Multiscale, Multiphysics Model of Thrombus Biomechanics in Aortic Dissection

Summary

Principal Investigator: George Karniadakis
Abstract: DESCRIPTION (provided by applicant): Aortic dissection is a life threatening event;it is responsible for significant morbidity and mortality in individuals ranging in age from children to young and older adults. When a dissection communicates with the true lumen and forms a so-called false lumen within the aortic wall, this false lumen may remain patent or become either partially or completely thrombosed. Increasing clinical evidence suggests that a completely thrombosed false lumen results in an improved prognosis whereas a partially thrombosed false lumen may render the wall more vulnerable to further dissection or rupture. Yet, there is a pressing need to understand better the mechanisms by which, and conditions under which, a false lumen is expected to develop either a partial or a full thrombus and why the latter is beneficial. We hypothesize that the extent of thrombus formation depends primarily on the hemodynamics within the false lumen and that partially thrombosed dissections are dangerous because the continued release of plasmin by an intramural thrombus in contact with flowing blood can activate constitutively produced, latent matrix metalloproteinases within the remnant aortic wall, which in turn weaken the wall. We will develop the first data-driven, multiscale, multiphysics model of the biomechanics of intramural throm- bus in aortic dissection. Specifically, we will extend and then couple a multiscale model of blood flow, platelet kinetics, fibrin organization, and plasmin transport (Karniadakis group) with a multiscale model of aortic wall mechanics and fibrin/collagen remodeling (Humphrey group) that will be informed and validated with extensive new imaging and immuno-histological data from the most widely accepted mouse model of dissecting aortic aneurysms (i.e., 28 day infusion of angiotensin II in the apolipoprotein null mouse). In addition, our model will be designed to simulate the potential benefits of two anti-coagulants in terms of the time(s) of delivery. Realization of our three Specific Aims will significantly increase our understanding of roles of thrombus in aortic dissection, with the promise of eventually leading to an improved prognostic capability and interventional planning. In addition, insight gained in this study will have important implications for a host of other vascular conditions, including dissections of other arteries, treatment of pseudo-aneurysms with thrombin following catheterization, and the different roles of intraluminal thrombus in abdominal aortic aneurysms and intracranial aneurysms. We submit, therefore, that this project has significant promise to increase our basic understanding of a key issue in vascular biology as well as to contribute to treating better a broad class of clinical problems. 1
Funding Period: 2013-09-01 - 2018-08-31
more information: NIH RePORT

Top Publications

  1. pmc Computational modelling suggests good, bad and ugly roles of glycosaminoglycans in arterial wall mechanics and mechanobiology
    S Roccabianca
    Department of Biomedical Engineering, Yale University, New Haven, CT, USA
    J R Soc Interface 11:20140397. 2014

Detail Information

Publications1

  1. pmc Computational modelling suggests good, bad and ugly roles of glycosaminoglycans in arterial wall mechanics and mechanobiology
    S Roccabianca
    Department of Biomedical Engineering, Yale University, New Haven, CT, USA
    J R Soc Interface 11:20140397. 2014
    ....

Research Grants30

  1. Mechanisms Underlying the Progression of Arterial Stiffness in Hypertension
    Jay D Humphrey; Fiscal Year: 2013
    ..abstract_text> ..
  2. Improved stent design through hemodynamics and vascular biology
    Juan Miguel Jimenez; Fiscal Year: 2013
    ....
  3. Model of Platelet Adhesion and Thrombus Formation
    Michael R King; Fiscal Year: 2013
    ..The simulation will be first applied to the clinical investigation and diagnosis of hereditary bleeding disorders, and in the future will enable phenotype prediction of patients treated with anticoagulants such as aspirin and Plavix. ..
  4. Gender Specific Evolution of Abdominal Aortic Aneurysm Composition and Properties
    Jay D Humphrey; Fiscal Year: 2013
    ..abstract_text> ..
  5. Biomechanical Mechanisms of Artery Tortuosity
    Hai Chao Han; Fiscal Year: 2013
    ..Understanding the biomechanical mechanisms how tortuosity initiates and develop will reveal its role in vascular disease and lead to new understanding of vascular disease and set a basis for development of new treatment. ..