Platelet Activation Due to Hemodynamic Shear Stresses: Damage Accumulation Model and Comparison to In Vitro Measurements

Abstract

The need to optimize the thrombogenic performance of blood recirculating cardiovascular devices, e.g., prosthetic heart valves (PHV) and ventricular assist devices (VAD), is accentuated by the fact that most of them require lifelong anticoagulation therapy that does not eliminate the risk of thromboembolic complications. The formation of thromboemboli in the flow field of these devices is potentiated by contact with foreign surfaces and regional flow phenomena that stimulate blood clotting, especially platelets. With the lack of appropriate methodology, device manufacturers do not specifically optimize for thrombogenic performance. Such optimization can be facilitated by formulating a robust numerical methodology with predictive capabilities of flow-induced platelet activation. In this study, a phenomenological model for platelet cumulative damage, identified by means of genetic algorithms (GAs), was correlated with in vitro experiments conducted in a Hemodynamic Shearing Device (HSD). Platelets were uniformly exposed to flow shear representing the lower end of the stress levels encountered in devices, and platelet activity state (PAS) was measured in response to six dynamic shear stress waveforms representing repeated passages through a device, and correlated to the predictions of the damage accumulation model. Experimental results demonstrated an increase in PAS with a decrease in "relaxation" time between pulses. The model predictions were in very good agreement with the experimental results.A recognized feature of the complex interplay regulating the pathogenesis of thrombosis is the effect of blood flow-induced mechanical forces on platelets. Physical agonists, such as these flow-induced forces, and chemical agonists, such as adenosine diphosphate and serotonin, trigger platelet activation. This process commences with the secretion of procoagulant and selfstimulating substances from granules, 1 which catalyze thrombin production. 2 As a direct consequence of activation, the platelets undergo a change in shape, marked by pseudopod extension. This increases the strength of adhesion to exogenous surfaces and decreases the resistance to aggregation.One of the major culprits in blood recirculating devices is the emergence of nonphysiologic (pathologic) flow patterns that enhance the hemostatic response. Elevated flow stresses that are present in the nonphysiologic geometries of blood recirculating devices enhance their propensity to initiate thromboembolism. In recent years, it has been demonstrated that flow induced thrombogenicity, caused by chronic platelet activation and the initiation of thrombus formation, is the salient aspect of mechanically induced blood trauma in devices. 3 This lends itself to the hypothesis that thromboembolism in prosthetic blood recirculating devices is

Biological effects of dynamic shear stress in cardiovascular pathologies and devices

“…Platelet activity decreased with increasing T2 or 'relaxation time' between the peak shear stress. The experimental results showing platelet damage and recovery under shear stress obtained herein were in excellent agreement with mathematical damage accumulation models proposed by Grigioni et al [72,73], originally developed for RBC hemolysis and adapted for platelets in the study described previously [65].…”

“…This may allow the platelets to recover or reverse their activated state and regain their discoid shape. The mechanics and kinetics of recovery of platelets after acute shear-stress exposure have been recently experimentally investigated in the HSD as discussed previously [65]. These results show remarkable agreement with numerical predictions from a cumulative damage accumulation model (i.e., cumulative effect of previous activated state, shear loading history and exposure time) originally proposed to investigate RBC hemolysis [72,73].…”

“…The dynamic capabilities are introduced via a programmable interface [24,47]. The device has been successfully used to investigate the shearinduced damage and subsequent recovery of human platelets [65]. A schematic of the device is shown in Figure 1.…”

“…In this study, platelets were exposed to varying shear stress of moderate-to-low magnitude (1.5-20 dynes/cm 2 , Figure 2) in the HSD [65] and their instantaneous activation state was measured over time. The platelet membrane damage measured in the HSD and platelet damage accumulation model based on SIPA and genetic algorithm (GA) that predicts this damage were effectively correlated.…”

Numerical method to measure velocity integration, stroke volume and cardiac output while rest: using 2D fluid-solid interaction model

“…Griffith and Peskin (2005) and Griffith et al (2007Griffith et al ( , 2009) provided a research included an immersed boundary procedure for computational analysis of fluid-structure interaction of flexible aortic valve for rest stage. Several aortic valve FSI simulations validated experimentally (De Hart et al, 2000Labrosse et al, 2010;Nobili et al, 2008). Such researches confirm the possibility of developing complex aortic valve dynamics.…”