AbstractFibrin is a fibrous protein network that entraps blood cells and platelets to form blood clots following vascular injury. As a biomaterial, fibrin acts a biochemical scaffold as well as a viscoelastic patch that resists mechanical insults. The biomechanics and biochemistry of fibrin have been well characterized independently, showing that fibrin is a hierarchical material with numerous binding partners. However, comparatively little is known about how fibrin biomechanics and biochemistry are coupled: how does fibrin deformation influence its biochemistry at the molecular level? In this study, we show how mechanically-induced molecular structural changes in fibrin affect fibrin biochemistry and fibrin-platelet interaction. We found that tensile deformation of fibrin lead to molecular structural transitions of α-helices to β-sheets, which reduced binding of tissue plasminogen activator (tPA), an enzyme that initiates fibrinolysis, at the network and single fiber level. Moreover, binding of tPA and Thioflavin T (ThT), a commonly used β-sheet marker, was primarily mutually exclusive such that tPA bound to native (helical) fibrin whereas ThT bound to strained fibrin. Finally, we demonstrate that conformational changes in fibrin suppressed the biological activity of platelets on mechanically strained fibrin due to attenuated αIIbβ3 integrin binding. Our work shows that mechanical strain regulates fibrin molecular structure and fibrin biological activity in an elegant mechano-chemical feedback loop, which likely influences fibrinolysis and wound healing kinetics.
Pathogenic Mutations Induce Partial Structural Changes in the Native β-Sheet Structure of Transthyretin and Accelerate Aggregation