HPS is a subtype of platelet storage pool deficiency (SPD), specifically δ-SPD. Platelet SPD is characterized by abnormally low contents of either platelet α granules, δ (dense) granules, or both. The dense granules store ADP, ATP, calcium and serotonin which trigger the secondary aggregation response of platelets. This disorder is associated with a bleeding diathesis and a prolonged bleeding time. The platelet function tests, generally demonstrate a normal primary aggregation in response to ADP and epinephrine [8
]. The secondary response, however, is diminished or entirely absent due to the lack of δ (dense) granule content secretion required for aggregation of surrounding platelets [8
]. Electron microscopy is necessary to observe deficient granule contents and to exclude secretion defects, which produces a similar pattern in platelet function assays [8
]. However, an observed absence of dense body contents and abnormal platelet function tests in conjunction with the clinical presentation are sufficient to confirm the diagnosis of HPS [3
]. δ-SPD is sometimes associated with Chediak-Higashi syndrome or Wiskott-Aldrich syndrome as well as HPS, but these diseases are clinically distinct from each other.
The signs and symptoms of HPS are related to various defects in protein trafficking resulting in dysfunction of lysosome-related organelles, which include melanosomes, platelet dense granules, and lamellar bodies of type II alveolar cells [5
]. The dysfunction of melanosomes accounts for the oculocutaneous albinism and visual impairments found in all HPS patients. The dysfunction of platelet dense granules accounts for the bleeding disorder which is usually the presenting complaint, and is perhaps the most well understood pathologically.
The pathogenesis of the pulmonary fibrosis which represents one of the greatest risks to HPS patients is less well understood. The underlying cause appears to be accumulation of ceroid lipofuscin which occurs systemically in HPS patients [3
]. It has been suggested that continual deposition of ceroid disrupts type II alveolar cells and leads to chronic inflammation and progressive fibrosis [9
]. Ceroid deposition may also be responsible for the reduced kidney function and granulomatous colitis found in some patients, as these are amongst the sites where it is highest [3
]. The dysfunction of lamellar bodies of type II alveolar cells is probably also a contributing factor. Histologically, these have been found to be degenerated and swollen by accumulation of surfactant in the lung tissue of HPS patients that died of pulmonary fibrosis (histologically identified as usual interstitial pneumonia), suggesting that this is either a triggering or at least contributing factor for its development [10