Familial Bleeding Tendency with Partial Platelet Thromboxane Synthetase Deficiency: Reorientation of Cyclic Endoperoxide Metabolism

Patients with chronic idiopathic thrombocytopenic purpura (CITP) have been described to have bleeding times (B.Ts) that were shorter than would be predicted by their platelet counts. This phenomenon was explained by the presence in CITP of a young platelet population with increased hemostatic competence (NEJM 287:155, ’72). In contradistinction, we have observed patients with CITP to have a bleeding tendency at platelet counts >75,000/cu mm. We therefore evaluated B.Ts and platelet arachidonic acid (AA) metabolism in 7 patients with CITP who demonstrated increased amounts of platelet associated IgG (PAIgG >3fg per platelet) and compared them to 20 healthy controls. 3/7 patients with CITP and platelet counts of >75,000/cu mm demonstrated marked prolongations in their B.Ts. (10’, 12’ and 14’, normal <7’). Marked abnormalities in the metabolism of AA through the cyclo-oxygenase (Thromboxane B2 and HHT) and lipoxygenase (HETE) pathways were also observed in patients with CITP. Platelets in CITP synthesized less amounts (p <0.005) of Thromboxane B2 (10.3 ± 3.1%) in comparison to controls (22.9 ± 1.8). Values for HHT were decreased (23.7 ± 4.9 vs 39.7 ± 1.9; p<0.005), while HETE production was increased (59.5 ± 7.8 vs 30.7 ± 1.8; p<0.001). No correlation was observed between PAIgG and platelet Thromboxane B2 formation. However, an inverse correlation (r=0.81, p<0.05 was observed between the B.T. and platelet Thromboxane B2 formation in patients with chronic ITP. We have demonstrated platelet dysfunction and impaired Thromboxane B2 formation in CITP. This association should be investigated in the individual patient, since the bleeding tendency in these patients is exacerbated by the superimposed impairment in platelet function.

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3-(1-imidazolylmethyl) indoles: potent and selective inhibitors of human blood platelet thromboxane synthetase

Agents and Actions ◽

10.1007/bf01967626 ◽

1981 ◽

Vol 11 (3) ◽

pp. 274-280 ◽

Cited By ~ 16

Author(s):

Peter E. Cross ◽

Roger P. Dickinson ◽

Michael J. Parry ◽

Michael J. Randall

Keyword(s):

Human Blood ◽

Blood Platelet ◽

Selective Inhibitors ◽

Human Blood Platelet ◽

Thromboxane Synthetase ◽

Platelet Thromboxane

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Inhibition of human platelet thromboxane synthetase by 9,11-azoprosta-5,13-dienoic acid.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.74.9.4007 ◽

1977 ◽

Vol 74 (9) ◽

pp. 4007-4011 ◽

Cited By ~ 69

Author(s):

R. R. Gorman ◽

G. L. Bundy ◽

D. C. Peterson ◽

F. F. Sun ◽

O. V. Miller ◽

...

Keyword(s):

Human Platelet ◽

Dienoic Acid ◽

Thromboxane Synthetase ◽

Platelet Thromboxane

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SQ 22536, an Adenylate-Cyclase Inhibitor, Prevents the Antiplatelet Effect of Dazoxiben, a Thromboxane-Synthetase Inhibitor

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661037 ◽

1984 ◽

Vol 51 (01) ◽

pp. 125-128 ◽

Cited By ~ 15

Author(s):

Vittorio Bertelé ◽

Anna Falanga ◽

Marian Tomasiak ◽

Chiara Cerletti ◽

Giovanni de Gaetano

Keyword(s):

Adenylate Cyclase ◽

Platelet Rich Plasma ◽

Thromboxane A2 ◽

Human Platelets ◽

Selective Inhibitor ◽

Prostaglandin D2 ◽

Plasma Samples ◽

Thromboxane Synthetase ◽

Camp Levels ◽

Platelet Thromboxane

SummaryThis study shows that dazoxiben, a selective inhibitor of thromboxane A2-synthetase in human platelets, inhibited arachidonic acid-induced platelet aggregation in platelet-rich plasma samples from four out of 16 healthy volunteers. In these four “responder” samples, the anti-aggregating effect of dazoxiben was prevented by the compound SQ 22536, a 9-substituted adenine analogue, endowed with an inhibitory activity on adenylate-cyclase. The compound SQ 22536 also counteracted the antiaggregating effect of prostaglandin D2, a known activator of platelet adenylate-cyclase. When platelet thromboxane A2-syn- thetase was blocked by dazoxiben, a marked increase of prostaglandin D2 was concomitantly observed both in “responder” and “non responder” samples. The compound SQ 22536 blunted the increase in platelet cAMP caused by either dazoxiben and sodium arachidonate or prostaglandin D2. It is suggested that the antiaggregating effect of dazoxiben is mediated by newly synthesized prostaglandin D2. The latter acts by stimulating adenylate-cyclase and increasing cAMP levels. The compound SQ 22536 prevents both phenomena. In “non responder” samples some factors - still to be defined - might counteract similarly to the compound SQ 22536 the antiaggregating activity of PGD2.

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A Thromboxane Synthetase Inhibitor Which Prolongs Bleeding Time In The Rat At Oral Doses Which Fail To Inhibit Platelet Aggregation In Vivo Or Ex Vivo

10.1055/s-0038-1652832 ◽

1981 ◽

Author(s):

K D Butler ◽

E D Maguire ◽

A A Turnbull ◽

R B Wallis ◽

A M White

Keyword(s):

Platelet Aggregation ◽

Bleeding Time ◽

Ex Vivo ◽

Inhibit Platelet Aggregation ◽

Thromboxane Synthetase ◽

Oral Doses ◽

Rat Tail ◽

Platelet Thromboxane

The role of thromboxane A2 (TXA2) in haemostasis was investigated with the use of a selective inhibitor of platelet thromboxane synthetase used in conjunction with radioimmunoassay of thromboxane B2 (TXB2). N-Carboxyheptylimidazole is such an inhibitor having no effect on platelet cyclooxygenase. An oral dose of this substance (10 mg/kg) to rats resulted in 85% (P < 0.001) suppression of platelet TXB2 production induced by collagen ex vivo while the ED50 and maximum rate of platelet aggregation were unchanged. It also caused a prolongation of tail bleeding time from 153±13 to 284±22 secs (P < 0.01). The thrombocytopenia resulting from the Arthus reaction in rats was unchanged, and the prothrombin and activated partial thromboplastin coagulation times were not affected by either 10 or 30 mg/kg p.o. It is concluded that the role of TXA2 in prevention of rat tail bleeding is not as an activator of platelet aggregation or blood coagulation. It is more likely that TXA2 prevents bleeding via its potent vaso-constricting properties. In addition the increased bleeding time may be due to change in the equilibrium of other vasoactive prostanoids.

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Inhibition of platelet thromboxane synthetase by sulfasalazine

Biochemical Pharmacology ◽

10.1016/0006-2952(83)90227-7 ◽

1983 ◽

Vol 32 (14) ◽

pp. 2205-2209 ◽

Cited By ~ 26

Author(s):

William F. Stenson ◽

Elizabeth Lobos

Keyword(s):

Thromboxane Synthetase ◽

Platelet Thromboxane

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POSSIBLE CONGENITAL DEFECT IN PLATELET THROMBOXANE SYNTHETASE

The Lancet ◽

10.1016/s0140-6736(77)92213-9 ◽

1977 ◽

Vol 309 (8014) ◽

pp. 760-761 ◽

Cited By ~ 36

Author(s):

HarveyJ. Weiss ◽

BruceA. Lages

Keyword(s):

Congenital Defect ◽

Thromboxane Synthetase ◽

Platelet Thromboxane

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Prolongation of Rat Tail Bleeding Time Caused by Oral Doses of a Thromboxane Synthetase Inhibitor Which Have Little Effect on Platelet Aggregation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657122 ◽

1982 ◽

Vol 47 (01) ◽

pp. 046-049 ◽

Cited By ~ 27

Author(s):

K D Butler ◽

E D Maguire ◽

J R Smith ◽

A A Turnbull ◽

R B Wallis ◽

...

Keyword(s):

Platelet Aggregation ◽

Oral Dose ◽

Bleeding Time ◽

Thrombus Formation ◽

Synthetase Inhibitor ◽

Thromboxane Synthetase Inhibitor ◽

Thromboxane Synthetase ◽

Oral Doses ◽

Induced Aggregation ◽

Platelet Thromboxane

SummaryN (7-carboxyheptyl) imidazole is an inhibitor of platelet thromboxane synthetase that has no effect on the cyclooxygenase activity. An oral dose of the substance to rats (10 mg/kg) prolonged tail bleeding time from 170 ± 13 sec to 284 ± 22 sec. This oral dose also inhibited platelet thromboxane B2 production induced by collagen ex vivo but had little effect on the aggregation dose response curve. There was no effect on thrombin-induced aggregation.Neither the thrombocytopenia induced by the Arthus reaction nor thrombus formation on an implanted cotton thread were inhibited by oral doses of carboxyheptylimidazole up to 30 mg/kg. Similarly neither the prothrombin nor activated partial thromboplastin time were affected.It is postulated that this thromboxane synthetase inhibitor prolongs bleeding time not by inhibiting platelet aggregation or blood coagulation but rather by preventing the vasoconstriction which would normally be caused by thromboxane A2.

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