Semin Thromb Hemost 2000; Volume 26(Number 01): 043-046
DOI: 10.1055/s-2000-9802
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4663)

Pathogenesis of a Bleeding Disorder Characterized by Platelet Unresponsiveness to Thromboxane A2

Ichiro Fuse, Wataru Higuchi, Yoshifusa Aizawa
  • First Department of Internal Medicine, Niigata University School of Medicine, Niigata, Japan
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Publikationsverlauf

Publikationsdatum:
31. Dezember 2000 (online)

 

ABSTRACT

A platelet disorder characterized by the absence of thromboxane A2 (TXA2)-induced platelet aggregation is a new clinical entity of platelet dysfunction. The platelets of three patients had the ability to bind exogenous TXA2, but synthetic TXA2 mimetic-induced postreceptor biochemical events, such as IP3 formation, Ca2+ mobilization, phosphatidic acid formation, and GTPase activities, were selectively defective, suggesting impaired coupling between the TXA2 receptor and phospholipase C activation. Gene analysis of the TXA2 receptor showed a substitution of Leu for Arg60 in the first cytoplasmic loop in all patients, and this mutation seemed to be responsible for this platelet disorder.

KEYWORD

Platelet unresponsiveness to thromboxane A2 (TXA2) - G-protein - phospholipase C - TXA2 receptor - point mutation

REFERENCES

  • 1 Wu K K, Le Breton C G, Tai H H, Chen Y C. Abnormal platelet response to thromboxane A2 .  J Clin Invest . 1981;  67 1801-1804
    PubMedGoogle Scholar
  • 2 Lages B, Malmsten C, Weiss H J, Samuelsson B. Impaired platelet response to thromboxane A2 and defective calcium mobilization in a patient with a bleeding disorder.  Blood . 1981;  57 545-552
    PubMedGoogle Scholar
  • 3 Samama M, Lecrubier C, Conard J. Constitutional thrombocytopathy with subnormal response to thromboxane A2 .  Br J Haematol . 1981;  48 293-303
    PubMedGoogle Scholar
  • 4 Hattori A, Takahashi H, Takahashi M, Shibata A, Okuma M. A new familial defect of platelet release mechanism (the intracellular Ca++ transport defect?).  Acta Haematol Jpn . 1981;  44 969-972
    PubMedGoogle Scholar
  • 5 Okuma M, Takayama H, Uchino H. Subnormal platelet response to thromboxane A2 in a patient with chronic myeloid leukemia.  Br J Haematol . 1982;  51 469-477
    PubMedGoogle Scholar
  • 6 Machin S J, Keenan J P, McVerry B A. Defective platelet aggregation to the calcium ionophore A23187 in a patient with a lifelong bleeding disorder.  J Clin Pathol . 1983;  36 1140-1144
    PubMedGoogle Scholar
  • 7 Hardisty R M, Machin S J, Nokes T JC, Rink T J, Smith S W. A new congenital defect of platelet secretion: Impaired responsiveness of the platelets to cytoplasmic free calcium.  Br J Haematol . 1983;  53 543-557
    PubMedGoogle Scholar
  • 8 Ushikubi F, Okuma M, Kanaji K. Hemorrhagic thrombocytopathy with platelet thromboxane A2 receptor abnormality: Defective signal transduction with normal binding activity.  Thromb Haemost . 1987;  57 158-164
    PubMedGoogle Scholar
  • 9 Fuse I, Mito M, Hattori A. Defective signal transduction induced by thromboxane A2 in a patient with a mild bleeding disorder: Impaired phospholipase C activation despite normal phospholipase A2 activation.  Blood . 1993;  81 994-1000
    PubMedGoogle Scholar
  • 10 Fuse I, Hattori A, Mito M. Pathogenetic analysis of five cases with a platelet disorder characterized by the absence of thromboxane A2 (TXA2)-induced platelet aggregation in spite of normal TXA2 binding activity.  Thromb Haemost . 1996;  76 1080-1085
    PubMedGoogle Scholar
  • 11 Hirata K, Kakizuka A, Ushikubi F. Arg60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder.  J Clin Invest . 1994;  94 1662-1667
    CrossrefPubMedGoogle Scholar