Fatty acid albumin conjugates mechanically weaken and disrupt degradation of fibrin networks

Cardiovascular diseases and stroke together account for the largest causes of death in Western countries. These pathologies are directly linked to the formation of blood clots that block blood flow to vital organs. Common risk factors for such clots are obesity, high blood pressure, diabetes, and high LDL cholesterol. Immediate thrombolytic treatment to dissolve fibrin-rich clots can save lives, but recent research has shown that pure fatty acids (FA) can inhibit thrombolysis via interaction with plasmin. However, since FAs are often complexed to serum albumin in the blood, it is unclear how FAs in blood interact with plasmin, or perhaps with clots, to modulate thrombolysis. Here, we studied how elevated levels of two abundant FAs (oleic and palmitic acid) complexed to bovine serum albumin (BSA) affect fibrin hydrogels and their degradation. We observed the binding of fatty acid-BSA (FABSA) conjugates to fibrin via Förster resonance energy transfer microscopy and noted the effects of FABSA on fibrin gels mechanics and fibrinolysis compared to pure fibrin networks. Specifically, with FABSA in the fibrin network, fibrin hydrogels were mechanically weakened and showed a significant decrease in fibrinolysis speed. These studies show that elevated fatty acid content modifies clot properties, making them mechanically weaker and more resistant to degradation. STATEMENT OF SIGNIFICANCE: Fibrin networks are the primary load-bearing element in blood clots, which are subject to various cyclic forces in the body and have excellent mechanical properties resulting from fibrin's hierarchical structure. These networks are formed in the presence fatty acids, lipoproteins, and albumin in the blood; however, little is known about how these additional constituents modify fibrin network properties. By imaging protein fiber orientation, molecular structure, and degradation in situ, we find that fibrin formation in the presence of elevated fatty acids conjugated to albumin modifies network structure, mechanically weakens fibrin networks, and slows fibrin network degradation considerably. Based on our findings, we suspect that increased fat in blood may lead impeded fibrin degradation and increased clot persistence.