Activation of contact pathway of blood coagulation on the lipopolysaccharide aggregatesстатья
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Дата последнего поиска статьи во внешних источниках: 9 ноября 2017 г.
Аннотация:Abstract. Coagulation of blood plasma is a complex network of biochemical reactions that
are usually divided into extrinsic and intrinsic pathways. The extrinsic pathway starts from
vessel injury, whereas the intrinsic one initiates from a contact with a foreign surface. The latter
consists of the proteolytic cleavages of plasma proteins factor XII (FXII) and prekallikrein (PK)
promoted by the surface and requiring a cofactor, high molecular weight kininogen (HMWK).
One of the frequently occurring events of contact pathway activation is bacterial infection. FXII
and PK seem to be activated by components of the outer leaflet of Gram-negative bacteria outer
membrane, lipopolysaccharides (LPS). The mechanisms of contact pathway activation by LPS
remains unclear.
Here we have constructed a mathematical model of contact pathway activation by LPS aggre-
gates based on in vitro experimental data for FXII-PK and FXII-PK-HMWK systems (Morisson
and Cochrane, J Exper Med (1974) 140:797-811; Kalter et al., J. Infect. Dis. (1983) 148:682-691).
The series of models consisted of 6-11 ordinary differential equations describing interactions of
proteins governed by mass action or Michaelis-Menten kinetics. The system was integrated by
LSODE method in COPASI (http://copasi.org).
The computational models described the phenomenon of apparent inhibition of contact activa-
tion by high LPS concentrations and the existence of optimal LPS concentration experimentally
observed in human plasma. The computational analysis suggested that, when LPS concentra-
tion is higher than the optimal one, surface concentrations of contact pathway factors decrease
because of the activating surface excess. In the case when LPS concentrations are smaller than
the optimal one, activating surface deficiency is the reason for the rate limitation. Thus, the
main mechanism of the contact system activation in presence of LPS is surface-dependent and
occurs due to the presence of LPS in plasma in aggregated state.