Formation of platelet strings and microthrombi in the presence of ADAMTS-13 inhibitor does not require P-selectin or beta3 integrin

A K Chauhan; T Goerge; S W Schneider; D D Wagner

doi:10.1111/j.1538-7836.2007.02361.x

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Formation of platelet strings and microthrombi in the presence of ADAMTS-13 inhibitor does not require P-selectin or beta3 integrin

Journal article

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Formation of platelet strings and microthrombi in the presence of ADAMTS-13 inhibitor does not require P-selectin or beta3 integrin

A K Chauhan, T Goerge, S W Schneider and D D Wagner

Journal of thrombosis and haemostasis, Vol.5(3), pp.583-589

03/2007

DOI: 10.1111/j.1538-7836.2007.02361.x

PMID: 17166247

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Abstract

Ultra-large von Willebrand factor (ULVWF) and the receptor P-selectin are released from endothelial Weibel-Palade bodies during injury or inflammation. VWF mediates platelet adhesion and P-selectin promotes leukocyte rolling. ADAMTS-13 limits the duration of platelet adhesion by cleaving the ULVWF. In the absence of ADAMTS-13, long VWF filaments decorated with platelets form. Recent in vitro studies suggested that P-selectin might anchor these platelet strings to endothelium, but whether the same mechanism exists in vivo remains to be elucidated. We address the role of P-selectin and beta(3) integrin in platelet string formation in vivo using intravital microscopy by infusing inhibitory ADAMTS-13 antibody in P-selectin-/- and beta(3)-deficient mice and activating the endothelium by injecting histamine. We show that inhibition of ADAMTS-13 combined with endothelial activation leads to similar extents of platelet string formation in wild-type, P-selectin- and integrin beta(3)-deficient mice. Further, in venules the platelet strings can coalesce into VWF-platelet aggregates. This process utilizes neither the platelet beta(3) integrin nor P-selectin. We also show in vitro that platelets can act as a bridge between the VWF fibers and that VWF can self-associate even in areas devoid of platelets. The formation or retention of the platelet strings does not require P-selectin or the endothelial VWF receptor alpha(v)beta(3). Furthermore, in the presence of low ADAMTS-13 activity, VWF-dependent and alpha(IIb)beta(3)-independent platelet clustering occurs in veins, as has been shown at high arterial shear rates. Our study further supports the importance of regulation of VWF multimer size upon secretion from Weibel-Palade bodies.

Platelet Adhesiveness

P-Selectin - metabolism

Stress, Mechanical

Endothelium, Vascular - drug effects

Metalloendopeptidases - metabolism

Microscopy, Video

Integrin beta3 - genetics

Thrombosis - blood

von Willebrand Factor - metabolism

Metalloendopeptidases - antagonists & inhibitors

Histamine - pharmacology

Mice, Inbred C57BL

Cells, Cultured

Metalloendopeptidases - immunology

P-Selectin - genetics

ADAMTS13 Protein

Mice, Knockout

Antibodies - pharmacology

Platelet Aggregation

Venules - metabolism

Integrin beta3 - metabolism

Thrombosis - metabolism

Animals

Blood Platelets - metabolism

Endothelium, Vascular - metabolism

Mice

Mice, Inbred BALB C

Details

Title: Subtitle: Formation of platelet strings and microthrombi in the presence of ADAMTS-13 inhibitor does not require P-selectin or beta3 integrin
Creators: A K Chauhan - CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
T Goerge
S W Schneider
D D Wagner
Resource Type: Journal article
Publication Details: Journal of thrombosis and haemostasis, Vol.5(3), pp.583-589
DOI: 10.1111/j.1538-7836.2007.02361.x
PMID: 17166247
ISSN: 1538-7933
eISSN: 1538-7836
Grant note: R37 HL41002 / NHLBI NIH HHS R37 HL041002 / NHLBI NIH HHS
Language: English
Date published: 03/2007
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094318102771

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