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Thromb Haemost 2007; 97(03): 478-486
DOI: 10.1160/TH06-08-0436
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Interaction of an annexin V homodimer (Diannexin) with phosphatidylserine on cell surfaces and consequent antithrombotic activity

Frans A. Kuypers
1   Children's Hospital Oakland Research Institute, Oakland, California, USA
,
Sandra K. Larkin
1   Children's Hospital Oakland Research Institute, Oakland, California, USA
,
Jef J. Emeis
2   TNO Prevention and Health, Leiden, The Netherlands
,
Anthony C. Allison
3   Alavita Inc., Mountain View, California, USA
› Author Affiliations
Further Information

Publication History

Received 07 August 2006

Accepted after resubmission 11 January 2007

Publication Date:
28 November 2017 (online)

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Summary

Annexin V(AV), a protein with anticoagulant activity, exerts antithrombotic activity by binding to phosphatidylserine (PS), inhibiting activation of serine proteases important in blood coagulation. The potential use of this protein as an anticoagulant is limited as it rapidly passes from the blood into the kidneys due to its relatively small size (36 kDa). We used recombinant DNA technology to produce a homodimer of human AV (DAV, 73 kDa), which exceeds the renal filtration threshold, and has a 6.5-hour half-life in the rat circulation. Human red blood cells with externalized PS were used to show that DAV had a higher affinity for PS-exposing cells than AV. DAV labeling sensitively identifies PS-exposing cells, was found to be a potent inhibitor of the activity of the prothombinase complexes and inhibits the ability of secretory phospholipase A2 to hydrolyze phospholipids of PS-exposing cells, reducing the formation of mediators of blood coagulation and reperfusion injury. DAV exerts dose-dependent antithrombotic activity in ratveins. This combination of activities suggests that DAV is a valuable probe to measure PS exposure and may be efficacious as a novel drug in a wide range of clinical situations.

Keywords

Phospholipids - annexins - haemostasis

This study was supported by National Institutes of Health grants HL 20985, U54 HL070583, and HL 66355.


 

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