Effect of RVAD Cannulation Length on Right Ventricular Thrombosis Risk: An In Silico Investigation.

Left ventricular assist devices (LVADs) have been used off-label as long-term support of the right heart due to the lack of a clinically approved durable right VAD (RVAD). Whilst various techniques to reduce RVAD inflow cannula protrusion have been described, the implication of the protrusion length on right heart blood flow and subsequent risk of thrombosis remains poorly understood. This study investigates the influence of RVAD diaphragmatic cannulation length on right ventricular thrombosis risk using a patient-specific right ventricle in silico model validated with particle image velocimetry. Four cannulation lengths (5, 10, 15 and 25 mm) were evaluated in a one-way fluid-structure interaction simulation with boundary conditions generated from a lumped parameter model, simulating a biventricular supported condition. Simulation results demonstrated that the 25-mm cannulation length exhibited a lower thrombosis risk compared to 5-, 10- and 15-mm cannulation lengths due to improved flow energy distribution (25.2%, 24.4% and 17.8% increased), reduced stagnation volume (72%, 68% and 49% reduction), better washout rate (13.0%, 11.6% and 9.1% faster) and lower blood residence time (6% reduction). In the simulated scenario, our findings suggest that a longer RVAD diaphragmatic cannulation length may be beneficial in lowering thrombosis risk; however, further clinical studies are warranted.

Current and future strategies to monitor and manage coagulation in ECMO patients.

Extracorporeal membrane oxygenation (ECMO) can provide life-saving support for critically ill patients suffering severe respiratory and/or cardiac failure. However, thrombosis and bleeding remain common and complex problems to manage. Key causes of thrombosis in ECMO patients include blood contact to pro-thrombotic and non-physiological surfaces, as well as high shearing forces in the pump and membrane oxygenator. On the other hand, adverse effects of anticoagulant, thrombocytopenia, platelet dysfunction, acquired von Willebrand syndrome, and hyperfibrinolysis are all established as causes of bleeding. Finding safe and effective anticoagulants that balance thrombosis and bleeding risk remains challenging. This review highlights commonly used anticoagulants in ECMO, including their mechanism of action, monitoring methods, strengths and limitations. It further elaborates on existing anticoagulant monitoring strategies, indicating their target range, benefits and drawbacks. Finally, it introduces several highly novel approaches to real-time anticoagulation monitoring methods including sound, optical, fluorescent, and electrical measurement as well as their working principles and future directions for research.

In silico Prediction of Thrombosis Risk in a Ventricular Assist Device Supported Right Heart: The Impact of Cannulation Site.

Right ventricular assist device (RVAD) associated thrombosis is a serious complication that may arise due to unfavorable blood flow dynamics (blood stasis) caused by RVAD cannula protrusion within the chambers. This study aims to investigate the thrombosis risk of cannulation via the right atrium (RA) and right ventricle (RV) (diaphragmatic) under full RVAD support using computational fluid dynamics. A HeartWare HVAD inflow cannula was virtually implanted in either the RA or RV of a rigid-walled right heart geometry (including RA, RV, superior, and inferior vena cava) extracted from computed tomography data of a biventricular support patient. Transient simulations, validated with particle image velocimetry, were performed with constant inflow. Thrombosis risk was predicted by analyzing the time-averaged blood velocity, blood stagnation volume, washout rate, and blood residence time (BRT). Results showed that RA cannulation disturbed the physiological swirling flow structure which can be found in an uncannulated RA. This led to a large low-velocity recirculation flow in the RV, increasing the thrombosis risk. Contrarily, RV diaphragmatic cannulation showed better preservation of swirling flow in the RA and flow ejection into the RV. Consequently, RV diaphragmatic cannulation exhibited a better washout rate (99% vs. 57% of old blood was replaced in 12 s), lower blood stagnation volume (0.13 ml vs. 32.85 ml), and BRT (4.2 s vs. 7.1 s) than the RA cannulation in this simulated non-pulsatile case. Our findings suggest that RV diaphragmatic cannulation had a lower thrombosis risk and might be more favorable in a full RVAD-supported setting.

Improved Drainage Cannula Design to Reduce Thrombosis in Veno-Arterial Extracorporeal Membrane Oxygenation.

Thrombosis is a potentially life-threatening complication in veno-arterial extracorporeal membrane oxygenation (ECMO) circuits, which may originate from the drainage cannula due to unfavorable blood flow dynamics. This study aims to numerically investigate the effect of cannula design parameters on local fluid dynamics, and thus thrombosis potential, within ECMO drainage cannulas. A control cannula based on the geometry of a 17 Fr Medtronic drainage cannula concentrically placed in an idealized, rigid-walled geometry of the right atrium and superior and inferior vena cava was numerically modeled. Simulated flow dynamics in the control cannula were systematically compared with 10 unique cannula designs which incorporated changes to side hole diameter, the spacing between side holes, and side hole angles. Local blood velocities, maximum wall shear stress (WSS), and blood residence time were used to predict the risk of thrombosis. Numerical results were experimentally validated using particle image velocimetry. The control cannula exhibited low blood velocities (59 mm/s) at the cannula tip, which may promote thrombosis. Through a reduction in the side hole diameter (2 mm), the spacing between the side holes (3 mm) and alteration in the side hole angle (30° relative to the flow direction), WSS was reduced by 52%, and cannula tip blood velocity was increased by 560% compared to the control cannula. This study suggests that simple geometrical changes can significantly alter the risk of thrombosis in ECMO drainage cannulas.

Novel Stenotic Microchannels to Study Thrombus Formation in Shear Gradients: Influence of Shear Forces and Human Platelet-Related Factors.

Thrombus formation in hemostasis or thrombotic disease is initiated by the rapid adhesion, activation, and aggregation of circulating platelets in flowing blood. At arterial or pathological shear rates, for example due to vascular stenosis or circulatory support devices, platelets may be exposed to highly pulsatile blood flow, while even under constant flow platelets are exposed to pulsation due to thrombus growth or changes in vessel geometry. The aim of this study is to investigate platelet thrombus formation dynamics within flow conditions consisting of either constant or variable shear. Human platelets in anticoagulated whole blood were exposed ex vivo to collagen type I-coated microchannels subjected to constant shear in straight channels or variable shear gradients using different stenosis geometries (50%, 70%, and 90% by area). Base wall shears between 1800 and 6600 s-1, and peak wall shears of 3700 to 29,000 s-1 within stenoses were investigated, representing arterial-pathological shear conditions. Computational flow-field simulations and stenosis platelet thrombi total volume, average volume, and surface coverage were analysed. Interestingly, shear gradients dramatically changed platelet thrombi formation compared to constant base shear alone. Such shear gradients extended the range of shear at which thrombi were formed, that is, platelets became hyperthrombotic within shear gradients. Furthermore, individual healthy donors displayed quantifiable differences in extent/formation of thrombi within shear gradients, with implications for future development and testing of antiplatelet agents. In conclusion, here, we demonstrate a specific contribution of blood flow shear gradients to thrombus formation, and provide a novel platform for platelet functional testing under shear conditions.

A-Disintegrin-And-Metalloproteinase (ADAM) 10 Activity on Resting and Activated Platelets.

The primary platelet collagen receptor, glycoprotein VI (GPVI), plays an important role in platelet activation and thrombosis. The ectodomain of human GPVI (sGPVI) is proteolytically shed from human platelets by a-disintegrin-and-metalloproteinase 10 (ADAM10). In this study, we used a novel ADAM10-sensitive fluorescence resonance energy transfer sensor to analyze ADAM10-mediated shedding of GPVI from human platelets in response to the exposure of GPVI ligands collagen-related peptide (10 µg/mL), collagen (10 µg/mL), and convulxin (0.1 µg/mL) to shear stress (1000-10000 s(-1), 5 min), or a generic activator of metalloproteinases, N-ethylmaleimide (NEM, 5 mM). Elevated shear, NEM, or ligand engagement of GPVI all induced shedding of GPVI, as detected by release of sGPVI; however, only shear or NEM significantly increased ADAM10 enzyme activity. ADAM10 activity was also detectable on the surface of thrombi formed on a collagen-coated surface under flow conditions. Our findings indicate different mechanisms regulate shear- and ligand-induced shedding and shear forces found within the vasculature can regulate ADAM10 activity.

Methods to Determine the Lagrangian Shear Experienced by Platelets during Thrombus Growth.

Platelets can become activated in response to changes in flow-induced shear; however, the underlying molecular mechanisms are not clearly understood. Here we present new techniques for experimentally measuring the flow-induced shear rate experienced by platelets prior to adhering to a thrombus. We examined the dynamics of blood flow around experimentally grown thrombus geometries using a novel combination of experimental (ex vivo) and numerical (in silico) methodologies. Using a microcapillary system, platelet aggregate formation was analysed at elevated shear rates in the presence of coagulation inhibitors, where thrombus formation is predominantly platelet-dependent. These approaches permit the resolution and quantification of thrombus parameters at the scale of individual platelets (2 µm) in order to quantify real time thrombus development. Using our new techniques we can correlate the shear rate experienced by platelets with the extent of platelet adhesion and aggregation. The techniques presented offer the unique capacity to determine the flow properties for a temporally evolving thrombus field in real time.

Functional imaging to understand biomechanics: a critical tool for the study of biology, pathology and the development of pharmacological solutions.

We present four case studies of the literature discussing the effects of physical forces on biological function. While the field of biomechanics has existed for many decades, it may be considered by some a poor cousin to biochemistry and other traditional fields of medical research. In these case studies, including cardiovascular and respiratory systems, we demonstrate that, in fact, many systems historically believed to be controlled by biochemistry are dominated by biomechanics. We discuss both the previous paradigms that have advanced research in these fields and the changing paradigms that will define the progressions of these fields for decades to come. In the case of biomechanical effects of flowing blood on the endothelium, this has been well understood for decades. In the cases of platelet activation and liquid clearance from the lungs during birth, these discoveries are far more recent and perhaps not as universally accepted. While only a few specific examples are examined here, it is clear that not enough attention is paid to the possible mechanical links to biological function. The continued development of these research areas, with the inclusion of physical effects, will hopefully provide new insight into disease development, progression, diagnosis and effective therapies.

Effect of hemodynamic forces on platelet aggregation geometry.

The shear rate dependence of platelet aggregation geometries is investigated using a combination of in vitro and numerical experiments. Changes in upstream shear rate, γ(Pw), are found to cause systematic changes in mature platelet aggregation geometries. However, γ(Pw) is not the only factor determining the shear rate experienced by a platelet moving over, and adhering to, a platelet aggregation: flow simulations demonstrate that naturally occurring variations in platelet aggregation geometry cause the local shear rate on the surface of a mature platelet aggregation to vary between zero and up to eight times γ(Pw). Additionally, as a platelet aggregation grows, systematic changes in geometry are found, indicating that the local shear field over a growing platelet aggregation will differ from that over mature platelet aggregations.

A shear gradient-dependent platelet aggregation mechanism drives thrombus formation.

Platelet aggregation at sites of vascular injury is essential for hemostasis and arterial thrombosis. It has long been assumed that platelet aggregation and thrombus growth are initiated by soluble agonists generated at sites of vascular injury. By using high-resolution intravital imaging techniques and hydrodynamic analyses, we show that platelet aggregation is primarily driven by changes in blood flow parameters (rheology), with soluble agonists having a secondary role, stabilizing formed aggregates. We find that in response to vascular injury, thrombi initially develop through the progressive stabilization of discoid platelet aggregates. Analysis of blood flow dynamics revealed that discoid platelets preferentially adhere in low-shear zones at the downstream face of forming thrombi, with stabilization of aggregates dependent on the dynamic restructuring of membrane tethers. These findings provide insight into the prothrombotic effects of disturbed blood flow parameters and suggest a fundamental reinterpretation of the mechanisms driving platelet aggregation and thrombus growth.

Modified control grid interpolation for the volumetric reconstruction of fluid flows.

Complex applications in fluid dynamics research often require more highly resolved velocity data than direct measurements or simulations provide. The advent of stereo PIV and PCMR techniques has advanced the state-of-the-art in flow velocity measurement, but 3D spatial resolution remains limited. Here a new technique is proposed for velocity data interpolation to address this problem. The new method performs with higher quality than competing solutions from the literature in terms of accurately interpolating velocities, maintaining fluid structure and domain boundaries, and preserving coherent structures.

Fluid dynamic assessment of three polymeric heart valves using particle image velocimetry.

Polymeric heart valves have the potential to reduce thrombogenic complications associated with current mechanical valves and overcome fatigue-related problems experienced by bioprosthetic valves. In this paper we characterize the in vitro velocity and Reynolds Shear Stress (RSS) fields inside and downstream of three different prototype trileaflet polymeric heart valves. The fluid dynamic differences are then correlated with variations in valve design parameters. The three valves differ in leaflet thickness, ranging from 80 to 120 mum, and commisural design, either closed, opened, or semi-opened. The valves were subjected to aortic flow conditions and the velocity measured using three-dimensional stereo Particle Image Velocimetry. The peak forward flow phase in the three valves was characterized by a strong central orifice jet of approximately 2 m/s with a flat profile along the trailing edge of the leaflets. Leakage jets, with principle RSS magnitudes exceeding 4,500 dyn/cm(2), were observed in all valves with larger leaflet thicknesses and also corresponded to larger leakage volumes. Additional leakage jets were observed at the commissural region of valves with the open and the semi-open commissural designs. The results of the present study indicate that commissural design and leaflet thickness influence valve fluid dynamics and thus the thrombogenic potential of trileaflet polymeric valves.

A comparison of flow field structures of two tri-leaflet polymeric heart valves.

Polymeric heart valves have the potential to reduce thrombogenic complications associated with current mechanical valves and overcome fatigue-related problems experienced by bioprosthetic valves. In this in vitro study, the velocity fields inside and downstream of two different prototype tri-lealfet polymeric heart valves were studied. Experiments were conducted on two 23 mm prototype polymeric valves, provided by AorTech Europe, having open or closed commissure designs and leaflet thickness of 120 and 80 microm, respectively. A two-dimensional LDV system was used to measure the velocity fields in the vicinity of the two valves under simulated physiological conditions. Both commissural design and leaflet thickness were found to affect the flow characteristics. In particular, very high levels of Reynolds shear stress of 13,000 dynes/cm2 were found in the leakage flow of the open commisure design. Maximum leakage velocities in the open and closed designs were 3.6 m/s and 0.5 m/s respectively; the peak forward flow velocities were 2.0 m/s and 2.6 m/s, respectively. In both valve designs, shear stress levels exceeding 4,000 dyne/cm2 were observed at the trailing edge of the leaflets and in the leakage and central orifice jets during peak systole. Additionally, regions of low velocity flow conducive to thrombus formation were observed in diastole. The flow structures measured in these experiments are consistent with the location of thrombus formation observed in preliminary animal experiments.

Comparison of the hinge flow fields of two bileaflet mechanical heart valves under aortic and mitral conditions.

BACKGROUND: Animal and clinical studies have shown that bileaflet mechanical heart valve designs are plagued by thromboembolic complications, with higher rates in the mitral than in the aortic position. This study evaluated the hinge flow dynamic of the 23 mm St. Jude Medical (SJM) Regent and the 23 mm CarboMedics (CM) valves under aortic conditions and compared these results with previous findings under mitral conditions. METHOD: Velocity and Reynolds shear stress fields were captured using two-component laser Doppler velocimetry. RESULTS: Under aortic conditions, both the SJM and CM hinge flow fields exhibited a strong forward flow pattern during systole (maximum velocities of 2.31 and 1.75 m/s, respectively) and two main leakage jets during diastole (maximum velocities of 3.08 and 2.27 m/s, respectively). CONCLUSIONS: Aortic and mitral flow patterns within the two hinges were similar, but with a more dynamic flow during the forward flow phase under aortic conditions. Velocity magnitudes and shear stresses measured under mitral conditions were generally higher than those obtained in the aortic position, which may explain the higher rates of thromboembolism in the mitral implants when compared with the aortic implants.