William P. Sheffield

, PhD

Professor
Pathology and Molecular Medicine

Division: Molecular Medicine

McMaster University
4N66 Health Sciences Centre
905-525-9140 ext. 22701
sheffiel@mcmaster.ca

Currently accepting Graduate Students
Currently accepting Post-Doctoral Fellows

Assistant: Arlene Scopaz

Education and Professional Standing

• PhD Biochemistry, McGill University, 1989
• BSc(Hons) Biochemistry, McGill University, 1983

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Interests

Research Focus

Research in the Sheffield laboratory focuses on plasma and plasma proteins in three general ways: in efforts to extend the circulatory lifetime of recombinant plasma proteins; in work aimed at producing novel plasma proteins with either procoagulant or anticoagulant properties; and in quality monitoring of plasma and plasma products. 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); and 4) Quality and efficacy of therapeutic plasma in vitro and in vivo. A variety of biochemical and molecular biological approaches are used, including site-directed and PCR-based mutagenesis of cDNAs, expression of recombinant proteins in bacterial, yeast, or cultured mammalian cell systems, protein characterisation using enzymatic, immunochemical and biochemical techniques, in vivo studies of recombinant or natural proteins or protein mixtures injected into rabbits and/or mice, and characterization of the ability of plasma to support in vitro clotting.

Academic Interests

My educational focus is on biochemical and molecular biological aspects of health sciences. I have experience of problem-based learning in both the general undergraduate and undergraduate medical settings, as well as lecture- and laboratory-based courses in molecular and vascular biology, and inquiry.In assessing students, I favour quantitative or problem-based methods of assessment where possible.

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Team Members

Lab Technicians

Varsha Bhakta, Sharon Gataiance, Louise Eltringham-Smith

Graduate Students

Alicja Puchta, Amanda Boyle, Richard Gierczak

Selected Publications

• Sheffield WP, Eltringham-Smith LJ, Gataiance S, Bhakta V. Addition of a sequence from a2-antiplasmin transforms human serum albumin into a blood clot component that speeds clot lysis. BMC Biotechnol. 2009; Mar 3;9:15.
• Sheffield WP. Eltringham-Smith LJ, Bhakta V, Gataiance S. A long-lasting, plasmin-activatable thrombin inhibitor aids in vitro clot lysis and does not promote bleeding in vivo. Thrombosis and Haemostasis 2009; 101: 867-77.
• Sutherland JS, Bhakta V, Sheffield WP. The appended tail region of heparin cofactor II and additional reactive centre loop mutations combine to increase the reactivity and specificity of alpha-1-proteinase inhibitor M358R for thrombin. Thrombosis and Haemostasis 2007; 98: 1014-1023.
• Sheffield WP, Gataiance S, Eltringham-Smith LJ. Combined administration of barbourin-albumin and hirudin-albumin fusion proteins limits fibrin(ogen) deposition on the rabbit balloon-injured aorta. Thromb Res 2007;119:195-207.
• Sutherland JS, Bhakta V, Filion M, Sheffield WP. The transferable tail: Fusion of the N-terminal acidic domain of heparin cofactor II to alpha-1-proteinase inhibitor M358R specifically increases the rate of thrombin inhibition. Biochemistry 2006; 45: 11444-52.
• Sutherland JS, Bhakta V, Sheffield WP. Investigating serpin-enzyme complex formation and stability via single and multiple residue reactive centre loop substitutions in heparin cofactor II. Thromb Res 2006; 117: 447-61.
• Sheffield WP, Bhakta V, Denomme GA. Sensitive detection of anti-Fya and anti-Fyb using recombinant fusion proteins containing the Duffy extracellular domain. Transfus Apher Sci 2006; 35:207-16
• Sheffield WP, Wilson B, Eltringham-Smith LJ, Gataiance S, Bhakta V. Superior inhibition of human but not rabbit platelet aggregation by a barbourin-albumin fusion protein compared to recombinant albumins with short amino-terminal extensions. Thromb Haemostas 2005; 93: 914-21.
• Begbie ME, Mamdani A, Gataiance S, Eltringham-Smith LJ, Bhakta V, Hortelano G, Sheffield WP. An important role for the activation peptide domain in controlling factor IX levels in the blood of haemophilia B mice. Thromb Haemostas 2005; 94: 1138-47
• Filion ML, Bhakta V, Nguyen LH, Liaw PS, Sheffield WP. Full or partial substitution of the reactive center loop of alpha-1-proteinase inhibitor by that of heparin cofactor II: P1 Arg is required for maximal thrombin inhibition. Biochemistry 2004; 43: 14864-72.