Submitted July 9, 2008
Accepted November 5, 2008
Lactadherin and clearance of platelet-derived microvesicles
Swapan K. Dasgupta, Hanan Abdel-Monem, Polly Niravath, Anhquyen Le, Ricardo V Bellera, Kimberly Langlois, Shigekazu Nagata, Rolando E. Rumbaut, and Perumal Thiagarajan*
Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, United States
Department of Pathology, Baylor College of Medicine, Houston, TX, United States
Department of Medicine, Baylor College of Medicine, Houston, TX, United States
Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
Department of Genetics, Osaka University Medical School, Osaka, Japan
* Corresponding author; email: perumalt{at}bcm.tmc.edu.
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 ~ 5 ng/ml. Lactadherin-deficient mice had increased number of platelet-derived microvesicles in their plasma compared to their wild type littermates (950 ± 165 versus 4760 ± 650, p=0.02) and generated two 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 cremastric venules, lactadherin-deficient mice had significantly shorter time for occlusion compared to their wild type littermate controls (5.93 ± 0.43 minutes versus 9.80 ± 1.14, P=0.01). 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.
