Thromboxane A2 and Prostacyclin Generation in the Microvasculature of Patients with Atherosclerosis – Effect of Low-Dose Aspirin

SummaryGeneration of thromboxane A2 (TxA2) and prostacyclin (PGI2) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine skin bleeding time was investigated in 7 patients with atherosclerosis (angiographically verified obstructions of the femoral arteries) and in 7 normal control subjects apparently free of atherosclerotic lesions. Similar amounts of TxA2 (measured as thromboxane B2, TxB2) were generated at the site of plug formation in the patients with peripheral vascular disease (PVD) and in the control subjects. Significantly lower levels of PGI2 (measured as 6-keto-prostaglandin F1α, 6-keto- PGF1α) were found in blood from an injury of the microvasculature in the patients compared with the controls. These data do not suggest a major role of the platelet prostaglandin metabolism in the development of atherosclerosis. However, decreased synthesis of PGI2 by endothelial cells might contribute to the development and/or progression of atherosclerotic lesions. In the patients with PVD, low-dose aspirin (50 mg/day for 7 days) resulted in a >90% inhibition of the TxB2 production at the site of plug formation. Following low-dose aspirin 6-keto-PcF1α levels were below 20 pg/ml (limit of sensitivity of our radioimmunoassay procedure) in the majority of the samples.We therefore conclude that in patients with PVD a decreased synthesis of PGI2 by endothelial cells might contribute to the progression of atherosclerosis. Furthermore, low-dose aspirin treatment results in a similar inhibition of the platelet prostaglandin generation as recently observed in healthy subjects.

Download Full-text

PROSTACYCLIN AND THROMBOXANE A2 GENERATION IN VIVO IN MAN -EFFECT OF LOW DOSE ASPIRIN

10.1055/s-0038-1643371 ◽

1987 ◽

Author(s):

P A Kyrle ◽

H G Eichler ◽

K Lechner

Keyword(s):

Vessel Wall ◽

Low Dose ◽

Bleeding Time ◽

Thromboxane A2 ◽

Significant Inhibition ◽

Prostaglandin Metabolism ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Wall Interaction

The effect of a low-dose aspirin regimen on platelet and vascular prostaglandin metabolism was studied in vivo in man. In a double-blind placebo-controlled cross-over study, 7 healthy male volunteers were treated with aspirin (35 mg.day−1 or placebo for 7 days. After a washout period of 2 weeks, the subject were crossed to the alternate treatment. 12 hours after the last dose of aspirin or placebo formation of thromboxane A2 (TxA2) and prostacyclin (FGI2) was measured in blood emerging from a standardized injury of the microvasculature made to determine bleeding time. TxA2 and PGI2 were measured as their stable degradation products, thromboxane B2 (TxB2) and 6-keto-prostaglandin F1α (6-keto PGF1α), using radioimmunoassay procedures. When subjects were treated with placebo, there was a rapid and substantial generation of both TxA2 and PGI2 at the site of plate-let-vessel wall interaction. This was reflected by an increase of TxB2 from 2.8±1 ng/ml and of 6-keto-PGF1α from 38.6±14.6pg/ml in the first minute to 4.5±0.6 ng/ml TxB2 and 154±50 pg/ml 6-keto-PGF1α after 4 minutes. Low-dose aspirin caused a significant inhibition of both TxA2 and PGI2 generation in bleeding time blood as represented by 65-92% and 81-84% inhibition of TxB2 and 6-keto-PGF1α Respectively throughout the 4 minute study period. We conclude that (a) rapid activation of both platelet prostaglandin metabolism and vascular PGI2 biosynthesis occurs at the site of platelet-vessel wall interaction and (b) low-dose aspirin results in a significant inhibition of platelet and vascular cyclo-oxygenase activity. Thus, our data fail to confirm the concept of a differential effect of low-dose aspirin on platelet and vascular prostaglandin synthesis in vivo in man.

Download Full-text

Inhibition of prostacyclin and thromboxane A2 generation by low-dose aspirin at the site of plug formation in man in vivo.

Circulation ◽

10.1161/01.cir.75.5.1025 ◽

1987 ◽

Vol 75 (5) ◽

pp. 1025-1029 ◽

Cited By ~ 65

Author(s):

P A Kyrle ◽

H G Eichler ◽

U Jäger ◽

K Lechner

Keyword(s):

Low Dose ◽

Thromboxane A2 ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Plug Formation

Download Full-text

Investigation of the Interaction of Blood Platelets with the Coagulation System at the Site of Plug Formation In Vivo in Man - Effect of Low-Dose Aspirin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651063 ◽

1987 ◽

Vol 57 (01) ◽

pp. 062-066 ◽

Cited By ~ 36

Author(s):

P A Kyrle ◽

J Westwick ◽

M F Scully ◽

V V Kakkar ◽

G P Lewis

Keyword(s):

Platelet Activation ◽

Thrombin Generation ◽

Low Dose ◽

Bleeding Time ◽

Blood Platelets ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Plug Formation ◽

Granule Release

SummaryIn 7 healthy volunteers, formation of thrombin (represented by fibrinopeptide A (FPA) generation, α-granule release (represented by β-thromboglobulin [βTG] release) and the generation of thromboxane B2 (TxB2) were measured in vivo in blood emerging from a template bleeding time incision. At the site of plug formation, considerable platelet activation and thrombin generation were seen within the first minute, as indicated by a 110-fold, 50-fold and 30-fold increase of FPA, TxB2 and PTG over the corresponding plasma values. After a further increase of the markers in the subsequent 3 minutes, they reached a plateau during the fourth and fifth minute. A low-dose aspirin regimen (0.42 mg.kg-1.day-1 for 7 days) caused >90% inhibition of TxB2formation in both bleeding time blood and clotted blood. At the site of plug formation, a-granule release was substantially reduced within the first three minutes and thrombin generation was similarly inhibited. We conclude that (a) marked platelet activation and considerable thrombin generation occur in the early stages.of haemostasis, (b) α-granule release in vivo is partially dependent upon cyclo-oxygenase-controlled mechanisms and (c) thrombin generation at the site of plug formation is promoted by the activation of platelets.

Download Full-text