Imbalance of thromboxane/prostacyclin biosynthesis in patients with lupus anticoagulant

Abstract

The mechanism involved in the association between antiphospholipid antibodies and thrombosis or fetal loss remains unclear. We assessed the biosynthesis of thromboxane A2 and prostacyclin in 31 samples from 25 patients with lupus anticoagulant and in 32 controls. The urinary excretion of the major thromboxane metabolite of platelet origin (11- dehydrothromboxane B2) was very significantly increased (P less than .0003) in the patients. In contrast, the urinary metabolite reflecting the vascular production of prostacyclin (2,3-dinor-6-keto-prostaglandin F1 alpha) was much less increased (P less than .02). We found no correlation between the levels of anticardiolipin antibodies and the urinary excretion of 11-dehydro-thromboxane B2. Six patients with elevated urinary 11-dehydrothromboxane B2 were treated with low-dose aspirin (20 mg/d during 7 days). In these patients, there was a close relationship between the extent of inhibition of the thromboxane urinary metabolite (72%) and serum thromboxane B2 (79%). In contrast, the urinary excretion of 2,3-dinor-6-ketoprostaglandin F1 alpha was nearly unchanged (13% reduction). In addition, the F(ab')2 fragments isolated from six patients presenting increased urinary 11-dehydro- thromboxane B2 enhanced the generation of thromboxane B2 (P = .04) and the release of 14C serotonin (P = .009) by normal washed platelets, as compared with F(ab')2 from controls. In summary, our study shows that in patients with lupus anticoagulant, platelet activation may occur without a compensatory increment in the vascular biosynthesis of prostacyclin. This observation may be crucial to cause or reflect an increased risk for thrombosis. In addition, our results may suggest a rationale for antiplatelet agents for the prophylaxis of thrombosis in many patients with the antiphospholipid syndrome.

Binding of anticardiolipin antibodies to protein C via β2-glycoprotein I (β2-GPI): a possible mechanism in the inhibitory effect of antiphospholipid antibodies on the protein C system

“…IgG containing aCL bound to cultured endothelial cells in the presence of b 2 -GPI, and induced cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) [56], which may lead to a procoagulant state. It is also known that aPL induce procoagulant substances such as tissue factor [57,58], plasminogen activator inhibitor-1 [59] and thromboxane A2 [60], in which processes aPL are likely to affect cells via b 2 -GPI or other phospholipid-binding proteins [61]. In terms of the binding mechanism of aPL, the binding of aCL to protein C with a combination of phospholipids and b 2 -GPI might be a similar phenomenon.…”

Risk of arterial thrombosis in patients with anticardiolipin antibodies and lupus anticoagulant

“…The mechanisms involved in the development of an arterial or venous thrombosis are not yet known, but it is postulated that an arterial or venous thrombosis probably has separate causes; antibodies which alter the prostacyclin/ thromboxane balance may be associated with arterial thrombosis (Lellouche et al, 1991), whereas antibodies that inhibit the protein C pathway may be associated with venous thrombosis (Triplett, 1992). Thus the antibodies to different epitopes may be related to the difference between arterial or venous thrombosis.…”

Antiphospholipid antibody‐dependent C5b‐9 formation

“…Direct activation of platelets by APA raised in rabbits was demonstrated by Lin & Wang (1992) and Shi et al (1993) showed that APA would only bind to platelets that have undergone activation. Indirect evidence of APA-dependent platelet activation was suggested by the presence of increased levels of urinary thromboxane B2 noted in patients with antiphospholipid syndrome (APS) (Lellouche et al, 1991;Arfors et al, 1990). However, other researchers have found that unstimulated resting platelets are not activated by purified APA (Campbell et al, 1995;Reverter et al, 1995).…”