A new congenital defect of platelet secretion: impaired responsiveness of the platelets to cytoplasmic free calcium

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Abstract
A 16-yr-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 [epinephrine], sodium arachidonate, U44069, PAF-acether, A23187 and low concentrations of collagen. Thrombin and higher concentrations of collagen produce a normal response. Secretion of .beta.-thromboglobulin and platelet factor 4 parallels that of 5-HT. Thromboxane B2 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 A2 aggregate aspirin-treated platelets, though his platelets are themselves unresponsive. cAMP is present at normal concentration in the patient''s unstimulated platelet-rich plasma, and PGI2 [prostaglandin I2] 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 .beta.-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 Ca ions, their responses to thrombin, whether in the presence or virtual absence of extracellular Ca2+, were entirely normal with respect to free Ca ions, secretion, shape-change and aggregation. In response to ionomycin, a normal increase in free Ca ions was accompanied by normal shape-change but virtually no aggregation or 5-HT secretion. The platelet calmodulin content was normal. The defect in this patient''s platelets apparently is of utilization of cytoplasmic Ca2+ for secretion and aggregation, rather than of Ca2+ uptake or mobilization of Ca2+ from intracellular storage sites. The most likely site of the defect apparently is the phosphorylation of 1 of the proteins concerned in the secretory mechanism.

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