Models of blood coagulation
ABSTRACT Our research aims to provide quantitatively transparent, biologically realistic descriptions of the processes involved in hemostasis which will permit predictions of the behavior of the coagulation system in normal and pathologic states. We use four models of coagulation: (1) numerical approximations of the tissue factor (Tf) pathway of thrombin generation based upon mechanism and dynamics; (2) Tf activation of the "blood coagulation proteome" from isolated cells and proteins; (3) Tf activated contact pathway inhibited whole blood in vitro; and (4) blood shed from standardized microvascular wounds in vivo. The results from these models are integrated in interactive assessments aimed at achieving convergence of biochemical rigor and biological authenticity. Microvascular injury is the most biologically secure but least accessible to mechanistic study. Numerical models while quantitatively transparent are biologically limited. By the integrated analyses of all four models, we establish observations which require inclusion or discovery of new parameters to achieve mechanistically interpretable biological reality. Discoveries made in this fashion have included thrombin's role in the initiation phase, TFPI/ATIII/APC synergy interactions, rfVIIa in fVII deficiency, the roles of fVIII and fIX in the Tf reaction, and the cleavage of fIX by fXa membrane. Ideally, our results will provide descriptions which predict the behavior of the biological blood coagulation system under normal and pathologic conditions.
- SourceAvailable from: Alexej Victorovich Sokolov
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- "ProT is the physiological precursor of mature α-thrombin (α-T) and is composed of F1 and F2 regions, and the protease domain . Pre2 is the shortest precursor of α-thrombin, differing from the mature enzyme only for having the Arg15-Ile16 bond intact (α-T numbering) . The recently solved crystallographic structures of ProT  and Pre2  reveal that , compared to α- T, major perturbations occur in the Na + -binding site, in the activation domain and in the insertion loops surrounding on the catalytic cleft. "
ABSTRACT: Human ceruloplasmin (CP) is a multifunctional copper-binding protein produced in the liver. CP oxidizes Fe(2+) to Fe(3+), decreasing the concentration of Fe(2+) available for generating harmful oxidant species. CP is also a potent inhibitor of leukocyte myeloperoxidase (MPO) (Kd=130nM), a major source of oxidants in vivo. Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting flexible joints and characterized by activation of both inflammatory and coagulation processes. Indeed, the levels of CP, MPO and thrombin are markedly increased in the synovial fluid of RA patients. Here we show that thrombin cleaves CP in vitro at (481)Arg-Ser(482) and (887)Lys-Val(888) bonds, generating a nicked species that retains the native-like fold and the ferroxidase activity of the intact protein, whereas the MPO inhibitory function of CP is abrogated. Analysis of the synovial fluid of 24 RA patients reveals that CP is proteolytically degraded to a variable extent, with a fragmentation pattern similar to that observed with thrombin in vitro, and that proteolysis is blocked by hirudin, a highly potent and specific thrombin inhibitor. Using independent biophysical techniques, we show that thrombin has intrinsic affinity for CP (Kd=60-270nM), independently of proteolysis, and inhibits CP ferroxidase activity (KI=220±20nM). Mapping of thrombin binding sites with specific exosite-directed ligands (i.e. hirugen, fibrinogen γ'-peptide) and thrombin analogues having the exosites variably compromised (i.e. prothrombin, prethrombin-2, βT-thrombin), reveals that the positively charged exosite-II of thrombin binds to the negatively charged upper region of CP, while the protease active site and exosite-I remain accessible. These results suggest that thrombin can exacerbate inflammation in RA by impairing via proteolysis the MPO inhibitory function of CP and by competitively inhibiting CP ferroxidase activity. Copyright © 2015. Published by Elsevier Inc.Free Radical Biology and Medicine 05/2015; 86:279-294. DOI:10.1016/j.freeradbiomed.2015.05.016 · 5.71 Impact Factor
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- "Attaullakhanov et al.  experimentally studied the spatio-temporal dynamics of blood coagulation and pattern formation. Mann et al.   developed models for blood coagulation and the dynamics of thrombin formation. Panteleev et al.  formulated mathematical models for the study of blood coagulation and platelet adhesion in their review and provided some clinical applications of the mathematical models. "
ABSTRACT: The pulsatile flow of a two-phase model for blood flow through axisymmetric and asymmetric stenosed narrow arteries is analyzed, treating blood as a two-phase model with the suspension of all the erythrocytes in the core region as the Herschel–Bulkley material and plasma in the peripheral layer as the Newtonian fluid. The perturbation method is applied to solve the resulting non-linear implicit system of partial differential equations. The expressions for various flow quantities are obtained. It is found that the pressure drop, plug core radius, wall shear stress increase as the yield stress or stenosis height increases. It is noted that the velocity increases, longitudinal impedance decreases as the amplitude increases. For asymmetric stenosis, the wall shear stress increases non-linearly with the increase of the axial distance. The estimates of the increase in longitudinal impedance to flow of the two-phase Herschel–Bulkley material are significantly lower than those of the single-phase Herschel–Bulkley material. The results show the advantages of two-phase flow over single-phase flow in small diameter arteries with stenosis.International Journal of Non-Linear Mechanics 01/2011; 46(1-46):296-305. DOI:10.1016/j.ijnonlinmec.2010.09.011 · 1.46 Impact Factor
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- "Fogelson and Guy  extended these continuum models further to study the platelet–wall interactions of platelet thrombosis, using numerical solution. Mann et al.   discussed extensively the models of blood coagulation and the dynamics of thrombin formation. Attaullakhanov et al.  have experimentally analyzed the spatio-temporal dynamics of blood coagulation and pattern formation. "
ABSTRACT: The pulsatile flow of blood through a catheterized artery is analyzed, assuming the blood as a two-fluid model with the suspension of all the erythrocytes in the core region as a Casson fluid and the peripheral region of plasma as a Newtonian fluid. The resulting non-linear implicit system of partial differential equations is solved using perturbation method. The expressions for shear stress, velocity, flow rate, wall shear stress and longitudinal impedance are obtained. The variations of these flow quantities with yield stress, catheter radius ratio, amplitude, pulsatile Reynolds number ratio and peripheral layer thickness are discussed. It is observed that the velocity distribution and flow rate decrease, while, the wall shear, width of the plug flow region and longitudinal impedance increase when the yield stress increases. It is also found that the velocity increases, but, the longitudinal impedance decreases when the thickness of the peripheral layer increases. The wall shear stress decreases non-linearly, while, the longitudinal impedance increases non-linearly when the catheter radius ratio increases. The estimates of the increase in the longitudinal impedance are considerably lower for the present two-fluid model than those of the single-fluid model.International Journal of Non-Linear Mechanics 05/2009; DOI:10.1016/j.ijnonlinmec.2008.12.008 · 1.46 Impact Factor