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Blood, 15 January 2008, Vol. 111, No. 2, pp. 475.
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INSIDE BLOOD
Comment on Shim et al, page 651
Platelet-VWF complexes get the chop
Michael C. Berndt, and
Robert K. Andrews
MONASH UNIVERSITY
In this issue of Blood, Shim and colleagues define a dual role for platelet glycoprotein (GP)Ib (the major ligand-binding subunit of the GPIb-IX-V complex) in regulating ADAMTS13-mediated cleavage of von Willebrand factor (VWF) under shear: it alleviates an inhibitory effect of the VWF A1 domain on cleavage of the A2 domain,1 and it allows tensile force to be exerted on the A2 domain through at least 2 platelets binding per VWF multimer via the A1 domain (see figure).
VWF is made up of subunits (consisting of domains D'-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2) forming disulfide-linked mutltimers of 20 million daltons or more. Multimer size is critical to the prothrombotic function of VWF, and regulation of multimer size by the ADAM (A Disintegrin And a Metalloproteinase)–family metalloproteinase ADAMTS13 controls a clinically important class of VWF-based pathologies, including thrombotic thrombocytopenic purpura (TTP). The more high molecular weight the VWF multimers (including those arising from ADAMTS13 dysfunction), the greater the potential for thrombosis.2 Establishing the mechanisms for regulating ADAMTS13-mediated VWF cleavage is the focus of much recent research because of the pathologic importance of understanding how this cleavage is regulated in vivo.1–3
One of VWF multimers' primary roles is to support formation of platelet adhesion and aggregation. VWF contains 2 major platelet-binding domains: the A1 domain, which binds GPIb of the GPIb-IX-V complex, and an Arg-Gly-Asp (RGD) sequence in the C1 domain that binds the platelet integrin IIbβ3 (GPIIb-IIIa). ADAMTS13 cleaves at Tyr842/Met843 within the A2 domain, between A1 (which binds GPIb) and A3 (which binds collagen). This cleavage, however, does not occur efficiently in native solution-phase VWF, and conformational changes of A2 are required to enable cleavage.2 Unlike A1 and A3, the A2 domain lacks an intra-domain disulfide bond, presumably enabling mechanical distortion and exposure of the cryptic Tyr842/Met843 cleavage site.
Previous studies suggest tensile stress applied across A1-A2-A3 facilitates ADAMTS13-dependent cleavage of A2.3 In this article, Shim et al use purified components in a reconstituted system under uniform shear conditions in a cone-and-plate viscometer to show shear-dependent platelet- and GPIb-dependent ADAMTS13-mediated cleavage of VWF (inhibitable by anti-GPIb antibodies or soluble GPIb fragments).Thus, platelet GPIb acts in 2 ways to favor VWF cleavage: by binding A1 (to remove an inhibitory effect on A2 cleavage)1 and by anchoring different A1 domains on an individual multimer to 2 or more platelets, interactions that under sufficient shear stress stretch the A2 domain and promote ADAMTS13-dependent proteolysis (see figure). Dong and colleagues have previously reported that ultralarge VWF strings expressed on activated endothelial cells (via P-selectin) can be decorated by multiple platelets under flow, and that in this form the VWF is susceptible to proteolysis by added plasma (ADAMTS13 dependent).2 These results suggest that a developing thrombus under arterial flow involving platelet attachment to VWF would be self-limiting in size, since shear applied to platelet-VWF-platelet complexes would promote ADAMTS13-mediated cleavage of VWF.
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests. 
REFERENCES
- Nishio K, Anderson PJ, Zheng XL, Sadler JE. Binding of platelet glycoprotein Ib to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13. Proc Natl Acad Sci U S A 2004; 101:10578–10583.[Abstract/Free Full Text]
- Dong JF. Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions. J Thromb Haemost 2005; 3:1710–1716.[CrossRef][Medline]
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- Gao W, Anderson PJ, Majerus EM, Tuley EA, Sadler JE. Exosite interactions contribute to tension-induced cleavage of von Willebrand factor by the antithrombotic ADAMTS13 metalloprotease. Proc Natl Acad Sci U S A 2006; 103:19099–19104.[Abstract/Free Full Text]
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Related Article in Blood Online:
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Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress
- Kyuhwan Shim, Patricia J. Anderson, Elodee A. Tuley, Erin Wiswall, and J. Evan Sadler
Blood 2008 111: 651-657.
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[Full Text]
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