Simulation and Analysis of the Blood Coagulation Cascade Accelerated on GPU

2014 ◽  
Author(s):  
Matteo Bellini ◽  
Daniela Besozzi ◽  
Paolo Cazzaniga ◽  
Giancarlo Mauri ◽  
Marco S. Nobile
Keyword(s):  
Blood Coagulation ◽  
Coagulation Cascade

Differential Drug Target Selection in Blood Coagulation: What can we get from Computational Systems Biology Models?

2020 ◽  
Vol 26 (18) ◽  
pp. 2109-2115 ◽  
Author(s):  
Mikhail A. Panteleev ◽  
Anna A. Andreeva ◽  
Alexey I. Lobanov
Keyword(s):  
Blood Coagulation ◽  
Biological Network ◽  
Target Selection ◽  
Anticoagulation Therapy ◽  
Differential Regulation ◽  
Coagulation Cascade ◽  
Computational Systems Biology ◽  
Analysis Strategies ◽  
Optimal Target ◽  
Computational Systems

Discovery and selection of the potential targets are some of the important issues in pharmacology. Even when all the reactions and the proteins in a biological network are known, how does one choose the optimal target? Here, we review and discuss the application of the computational methods to address this problem using the blood coagulation cascade as an example. The problem of correct antithrombotic targeting is critical for this system because, although several anticoagulants are currently available, all of them are associated with bleeding risks. The advantages and the drawbacks of different sensitivity analysis strategies are considered, focusing on the approaches that emphasize: 1) the functional modularity and the multi-tasking nature of this biological network; and 2) the need to normalize hemostasis during the anticoagulation therapy rather than completely suppress it. To illustrate this effect, we show the possibility of the differential regulation of lag time and endogenous thrombin potential in the thrombin generation. These methods allow to identify the elements in the blood coagulation cascade that may serve as the targets for the differential regulation of this system.

scholarly journals Bioactive Lipids Metabolites in Amanita Virosa

2012 ◽  
Vol 7 (11) ◽  
pp. 1934578X1200701 ◽  
Author(s):  
Francesca Cateni ◽  
Marina Zacchigna ◽  
Bojan Doljak ◽  
Marko Anderluh ◽  
Giuseppe Procida ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Blood Coagulation ◽  
Inhibitory Activity ◽  
Complex Mixture ◽  
Serine Proteinase ◽  
Coagulation Cascade ◽  
Bioactive Lipids ◽  
Thrombin Inhibition ◽  
Suitable Target

Thrombin is the key serine proteinase of the coagulation cascade and, therefore, a suitable target for inhibition of blood coagulation. An extract of Amanita virosa considerably inhibited thrombin (48%), but showed no inhibitory activity on trypsin. On the basis of inhibition selectivity between thrombin and trypsin and potency of thrombin inhibition, A. virosa constitutes a good starting material for the isolation of further compounds that are active against thrombin. Bioassay oriented fractionation of the extract of A. virosa led to the isolation of a complex mixture of triglycerides (TGs), monoacylglycerols (MAGs), free fatty acids (FAs) and ergosterol. The structures of the isolated lipids metabolites were determined on the basis of chemical and spectroscopic evidences.

Effects of Tannins fromGeumjaponicumon the Catalytic Activity of Thrombin and Factor Xa of Blood Coagulation Cascade

1998 ◽  
Vol 61 (11) ◽  
pp. 1356-1360 ◽  
Author(s):  
Hui Dong ◽  
Shao-Xing Chen ◽  
R. Manjunatha Kini ◽  
Hong-Xi Xu
Keyword(s):  
Catalytic Activity ◽  
Blood Coagulation ◽  
Factor Xa ◽  
Coagulation Cascade

The inhibition of pancreatic cancer invasion-metastasis cascade in both cellular signal and blood coagulation cascade of tissue factor by its neutralisation antibody

2011 ◽  
Vol 47 (14) ◽  
pp. 2230-2239 ◽  
Author(s):  
Yohei Saito ◽  
Yuki Hashimoto ◽  
Jun-ichiro Kuroda ◽  
Masahiro Yasunaga ◽  
Yoshikatsu Koga ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Cancer Invasion ◽  
Coagulation Cascade ◽  
Cellular Signal

MECHANISM OF ACTIVATION OF BLOOD COAGULATION BY LEUKOCYTE PROCOAGULANT ACTIVITY

1987 ◽  
Author(s):  
N Narahara ◽  
H Sadakata ◽  
T Uchiyama ◽  
K Andoh ◽  
H Tanaka ◽  
...  
Keyword(s):  
Blood Coagulation ◽  
Calf Serum ◽  
Leukemia Cell ◽  
Specific Radioactivity ◽  
Activation Mechanism ◽  
Leukemia Cell Line ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Factor X ◽  
Viii And Ix

To investigate the process of activation mechanism of blood coagulation by leukocytes, binding of radiolabelled Factor X and the activation of Factor X on the cell surface of leukocytes were studied by using cultured leukemia cell line, Molt-4 cells. Cells were cultured in RPMI 1640 medium with 10% inactivated fetal, calf serum at a concentration of 1x106cells/ml. After 6 hours' stimulation with 1 ug/ml of endotoxin(LPS: Escherichia coli 026:B6), cells were separated by centrifugation, washed three times with Tris containing NaCl buffer(pH 7.5, TBS), and then suspended in TBS containing 0.5% bovine serum albumin(TBS-BSA) to the concentration of 5x106 cells/ml. Factors X, VII and IX were purified from fresh-frozen human plasma by the method of Bajaj in a modified version. Factor VIII was purified from cryoprecipitate as starting material. Factor X labelled with 1-125 by the method of McFarlane showed a single band on autoradiography. Specific radioactivity was 0.3 mCi/mg. For the study on binding of Factor X, TBS-BSA solution containing 4 mM of CaClp, various amounts of radiolabelled Factor X with/without purified Factors VII, VIII and IX were added to the LPS-stimulated washed cell suspension and mixed well. N-butyl-phtalate was layered over the reaction mixture after incubation at room temperature for various minutes. Total amount of bound Factor X was calculated from the radioactivity of the cell pellet separated by centrifugation of the reaction mixture. The Xa activity generated in the supernatants was assayed using S2222.Results: Factor X bound specifically to the LPS-stimulated Molt-4 cells. Amount of bound Factor X and the dissociation constant was 1.0 ng/5x10bcells (5.2x103sites/cell) and 5x106M, respectively. More amounts of Factor X bound when Factors VIII and IX were present in the reaction mixture than their absence. Five times more Factor Xa was generated when Factors VII, VIII and IX were present in the reaction mixture as compared with presence of Factor VII, alone. These results suggest that blood coagulation cascade proceeds on the LPS-stimulated leukocyte surface.

scholarly journals How Na+ activates thrombin – a review of the functional and structural data

2008 ◽  
Vol 389 (8) ◽  
Author(s):  
James A. Huntington
Keyword(s):  
Crystal Structures ◽  
Blood Coagulation ◽  
Protein C ◽  
Coagulation Factor ◽  
Structural Data ◽  
Monovalent Cation ◽  
Coagulation Cascade ◽  
Structural Basis ◽  
Thrombin Activity ◽  
Great Relevance

Abstract Thrombin is the ultimate coagulation factor; it is the final protease generated in the blood coagulation cascade and is the effector of clot formation. Regulation of thrombin activity is thus of great relevance to determining the correct haemostatic balance, with dysregulation leading to bleeding or thrombosis. One of the most enigmatic and controversial regulators of thrombin activity is the monovalent cation Na+. When bound to Na+, thrombin adopts a ‘fast’ conformation which cleaves all procoagulant substrates more rapidly, and when free of Na+, thrombin reverts to a ‘slow’ state which preferentially activates the protein C anticoagulant pathway. Thus, Na+-binding allosterically modulates the activity of thrombin and helps determine the haemostatic balance. Over the last 30 years, there has been much research investigating the structural basis of thrombin allostery. Biochemical and mutagenesis studies established which regions and residues are involved in the slow→fast conformational change, and recently several crystal structures of the putative slow form have been solved. In this article, the biochemical and crystallographic data are reviewed to see if we are any closer to understanding the conformational basis of the Na+ activation of thrombin.

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