Thrombus Formation at High Shear Rates.

The final common pathway in myocardial infarction and ischemic stroke is occlusion of blood flow from a thrombus forming under high shear rates in arteries. A high-shear thrombus forms rapidly and is distinct from the slow formation of coagulation that occurs in stagnant blood. Thrombosis at high shear rates depends primarily on the long protein von Willebrand factor (vWF) and platelets, with hemodynamics playing an important role in each stage of thrombus formation, including vWF binding, platelet adhesion, platelet activation, and rapid thrombus growth. The prediction of high-shear thrombosis is a major area of biofluid mechanics in which point-of-care testing and computational modeling are promising future directions for clinically relevant research. Further research in this area will enable identification of patients at high risk for arterial thrombosis, improve prevention and treatment based on shear-dependent biological mechanisms, and improve blood-contacting device design to reduce thrombosis risk.

Role of high shear rate in thrombosis.

Acute arterial occlusions occur in high shear rate hemodynamic conditions. Arterial thrombi are platelet-rich when examined histologically compared with red blood cells in venous thrombi. Prior studies of platelet biology were not capable of accounting for the rapid kinetics and bond strengths necessary to produce occlusive thrombus under these conditions where the stasis condition of the Virchow triad is so noticeably absent. Recent experiments elucidate the unique pathway and kinetics of platelet aggregation that produce arterial occlusion. Large thrombi form from local release and conformational changes in von Willebrand factor under very high shear rates. The effect of high shear hemodynamics on thrombus growth has profound implications for the understanding of all acute thrombotic cardiovascular events as well as for vascular reconstructive techniques and vascular device design, testing, and clinical performance.

Geometric design of microfluidic chambers: platelet adhesion versus accumulation.

Arterial, platelet-rich thrombosis depends on shear rates and integrin binding to either a collagen surface or to the growing thrombus, which are mechanistically different. In general, small microfluidic test sections may favor platelet-surface adhesion without testing for the primary mode of intra-arterial thrombosis, i.e. platelet-platelet bonding and accumulation. In the present report, the ratio of platelet-platelet to platelet-surface interactions, R, and the percentage of platelet-platelet interactions, P, are estimated using an analytical approach for circular and rectangular test sections. Results show that the test section geometry strongly affects both R and P, with test section height in low-aspect ratio channels or diameter greater than 90 µm dominated by platelet-platelet interactions (R >10). Increasing rectangular test section aspect ratio decreases the required height. R increases linearly while P approaches 100 % asymptotically with increasing channel dimension. Analysis of platelet shape shows that the assumption of spherical platelets has a small effect on R compared to discoid platelets adhering flat against test section wall. However, an increase in average platelet volume resulted in a large decrease in R. Nonetheless, Monte Carlo simulations of a typical distribution of human platelet sizes show intrasubject variation in platelet size has only a 10 % net effect on R. Finally, experiments of thrombus formation show that platelet-surface lag times and platelet-platelet accumulation are similar for rectangular microfluidic test sections and round test sections when R >10. The findings show that the size of a microfluidic test section should be carefully considered in studies of cell-cell accumulation versus cell-surface adhesion.

Correction to: A Predictive Model of High Shear Thrombus Growth.

This erratum is to correct the heading of column 2 (titled "b") in Table 1, which was missing proper units. The heading for that column was revised to include proper units, reading "b (× 10-6 s)".

Choice of a hemodynamic model for occlusive thrombosis in arteries.

Intravascular thrombosis can lead to heart attacks and strokes that together are the leading causes of death in the US (Kochanek, K.D., Murphy, S.L., Xu, J.Q., 2014). The ability to identify the offending biofluid mechanical conditions and predict the timescale of thrombotic occlusion in vessels and devices may improve patient outcomes. A computational model was developed to describe the growth of thrombus based on the local hemodynamic shear rate. The model predicts thrombus deposition based on initial geometric and fluid mechanical conditions, which are updated throughout the simulation to reflect the changing lumen dimensions. Thrombus growth and occlusion from whole blood was measured in in vitro experiments using stenotic glass capillary tubes, a PDMS microfluidic channel, and a PTFE stenotic aorto-iliac graft. Comparison of the predicted occlusion times to experimental results shows excellent agreement. The results indicate that local shear rate plays a critical role in acute thrombosis, and that hemodynamic characterization may have clinical utility.

A Predictive Model of High Shear Thrombus Growth.

The ability to predict the timescale of thrombotic occlusion in stenotic vessels may improve patient risk assessment for thrombotic events. In blood contacting devices, thrombosis predictions can lead to improved designs to minimize thrombotic risks. We have developed and validated a model of high shear thrombosis based on empirical correlations between thrombus growth and shear rate. A mathematical model was developed to predict the growth of thrombus based on the hemodynamic shear rate. The model predicts thrombus deposition based on initial geometric and fluid mechanic conditions, which are updated throughout the simulation to reflect the changing lumen dimensions. The model was validated by comparing predictions against actual thrombus growth in six separate in vitro experiments: stenotic glass capillary tubes (diameter = 345 µm) at three shear rates, the PFA-100(®) system, two microfluidic channel dimensions (heights = 300 and 82 µm), and a stenotic aortic graft (diameter = 5.5 mm). Comparison of the predicted occlusion times to experimental results shows excellent agreement. The model is also applied to a clinical angiography image to illustrate the time course of thrombosis in a stenotic carotid artery after plaque cap rupture. Our model can accurately predict thrombotic occlusion time over a wide range of hemodynamic conditions.

In vitro assessment of available coaptation area as a novel metric for the quantification of tricuspid valve coaptation.

Tricuspid regurgitation (TR) is associated with increased mortality in patients undergoing mitral valve repair. In recent decades, TR has been addressed using annuloplasty concomitantly with mitral valve repair by some surgeons. However, repair efficacy and durability are often suboptimal. Increased understanding of tricuspid valve coaptation and the effects of pathological and repair conditions may be useful to inform future repair design. In the present study, we propose a two-dimensional in vitro technique, available coaptation area (ACA), to quantify the area of each tricuspid leaflet available for coaptation. Preliminary results showed that annular dilatation caused a significant (p<0.05) decrease in anterior leaflet ACA (0.92±0.18cm(2)), and combined annular dilatation and papillary muscle (PM) displacement resulted in a significant decrease in posterior leaflet ACA (0.87±0.15cm(2)). Isolated PM displacement did not have a significant effect on ACA, and the septal leaflet showed no changed in ACA under the conditions tested. In addition to quantifying ACA, our technique allows for the detailed mapping of leaflet coaptation, which may be used to reveal specific sites of malcoaptation on each leaflet. Application of the ACA method in future studies may lead to the development of specialized tricuspid repair strategies and annuloplasty ring designs that target specific regions of the tricuspid valve based on underlying pathological conditions.

Impact of pulmonary hypertension on tricuspid valve function.

Pulmonary arterial hypertension (PAH) results in increased right ventricle (RV) afterload leading to RV remodeling, tricuspid regurgitation (TR), and RV failure. Though characterizing the mechanisms of TR in PAH may suggest new treatment strategies, the mechanisms leading to TR in PAH have not been characterized. In the present study, eleven porcine tricuspid valves were studied in an in vitro right heart simulator. Annular dilatations of 1.2 and 1.4 times normal area, papillary muscle (PM) displacement simulating concentric RV dilatation and eccentric RV dilatation due to concomitant left ventricle dysfunction, and two levels of PAH hemodynamics were simulated independently and in combination. Relative TR, tenting area (TA) along each coaptation line, and coaptation area (CA) of each leaflet were quantified. Results showed a significant increase (p ≤ 0.05) in TR with both increased mean pulmonary artery pressure (mPAP) and annular dilatation of 1.4 times normal. Increased mPAP significantly decreased TA but tended to increase CA, while PM displacement significantly increased TA but did not affect CA, suggesting competing effects of transvalvular pressure and leaflet tethering. Annular dilatation significantly decreased anterior and posterior CA but did not affect TA. These results may inform future TV repairs in PAH to reduce TR and improve RV hemodynamics.