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: Anish Sharda, Sarah H Kim, Reema Jasuja, Srila Gopal, Robert Flaumenhaft, Barbara C Furie, Bruce Furie
• Journal: Blood (Blood) Vol. 125 Issue 10 Pg. 1633-42 (Mar 05 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25593336 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• HPS6 protein, human
• Hps6 protein, mouse
• Intracellular Signaling Peptides and Proteins
• RNA, Small Interfering
• Vesicular Transport Proteins
• Adenosine Diphosphate
• Fibrin
• Thrombin
• Apyrase
• Protein Disulfide-Isomerases

Topics

• Adenosine Diphosphate (deficiency, metabolism, pharmacology)
• Animals
• Apyrase (metabolism, pharmacology)
• Blood Platelets (drug effects, enzymology)
• Cell Degranulation
• Disease Models, Animal
• Endothelial Cells (enzymology, pathology)
• Exocytosis (drug effects)
• Female
• Fibrin (biosynthesis)
• Hermanski-Pudlak Syndrome (blood, enzymology, genetics)
• Human Umbilical Vein Endothelial Cells
• Humans
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, blood, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Platelet Aggregation
• Protein Disulfide-Isomerases (blood, metabolism)
• RNA, Small Interfering (genetics)
• Thrombin (metabolism)
• Thrombosis (blood, enzymology)
• Vesicular Transport Proteins (deficiency, genetics)