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Blood, 5 February 2009, Vol. 113, No. 6, pp. 1332-1339. Prepublished online as a Blood First Edition Paper on November 20, 2008; DOI 10.1182/blood-2008-07-167148.
PLATELETS AND THROMBOPOIESIS Lactadherin and clearance of platelet-derived microvesicles1 Michael E. DeBakey VA Medical Center, Houston, TX; Departments of2 Pathology, 3 Medicine, and 4 Pediatrics, Baylor College of Medicine, Houston, TX; and 5 Department of Genetics, Osaka University Medical School, Osaka, Japan
The transbilayer movement of phosphatidylserine from the inner to the outer leaflet of the membrane bilayer during platelet activation is associated with the release of procoagulant phosphatidylserine-rich small membrane vesicles called platelet-derived microvesicles. We tested the effect of lactadherin, which promotes the phagocytosis of phosphatidylserine-expressing lymphocytes and red blood cells, in the clearance of platelet microvesicles. Platelet-derived microvesicles were labeled with BODIPY-maleimide and incubated with THP-1–derived macrophages. The extent of phagocytosis was quantified by flow cytometry. Lactadherin promoted phagocytosis in a concentration-dependent manner with a half-maximal effect at approximately 5 ng/mL. Lactadherin-deficient mice had increased number of platelet-derived microvesicles in their plasma compared with their wild-type littermates (950 ± 165 vs 4760 ± 650; P = .02) and generated 2-fold more thrombin. In addition, splenic macrophages from lactadherin-deficient mice showed decreased capacity to phagocytose platelet-derived microvesicles. In an in vivo model of light/dye-induced endothelial injury/thrombosis in the cremasteric venules, lactadherin-deficient mice had significantly shorter time for occlusion compared with their wild-type littermate controls (5.93 ± 0.43 minutes vs 9.80 ± 1.14 minutes;P = .01). These studies show that lactadherin mediates the clearance of phosphatidylserine-expressing platelet-derived microvesicles from the circulation and that a defective clearance can induce a hypercoagulable state.
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