Biomedical subjects

A V Pokhilko

Publications and source records attributed to A V Pokhilko.

6 recordsLinked to original sources

PubMed2000

Intrinsic coagulation pathway: an activation threshold.

The activation threshold for the intrinsic pathway of coagulation was experimentally determined in stirred recalcified plasma from the dependence of plasma clotting time after activation by celite. Concentration of factor XIa was used as a measure of activation. At free calcium concentrations below 0.45 mM, plasma clotting time depended nonlinearly on the factor XIa concentration: with decreasing concentration of factor XIa (or celite), the clotting time dramatically increased until no coagulation was observed at concentrations of factor XIa below the threshold. As the free calcium concentration increased, the threshold concentration of factor XIa sharply decreased, from 30 pM at 0.35 mM free calcium to less than 3 pM at 0.45 mM. In the range of free calcium concentrations from 0.45 mM to physiologic ones, plasma coagulated even in the absence of celite in plastic cuvettes. This fact and extremely low threshold concentrations of factor XI (on the order of 0.5 pM) preclude determining the factor XI threshold at physiologic free calcium. As factor XIa is localized to the activating surfaces, observing the local surface concentrations of factor XIa and the dynamics of fibrin formation in systems without stirring may solve the problem.

Adult↗

PubMed1998

Contact activation of blood coagulation: trigger properties and hysteresis. Kinetic recognition of foreign surfaces upon contact activation of blood coagulation: a hypothesis.

A mathematical model of contact activation of blood coagulation was developed and analysed. The model variables are concentrations of factor XIIa, kallikrein and activated high-molecular-weight kininogen. Concentrations of active factors were shown to depend on the activating signal value in a hysteretic manner. Within a range of relatively small signals, two (activated and non-activated) stable states coexist (bistability). Signals of the natural environment (surfaces of endothelial and blood cells) seem to be in the range of bistability; therefore, contact activation that persists for a short time can induce a transition of the system to the activated state, and, correspondingly, the formation of a clot. The system cannot return to the initial state, which is characterized by low activation levels, until the activating signals decrease significantly below those present in the circulation.

Blood Coagulation↗

PubMed1996

A mathematical model for the spatio-temporal dynamics of intrinsic pathway of blood coagulation. II. Results.

This paper continues our study (see Part I) where we modeled the spatio-temporal dynamics of the intrinsic pathway of blood coagulation. Here, we analyzed this model and showed that it describes the threshold behavior of coagulation. When activation is subthreshold (which produces not more than 0.07 nM factor XIa at saturating free calcium concentrations of 2 mM or higher), the concentration of generated thrombin remains below 0.01 nM. At the abovethreshold activation corresponding to factor XIa exceeding 0.07 nM, the concentration of thrombin explosively increases and then abruptly decreases. The peak concentration of thrombin reaches hundreds nM. With respect to free calcium concentration, the system also behaves in a threshold manner. For activation corresponding to 0.3 nM factor XIa, the threshold concentration of free calcium where the outburst of explosive thrombin generation occur is equal to 0.21 mM. The model simulations are in a good agreement with the experimentally recorded kinetics of thrombin generation at different concentrations of free calcium (1). Analysis of the spatial dynamics of coagulation showed that if activation exceeded the threshold level at a certain point, the concentration wave of thrombin arises and propagates at a high speed from the activation zone. The parameters of this wave depends mainly on the efficiency of the feedback loops. The feedback loops through the backbone factors of the intrinsic pathway (autoactivation of factor X or activation of factor XI by thrombin) has a potential for the unlimited propagation of the thrombin wave. With increasing activity of activated protein C (the effect equivalent to that of thrombomodulin), oscillating regimes arise in the model. The first thrombin wave is followed by several secondary running waves. The amplitudes of secondary waves increases to the periphery of the clot consolidating its surface layer.

Blood Coagulation↗

PubMed1996

A mathematical model for the spatio-temporal dynamics of intrinsic pathway of blood coagulation. I. The model description.

We developed and analyzed the mathematical model of the intrinsic pathway based on the current biochemical data on the kinetics of blood coagulation individual stages. The model includes eight differential equations describing the spatio-temporal dynamics of activation of factors XI, IX, X, II, I, VIII, V, and protein C. The assembly of tenase and prothrombinase complexes is considered as a function of calcium concentration. The spatial dynamics of coagulation was analyzed for the one-dimensional case. We examined the formation of active factors, their spreading, and growth of the clot from the site of injury in the direction perpendicular to the vessel wall, into the blood thickness. We assumed that the site of injury (in the model one boundary of the space segment under examination) becomes a source of the continuous influx of factor XIa. In the first part, we described the model, selected the parameters, etc. In the second part, we compared the model with experimental data obtained in the homogeneous system and analyzed the spatial dynamics of the clot growth.

Blood Coagulation↗

PubMedDate not supplied

[A simulated mathematical model of the blood coagulation system intrinsic pathway].

A mathematical model of the blood coagulation system intrinsic pathway is developed based on a reaction cascade scheme with two positive feedbacks. The model describes quantitatively well-known experimental data on blood plasma coagulation kinetics for various levels of activation and varying calcium concentrations. In the limit of experimental variety of the values of the rate for individual stages of coagulation cascade, obtained in [5-12], a good agreement with experimental data was shown for two discrete sets of the constants. The model relates unambiguously the threshold properties in coagulation activation by calcium with existence of the activation threshold. The model allows numerical estimates of the threshold activation values for various calcium concentrations. At calcium concentration of 0.2 mM, corresponding to normal calcium content in blood, the activation threshold is equal to 0.00016 nM and 0.0019 nM of Factor XIa for the first and the second sets of the system parameters, respectively.

Blood Coagulation↗

PubMedDate not supplied

[Threshold behavior of the blood coagulation system upon changes in calcium concentration].

Dependence of the citrate human blood plasma clotting kinetics on free calcium concentration under its titration with calcium has been studied in vitro. Activation of factor XI is shown to be independent on calcium, while of thrombin concentration increases non-linearly at calcium concentrations in the range 0.2-0.3 mM. Kinetics of the thrombin generation fits well by the exponential function. Power indexes of the exponents rise steeply as calcium concentration increases from 0.2-0.5 mM and reach plateau at higher concentrations. At free calcium concentrations under 0.2 mM the thrombin level does not increase and remains lower than 10 pmol/ml as seen by our measuring system whose sensitivity threshold is surely less than 10 pmol/ml. Thus, the blood coagulation system behaves in a threshold manner under changes of calcium concentration. The threshold concentration of free calcium is equal to 0.2 mM.

Blood Coagulation↗