Defective release of α granule and lysosome contents from platelets in mouse Hermansky-Pudlak syndrome models

Blood. 2015 Mar 5;125(10):1623-32. doi: 10.1182/blood-2014-07-586727. Epub 2014 Dec 4.


Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, bleeding diathesis, and other variable symptoms. The bleeding diathesis has been attributed to δ storage pool deficiency, reflecting the malformation of platelet dense granules. Here, we analyzed agonist-stimulated secretion from other storage granules in platelets from mouse HPS models that lack adaptor protein (AP)-3 or biogenesis of lysosome-related organelles complex (BLOC)-3 or BLOC-1. We show that α granule secretion elicited by low agonist doses is impaired in all 3 HPS models. High agonist doses or supplemental adenosine 5'-diphosphate (ADP) restored normal α granule secretion, suggesting that the impairment is secondary to absent dense granule content release. Intravital microscopy following laser-induced vascular injury showed that defective hemostatic thrombus formation in HPS mice largely reflected reduced total platelet accumulation and affirmed a reduced area of α granule secretion. Agonist-induced lysosome secretion ex vivo was also impaired in all 3 HPS models but was incompletely rescued by high agonist doses or excess ADP. Our results imply that (1) AP-3, BLOC-1, and BLOC-3 facilitate protein sorting to lysosomes to support ultimate secretion; (2) impaired secretion of α granules in HPS, and to some degree of lysosomes, is secondary to impaired dense granule secretion; and (3) diminished α granule and lysosome secretion might contribute to pathology in HPS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 3 / deficiency
  • Adaptor Protein Complex 3 / genetics
  • Adaptor Protein Complex 3 / physiology
  • Adenosine Diphosphate / pharmacology
  • Animals
  • Blood Platelets / physiology*
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology
  • Cell Degranulation / physiology
  • Disease Models, Animal
  • Guanine Nucleotide Exchange Factors
  • Hermanski-Pudlak Syndrome / blood*
  • Hermanski-Pudlak Syndrome / etiology
  • Hermanski-Pudlak Syndrome / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lectins / deficiency
  • Lectins / genetics
  • Lectins / physiology
  • Lysosomes / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • P-Selectin / blood
  • SNARE Proteins / blood
  • Secretory Vesicles / physiology
  • Thrombin / pharmacology
  • Thrombosis / blood
  • Thrombosis / etiology
  • Vesicular Transport Proteins / deficiency
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / physiology


  • Adaptor Protein Complex 3
  • Bloc1s6 protein, mouse
  • Carrier Proteins
  • Guanine Nucleotide Exchange Factors
  • Hps4 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Lectins
  • P-Selectin
  • SNARE Proteins
  • Vesicular Transport Proteins
  • Adenosine Diphosphate
  • Thrombin