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Thank you for attending THSNA 2026. The virtual meeting is now closed.
Thank you for attending THSNA 2026. The virtual meeting is now closed.
Presentation Details
| Acceleration of internal lysis of contracted clots is driven by bundling and alignment of fibrin fibers (THSNA �Travel Awardee) Rebecca Risman1, 2, Eva Iungbludt2, Joshua Packer3, Nathan Hudson3, John Weisel1, Valerie Tutwiler2. 1University of Pennsylvania, Philadelphia, PA, USA.2Rutgers University, New Brunswick, NJ, USA.3Eastern Carolina University, Greenville, NC, USA |
Abstract
Background: Clot contraction is the volume shrinkage of a blood clot due to platelet-driven contractile forces. It is known that clot contraction accelerates internal fibrinolysis (the physiological degradation of the fibrin network) but restricts external fibrinolysis (the exogenous delivery of fibrinolytic agents) in whole blood. We previously showed that external fibrinolysis is limited in contracted clots due to the densified fibrin network in the periphery that impairs the diffusion of tissue plasminogen activator into the core of the clot, but the mechanism of acceleration of internal lysis remains unknown. An improved understand of the regulation of internal fibrinolysis of contracted clots can inform about methods to design better therapeutics to effectively degrade stubborn contracted clots. Methods: A comprehensive array of experiments at micro- and macroscopic levels were used to systematically disentangle the dominating mechanism leading to faster fibrinolysis of contracted clots during internal fibrinolysis. Turbidimetric assays were used to visualize clot formation and fibrinolysis of clots with and without platelets, as well as with constrained clots and the impairment of contractile forces. Scanning electron and confocal microscopy were used to visualize clots made with platelet-rich plasma and platelet-poor plasma to study the fibrin network structure. Platelet-driven tension was mimicked at the macroscale with large clots in a mechanical tenser to identify the role of tension and network configuration (Figure 2A). Conversely, microscale lysis experiments were performed with individual fibers under tension to isolate tension alone (Figure 2D). Results: Unconstrained clots made with platelet-rich plasma lysed faster than clots without platelets, constrained volume shrinkage, or impairment of tension (Figure 1A-D). This suggested that tension alone was not the mechanism of accelerated lysis of contracted clots— rather, it was due to changes in fibrin network structure. Notably, clot contraction resulted in a dense periphery and heterogeneous core, unlike the other clots that possessed a homogeneous network (Figure 1E, F). Moreover, contracted clots had bundled and aligned fibers because of fibrin rearrangement. Clots with applied tension lysed faster than those with less tension (Figure 2B) due to bundling of fibers (Figure 2C). Tension delays lysis of individual fibers but speeds up lysis when fibers bundle with high percent strain (Figure 2F). Conclusion: Artificial thickening of fibers due to fibrin bundling as a result platelet-driven fibrin rearrangement drove the acceleration of internal fibrinolysis of contracted clots, rather than platelet-driven tension on fibers. We propose that contracted clots have fewer, thicker bundled fibers that provided an easier platform for plasmin to transversely crawl and cut a fiber for degradation.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.