Concomitant defect in internal release and influx of calcium in patients with congenital platelet dysfunction and impaired agonist-induced calcium mobilization. Thromboxane production is not required for internal release of calcium.
The rise in cytoplasmic ionized calcium concentration ([Ca2+]i) on platelet activation is a combination of Ca2+ release from internal stores and influx of extracellular Ca2+. To understand the underlying mechanisms, we studied internal release and influx of Ca2+ in platelets from four patients with impaired agonist-induced Ca2+ mobilization and abnormal platelet aggregation and secretion responses. In normal platelets, thrombin caused a dose-dependent increase in internal release and influx; aspirin inhibited the total rise in [Ca2+]i and influx but not internal release, indicating that internal release occurs independent of cyclooxygenase products. In the four patients, both internal release and influx of Ca2+ induced by thrombin and adenosine diphosphate were diminished; the defect was more striking at lower agonist concentrations. To determine whether the Ca2+ storage organelles of these platelets had a diminished responsiveness to inositol 1,4,5-triphosphate (IP3) we studied IP3 (0.05 to 5 mumol/L) induced Ca2+ release and found it to be normal in all patients. We conclude that the impaired Ca2+ mobilization in our patients is due to abnormalities in both internal release and influx and that it is unlikely to be due to impaired platelet responsiveness to IP3 or defective thromboxane production. The impaired Ca2+ mobilization may be due to defects in phospholipase C activation and IP3 production. These patients provide direct evidence that internal release and influx of Ca2+ on platelet activation are closely interrelated.
Rao
A K
AK
Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, PA 19140.
Disa
J
J
Yang
X
X
D001791:Blood Platelet Disorders / Q000097:blood / Q000151:congenital / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology*; D008297:Male; D012016:Reference Values; D013931:Thromboxanes / Q000096:biosynthesis*
D016861:Cyclooxygenase Inhibitors; D013931:Thromboxanes; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium