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A new congenital defect of platelet secretion: impaired responsiveness of the platelets to cytoplasmic free calcium
Author(s) -
Hardisty R. M.,
Machin S. J.,
Nokes T. J. C.,
Rink T. J.,
Smith Sharon W.
Publication year - 1983
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.1983.tb07306.x
Subject(s) - platelet , thrombin , chemistry , calcium , medicine , endocrinology , ionomycin , platelet factor 4 , secretion , thromboxane a2 , thromboxane , platelet rich plasma , biochemistry
S ummary . A 16‐year‐old boy with a bleeding disorder since infancy has a long bleeding time, normal platelet count and morphology and normal plasma factor‐VIII activities. His platelets undergo normal shape change and primary aggregation in response to ADP but show defective 5‐hydroxytryptamine (5‐HT) secretion and aggregation in response to adrenaline, sodium arachidonate, U44069, PAF‐acether, A23187 and low concentrations of collagen. Thrombin and higher concentrations of collagen produce a normal response. Secretion of β‐thromboglobulin and platelet factor 4 parallels that of 5‐HT. Thromboxane B 2 is produced normally in response to exogenous arachidonate and to stimulation by thrombin, collagen and A23187 in all concentrations tested. The patient's endoperoxides and thromboxane A 2 aggregate aspirin‐treated platelets, though his platelets are themselves unresponsive. Cyclic AMP is present at normal concentration in the patient's unstimulated platelet‐rich plasma, and PGI 2 inhibits platelet aggregation by ADP and thrombin in a normal dose‐related manner. Platelet ultrastructure, 5‐HT uptake and content of adenine nucleotides, platelet factor 4 and β‐thromboglobulin are all within normal limits. When the patient's platelets were loaded with the fluorescent dye quin 2, which serves as an indicator of cytoplasmic free calcium ions, their responses to thrombin, whether in the presence or virtual absence of extracellular Ca2+, were entirely normal in respect of free calcium ions, secretion, shape‐change and aggregation. In response to ionomycin, however, a normal increase in free calcium ions was accompanied by normal shape‐change but virtually no aggregation or 5‐HT secretion. The platelet calmodulin content was normal. These findings show that the defect in this patient's platelets is of utilization of cytoplasmic Caz+ for secretion and aggregation, rather than of Ca2+ uptake or mobilization of Ca2+ from intracellular storage sites. It is suggested that the most likely site of the defect is the phosphorylation of one of the proteins concerned in the secretory mechanism.