The storage pool deficiency in platelets from humans with the Chédiak‐Higashi syndrome: study of six patients

Abstract

Functional and biochemical studies of platelets from human Chédiak-Higashi syndrome (CHS) are scarce and/or incomplete. In the present report, the aggregation response to a variety of inducers of platelet aggregation, the content of the dense granule constituents ATP, ADP, serotonin and calcium, the secretion of ATP, ADP, and calcium induced by thrombin, the total content of magnesium, the incorporation of 14C-adenine in the cytoplasmic pool of adenine nucleotides, as well as the content of intracellular cyclic-AMP, have been quantitated in six patients with CHS. Furthermore, data is presented on the kinetics of uptake of radiolabelled serotonin and its storage in human CHS platelets. An abnormal aggregation behaviour was found in all patients. However, the response of CHS platelets to the different inducers studied did not show a uniform pattern. The total content and the maximal amounts of the dense granule constituents secretable by thrombin were greatly decreased in all six patients. Total magnesium content was similar to that of normal platelets. The ATP/ADP ratio was higher than in controls. Uptake of radiolabelled serotonin by CHS platelets closely followed the uptake by normal platelets; during the first 2-3 min, however, incorporation of the amine by CHS platelets came rapidly to a plateau which contrasts with the steady, linear increase in uptake found in controls. CHS platelets loaded with radiolabelled serotonin and gel-filtered, showed a spontaneous release of radioactivity not observed in normal platelets under the same conditions. The cyclic-AMP content of CHS platelets was similar to that of normals. In contrast to platelets from patients with storage pool disease, the secretable calcium from CHS platelets represents a 67% of total platelet calcium (61% in normals), suggesting that the absolute values for the non-secretable portion in CHS platelets must be very low. The results reported confirm the existence of a true storage pool deficiency of the dense granule constituents as a common defect in CHS platelets. The variety of responses among patients, to the different aggregatory stimuli studied, can not be solely ascribed to the storage pool deficiency described.

Clinical, laboratory and molecular signs of immunodeficiency in patients with partial oculo-cutaneous albinism

“…Clinical diagnosis is firstly supported by the presence of peroxidase-positive giant inclusions in white blood cells, by detection of pigment clumping in the light microscopy analysis of hair and eventually by studies revealing abnormal platelet aggregation [14]. Electron microscopy can demonstrate reduced number and irregular morphology of platelet dense-bodies [29,30]. Of note, giant granules resembling those seen in CHS may be revealed in acute and chronic myeloid leukemia.…”

Molecular mechanism and functional implications of thrombin-mediated tyrosine phosphorylation of PKCδ in platelets

“…The importance of secretion in platelet function is emphasized by the bleeding tendencies seen in patients with storage pool disease. [4][5][6][7] Multiple studies have shown that both increase in intracellular calcium and activation of protein kinase C (PKC) are required to mediate granule release. [8][9][10][11][12][13][14][15] Following platelet activation, tyrosine phosphorylation events of many proteins ensue.…”

Platelet Dysfunction in Chediak-Higashi Syndrome-Affected Cattle.

“…2A). Besides, in human patients with CHS, impairment of epinephrine-induced aggregation was also observed [1,5,12]. Platelet aggregation by ADP is normal or sometimes slightly decreased with a tendency to disaggregate in CHS platelets.…”

“…A decrease in TXA 2 production could be a case in human CHS platelets because aggregation to exogenous arachidonic acid, which is converted to TXA 2 , was reported to decline in two human CHS cases [1,73]. Suzuki et al suggested that impairment of …”