High Frequency Components of Hemodynamic Shear Stress Profiles are a Major Determinant of Shear-Mediated Platelet Activation in Therapeutic Blood Recirculating Devices

Filippo Consolo, Jawaad Sheriff, Silvia Gorla, Nicolò Magri, Danny Bluestein, Federico Pappalardo, Marvin J Slepian, Gianfranco B Fiore, Alberto Redaelli, Filippo Consolo, Jawaad Sheriff, Silvia Gorla, Nicolò Magri, Danny Bluestein, Federico Pappalardo, Marvin J Slepian, Gianfranco B Fiore, Alberto Redaelli

Abstract

We systematically analyzed the relative contributions of frequency component elements of hemodynamic shear stress waveforms encountered in cardiovascular blood recirculating devices as to overall platelet activation over time. We demonstrated that high frequency oscillations are the major determinants for priming, triggering and yielding activated "prothrombotic behavior" for stimulated platelets, even if the imparted shear stress has low magnitude and brief exposure time. Conversely, the low frequency components of the stress signal, with limited oscillations over time, did not induce significant activation, despite being of high magnitude and/or exposure time. In vitro data were compared with numerical predictions computed according to a recently proposed numerical model of shear-mediated platelet activation. The numerical model effectively resolved the correlation between platelet activation and the various frequency components examined. However, numerical predictions exhibited a different activation trend compared to experimental results for different time points of a stress activation sequence. With this study we provide a more fundamental understanding for the mechanobiological responsiveness of circulating platelets to the hemodynamic environment of cardiovascular devices, and the importance of these environments in mediating life-threatening thromboembolic complications associated with shear-mediated platelet activation. Experimental data will guide further optimization of the thromboresistance of cardiovascular implantable therapeutic devices.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
(A) Hemodynamic shear stress profiles characteristics of the trileaflet PHV are shown in the time-domain: the two curves, named Original_A (left) and Original_B (right) were computed from simulated trajectories of platelets flowing through two selected gap regions between the leaflet and the valve annulus, indicated by arrows. (B) Power spectrum (PS) of the curves allows representing Original_A (left) and Original_B (right) in the frequency-domain: the principal frequency components of the PS are indicated by red triangles (Peak_1A–4A, Peak_1B–4B).
Figure 2
Figure 2
The test-curve data set: (A) Original curves; time-domain reconstructed curves corresponding to the (B) low- (Peak_1A and Peak_1B), (C) medium- (Peak_2A and Peak_3B) and (D) high-frequency (Peak_4A and Peak_4B) component elements of the power spectrum of Original_A and Original_B; (E) the time-constant and low-stress amplitude negative control (NC) curve.
Figure 3
Figure 3
Values of SA and SR of each of the test-curves: by selecting specific frequency components of the spectrum of Original curves, we obtained a set of shear stress waveforms modulating the SA and SR values. (A): Original_A; (B) Original_B.
Figure 4
Figure 4
Experimental dynamics of SMPA (PAS values over time) of HSD-stimulated platelets as measured through the PAS assay; (A) Original_A; (B) Original_B.
Figure 5
Figure 5
Comparison of numerical predictions of the dynamics of PA over time and experimental in vitro values: (A) NC curve; (B) Original curves; (C) low-frequency curves; (D) medium- frequency curves; (E) high-frequency curves.
Figure 6
Figure 6
PAS values (mean ± SD) obtained after a 10-min stimulation period are plotted against values of SA (A) and SR (B) characterizing the curves of our data set; SA and SR are reported as for 1 stimulation cycle. Numerical PAS values are reported as computed according to ref. .
Figure 7
Figure 7
Experimental values of PASt10 are plotted in the SR-SA plane, allowing to comprehensively evaluate the effect of simultaneous variations of SA and SR in terms of induced PA: higher PAS values correspond to curves characterized by high values of both SA and SR; high values of SA alone do not induce any significant increase of PAS; increasing values of SR allows to significantly activate platelets. SA and SR are reported as for 1 stimulation cycle.

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