Elucidating the physical basis of blood clot stability

Summary

Whenever we cut ourselves, proteins and cells in our blood stream rapidly form a stiff blood clot that seals off the wound to prevent bleeding. Fibrin, the main structural component of blood clots, provides a highly extensible scaffold that stiffens upon deformation, conferring the clot with the mechanical durability it needs to withstand blood flow and tissue remodeling. Once the wound has healed, the clot needs to rapidly and completely disappear to ensure normal blood circulation. This “all-or-nothing” behavior is a unique property of blood clots, not found in any other biomaterial. Extensive biochemical and biomedical research has identified and characterized the main molecular players involved. But how does the molecular system ‘know’ when the fibrin scaffold is needed and when it must disappear? Interestingly, clots under mechanical strain have been shown to be protected against enzymatic degradation. This observation strongly suggests that clot stability may be regulated by a physical mechanism involving mechanical regulation of protein activities. Here, I will for the first time use a quantitative and multiscale biophysical approach to elucidate the role of mechanical strain in clot stability. I will work with a minimal reconstituted system composed of fibrin and plasmin, the main enzyme dissolving fibrin. I will use advanced biophysical techniques that integrate force measurements with in situ fluorescence imaging to measure plasmin-mediated fibrin lysis as a function of strain. This multiscale approach should allow me to distinguish between the mechanisms involving strain-induced changes in the structure at the network scale which modify the access of proteolytic enzymes, from mechanisms involving strain-induced structural changes of the fibers. By using a quantitative physics approach, this research will provide a basis to understand how blood clots balance mechanical stability and degradation.

Details

Project number

680-47-462

Main applicant

Dr. C. Martinez Torres

Affiliated with

Nederlandse Organisatie voor Wetenschappelijk Onderzoek, NWO-institutenorganisatie, AMOLF

Duration

01/01/2018 to 30/11/2019