Potentiation of thrombus instability: a contributory mechanism to the effectiveness of antithrombotic medications

© The Author(s) 2018The stability of an arterial thrombus, determined by its structure and ability to resist endogenous fibrinolysis, is a major determinant of the extent of infarction that results from coronary or cerebrovascular thrombosis. There is ample evidence from both laboratory and clinical studies to suggest that in addition to inhibiting platelet aggregation, antithrombotic medications have shear-dependent effects, potentiating thrombus fragility and/or enhancing endogenous fibrinolysis. Such shear-dependent effects, potentiating the fragility of the growing thrombus and/or enhancing endogenous thrombolytic activity, likely contribute to the clinical effectiveness of such medications. It is not clear how much these effects relate to the measured inhibition of platelet aggregation in response to specific agonists. These effects are observable only with techniques that subject the growing thrombus to arterial flow and shear conditions. The effects of antithrombotic medications on thrombus stability and ways of assessing this are reviewed herein, and it is proposed that thrombus stability could become a new target for pharmacological intervention.Peer reviewedFinal Published versio

Effect of tube diameter and capillary number on platelet margination and near-wall dynamics

The effect of tube diameter $D$ and capillary number $Ca$ on platelet margination in blood flow at $\approx 37\%$ tube haematocrit is investigated. The system is modelled as three-dimensional suspension of deformable red blood cells and nearly rigid platelets using a combination of the lattice-Boltzmann, immersed boundary and finite element methods. Results show that margination is facilitated by a non-diffusive radial platelet transport. This effect is important near the edge of the cell-free layer, but it is only observed for $Ca > 0.2$, when red blood cells are tank-treading rather than tumbling. It is also shown that platelet trapping in the cell-free layer is reversible for $Ca \leq 0.2$. Only for the smallest investigated tube ($D = 10 \mu\text{m}$) margination is essentially independent of $Ca$. Once platelets have reached the cell-free layer, they tend to slide rather than tumble. The tumbling rate is essentially independent of $Ca$ but increases with $D$. Tumbling is suppressed by the strong confinement due to the relatively small cell-free layer thickness at $\approx 37\%$ tube haematocrit.Comment: 16 pages, 10 figure

Biochemical­­– and biophysical–induced barriergenesis in the blood brain barrier: a review of barriergenic factors for use in in vitro models

Central nervous system (CNS) pathologies are a prevalent problem in aging populations, creating a need to understand the underlying events in these diseases and develop efficient CNS‐targeting drugs. The importance of the blood‐brain barrier (BBB) has become evident, acting both as a physical barrier to drug entry into the CNS, and potentially as the cause or aggravator of CNS diseases. The development of a biomimetic BBB in vitro model is required for the understanding of BBB‐related pathologies and in the screening of drugs targeting the CNS. There is currently a great interest in understanding the influence of biochemical and biophysical factors, as these have the potential to greatly improve the barrier function of brain microvascular endothelial cells (BMECs). Recent advances in understanding how these may regulate barriergenesis in BMECs can help promote the development of improved BBB in vitro models, and therefore novel interventional therapies for pathologies related to its disruption. This review provides an overview of specific biochemical and biomechanical cues in the formation of the BBB, with a focus on in vitro models and how these might recapitulate BBB function

COMPARING STATIC AND DYNAMIC THRESHOLD BASED CONTROL STRATEGIES

This research extends a static threshold based control strategy used to control headway variation to a dynamic threshold based control strategy. In the static strategy, buses are controlled by setting a threshold value that holds buses at a control point for a certain amount of time before allowing the bus to continue along the route. The threshold remains constant each time the bus stops at the control point. The dynamic strategy involves the same principle of holding buses at a bus stop; however, a different threshold value is chosen each time the bus holds at a control point. The results indicate that in cases where the static threshold is et equal to the scheduled headway, very low headway variation and passenger system times result; however, passengers on board the bus are penalized by extra delay on the bus while waiting at the control point. The dynamic strategy reduces the penalty to passengers delayed on-board the bus at a control point at the expense of a slight increase in overall passenger system time