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CHAPTER 2: PHYSIOLOGICAL COFACTORS FACTOR VIII AND

PLATELETS SYNERGISTICALLY REGULATE ADAMTS13

PROTEOLYTIC ACTIVITY

(Manuscript Title: Factor VIII and platelets synergistically accelerate cleavage of von Willebrand factor by ADAMTS13 under fluid shear stress)

Christopher G. Skipwith1,2, Wenjing Cao2, and X. Long Zheng1,2

(This work is published in the Journal of Biological Chemistry, 2010 Sep 10; 285(37):28596-603.)

From 1Biochemistry and Molecular Biophysics Graduate Group and 2Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia and The University of Pennsylvania Medical Center, Philadelphia, PA 19104

38 2.1 Overview

Previous studies have demonstrated that factor VIII (FVIII) or platelets alone increase cleavage of von Willebrand factor (VWF) by ADAMTS13 under mechanically-induced shear stresses. We show in this study that the combination of FVIII and platelets at physiological concentrations is more effective than either one alone. In the absence of FVIII, lyophilized platelets increase the formation of cleavage product by 2-3 fold. However, in the presence of physiological concentrations of FVIII (1 nM), the formation of the VWF cleavage product dramatically increases as a function of increasing platelets with a maximal rate enhancement of ∼8 fold. Conversely, in the presence of a physiological concentration of lyophilized platelets (150×103/µl), the half maximal concentration of FVIII required to accelerate VWF proteolysis by ADAMTS13 reduces by ∼10 fold (to ~0.3 nM) compared with that in the absence of platelets (∼3.0 nM). Further studies using a FVIII derivative that lacks an acidic region (a3), an anti-platelet glycoprotein 1bα (GP1bα) IgG, and a purified recombinant VWF-A1 domain or GP1bα- stripped platelets demonstrate that the synergistic rate enhancing effect of FVIII and platelets depends on their specific binding interactions with VWF. Our findings suggest that FVIII and platelets are cofactors that regulate proteolysis of multimeric VWF by ADAMTS13 under physiological conditions.