Fibrin networks regulate protein transport during thrombus development

PLoS Comput Biol. 2013;9(6):e1003095. doi: 10.1371/journal.pcbi.1003095. Epub 2013 Jun 13.

Abstract

Thromboembolic disease is a leading cause of morbidity and mortality worldwide. In the last several years there have been a number of studies attempting to identify mechanisms that stop thrombus growth. This paper identifies a novel mechanism related to formation of a fibrin cap. In particular, protein transport through a fibrin network, an important component of a thrombus, was studied by integrating experiments with model simulations. The network permeability and the protein diffusivity were shown to be important factors determining the transport of proteins through the fibrin network. Our previous in vivo studies in mice have shown that stabilized non-occluding thrombi are covered by a fibrin network ('fibrin cap'). Model simulations, calibrated using experiments in microfluidic devices and accounting for the permeable structure of the fibrin cap, demonstrated that thrombin generated inside the thrombus was washed downstream through the fibrin network, thus limiting exposure of platelets on the thrombus surface to thrombin. Moreover, by restricting the approach of resting platelets in the flowing blood to the thrombus core, the fibrin cap impaired platelets from reaching regions of high thrombin concentration necessary for platelet activation and limited thrombus growth. The formation of a fibrin cap prevents small thrombi that frequently develop in the absence of major injury in the 60000 km of vessels in the body from developing into life threatening events.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Fibrin / metabolism*
  • Hemodynamics
  • Mice
  • Microfluidics / instrumentation
  • Protein Transport
  • Proteins / metabolism*
  • Thrombosis / pathology*

Substances

  • Proteins
  • Fibrin

Grants and funding

We acknowledge partial support from the National Science Foundation grants DMS-0800612 (OVK, ZX, and MSA), MCB 0951264 (MSA), DMS-1115887 (ZX), and Gerber Foundation (OK and MSA). Use of the Center for Nanoscale Materials was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.