a haemodynamic predictor of intraluminal thrombus

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, 20140163, published 8 October 2014470 2014 Proc. R. Soc. A   P. Di Achille, G. Tellides, C. A. Figueroa and J. D. Humphrey   thrombus formation in abdominal aortic aneurysms A haemodynamic predictor of intraluminal    
Supplementary data
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Received: 27 February 2014 Accepted: 13 August 2014
Subject Areas: biomedical engineering, computer modelling and simulation
Keywords: platelet activation, endothelial dysfunction, computational fluid dynamics, thrombosis
Author for correspondence: J. D. Humphrey e-mail: [email protected]
Electronic supplementary material is available at http://dx.doi.org/10.1098/rspa.2014.0163 or via http://rspa.royalsocietypublishing.org.
A haemodynamic predictor of intraluminal thrombus formation in abdominal aortic aneurysms P. Di Achille1, G. Tellides2,3, C. A. Figueroa4
and J. D. Humphrey1,3
1Department of Biomedical Engineering, Yale University, New Haven, CT, USA 2Department of Surgery, and 3Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA 4Department of Surgery and Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
Intraluminal thrombus (ILT) is present in over 75% of all abdominal aortic aneurysms (AAAs) and probably contributes to the complex biomechanics and pathobiology of these lesions. A reliable predictor of thrombus formation in enlarging lesions could thereby aid clinicians in treatment planning. The primary goal of this work was to identify a new phenomenological metric having clinical utility that is motivated by the hypothesis that two basic haemodynamic features must coincide spatially and temporally to promote the formation of a thrombus on an intact endothelium—platelets must be activated within a shear flow and then be presented to a susceptible endothelium. Towards this end, we propose a new thrombus formation potential (TFP) that combines information on the flow-induced shear history experienced by blood-borne particles that come in close proximity to the endothelium with information on both the time-averaged wall shear stress (WSS) and the oscillatory shear index (OSI) that locally affect the endothelial mechanobiology. To illustrate the possible utility of this new metric, we show computational results for 10 carotid arteries from five patients where regions of low WSS and high OSI tend not to be presented with activated platelets (i.e. they have a low TFP), consistent with the thrombo-resistance of the healthy carotid despite its complex haemodynamics. Conversely, we show
2014 The Author(s) Published by the Royal Society. All rights reserved.
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results for three patients that high TFP co-localizes with regions of observed thin thrombus in AAAs, which contrasts with findings of low TFP for the abdominal aorta of three healthy subjects. We submit that these promising results suggest the need for further consideration of the TFP, or a similar combined metric, as a potentially useful clinical predictor of the possible formation of ILT in AAAs.
1. Introduction Abdominal aortic aneurysms (AAAs) are responsible for significant morbidity and mortality, particularly in older males. Over 75% of these lesions contain an intraluminal thrombus (ILT), which, in many cases, fills the lesion and yields a lumen of nearly normal size despite the extreme dilatation of the aortic wall. There remains a significant controversy over the precise roles an ILT may play in the enlargement and potential rupture of these aneurysms, but it appears that thrombus is important both biomechanically and biochemically [1–3]. There is, therefore, a pressing need to understand better the conditions that lead to the formation of an ILT within these potentially life-threatening lesions.
The natural history of an ILT can be thought to consist of three basic phases: an initial change in platelet activity, the formation of an associated insoluble fibrin clot and possible fibrinolysis. The first phase actually involves three steps as well: the activation, adhesion and aggregation of platelets. Many prior studies have focused on specific aspects of the mechanisms underlying thrombus formation within a general haemodynamic field as revealed by multiple papers [4–6]. In particular, there has been an appropriate move towards multiscale models wherein one can capture contributions ranging from molecular-level chemical reaction kinetics to macroscopic haemodynamics. Notwithstanding these many advances, Cito et al. [6, p. 122] correctly conclude that ‘there is not any validated tool capable of informing clinicians in terms of predictive diagnostics and surgical planning of diseases wherein blood clotting plays a relevant role, such as aneurysm’.
In this paper, we adopted a different, complementary, approach to understand conditions that can lead to thrombus development in AAAs. Rather than including complexities of the molecular mechanisms, we sought a phenomenological metric that could reveal a haemodynamic threshold that stratifies the risk of forming a thrombus within a complex unsteady flow field. Moreover, different from most prior studies that focus on stenoses, ruptured atherosclerotic plaques or implanted devices wherein thrombus tends to form, we focused first on a region of the normal vasculature that is not susceptible to thrombus formation despite its complex geometry and haemodynamics. That is, we suggest that one can unveil lower bounds of useful haemodynamic metrics by identifying values for which thrombus does not occur and then contrast these values with those associated with clinical cases wherein thrombus has been observed. Towards this end, we focused first on the non-thrombogenic human carotid artery, including the bifurcation and the sinus, which is characterized by a local dilatation of the wall, and then examined three counter-examples based on AAAs harbouring a thin ILT. To complete the study, we also examined three models of healthy abdominal aorta free of thrombus. From these three cases, we found a new ‘thrombus formation potential’ (TFP) that appears to predict the location of thrombus formation within AAAs while explaining why normal regions of the arterial tree typically remain thrombus free.
2. Material and methods Retrospective de-identified computed tomography (CT) or magnetic resonance (MR) images were collected for 11 patients, five to study the paired carotid arteries, three to study non-thrombotic infrarenal aortas and three to study AAAs harbouring a hint of ILT.
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Table 1. Imaging modality and resolution of the 11 analysed datasets. C1–5 denote images from which the 10 carotid models were derived. IAA1–3 denote images from which the three healthy infrarenal abdominal aortic models were derived. AAA1–3 denote images from which the three AAA models were derived.
patient imaging modality dimensions (voxels) resolution (mm)
C1 head CTA 512 × 512 × 130 0.506 × 0.506 × 2.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C2 head CTA 512 × 512 × 561 0.438 × 0.438 × 0.625 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C3 head MRA 448 × 120 × 576 0.677 × 0.800 × 0.677 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C4 head CTA 512 × 512 × 289 0.391 × 0.391 × 0.625 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C5 head CTA 512 × 512 × 709 0.352 × 0.352 × 0.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IAA1 abdominal CTA 512 × 512 × 743 0.559 × 0.559 × 0.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IAA2 abdominal MRA 512 × 124 × 512 0.781 × 1.499 × 0.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IAA3 abdominal MRA 384 × 72 × 448 0.781 × 1.599 × 0.78 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AAA1 abdominal CTA 512 × 512 × 226 0.735 × 0.735 × 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AAA2 abdominal CTA 512 × 512 × 288 0.742 × 0.742 × 1.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AAA3 abdominal CTA 512 × 512 × 1534 0.781 × 0.781 × 0.301 . . . . .…