Researchers uncover new facets of fibrin

Fibrin

Researchers in the Netherlands were able to learn how fibrin maintains such strong elastic resilience and hope to use this information to explain what causes clot failure.

“To better understand the superior elasticity of fibrin networks, we measured the mechanical behavior of purified fibrin gels on multiple scales,” said the senior author of the study, Gijsje Koenderink, PhD, from the Biological Soft Matter Group and the FOM Institute AMOLF in the Netherlands. “We found that the fibrin has a series of molecular domains that are stretched out sequentially, on smaller and smaller scales, when clots are deformed. This stretching leads to gel stiffening, which protects the clot from damage.”

The team learned that fibrin fibers are porous loose bundles of thin filaments connected by crosslinkers. Because the structure is open and 80% water, fibers are 100-fold more flexible than once thought, while the straightening out of bundles also allows the structure to become rigid.

“Our data reveal molecular design principles that allow blood clots to recover from large forces, such as shear forces from blood flow, furthering our understanding of how pathological alterations in fibrin cause clot rupture and bleeding or thrombosis,” said Dr Koenderink.

The study was published May 18 in Biophysical Journal.

In Georgia, another group of researchers at Georgia Tech and Emory University found a better way to inhibit fibrin formation and prevent clotting.

When fibrinogen is modified to form fibrin, “knobs” are exposed, and these knobs fit into “holes” at either end of fibrinogen molecules. The group investigated fibrin polypeptide knobs to better understand fibrin assembly mechanisms and polymerization in hopes of finding better synthetic knobs. They measured characteristics of 6 knob sequences to evaluate backbone stabilization and charge distribution. Structural properties of knob peptides had not been examined in an aqueous environment before now because small peptides could not be crystallized for structural X-ray studies.

Using surface plasmon resonance (SPR), the team, led by Thomas Barker, PhD, an assistant professor at Georgia Tech and Emory University, found that the presence of the amino acids proline and phenylalanine most strongly encouraged the binding of knobs and holes among fibrin molecules by increasing stabilization and by encouraging formation of peptides with charged configurations in the 6th and 7th positions of their amino acid sequences.

The novel knob peptide mimic GPRPFPAC causes the connecting of knobs and holes on fibrin molecules 10-fold higher than current gold standard synthetics. In the future, the team would like to modify the peptide to enhance its ability to inhibit fibrin formation when necessary.

“An additional goal for this technology is to develop a viable delivery strategy for synthetically engineered fibrin glue so that we can guide and control the body’s response to an injury,” said Barker.

The study was published online May 19 in the journal Blood.