Blood coagulation, fibrin fibers, heart attacks & strokes – understanding & treatment

AFM-FM set-up

Blood clots stem the flow of blood, which is essentially a mechanical task. Hence, there has been a longstanding interest, initiated by Ferry, in the mechanical properties of clots. The major structural component of a clot are tiny, nanoscopic fibers called fibrin fibers (~ 100 nm diameter).

We are using a combined atomic force & fluorescence microscope to determine the mechanical and physical properties of biological fibers and molecules.  We are studying fibrin fibers, which are the principal structural component of a blood clot.  Thus, this work will advance our understanding of heart attacks and strokes, and it may yield novel treatment options for heart attacks and strokes.  This work is done in collaboration with the Wake Forest University Biochemistry department, the University of North Carolina, University of Leeds (UK) and North-West University (South Africa). 

We are currently investigating the correlation between diseases and single fiber properties, and we are trying to understand clot dissolution.

The following links show movies of fibrin fiber manipulations.

S1_Fig. 1 Breaking uncrosslinked batroxobin fiber. Uncrosslinked batroxobin fiber (The arms break at 183% and 278% strain)

S2_Fig 2 Snap-back of crosslinked thrombin. Crosslinked thrombin fiber Elastic snap-back from 80%, permanent damage at 230% strain)

S3_525%_extensibility_T_X. This fiber gets strain 525% (6.25 its length) before breaking.

S4_150% elastic 240% rupture. Crosslinked thrombin fiber (150% strain elastic, 240% permanent damage)

S5_Lolo Snap-back. Uncrosslinked thrombin (Nice, elastic snap-back)

 

Fibrin fiber specific publications:

  1. Helms, C. C., Ariëns, R. A. S., de Willige, S. U., Standeven, K.. S., Guthold, M. “a-a Crosslinks Increase Fibrin Fiber Elasticity and Stiffness” Biophysical Journal (2012), (in press).
  2. Guthold, M., Cho, S. S. “Fibrinogen Unfolding Mechanisms Are Not Too Much of a Stretch” Structure (2011) 19, 1536-38.
  3. Carlisle, R.C., Sparks, E.A., Der Loughian, C., Guthold, M., “Strength and Failure of Fibrin Fiber Branch Points”, J. Thrombosis and Haemostasis (2010) 8, 1135-38.
  4. Liu, W., Carlisle, R.C., Sparks, E.A., Guthold, M., “The mechanical properties of single fibrin fibers”, J. Thrombosis and Haemostasis (2010) 8, 1030-1036.
  5. M. Guthold, W. Liu, E. A. Sparks, L. M. Jawerth, L. Peng, M. Falvo, R. Superfine, R. R. Hantgan, S. T. Lord (2007) “A comparison of the mechanical and structural properties of fibrin fibers with other protein fibers” Cell Biochemistry and Biophysics 49, 165-181.
  6. Liu, W., Jawerth, L. M., Sparks, E. A ., Falvo, M. R., Hantgan, R. R., Superfine, R., Lord, S. T., Guthold, M., (2006)  “Fibrin Fibers have Extraordinary Extensibility and Elasticity” Science 313, 634
  7. Guthold, M., Liu, W., Stephens, B. J., Lord, S. T., Hantgan, R. R., Erie, D. A., Taylor, R. M., Superfine, R. (2004) “Visualization and Mechanical Manipulations of Individual Fibrin Fibers Suggest that Fiber Cross-Section has Fractal Dimension 1.3”  Biophys. J. 87, 4226-36

Funding from the NSF.