Fibrin in blood clots forms natural amyloid

Fibrin polymers are formed in response to vascular damage and act as a wound sealant in blood clots to prevent excessive blood loss. The fibrin polymers are degraded by the serine protease plasmin (fibrinolysis). The fibrin polymer initiates this process, by binding to- and activation of tissue-type plasminogen activator (tPA), which converts the zymogen plasminogen into plasmin. However, despite extensive research and elucidation of putative sites in fibrin that activate tPA, the structural requirements for the activation of fibrinolysis by fibrin are unknown [1]. tPA is also activated by numerous other protein aggregates and it was shown that the common denominator among these activators is resemble amyloid [2]. Amyloids are fibrillar protein aggregates found in plaques associated with the pathogenesis of degenerative diseases such as Alzheimer's disease and Creutzfeld- Jakob's disease (amyloidoses). Amyloid fibrils are composed of stacked beta-sheets with a 4.7 Å distance between the amino-acid strands that run perpendicular to the fibril axis. This structure has been named cross-beta structure and can arise irrespective of a specific amino-acid sequence [3]. Fibrinolysis has been reported in various amyloidoses [4] and it can be directly induced by the pathological protein aggregates [2]. Recently, it was observed that the interaction of tPA with both fibrin and amyloid is mediated by one and the same domain, the fibronectin type I domain [5]. Together, this leads to the question if there is a common feature in both fibrin and amyloid fibrils. Using various methods we here report that fibrin forms amyloid cross-beta structure, implicating that cross-beta structure triggers fibrinolysis, contributing to removal of obsolete proteins such as fibrin in blood clots.