Blood flow controls coagulation onset via the positive feedback of factor VII activation by factor Xa
Abstract
Background: Blood coagulation is a complex network of biochemical reactions, which
is peculiar in that it is time- and space-dependent, and has to function in the presence
of rapid flow. Recent experimental reports suggest that flow plays a significant role
in its regulation. The objective of this study was to use systems biology techniques
to investigate this regulation and to identify mechanisms creating a flow-dependent
switch in the coagulation onset. Results: Using a detailed mechanism-driven model
of tissue factor (TF)-initiated thrombus formation in a two-dimensional channel we
demonstrate that blood flow can regulate clotting onset in the model in a threshold-like
manner, in agreement with existing experimental evidence. Sensitivity analysis reveals
that this is achieved due to a combination of the positive feedback of TF-bound factor
VII activation by activated factor X (Xa) and effective removal of factor Xa by flow
from the activating patch depriving the feedback of "ignition". The level of this
trigger (i.e. coagulation sensitivity to flow) is controlled by the activity of tissue
factor pathway inhibitor. Conclusions: This mechanism explains the difference between
red and white thrombi observed in vivo at different shear rates. It can be speculated
that this is a special switch protecting vascular system from uncontrolled formation
and spreading of active coagulation factors in vessels with rapidly flowing blood.
Type
Other articleSubject
tissue factor pathwaythrombin generation
shear rate
propagation
inhibition
hemophilia
initiation
threshold
mechanism
mathematical & computational biology
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https://hdl.handle.net/10161/4386Published Version (Please cite this version)
10.1186/1752-0509-4-5Citation
Shibeko,Alexey M.;Lobanova,Ekaterina S.;Panteleev,Mikhail A.;Ataullakhanov,Fazoil
I.. 2010. Blood flow controls coagulation onset via the positive feedback of factor
VII activation by factor Xa. Bmc Systems Biology 4( ): 5-5.
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