Systemic antithrombotic effects of ADAMTS13

Anil K Chauhan; David G Motto; Colin B Lamb; Wolfgang Bergmeier; Michael Dockal; Barbara Plaimauer; Friedrich Scheiflinger; David Ginsburg; Denisa D Wagner

doi:10.1084/jem.20051732

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Systemic antithrombotic effects of ADAMTS13

Journal article

Open access

Peer reviewed

Systemic antithrombotic effects of ADAMTS13

Anil K Chauhan, David G Motto, Colin B Lamb, Wolfgang Bergmeier, Michael Dockal, Barbara Plaimauer, Friedrich Scheiflinger, David Ginsburg and Denisa D Wagner

The Journal of experimental medicine, Vol.203(3), pp.767-776

03/20/2006

DOI: 10.1084/jem.20051732

PMCID: PMC2118248

PMID: 16533881

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Abstract

The metalloprotease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats 13) cleaves highly adhesive large von Willebrand factor (VWF) multimers after their release from the endothelium. ADAMTS13 deficiency is linked to a life-threatening disorder, thrombotic thrombocytopenic purpura (TTP), characterized by platelet-rich thrombi in the microvasculature. Here, we show spontaneous thrombus formation in activated microvenules of Adamts13-/- mice by intravital microscopy. Strikingly, we found that ADAMTS13 down-regulates both platelet adhesion to exposed subendothelium and thrombus formation in injured arterioles. An inhibitory antibody to ADAMTS13 infused in wild-type mice prolonged adhesion of platelets to endothelium and induced thrombi formation with embolization in the activated microvenules. Absence of ADAMTS13 did not promote thrombi formation in alphaIIbbeta3 integrin-inhibited blood. Recombinant ADAMTS13 reduced platelet adhesion and aggregation in histamine-activated venules and promoted thrombus dissolution in injured arterioles. Our findings reveal that ADAMTS13 has a powerful natural antithrombotic activity and recombinant ADAMTS13 could be used as an antithrombotic agent.

Venules - pathology

von Willebrand Factor - immunology

Endothelium, Vascular - injuries

Humans

Metalloendopeptidases - deficiency

Fibrinolytic Agents - metabolism

Metalloendopeptidases - metabolism

Platelet Adhesiveness - genetics

Purpura, Thrombotic Thrombocytopenic - drug therapy

Purpura, Thrombotic Thrombocytopenic - genetics

Purpura, Thrombotic Thrombocytopenic - metabolism

Antigens - metabolism

Metalloendopeptidases - administration & dosage

ADAMTS13 Protein

Mice, Knockout

Platelet Adhesiveness - drug effects

Arterioles - pathology

Venules - metabolism

Purpura, Thrombotic Thrombocytopenic - pathology

Animals

Arterioles - metabolism

Blood Coagulation - drug effects

Antibodies, Monoclonal - administration & dosage

Endothelium, Vascular - metabolism

Arterioles - injuries

Blood Coagulation - genetics

Endothelium, Vascular - pathology

Fibrinolytic Agents - administration & dosage

Mice

Details

Title: Subtitle: Systemic antithrombotic effects of ADAMTS13
Creators: Anil K Chauhan - CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
David G Motto
Colin B Lamb
Wolfgang Bergmeier
Michael Dockal
Barbara Plaimauer
Friedrich Scheiflinger
David Ginsburg
Denisa D Wagner
Resource Type: Journal article
Publication Details: The Journal of experimental medicine, Vol.203(3), pp.767-776
DOI: 10.1084/jem.20051732
PMID: 16533881
PMCID: PMC2118248
ISSN: 0022-1007
eISSN: 1540-9538
Grant note: R01 HL039693 / NHLBI NIH HHS R37 HL41002 / NHLBI NIH HHS R01 HL041002 / NHLBI NIH HHS R01 HL39693 / NHLBI NIH HHS P01 HL057346 / NHLBI NIH HHS R37 HL041002 / NHLBI NIH HHS
Language: English
Date published: 03/20/2006
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094556802771

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