title: Factor XIII stiffens fibrin clots by causing fiber compaction.
abstract: BACKGROUND
  Factor XIII-induced cross-linking has long been associated with the ability of fibrin blood clots to resist mechanical deformation, but how FXIII can directly modulate clot stiffness is unknown.
  
  
  OBJECTIVE
  We hypothesized that FXIII affects the self-assembly of fibrin fibers by altering the lateral association between protofibrils. To test this hypothesis, we studied the cross-linking kinetics and the structural evolution of the fibers and clots during the formation of plasma-derived and recombinant fibrins by using light scattering, and the response of the clots to mechanical stresses by using rheology.
  
  
  RESULTS
  We show that the lateral aggregation of fibrin protofibrils initially results in the formation of floppy fibril bundles, which then compact to form tight and more rigid fibers. The first stage is reflected in a fast (10 min) increase in clot stiffness, whereas the compaction phase is characterized by a slow (hours) development of clot stiffness. Inhibition of FXIII completely abrogates the slow compaction. FXIII strongly increases the linear elastic modulus of the clots, but does not affect the non-linear response at large deformations.
  
  
  CONCLUSIONS
  We propose a multiscale structural model whereby FXIII-mediated cross-linking tightens the coupling between the protofibrils within a fibrin fiber, thus making the fiber stiffer and less porous. At small strains, fiber stiffening enhances clot stiffness, because the clot response is governed by the entropic elasticity of the fibers, but once the clot is sufficiently stressed, the modulus is independent of protofibril coupling, because clot stiffness is governed by individual protofibril stretching.
authors.affiliation: FOM Institute AMOLF, Amsterdam, the Netherlands.
authors.forename: N A
authors.initials: NA
authors.lastname: Kurniawan
authors.forename: J
authors.initials: J
authors.lastname: Grimbergen
authors.forename: J
authors.initials: J
authors.lastname: Koopman
authors.forename: G H
authors.initials: GH
authors.lastname: Koenderink
mesh_terms: D001777:Blood Coagulation; D003432:Cross-Linking Reagents / Q000737:chemistry; D004548:Elasticity; D005176:Factor XIII / Q000737:chemistry*; D005337:Fibrin / Q000737:chemistry*; D005340:Fibrinogen / Q000737:chemistry; D006801:Humans; D008027:Light; D018613:Microscopy, Confocal; D009391:Nephelometry and Turbidimetry; D011108:Polymers / Q000737:chemistry; D012212:Rheology; D012542:Scattering, Radiation; D013314:Stress, Mechanical
chemical_list: D003432:Cross-Linking Reagents; D011108:Polymers; D005337:Fibrin; D005340:Fibrinogen; D005176:Factor XIII
keywords: blood coagulation; elasticity; factor XIII; fibrin; turbidimetry