Continuous Registration of Thrombin Generation in Plasma, Its Use for the Determination of the Thrombin Potential

Hemker, H. Cœnraad; Wielders, Simone J.H.; Kessels, H.; Béguin, S.

doi:10.1055/s-0038-1649638

Cited by 326 publications

(301 citation statements)

References 12 publications

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“…Although it was developed half a century ago [1,2], it is only during the last one and a half decade that the thrombin generation test has attracted increasing attention. It appears that this test may replace coagulation based tests in many cases in the future [3,4], more so as computer aided models of the events leading to coagulation have been developed and been shown to correlate well with biochemical observations [5,6].…”

Section: Introductionmentioning

confidence: 99%

Calibrating Thrombin Generation in Different Samples: Less Effort with a Less Efficient Substrate

Tapp¹,

Grundmann²,

Kusch³

et al. 2009

TOATHERTJ

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Abstract:The technique of thrombin generation has been established as a promising tool for the diagnosis, risk estimation, and perhaps prognosis of coagulation insufficiencies. Without further experimentation an indication can be obtained if a sample donor carries the risk for haemophilia or thrombophilia, either congenital or acquired. A comparison of two different thrombin generation assays is presented, demonstrating that a currently not commercially available test allows an easier and cheaper calibration than its commercial counterpart. This is achieved by employment of a less efficient but highly specific peptide substrate for thrombin and the involvement of low amounts of analyte (plasma samples).

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Section: Introductionmentioning

confidence: 99%

Calibrating Thrombin Generation in Different Samples: Less Effort with a Less Efficient Substrate

Tapp¹,

Grundmann²,

Kusch³

et al. 2009

TOATHERTJ

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show abstract

“…To mimic this process, several laboratory techniques have been devised including the thrombin generation time (TGT) and endogenous thrombin potential (ETP). (46,47) Employing such techniques, it has been shown that the amount of thrombin generated is also dependent on the concentration of prothrombin in plasma. This effect is primarily based on an increase in the peak of thrombin produced and not on any change in the rate of thrombin formation.…”

Section: Introductionmentioning

confidence: 99%

The blood coagulation system as a molecular machine

2003

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The human blood coagulation system comprises a series of linked glycoproteins that upon activation induce the generation of downstream enzymes ultimately forming fibrin. This process is primarily important to arrest bleeding (hemostasis). Hemostasis is a typical example of a molecular machine, where the assembly of substrates, enzymes, protein cofactors and calcium ions on a phospholipid surface markedly accelerates the rate of coagulation. Excess, pathological, coagulation activity occurs in “thrombosis”, the formation of an intravascular clot, which in the most dramatic form precipitates in the microvasculature as disseminated intravascular coagulation. Thrombosis occurs according to a biochemical machine model in the case of atherothrombosis on a ruptured atherosclerotic plaque, but may develop at a slower rate in venous thrombosis, illustrating that the coagulation machinery can act at different velocities. The separate coagulation enzymes are also important in other biological processes, including inflammation for which the rapid conversion of one coagulation factor by the other is not a prerequisite. The latter role of coagulation enzymes may be related to the old and probably maintained function of the coagulation machine in innate immunity. BioEssays 25:1220–1228, 2003. © 2003 Wiley Perioicals, Inc.

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“…1 from left to right). Defibrination with Arvin is known to precipitate fibrin but not otherwise to affect the clotting system [14].…”

mentioning

confidence: 99%

During coagulation, thrombin generation shifts from chemical to diffusional control

Hemker

Smedt

Hemker

2005

Journal of Thrombosis and Haemostasis

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See also Orfeo T, Mann KG. Mathematical and biological models of blood coagulation. This issue, pp 2397-8.Hemostasis and thrombosis hinge on the formation of thrombin. The underlying reaction mechanism is a web of proenzyme-enzyme conversions, controlled by positive and negative feedback reactions [1]. Current paradigm has it that thrombin formation is the results of chemical interactions between the components of this web and therefore is uniquely determined by the initial concentrations and reaction constants of its components [2,3].Essential steps of the thrombin forming process occur at membranes that contain negatively charged phospholipids [1].In an in vitro model system such procoagulant phospholipids are normally added in the form of relatively small vesicles that remain in suspension, so that the binding sites for the clotting factors are available in free solution. In vivo the binding takes place on membrane surfaces that present in a wound or ruptured plaque [4]. Factor VII(a) binds to tissue factor incorporated in cell membranes and factors II, X(a), V(a), IX(a) and VII(a) on adhering and aggregating activated platelets and on membrane remnants. Experiments in the presence of platelets and tissue factor bearing cells suggest that, as soon as such structures are present, physical transport through diffusion might play a role in determining thrombin generation velocities [5,6,7]. In coagulation experiments in plasma in vitro, procoagulant phospholipids are added to platelet-poor plasma (PPP) in the form of vesicles; in plateletrich plasma (PRP), they are provided by activated platelets [8].At the moment that a clot forms, $98% of thrombin is still to be generated [9,10]. The total amount of thrombin formed is an important determinant of the quality of hemostasis or the extent of thrombosis [11] and this thrombin is almost all formed within the fibrin mesh of the clot. In that mesh, the plasma is stagnant and the procoagulant surfaces of blood platelets and membrane fragments stick to the fibrin fibers [12]. Prothrombin conversion and other activation reactions thus are likely to be located on the insoluble fibrin mesh rather than in free and homogeneous solution and it is conceivable that not only chemical reaction rates but also diffusional transport to these surfaces determines the rate of thrombin formation.Whether diffusion or chemical interaction is rate limiting can be decided on the basis of temperature dependence. Diffusion velocity is proportional to absolute temperature, i.e. it will show a $14% increase between 10 and 50°C, whereas biochemical reactions will roughly double their pace if the temperature is raised by 10°C (see e.g. 13). Here, we show that the temperature dependency of thrombin generation in clotting plasma is such that we must assume that, when a clot has formed, diffusion starts to co-determine the rate of thrombin formation.Thrombin inactivation, on the contrary, is caused by stoichiometric reaction with specific plasma proteins, the most important of which is antithrombin. ...

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Continuous Registration of Thrombin Generation in Plasma, Its Use for the Determination of the Thrombin Potential

Cited by 326 publications

References 12 publications

Calibrating Thrombin Generation in Different Samples: Less Effort with a Less Efficient Substrate

Calibrating Thrombin Generation in Different Samples: Less Effort with a Less Efficient Substrate

The blood coagulation system as a molecular machine

During coagulation, thrombin generation shifts from chemical to diffusional control

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