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Global measurement of coagulation in plasma from normal and haemophilia dogs using a novel modified thrombin generation test - Demonstrated in vitro and ex vivo.

ABSTRACT: Canine models of severe haemophilia resemble their human equivalents both regarding clinical bleeding phenotype and response to treatment. Therefore pre-clinical studies in haemophilia dogs have allowed researchers to make valuable translational predictions regarding the potency and efficacy of new anti-haemophilia drugs (AHDs) in humans. To refine in vivo experiments and reduce number of animals, such translational studies are ideally preceded by in vitro prediction of compound efficacy using a plasma based global coagulation method. One such widely used method is the thrombin generation test (TGT). Unfortunately, commercially available TGTs are incapable of distinguishing between normal and haemophilia canine plasma, and therefore in vitro prediction using TGT has so far not been possible in canine plasma material.Establish a modified TGT capable of: 1) distinguishing between normal and haemophilia canine plasma, 2) monitoring correlation between canine plasma levels of coagulation factor VIII (FVIII) and IX (FIX) and thrombin generation, 3) assessing for agreement between compound activity and thrombin generation in ex vivo samples.A modified TGT assay was established where coagulation was triggered using a commercially available activated partial thromboplastin time reagent.With the modified TGT a significant difference was observed in thrombin generation between normal and haemophilia canine plasma. A dose dependent thrombin generation was observed when assessing haemophilia A and B plasma spiked with dilution series of FVIII and FIX, respectively. Correlation between FVIII activity and thrombin generation was observed when analyzing samples from haemophilia A dogs dosed with canine FVIII. Limit of detection was 0.1% (v/v) FVIII or FIX.A novel modified TGT suitable for monitoring and prediction of replacement therapy efficacy in plasma from haemophilia A and B dogs was established.

SUBMITTER: Madsen DE

PROVIDER: S-EPMC5383133 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Global measurement of coagulation in plasma from normal and haemophilia dogs using a novel modified thrombin generation test - Demonstrated in vitro and ex vivo.

Madsen Daniel Elenius DE Nichols Timothy C TC Merricks Elizabeth P EP Waters Emily K EK Wiinberg Bo B

PloS one 20170406 4

<h4>Introduction</h4>Canine models of severe haemophilia resemble their human equivalents both regarding clinical bleeding phenotype and response to treatment. Therefore pre-clinical studies in haemophilia dogs have allowed researchers to make valuable translational predictions regarding the potency and efficacy of new anti-haemophilia drugs (AHDs) in humans. To refine in vivo experiments and reduce number of animals, such translational studies are ideally preceded by in vitro prediction of comp ...[more]

PMID: 28384182

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Project description:Pulse wave attenuation characteristics reflect compliance and resistance properties of the vessel wall as well as initial pulse generation factors. Recently, it has become possible to measure and map the retinal vessel wall pulse wave amplitudes. Predictable pulse wave amplitude distribution may allow inferences to be made concerning vascular compliance and resistance. Twenty-eight eyes from sixteen subjects (8 male and 8 female) were examined using modified retinal photoplethysmography with simultaneous ophthalmodynamometry. This allowed the assessment of vessel wall pulsation amplitudes under a dynamic range of intraocular pressures. Pulse amplitudes were calculated using harmonic regression analysis. The pulse wave attenuation was measured under different ranges of ophthalmodynamometric force (ODF) as a function of distance along the vessel (VDist), which in turn was calculated in disc diameters (DD) from the center of the optic disc. A linear mixed-effects model with randomized slopes and intercepts was used to estimate the correlations between the logarithmically transformed harmonic regression wave amplitude (HRWa) and the Fourier trigonometric coefficients with the predictors (VDist and ODF). The retinal venous harmonic regression wave attenuation (coefficient value±standard error) -0.40±0.065/DD, (p-value < 0.00001, 95% confidence interval (CI) -0.53 to -0.27), which was approximately twice that of the arterial -0.17±0.048/DD, (p-value < 0.0004, 95% CI = -0.27 to -0.08). There was a positive correlation between attenuation of the harmonic regression wave and ophthalmodynamometric force in both vascular systems. The attenuation of all but the sine coefficient of the second Fourier harmonic (bn2) achieved statistical significance in the correlation with VDist. The cosine coefficient of the first Fourier harmonic an1 was the only coefficient to achieve statistical significance in the correlation with the predictors VDist and ODF in both vascular systems. The an1 coefficient value in the correlation with VDist was -3.79±0.78 and -1.269±0.37 (p < 0.0006), while this coefficient value in the correlation with ODF was 0.026±0.0099 and 0.009±0.04 (p < 0.01) in both the retinal veins and arteries respectively. The predictable attenuation characteristics in normal subjects suggest that this technique may allow the non-invasive quantification of retinal vascular compliance and other hemodynamic parameters.

Dataset Information

Global measurement of coagulation in plasma from normal and haemophilia dogs using a novel modified thrombin generation test - Demonstrated in vitro and ex vivo.

Publications

Global measurement of coagulation in plasma from normal and haemophilia dogs using a novel modified thrombin generation test - Demonstrated in vitro and ex vivo.

Similar Datasets

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