PLATELETS AND THROMBOPOIESIS Lactadherin and clearance of platelet-derived microvesicles

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 phosphatidylserineexpressing lymphocytes and red blood cells, in the clearance of platelet microvesicles. Platelet-derived microvesicles were labeled with BODIPYmaleimide 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. Lactadherindeficient 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, lactadherindeficient 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 plateletderived microvesicles from the circulation and that a defective clearance can induce a hypercoagulable state. (Blood. 2009;113:1332-1339)