Abstract
The ability of a blood clot to modulate blood flow is determined by the clot’s resistance, which depends on its structural features. For a flow with arterial shear, we investigated the characteristic patterns relating to clot shape, size, and composition on the one hand, and its viscous resistance, intraclot axial flow velocity, and shear distributions on the other. We used microfluidic technology to measure the kinetics of platelet, thrombin, and fibrin accumulation at a thrombogenic surface coated with collagen and tissue factor (TF), the key clot-formation trigger. We subsequently utilized the obtained data to perform additional calibration and validation of a detailed computational fluid dynamics model of spatial clot growth under flow. We then ran model simulations to gain insights into the resistance of clots formed under our experimental conditions. We found that increased thrombogenic surface length and TF surface density enhanced the bulk thrombin and fibrin generation in a nonadditive, synergistic way. The height of the platelet deposition domain—and, therefore, clot occlusivity—was rather robust to thrombogenic surface length and TF density variations, but consistently increased with time. Clot viscous resistance was non-uniform and tended to be higher in the fibrin-rich, inner “core” region of the clot. Interestingly, despite intraclot structure and viscous resistance variations, intraclot flow velocity variations were minor compared to the abrupt decrease in flow velocity around the platelet deposition region. Our results shed new light on the connection between the structure of clots under arterial shear and spatiotemporal variations in their resistance to flow.
Highlights
The formation of blood clots in vivo occurs under flow, which makes blood flow an essential regulator of the clotting process (Casa and Ku 2017; Fogelson and Neeves 2015; Hathcock 2006; Rana and Neeves 2016)
We found that increased thrombogenic surface length and tissue factor (TF) surface density synergistically enhance thrombin and fibrin accumulation
Existing data suggest increased platelet adhesion and aggregation under arterial shear due to the involvement of von Willebrand factor (Ruggeri et al 1999; Savage et al 1998; Schneider et al 2007). In accord with this evidence, we expected that increasing the platelet adhesion rate in the model would enhance model accuracy for platelet deposition and, for thrombin generation and fibrin accumulation
Summary
The formation of blood clots in vivo occurs under flow, which makes blood flow an essential regulator of the clotting process (Casa and Ku 2017; Fogelson and Neeves 2015; Hathcock 2006; Rana and Neeves 2016). Platelets form the body of the clot and provide catalytic surfaces for the blood coagulation biochemistry (Fogelson and Neeves 2015). Understanding and predicting the net outcome of these concurrent processes are challenging due to the spatial and temporal variations in the flow, as well as to the presence of interlinked functional feedback loops and of biochemical reactions that can accelerate or inhibit clot growth. Certain pathologies, such as venous and arterial thrombosis, can lead to persistent changes in local blood flow (Hathcock 2006; Jackson 2011). The need to develop advanced approaches to treat cardiovascular disease necessitates detailed investigations of blood coagulation under flow
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