Defective signal transduction induced by thromboxane A2 in a patient with a
mild bleeding disorder: impaired phospholipase C activation despite normal
phospholipase A2 activation
I Fuse, M Mito, A Hattori, W Higuchi, A Shibata, F Ushikubi, M Okuma and K Yahata
First Department of Internal Medicine, Niigata University School of
Medicine, Japan.
A patient with a mild bleeding disorder whose platelets responded
defectively to thromboxane A2 (TXA2) was identified, and the mechanism of
this dysfunction was analyzed. The platelets were defective in shape
change, aggregation, and release reaction in response to synthetic TXA2
mimetic (STA2). When the platelet TXA2 receptor was examined with both a
125I-labeled derivative of a TXA2 receptor antagonist ([125I]-PTAOH) and
[3H]-labeled TXA2 agonist ([3H]U-46619), the equilibrium dissociation rate
constants (kd) and the maximal concentrations of binding sites (Bmax) of
the platelets to both ligands were within normal ranges, suggesting that
the binding capacity of their TXA2 receptor was normal. STA2 could not
induce IP3 formation and intracellular Ca2+ mobilization, whereas these
responses to thrombin were within normal ranges. GTPase activity was also
decreased when the patient's platelet membrane was challenged with STA2. On
the other hand, lysophosphatidylinositol formation, which is a direct
indicator of phospholipase A2 (PLA2) activation, was found to be normal
when the [3H]-inositol-labeled platelets were challenged with STA2.
Thromboxane B2 (TXB2) was also produced in response to STA2. These results
suggested that the abnormality in these platelets was impaired coupling
between TXA2 receptor and phospholipase C (PLC) activation. Furthermore, it
is also suggested that the activation of PLA2 and PLC are separable events
in thromboxane-induced platelet activation.
Volume 81,
Issue 4,
pp. 994-1000,
02/15/1993
Copyright © 1993 by The American Society of Hematology
