title: Lactadherin and clearance of platelet-derived microvesicles.
abstract: 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.
authors.affiliation: Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA.
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Dasgupta
authors.forename: Hanan
authors.initials: H
authors.lastname: Abdel-Monem
authors.forename: Polly
authors.initials: P
authors.lastname: Niravath
authors.forename: Anhquyen
authors.initials: A
authors.lastname: Le
authors.forename: Ricardo V
authors.initials: RV
authors.lastname: Bellera
authors.forename: Kimberly
authors.initials: K
authors.lastname: Langlois
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Nagata
authors.forename: Rolando E
authors.initials: RE
authors.lastname: Rumbaut
authors.forename: Perumal
authors.initials: P
authors.lastname: Thiagarajan
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D017209:Apoptosis; D001792:Blood Platelets / Q000502:physiology*; D001896:Boron Compounds; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D008262:Macrophage Activation; D008301:Maleimides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins; D010587:Phagocytosis; D010616:Phenanthrenes / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism*
chemical_list: C410511:1-keto-1,2,3,4-tetrahydrophenanthrene; D000954:Antigens, Surface; D001896:Boron Compounds; C098942:MFGE8 protein, human; D008301:Maleimides; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D010616:Phenanthrenes; D010718:Phosphatidylserines; C530427:bodipy FL N-(2-aminoethyl)maleimide; D013917:Thrombin