title: Defective PDI release from platelets and endothelial cells impairs thrombus formation in Hermansky-Pudlak syndrome.
abstract: Protein disulfide isomerase (PDI), secreted from platelets and endothelial cells after injury, is required for thrombus formation. The effect of platelet and endothelial cell granule contents on PDI-mediated thrombus formation was studied by intravital microscopy using a mouse model of Hermansky-Pudlak syndrome in which platelet dense granules are absent. Platelet deposition and fibrin generation were nearly absent, and extracellular PDI was significantly reduced in HPS6(-/-) mice after vascular injury. HPS6(-/-) platelets displayed impaired PDI secretion and impaired exocytosis of α granules, lysosomes, and T granules due to decreased sensitivity to thrombin, but these defects could be corrected by addition of subthreshold amounts of adenosine 5'-diphosphate (ADP). Human Hermansky-Pudlak syndrome platelets demonstrated similar characteristics. Infusion of wild-type platelets rescued thrombus formation in HPS6(-/-) mice. Human umbilical vein endothelial cells in which the HPS6 gene was silenced displayed impaired PDI secretion and exocytosis of Weibel-Palade bodies. Defective thrombus formation in Hermansky-Pudlak syndrome, associated with impaired exocytosis of residual granules in endothelial cells and platelets, the latter due to deficiency of ADP, is characterized by a defect in T granule secretion, a deficiency in extracellular PDI secretion, and impaired fibrin generation and platelet aggregation. Hermansky-Pudlak syndrome is an example of a hereditary disease whereby impaired PDI secretion contributes to a bleeding phenotype.
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Anish
authors.initials: A
authors.lastname: Sharda
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Reema
authors.initials: R
authors.lastname: Jasuja
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Srila
authors.initials: S
authors.lastname: Gopal
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Robert
authors.initials: R
authors.lastname: Flaumenhaft
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Furie
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Furie
mesh_terms: D000244:Adenosine Diphosphate / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001081:Apyrase / Q000378:metabolism / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D015550:Cell Degranulation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D005089:Exocytosis / Q000187:drug effects; D005260:Female; D005337:Fibrin / Q000096:biosynthesis; D022861:Hermanski-Pudlak Syndrome / Q000097:blood* / Q000201:enzymology* / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010974:Platelet Aggregation; D019704:Protein Disulfide-Isomerases / Q000097:blood / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood* / Q000201:enzymology*; D033921:Vesicular Transport Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: C493901:HPS6 protein, human; C554282:Hps6 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins; D000244:Adenosine Diphosphate; D005337:Fibrin; D013917:Thrombin; D001081:Apyrase; D019704:Protein Disulfide-Isomerases