ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions

Blood - Tập 100 Số 12 - Trang 4033-4039 - 2002
Jing-fei Dong1,2,3, Joel L. Moake1,2,3, Leticia Nolasco1,2,3, Aubrey Bernardo1,2,3, Wendy Arceneaux1,2,3, Corie N. Shrimpton1,2,3, Alicia J. Schade1,2,3, Larry V. McIntire1,2,3, Kazuo Fujikawa1,2,3, José A. López1,2,3
1Department of Biochemistry, University of Washington, Seattle
2From the Thrombosis Research Section, Department of Medicine, and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Department of Biochemistry, University of Washington, Seattle; and the Cox Laboratory for Bioengineering, Rice University, Houston, TX.
3the Cox Laboratory for Bioengineering, Rice University, Houston, TX.

Tóm tắt

Thrombotic thrombocytopenic purpura (TTP) is a devastating thrombotic disorder caused by widespread microvascular thrombi composed of platelets and von Willebrand factor (VWF). The disorder is associated with a deficiency of the VWF-cleaving metalloprotease, ADAMTS-13, with consequent accumulation of ultralarge (UL) VWF multimers in the plasma. ULVWF multimers, unlike plasma forms of VWF, attach spontaneously to platelet GP Ibα, a component of the GP Ib-IX-V complex. We have found that ULVWF multimers secreted from stimulated endothelial cells (ECs) remained anchored to the endothelial surface where platelets and Chinese hamster ovary cells expressing the GP Ib-IX-V complex attached to form long beads-on-a-string structures in the presence of fluid shear stresses in both the venous (2.5 dyne/cm2) and arterial (20 and 50 dyne/cm2) ranges. Although measurement of the activity of the ADAMTS-13 VWF-cleaving metalloprotease in vitro requires prolonged incubation of the enzyme with VWF under nonphysiologic conditions, EC-derived ULVWF strings with attached platelets were cleaved within seconds to minutes in the presence of normal plasma (containing approximately 100% ADAMTS-13 activity) or in the presence of partially purified ADAMTS-13. By contrast, the strings persisted for the entire period of perfusion (10 minutes) in the presence of plasma from patients with TTP containing 0% to 10% ADAMTS-13 activity. These results suggest that cleavage of EC-derived ULVWF multimers by ADAMTS-13 is a rapid physiologic process that occurs on endothelial cell surfaces.

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Blood

Tập 100 Số 12

4033-4039

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