% of circulating fibrinogen; FGB is not alternatively spliced. Hence, the final fibrinogen product is composed principally of Aα, Bβ, and γ chains with a small percentage of it containing AαE and/or γ' chains in place of Aα and/or γ chains, respectively.

The three genes are transcribed and translated in co-ordination by a mechanism(s) which remains incompletely understood.

The coordinated transcription of these three fibrinogen genes is rapidly and greatly increased by systemic conditions such as inflammation and tissue injury. Cytokines produced during these systemic conditions, such as interleukin 6 and interleukin 1β, appear responsible for up-regulating this transcription.

[1] Mosesson MW (2005). Fibrinogen and fibrin structure and functions. Journal of Thrombosis and Haemostasis. 3 (8): 1894–904. doi:10.1111/j.1538-7836.2005.01365.x

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