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Clots in Blood Vessels

#3868


Study and Modeling of the Development of Clots in Blood Vessels and the Resultant Abnormalities in Hemodynamics

Tech Area / Field

  • MED-DID/Diagnostics & Devices/Medicine

Status
8 Project completed

Registration date
15.05.2008

Completion date
11.06.2013

Senior Project Manager
Ryzhova T B

Leading Institute
VNIIEF, Russia, N. Novgorod reg., Sarov

Supporting institutes

  • Kazan State University / Scientific Research Institute of Mathematics and Mechanics, Russia, Tatarstan, Kazan

Collaborators

  • Centro di Ricerca, Sviluppo e Studi Superiori in Sardegna, Italy, Sardinia, Pula

Project summary

During recent years, investigation of self-assembly processes in molecular systems and studying properties of supramolecular complexes have become an issue of the day. Of special importance are the investigations of biological systems that are among the most complex molecular systems from regarding their structural organization and functional mechanisms. Blood is one of such systems and blood clotting is a vitally important defense reaction of an organism. Clotting of blood is a multi-step cascade biochemical process involving a set of substances called “clotting factors”, namely: enzymes, Ca2+, etc. For example, damage of a blood vessel most often induces the cascade reactions that successively activate the clotting factors. Clotting results in formation of a 3D fibrin network, a supramolecular matrix that provides the structural basis for a thrombus. Activation of the blood coagulation system is followed by the process of fibrinolysis (dissolution of a clot). This is the process that eventually leads to splitting of fibrin into soluble peptides by the enzyme named plasmin and, therefore, to disappearance of the thrombus and recovery of blood vessel lumen.

Disorders of the coagulation and fibrinolytic systems result in uncontrolled formation of fibrin inside blood vessels. If the clots are not properly dissolved, they may cause partial occlusion of the blood vessel lumen or even its complete obstruction leading to ischemia of the supplied tissues. This is a life threatening condition, especially if a clot forms in a coronary artery or in a brain vessel. However, there is one more risk: detachment or rupture of the clot resulting in thromboembolism, i.e., occlusion of a remote vessel by a separated piece of fibrin.

The probability of one or another outcome is determined by multiple circumstances including blood rheology, vessel wall integrity, activity of platelets and clotting factors as well as structure, mechanical properties and permeability of the clot. Thus, studying the processes of formation and dissolution of fibrin clots and thrombi remains a challenging problem of great theoretical and practical importance for biology and medicine.

Experimental investigations will be carried out mainly by means of pulse NMR (nuclear magnetic resonance) techniques with pulse magnetic field gradient (NMR PMFG) allowing the direct investigation of the translation dynamics of molecule components in complex molecular systems. In addition to the characteristic features related to the structure and mobility of the system components under consideration, the issues concerning the kinetics of processes, including investigations of stochastic supramolecular structures, will also be studied. The effect of various factors (pH of solution, concentrations of reagents) on the structural and dynamic features of fibrin gels will be studied. Attention will also be paid to studying the influence of the gel network on mobility of water and other molecules (proteins, pharmaceutical preparations) contained in it. The structural organization of the gel network itself and other components will be investigated using NMR relaxation methods and by examining the proton exchange. The methods for studying the spin diffusion (for example, the well-known Goldman-Shen sequence) will also be used, if necessary. The experiments on examining the translation dynamics of molecules will be based on the comprehensive analysis of the form of diffusion attenuations depending both on the diffusion time and other times in the experiment related to nuclear magnetic relaxation. This will allow the cooperative (multidimensional) study of the nuclear magnetic relaxation and self-diffusion and acquisition of additional data on the specific features of the molecular structure and dynamics of objects. Studying the dependences on the diffusion times will help testing cases of “abnormal” diffusion which is inherent to the dynamic development of chains of the gel network and, in particular, to molecule mobility in media of bound geometries. Investigations of the relaxation and diffusion features of systems will be conducted using the NMR facility with resonance frequency 300 MHz (for 1H) and maximum magnetic field gradient 50 T/m. In addition, classical clinical investigations into blood motion and vessel occlusion will be carried out using angiography and dopplerometry.

The goal of the simulation is to calculate the process of clot formation and to assess and predict the risk of its detachment depending on different and changeable circumstances. The original model of solution flow in porous medium with a swelling matrix developed at NII MM will be used as the prototype model. A clot will be simulated so as to consider the porous matrix strains occurring during the supramolecular grid swelling, with a special factor being introduced to the model to allow consideration of abnormalities in the process of healing the vessel wall. Additional strains non-uniformly distributed over the whole supramolecular matrix emerge as the clot continues to grow. With the limit values exceeded, the detachment of the whole clot from the vessel wall or its rupture occur. Since the object is highly specific, the investigation of the transport features of the intra-clot space is impossible using traditional methods. Accordingly, it is proposed that the NMR relaxation and self-diffusion data will be used to determine these parameters.

Expected results

  1. The abnormal diffusion parameters, relaxation times, and relaxation and self-diffusion time spectra will allow us to determine the structural-and-dynamic properties of fibrin gels obtained by varying the solution pH value and concentrations of fibrinogen and thrombin in it. The pore size of the network will be estimated and its influence on mobility of water and other molecules will be assessed.
  2. Based on analysis of proton exchange features and data on the nuclear relaxation times, conclusions concerning the structure of fibrin fibers in clots obtained under various conditions will be made. To establish the degree of exposure of fibrin molecules within the clot network, the mean values of proton life periods will be determined for them.
  3. Data on the latency times and the rates of fibrin clot formation/digestion processes, as well as data on the kinetic dependences for dynamic characteristics of the gel network will be obtained based on the kinetic dependences found for self-diffusion constants, nuclear magnetic relaxation times and characteristic features of spectra of these values.
  4. Conclusions concerning the uniformity (or non-uniformity) of the gel dissolving process will be made according to the results of examination of the self-diffusion coefficient spectra of fibrin macromolecules during various phases of the degradation process.
  5. Based on the experimental dependences revealed, a problem about time-dependent blood flow in blood vessels (capillaries) under changed occlusion conditions resulting from clotting will be solved. Simulation data will be used to study the abnormalities in hemodynamics during the occurrence and development of thrombosis.
  6. A problem about clot detachment and transport by the blood flow will be solved using the original model of a piece of capillary wall substance detached by a flow developed at NII MM. Simulation data will be used to assess the risk of vessel occlusion by a detached thrombus.

Numerical simulation data and results would help to predict the dynamics of clot growth, the development of internal strains in matrix, as well as to predict probabilities of the clot detachment and rupture. In addition, this will enable us to calculate the rate of ischemia development in the clot-affected region during the phase of clot growth below the critical values of internal strains.


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