Comparative Thrombin Generation in Animal Plasma: Sensitivity to Human Factor XIa and Tissue Factor
Preclinical evaluation of drugs in animals helps researchers to select potentially informative clinical laboratory markers for human trials. To assess the utility of animal thrombin generation (TG) assay, we studied the sensitivity of animal plasmas to triggers of TG, human Tissue Factor (TF), and A...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-08-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/16/12920 |
| _version_ | 1797584448183599104 |
|---|---|
| author | Yideng Liang Ivan Tarandovskiy Stepan S. Surov Mikhail V. Ovanesov |
| author_facet | Yideng Liang Ivan Tarandovskiy Stepan S. Surov Mikhail V. Ovanesov |
| author_sort | Yideng Liang |
| collection | DOAJ |
| description | Preclinical evaluation of drugs in animals helps researchers to select potentially informative clinical laboratory markers for human trials. To assess the utility of animal thrombin generation (TG) assay, we studied the sensitivity of animal plasmas to triggers of TG, human Tissue Factor (TF), and Activated Factor XI (FXIa). Pooled human, mouse, rat, guinea pig, rabbit, bovine, sheep, and goat plasmas were used in this study. TF- or FXIa-triggered TG and clotting were measured via fluorescence and optical density, respectively. Thrombin peak height (TPH) and time (TPT), clot time (CT), and fibrin clot density (FCD) were all analyzed. The trigger low and high sensitivity borders (LSB and HSB) for each assay parameter were defined as TF and FXIa concentrations, providing 20 and 80% of the maximal parameter value, unless the baseline (no trigger) value exceeded 20% of the maximal, in which case, LSB was derived from 120% of baseline value. Normal human samples demonstrated lower TPH HSB than most of the animal samples for both TF and FXIa. Animal samples, except mice, demonstrated lower TPT LSB for FXIa versus humans. Most rodent and rabbit samples produced baseline TG in the absence of TG triggers that were consistent with the pre-activation of blood coagulation. FCD was not sensitive to both TF and FXIa in either of the plasmas. Animal plasmas have widely variable sensitivities to human TF and FXIa, which suggests that optimization of trigger concentration is required prior to test use, and this complicates the extrapolation of animal model results to humans. |
| first_indexed | 2024-03-10T23:52:51Z |
| format | Article |
| id | doaj.art-e16746b1151943d782d321b47ae4bd87 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:52:51Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e16746b1151943d782d321b47ae4bd872023-11-19T01:32:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124161292010.3390/ijms241612920Comparative Thrombin Generation in Animal Plasma: Sensitivity to Human Factor XIa and Tissue FactorYideng Liang0Ivan Tarandovskiy1Stepan S. Surov2Mikhail V. Ovanesov3Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USAOffice of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USAOffice of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USAOffice of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USAPreclinical evaluation of drugs in animals helps researchers to select potentially informative clinical laboratory markers for human trials. To assess the utility of animal thrombin generation (TG) assay, we studied the sensitivity of animal plasmas to triggers of TG, human Tissue Factor (TF), and Activated Factor XI (FXIa). Pooled human, mouse, rat, guinea pig, rabbit, bovine, sheep, and goat plasmas were used in this study. TF- or FXIa-triggered TG and clotting were measured via fluorescence and optical density, respectively. Thrombin peak height (TPH) and time (TPT), clot time (CT), and fibrin clot density (FCD) were all analyzed. The trigger low and high sensitivity borders (LSB and HSB) for each assay parameter were defined as TF and FXIa concentrations, providing 20 and 80% of the maximal parameter value, unless the baseline (no trigger) value exceeded 20% of the maximal, in which case, LSB was derived from 120% of baseline value. Normal human samples demonstrated lower TPH HSB than most of the animal samples for both TF and FXIa. Animal samples, except mice, demonstrated lower TPT LSB for FXIa versus humans. Most rodent and rabbit samples produced baseline TG in the absence of TG triggers that were consistent with the pre-activation of blood coagulation. FCD was not sensitive to both TF and FXIa in either of the plasmas. Animal plasmas have widely variable sensitivities to human TF and FXIa, which suggests that optimization of trigger concentration is required prior to test use, and this complicates the extrapolation of animal model results to humans.https://www.mdpi.com/1422-0067/24/16/12920thrombin generationfibrin clot formationanimal modeltissue factoractivated factor XIassay sensitivity |
| spellingShingle | Yideng Liang Ivan Tarandovskiy Stepan S. Surov Mikhail V. Ovanesov Comparative Thrombin Generation in Animal Plasma: Sensitivity to Human Factor XIa and Tissue Factor International Journal of Molecular Sciences thrombin generation fibrin clot formation animal model tissue factor activated factor XI assay sensitivity |
| title | Comparative Thrombin Generation in Animal Plasma: Sensitivity to Human Factor XIa and Tissue Factor |
| title_full | Comparative Thrombin Generation in Animal Plasma: Sensitivity to Human Factor XIa and Tissue Factor |
| title_fullStr | Comparative Thrombin Generation in Animal Plasma: Sensitivity to Human Factor XIa and Tissue Factor |
| title_full_unstemmed | Comparative Thrombin Generation in Animal Plasma: Sensitivity to Human Factor XIa and Tissue Factor |
| title_short | Comparative Thrombin Generation in Animal Plasma: Sensitivity to Human Factor XIa and Tissue Factor |
| title_sort | comparative thrombin generation in animal plasma sensitivity to human factor xia and tissue factor |
| topic | thrombin generation fibrin clot formation animal model tissue factor activated factor XI assay sensitivity |
| url | https://www.mdpi.com/1422-0067/24/16/12920 |
| work_keys_str_mv | AT yidengliang comparativethrombingenerationinanimalplasmasensitivitytohumanfactorxiaandtissuefactor AT ivantarandovskiy comparativethrombingenerationinanimalplasmasensitivitytohumanfactorxiaandtissuefactor AT stepanssurov comparativethrombingenerationinanimalplasmasensitivitytohumanfactorxiaandtissuefactor AT mikhailvovanesov comparativethrombingenerationinanimalplasmasensitivitytohumanfactorxiaandtissuefactor |