Microfluidic hemophilia models using blood from healthy donors

Abstract Background Microfluidic clotting assays permit drug action studies for hemophilia therapeutics under flow. However, limited availability of patient samples and Inter‐donor variability limit the application of such assays, especially with many patients on prophylaxis. Objective To develop ap...

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Autores principales:	Xinren Yu, Karen A. Panckeri, Lacramioara Ivanciu, Rodney M. Camire, Carmen H. Coxon, Adam Cuker, Scott L. Diamond
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2020
Materias:	drug evaluation fibrin hemophilia hemostasis microfluidics Diseases of the blood and blood-forming organs RC633-647.5
Acceso en línea:	https://doaj.org/article/71da544d77aa43e085358a8ca40dc390
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spelling	oai:doaj.org-article:71da544d77aa43e085358a8ca40dc3902021-11-15T06:10:44ZMicrofluidic hemophilia models using blood from healthy donors2475-037910.1002/rth2.12286https://doaj.org/article/71da544d77aa43e085358a8ca40dc3902020-01-01T00:00:00Zhttps://doi.org/10.1002/rth2.12286https://doaj.org/toc/2475-0379Abstract Background Microfluidic clotting assays permit drug action studies for hemophilia therapeutics under flow. However, limited availability of patient samples and Inter‐donor variability limit the application of such assays, especially with many patients on prophylaxis. Objective To develop approaches to phenocopy hemophilia using modified healthy blood in microfluidic assays. Methods Corn trypsin inhibitor (4 µg/mL)‐treated healthy blood was dosed with either anti–factor VIII (FVIII; hemophilia A model) or a recombinant factor IX (FIX) missense variant (FIX‐V181T; hemophilia B model). Treated blood was perfused at 100 s−1 wall shear rate over collagen/tissue factor (TF) or collagen/factor XIa (FXIa). Results Anti‐FVIII partially blocked fibrin production on collagen/TF, but completely blocked fibrin production on collagen/FXIa, a phenotype reversed with 1 µmol/L bispecific antibody (emicizumab), which binds FIXa and factor X. As expected, emicizumab had no significant effect on healthy blood (no anti‐FVIII present) perfused over collagen/FXIa. The efficacy of emicizumab in anti‐FVIII‐treated healthy blood phenocopied the action of emicizumab in the blood of a patient with hemophilia A perfused over collagen/FXIa. Interestingly, a patient‐derived FVIII‐neutralizing antibody reduced fibrin production when added to healthy blood perfused over collagen/FXIa. For low TF surfaces, reFIX‐V181T (50 µg/mL) fully blocked platelet and fibrin deposition, a phenotype fully reversed with anti‐TFPI. Conclusion Two new microfluidic hemophilia A and B models demonstrate the potency of anti‐TF pathway inhibitor, emicizumab, and a patient‐derived inhibitory antibody. Using collagen/FXIa‐coated surfaces resulted in reliable and highly sensitive hemophilia models.Xinren YuKaren A. PanckeriLacramioara IvanciuRodney M. CamireCarmen H. CoxonAdam CukerScott L. DiamondWileyarticledrug evaluationfibrinhemophiliahemostasismicrofluidicsDiseases of the blood and blood-forming organsRC633-647.5ENResearch and Practice in Thrombosis and Haemostasis, Vol 4, Iss 1, Pp 54-63 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	drug evaluation fibrin hemophilia hemostasis microfluidics Diseases of the blood and blood-forming organs RC633-647.5
spellingShingle	drug evaluation fibrin hemophilia hemostasis microfluidics Diseases of the blood and blood-forming organs RC633-647.5 Xinren Yu Karen A. Panckeri Lacramioara Ivanciu Rodney M. Camire Carmen H. Coxon Adam Cuker Scott L. Diamond Microfluidic hemophilia models using blood from healthy donors
description	Abstract Background Microfluidic clotting assays permit drug action studies for hemophilia therapeutics under flow. However, limited availability of patient samples and Inter‐donor variability limit the application of such assays, especially with many patients on prophylaxis. Objective To develop approaches to phenocopy hemophilia using modified healthy blood in microfluidic assays. Methods Corn trypsin inhibitor (4 µg/mL)‐treated healthy blood was dosed with either anti–factor VIII (FVIII; hemophilia A model) or a recombinant factor IX (FIX) missense variant (FIX‐V181T; hemophilia B model). Treated blood was perfused at 100 s−1 wall shear rate over collagen/tissue factor (TF) or collagen/factor XIa (FXIa). Results Anti‐FVIII partially blocked fibrin production on collagen/TF, but completely blocked fibrin production on collagen/FXIa, a phenotype reversed with 1 µmol/L bispecific antibody (emicizumab), which binds FIXa and factor X. As expected, emicizumab had no significant effect on healthy blood (no anti‐FVIII present) perfused over collagen/FXIa. The efficacy of emicizumab in anti‐FVIII‐treated healthy blood phenocopied the action of emicizumab in the blood of a patient with hemophilia A perfused over collagen/FXIa. Interestingly, a patient‐derived FVIII‐neutralizing antibody reduced fibrin production when added to healthy blood perfused over collagen/FXIa. For low TF surfaces, reFIX‐V181T (50 µg/mL) fully blocked platelet and fibrin deposition, a phenotype fully reversed with anti‐TFPI. Conclusion Two new microfluidic hemophilia A and B models demonstrate the potency of anti‐TF pathway inhibitor, emicizumab, and a patient‐derived inhibitory antibody. Using collagen/FXIa‐coated surfaces resulted in reliable and highly sensitive hemophilia models.
format	article
author	Xinren Yu Karen A. Panckeri Lacramioara Ivanciu Rodney M. Camire Carmen H. Coxon Adam Cuker Scott L. Diamond
author_facet	Xinren Yu Karen A. Panckeri Lacramioara Ivanciu Rodney M. Camire Carmen H. Coxon Adam Cuker Scott L. Diamond
author_sort	Xinren Yu
title	Microfluidic hemophilia models using blood from healthy donors
title_short	Microfluidic hemophilia models using blood from healthy donors
title_full	Microfluidic hemophilia models using blood from healthy donors
title_fullStr	Microfluidic hemophilia models using blood from healthy donors
title_full_unstemmed	Microfluidic hemophilia models using blood from healthy donors
title_sort	microfluidic hemophilia models using blood from healthy donors
publisher	Wiley
publishDate	2020
url	https://doaj.org/article/71da544d77aa43e085358a8ca40dc390
work_keys_str_mv	AT xinrenyu microfluidichemophiliamodelsusingbloodfromhealthydonors AT karenapanckeri microfluidichemophiliamodelsusingbloodfromhealthydonors AT lacramioaraivanciu microfluidichemophiliamodelsusingbloodfromhealthydonors AT rodneymcamire microfluidichemophiliamodelsusingbloodfromhealthydonors AT carmenhcoxon microfluidichemophiliamodelsusingbloodfromhealthydonors AT adamcuker microfluidichemophiliamodelsusingbloodfromhealthydonors AT scottldiamond microfluidichemophiliamodelsusingbloodfromhealthydonors
_version_	1718428558950400000

Microfluidic hemophilia models using blood from healthy donors

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