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.
Highlights
Contribute to platelet activation[8]
Two further effects contribute to SMPA in BRDs: first, platelet damage increases with repetitive passes through a device, suggesting that platelets accumulate cyclic shear stress exposures; second, shear stress has a sensitizing effect on platelets, so that platelets exposed to very high shear stress - even for brief exposures, such as during passage through BRDs - continue to activate despite subsequent exposure to low shear stress - as is encountered downstream of BRDs - with a residual incremental response compounding that of the initial high shear pulses or waveforms[10,11,12]
We hypothesized that deconstructing and analyzing clinically accurate hemodynamic stress waveforms associated with platelet passage through BRDs would yield component elements, including: the distribution of frequency components, SA and SR, that would be more predictive of platelet activation than use of the waveform alone as a whole
Summary
Contribute to platelet activation[8]. Two further effects contribute to SMPA in BRDs: first, platelet damage increases with repetitive passes through a device, suggesting that platelets accumulate cyclic shear stress exposures; second, shear stress has a sensitizing effect on platelets, so that platelets exposed to very high shear stress - even for brief exposures, such as during passage through BRDs - continue to activate despite subsequent exposure to low shear stress - as is encountered downstream of BRDs - with a residual incremental response compounding that of the initial high shear pulses or waveforms[10,11,12]. Different approaches and methodologies have been developed to elucidate the mechanisms driving SMPA and to identify possible design solutions to refine and minimize the device-associated thrombogenicity These include numeric and experimental tools, often used in combination, to model shear stress waveforms and to predict and characterize the phenomenological platelet response[18,19,20]. This model was based on a general reaction equation, including terms accounting for different hemodynamic characteristics of the shear stress, namely the shear stress magnitude and the corresponding exposure time, which together define the stress accumulation (SA, i.e., the integral of the scalar shear stress over time), and the stress rate (SR, i.e. the shear stress loading rate, or the variation of the shear stress over time) This model successfully described experimental observations of platelet response to a variety of time-constant and dynamic shear stress conditions, properly describing platelet sensitization[23]. We selected specific frequency components of the spectrum of two PHV-shear stress profiles (from low- to high-frequency components) to obtain a set of test-curves yielding different values of SA and SR, respectively
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