William Sheffield
Directeur adjoint de la Recherche, Chercheur principal
Société canadienne du sang
Professeur
Département de pathologie et de médecine moléculaire – Université McMaster
Formation
- Doctorat en biochimie, Université McGill
- Baccalauréat en sciences en biochimie, Université McGill
Publications
Le plasma, source de médicaments et d’inspiration
Les travaux du laboratoire de M. Sheffield portent sur le plasma, la partie liquide du sang. Les constituants du plasma régulent l’hémostase, et le plasma est le seul produit de la transformation du sang total qui puisse facilement être congelé et décongelé avant d’être transfusé.
Pourquoi est-ce important?
Comprendre les fonctions biologiques des constituants du plasma et leur efficacité dans la régulation de l’hémostase peut ouvrir la voie à l’amélioration des pratiques transfusionnelles et à une utilisation plus efficace des dons de plasma.
Plasma is usually transfused in patients to prevent or stop excessive bleeding. We investigate the use of transfusable plasma as a biological medication by testing its ability to support in vitro clotting, or to suppress bleeding, in mouse models. We compare these results with those obtained with proposed alternatives to transfusable plasma, such as prothrombin complex concentrates (PCC) – a plasma protein product. To facilitate this work, we have created a mouse model of global plasma protein deficiency to test the role of various plasma components in regulating coagulation. Our results led us to propose that high fibrinogen levels, not FVIII levels, in the transfused plasma, more reliably reduce bleeding. We also investigate the ability of plasma or PCC to reverse the anticoagulant properties of ‘blood-thinning’ drugs. Such intervention is necessary when a patient on blood thinning medication requires emergency surgery. Our research in this area has shown that, for some oral anticoagulants, PCC is superior to plasma transfusion to achieve reversal. For other anticoagulants, neither plasma nor PCCs were effective. These findings correlate well with clinical studies and provide further evidence on the best use of plasma and plasma protein products. We have also investigated a potential antidote.
Publications choisies
- Eltringham-Smith LJ, Lei X, Reheman A, Lambourne MD, Pryzdial EL, Ni H, Sheffield WP: The fibrinogen but not the Factor VIII content of transfused plasma determines its effectiveness at reducing bleeding in coagulopathic mice. Transfusion 2015; 55:1040-1050.<
- Sheffield WP, Lambourne MD, Eltringham-Smith LJ, Bhakta V, Arnold DM, Crowther MA: γT -S195A thrombin reduces the anticoagulant effects of dabigatran in vitro and in vivo. J Thromb Haemost 2014; 12:1110–1115.
- Lambourne MD, Eltringham‐Smith LJ, Gataiance S, Arnold DM, Crowther MA, Sheffield WP: Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J. Thromb Haemost 2012; 10:1830–1840.
Préparation du plasma et évaluation de la qualité
Les travaux de l’équipe de M. Sheffield visent à assurer la disponibilité de plasma et de produits plasmatiques de grande qualité pour les patients canadiens.
Pourquoi est-ce important?
Ces travaux fournissent au système d’approvisionnement en sang des données probantes pouvant servir à établir une réglementation plus rationnelle ou à améliorer les processus.
We seek to better understand the quality of stored plasma products for transfusion, and the impact of the manufacturing and storing process on these products. Recently, we have investigated levels of FVIII and seven other factors in frozen plasma, and we have demonstrated that thawed cryosupernatant plasma can be refrigerated for up to five days (compared with current regulation of 24 hours) prior to transfusion without compromising the quality or the safety of the thawed product.
Publications choisies
- Bhakta V, Jenkins C, Ramirez‐Arcos S, Sheffield WP: Stability of relevant plasma protein activities in cryosupernatant plasma units during refrigerated storage for up to 5 days postthaw. Transfusion 2014; 54:418–425.
- Sheffield WP, Bhakta V, Talbot K, Pryzdial ELG, Jenkins C: Quality of frozen transfusable plasma prepared from whole blood donations in Canada: An update. Transfus Apher Sci 2013; 49:440–446.
- Sheffield WP: ResearchUnit: Etude en faveur d'un changement de la réglementation relative à l'entreposage du plasma surnageant de cryoprécipité. 2013; Blood.ca website.
- Sheffield WP, Bhakta V, Jenkins C, Devine DV: Conversion to the buffy coat method and quality of frozen plasma derived from whole blood donations in Canada. Transfusion 2012; 50:1043–1049.
Protéines plasmatiques et protéines plasmatiques synthétiques recombinantes
Inspirés par les propriétés des protéines plasmatiques naturelles et à l’aide de la technologie de l’ADN recombinant, M. Sheffield et ses collaborateurs mettent au point des protéines plasmatiques novatrices aux fins d’applications thérapeutiques spécifiques.
Pourquoi est-ce important?
Il reste des besoins thérapeutiques à combler dans le domaine de la coagulation et les travaux de M. Sheffield ont pour objectif d’accélérer les découvertes en la matière, par l’optimisation de protéines plasmatiques naturelles. Ses recherches dans ce domaine permettent à son équipe d’évaluer de nouvelles protéines plasmatiques commerciales et de déterminer si celles-ci doivent être distribuées par la Société canadienne du sang.
We alter the structure of plasma proteins to modify their procoagulant or anticoagulant properties, or their circulatory lifetime. Ongoing projects include: 1) Structure/function studies of the serine protease inhibitor (serpin) family members alpha-1-proteinase inhibitor, antithrombin, heparin cofactor II, and alpha-2-antiplasmin; 2) Fate of mutant albumin molecules in vivo in rabbits and mice, and efficacy in animal models of hemorrhage or thrombosis; 3) Gene fusion approaches to altering the clearance or distribution of plasma proteins (e.g. factors VII and VIII).
Publications choisies
- Sheffield WP, Eltringham-Smith LJ, Gataiance S, Bhakta V: A plasmin-activatable thrombin inhibitor reduces experimental thrombosis and assists experimental thrombolysis in murine models. J Thromb Thrombolysis 2015; 39:443-51.
- Scott BM, Matochko WL, Gierczak RF, Bhakta V, Derda R, Sheffield WP: Phage display of the serpin alpha-1 proteinase inhibitor randomized at consecutive residues in the reactive centre loop and biopanned with or without thrombin. PLoS One 2014; 9:e84491.
- Bhakta V, Gierczak RF, Sheffield WP: Expression screening of bacterial libraries of recombinant alpha-1 proteinase inhibitor variants for candidates with thrombin inhibitory capacity. J Biotech 2013; 168:373–381.
Pour plus de renseignements sur la recherche au Service de Sang Canadian, veuillez nous contractez au:
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Société canadienne du sang
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