SCIENCE & TECHNOLOGY

Fibrinogen Structure – Function

The heart of Fibriant’s science and technology is fibrinogen, a soluble blood protein that can rapidly be converted into an insoluble three-dimensional fibrin network. In vivo this conversion takes place as a result of tissue injury and / or blood vessel damage that triggers the coagulation cascade which ultimately leads to the generation of thrombin. Active thrombin releases small peptides from fibrinogen, activating sites by which the now fibrin monomer molecules can interact with each other and assemble into fibrin polymer strands, which subsequently become integrated into the insoluble three dimensional fibrin network (see Fig 1)

Fibrin polymerisation

Figure 1: On the left a schematic representation of thrombin induced fibrin formation is shown. On the right electron microscopy pictures of individual fibrinogen molecules before activation (top) and a fibrin polymer network after polymerization (bottom) are shown.

The fibrin network is predominantly known for its important role in blood clotting where it provides a scaffold for platelets and other blood cells to form a mature haemostatic plug that seals the injury to the vessel wall, preventing further blood loss and initiating subsequent tissue healing. Recent scientific evidence demonstrates that the structure of the fibrin network plays an important role in tissue repair, remodelling and regeneration by supporting cell migration and influencing cellular phenotype.

Fibrin and fibrinogen also appear to regulate processes such as wound healing, tissue re-modelling, cell differentiation, inflammation and immune response. Elucidation of the exact mechanisms involved in these non-haemostasis functions of fibrin and fibrinogen could identify them as therapeutic targets to treat or prevent diseases in which one or more of these (patho) physiological processes play a role.

The fibrinogen molecule occurs in vivo in many different forms and shapes. Each of these fibrinogen variants has unique functional properties and can form fibrin matrices with different structural and functional characteristics (see Fig 2). Several of these fibrin polymers have interesting properties which can be explored for unique healthcare applications.

Fibrin matrices

Figure 2:
Electron microscopic images of fibrin matrices formed form different variants of fibrinogen. The 3D fibrin matrices differ in diameter of individual fibers, pore size of the network, number of branch points and have different biomechanical properties.

Fibrinogen Technology Platform

Fibriant is developing a Fibrinogen technology platform that has the potential to create a large number of new, high-added value, customized fibrinogen products with healthcare potential.

Most of the fibrinogen variants occur at low quantities in blood and in variable amounts and therefore it is not possible to obtain sufficient material of consistent quality by purification from human donor plasma. Fibriant has established a recombinant expression system for the production of functional recombinant human fibrinogen, using mammalian cell culture, that can be used to produce individual fibrinogen variants at sufficient quantity and quality for R & D applications and which can be scaled up to commercial scale.

To characterize the different variants of fibrinogen, Fibriant has developed several analytical methods that allow detailed structure-function analysis and can be used to determine quantity, purity and stability under various conditions.