Activation of Contact Pathway of Blood Coagulation on the Lipopolysaccharide Aggregates

¹ Institut Camille Jordan, University Lyon 1, 43 bd 11 Novembre 1918, Villeurbanne, 69622 France
² INRIA Team Dracula, INRIA Antenne Lyon la Doua, Villeurbanne, 69603 France
³ Department of Biophysics, Faculty of Biology, Lomonosov Moscow State University, 1/24 Leninskie gory, Moscow, 119992 Russia
⁴ Faculty of Physics, Lomonosov Moscow State University, 1/2 Leninskie gory, Moscow, 119991 Russia
⁵ Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, 4 Kosygina St, Moscow, 119991 Russia
⁶ National Scientific and Practical Centre of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev, 1 Samory Mashela St, Moscow, 117198 Russia

^** Corresponding author. E-mail: agolomy@gmail.com

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 aggregates 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 activation by high LPS concentrations and the existence of optimal LPS concentration experimentally observed in human plasma. The computational analysis suggested that, when LPS concentration 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.