Abstract
The major structural component of a blood clot is a mesh of fibrin fibers. Our goal was to determine whether fibrinogen glycation and fibrin fiber diameter have an effect on the mechanical properties of single fibrin fibers. We used a combined atomic force microscopy/fluorescence microscopy technique to determine the mechanical properties of individual fibrin fibers formed from blood plasma. Blood samples were taken from uncontrolled diabetic patients as well as age-, gender-, and body-mass-index-matched healthy individuals. The patients then underwent treatment to control blood glucose levels before end blood samples were taken. The fibrinogen glycation of the diabetic patients was reduced from 8.8 to 5.0 mol glucose/mol fibrinogen, and the healthy individuals had a mean fibrinogen glycation of 4.0 mol glucose/mol fibrinogen. We found that fibrinogen glycation had no significant systematic effect on single-fiber modulus, extensibility, or stress relaxation times. However, we did find that the fiber modulus, Y, strongly decreases with increasing fiber diameter, D, as Y∝D−1.6. Thin fibers can be 100 times stiffer than thick fibers. This is unusual because the modulus is a material constant and should not depend on the sample dimensions (diameter) for homogeneous materials. Our finding, therefore, implies that fibrin fibers do not have a homogeneous cross section of uniformly connected protofibrils, as is commonly thought. Instead, the density of protofibril connections, ρPb, strongly decreases with increasing diameter, as ρPb∝D−1.6. Thin fibers are denser and/or have more strongly connected protofibrils than thick fibers. This implies that it is easier to dissolve clots that consist of fewer thick fibers than those that consist of many thin fibers, which is consistent with experimental and clinical observations.
Highlights
In the event of injury to a blood vessel, platelets aggregate at the injury site and the clotting cascade is initiated to form a blood clot that will stop blood flow through the injured blood vessel
The uncontrolled diabetic patients had an average fibrinogen glycation of 8.8 5 3.4 mol glucose/mol fibrinogen, which decreased to an average of 5.0 5 2.4 after intervention
1) Our combined atomic force microscopy (AFM)/ inverted optical microscopy technique is suitable for testing complex plasma samples, in addition to the samples formed from purified fibrinogen that have been tested in the past
Summary
In the event of injury to a blood vessel, platelets aggregate at the injury site and the clotting cascade is initiated to form a blood clot that will stop blood flow through the injured blood vessel. The clotting cascade is a complex series of protein activations culminating in the activation of fibrinogen by activated thrombin. Fibrinogen is an abundant blood protein that consists of a central, globular E region and two distal D regions that are connected by two triple a-helical coiled coils (Fig. 1). Thrombin proteolytically removes two fibrinopeptides A and two fibrinopeptides B from the N-termini of the a- and b-chains in the central E region, thereby exposing two knobs ‘‘A’’ (Gly-Pro-Arg) on the a-chain and two knobs ‘‘B’’ (Gly-His-Arg) on the b-chain, and converting fibrinogen to fibrin. The key interactions for protofibril formation are the A:a and B:b knob-hole interactions, in which the charged knobs ‘‘A’’ and knobs ‘‘B’’ bind to holes ‘‘a’’ and holes ‘‘b’’ in the distal D region, and the D:D interactions of abutting D regions (Fig. 1). Protofibrils aggregate laterally (radially) to form the mature, ~130-nm-thick fibrin fibers of a blood clot. Lateral aggregation of protofibrils is poorly understood, but there is evidence that interactions between the long, largely unstructured a-C regions play a key role [1,2] in lateral aggregation
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