Antiphospholipid Antibodies Enhance Thrombin-Induced Platelet Activation and Thromboxane Formation

Martinuzzo, Marta; Maclouf, Jacques; Carreras, L; Lévy-Toledano, S

doi:10.1055/s-0038-1649646

Cited by 135 publications

(78 citation statements)

References 37 publications

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“…The prothrombotic properties of aPL may be explained in part by their ability to enhance the activation of platelets. Moreover, aPL have been shown to increase production of TXB 2 in the presence of low doses of ADP, collagen, or thrombin (7,10,26,27). A recent study by our group showed a significant increase in the expression of activated glycoprotein IIb/IIIa on platelets treated with aPL and TRAP (8).…”

Section: Discussionmentioning

confidence: 89%

Intracellular events in platelet activation induced by antiphospholipid antibodies in the presence of low doses of thrombin

Vega-Ostertag

Harris

Pierangeli

2004

Arthritis & Rheumatism

118

102

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Objective. Thrombosis and thrombocytopenia are features of the antiphospholipid syndrome (APS), suggesting that antiphospholipid antibodies (aPL) may bind platelets, causing activation and aggregation of platelets and thrombosis. The intracellular events involved in aPL-mediated platelet activation are not fully understood and are therefore the subject of this study.Methods. IgG fractions and their F(ab) 2 fragments were purified from the sera of 7 patients with APS and from the pooled sera of 10 healthy subjects (as controls). Phosphorylation of p38 MAPK, ERK-1/2, and [Ca 2؉ ]-dependent cytosolic phospholipase A 2 (cPLA 2 ) was determined in lysates of washed platelets pretreated with low doses of thrombin and aPL or control IgG or their F(ab) 2 fragments, by immunoblot. The effects of aPL on platelet aggregation in the presence or absence of a p38 MAPK inhibitor, SB203580, were examined. Thromboxane B 2 (TXB 2 ) production was detected by enzyme-linked immunosorbent assay on gel-filtered platelets treated with aPL and thrombin, with or without SB203580. Calcium mobilization studies were done utilizing a fluorometric assay.Results. Treatment of platelets with IgG aPL, or their F(ab) 2 fragments, in conjunction with subactivating doses of thrombin resulted in a significant increase in phosphorylation of p38 MAPK. Neither the IgG aPL nor their F(ab) 2 fragments increased significantly the phosphorylation of ERK-1/2 MAPKs. Furthermore, pretreatment of platelets with SB203580 completely abrogated the aPL-mediated enhanced aggregation of the platelets. Platelets treated with F(ab) 2 aPL and thrombin produced significantly larger amounts of TXB 2 when compared with controls, and this effect was completely abrogated by treatment with SB203580. In addition, cPLA 2 was also significantly phosphorylated in platelets treated with thrombin and F(ab) 2 aPL. There were no significant changes in intracellular [Ca 2؉ ] when platelets were treated with aPL and low doses of thrombin.Conclusion. The data strongly indicate that aPL in the presence of subactivating doses of thrombin induce the production of TXB 2 mainly through the activation of p38 MAPK and subsequent phosphorylation of cPLA 2 . The ERK-1/2 pathway does not seem to be involved in this process, at least in the early stages of aPL-mediated platelet activation.

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Section: Discussionmentioning

confidence: 89%

Intracellular events in platelet activation induced by antiphospholipid antibodies in the presence of low doses of thrombin

Vega-Ostertag

Harris

Pierangeli

2004

Arthritis & Rheumatism

118

102

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“…31) Studies indicate that aCL antibodies are not generated by tissue necrosis but rather that they participate in the pathogenesis of MI. 4,30) This hypothesis is biologically plausible because of the inflammatory 8,32,33) and procoagulant [34][35][36] properties of these antibodies.…”

Section: Discussionmentioning

confidence: 99%

Association Between Anticardiolipin Antibodies and Recurrent Cardiac Events in Patients With Acute Coronary Syndrome

et al. 2005

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SUMMARYTo determine whether the presence of anticardiolipin (aCL) antibodies in patients with acute coronary syndome is predictive of recurrent cardiac events in hospital stay and follow-up.The study population consisted of 80 patients with acute coronary syndrome. IgM and IgG aCL levels were determined before hospital discharge. We divided the patients into those with an aCL IgG ≥ 40 IgG phospholipid units (group I, n = 30) and those with an aCL IgG < 40 IgG phospholipid units (group II, n = 50). All patients underwent coronary angiography. Follow-up coronary angiography was performed 12 months after percutaneous coronary intervention (PCI). Infectious and autoimmune diseases were exclusion criteria. Patients were observed to determine overall mortality, reinfarction, and restenosis.There were no differences between the groups with respect to the prevalence of hypertension, diabetes mellitus, and cigarette smoking, sex, or ejection fraction. The prevalence of left ventricular thrombus was similar between the groups (group I: 16% versus group II: 16.7%, P > 0.05). Although the presence of left atrial thrombus was much more frequent in cardiolipin positive patients (13% versus 4%, respectively), the difference was not statistically significant (P = 0.19). Restenosis was observed in 40% of the cardiolipin positive patients and 14% of the cardiolipin negative patients (P < 0.01). There was no significant association between reinfarction and anticardiolipin positivity during followup (26% versus 10%, P > 0.05). In group I patients, in-hospital mortality was somewhat more frequent compared to group II patients (4% versus 10%), but the difference was not statistically significant (P = 0.27). One year mortality was similar between the groups.These results suggest that 1) restenosis occurs more frequently in anticardiolipin positive patients and 2) no association is evident between positive aCL and mortality, reinfarction, and intracardiac thrombus. (Int Heart J 2005; 46: 631-638)

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“…It is also possible that part of the effect of aspirin on thrombosis prophylaxis in APLA patients relies on platelet thromboxane inhibition. It has been shown that the urine of APLA patients has increased quantities of thromboxane metabolites [26,27] and that purified APLA increase platelet thromboxane production after minimal thrombin stimulation in vitro [28]. However, the ability of APLA to activate platelets directly is still debated, since, for example, incubation with APS sera resulted in an increase of platelet-associated IgG without any clear activation in one study [29].…”

Section: Discussionmentioning

confidence: 99%

Aspirin inhibits endothelial cell activation induced by antiphospholipid antibodies

Dunoyer‐Geindre

Kruithof

Boehlen

et al. 2004

Journal of Thrombosis and Haemostasis

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Summary. Background: Antiphospholipid antibodies (APLA) have been shown to activate endothelial cells (EC) in vitro, as documented by an increased expression of tissue factor as well as leukocyte adhesion molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule (VCAM)-1 and E-selectin. Currently, treatment of patients with the antiphospholipid syndrome includes aspirin, particularly for women with recurrent fetal loss. Objective: The present study was undertaken to investigate whether aspirin interferes with EC activation induced by APLA in vitro. Methods: IgG from 14 patients with APLA, and suffering from thrombotic complications and/or pregnancy morbidity, and control IgG were tested for their ability to modify the expression of VCAM-1 in human umbilical vein endothelial cells. VCAM-1 antigen was measured by flow cytometry and its mRNA by quantitative reverse transcriptase-polymerase chain reaction. Results: Incubation of EC with IgG from most of the patients led to a higher VCAM-1 expression compared with incubation with control IgG. The effect of aspirin was studied for the eight IgG samples that induced a more than 50% increase in VCAM-1. Aspirin (10 mM) treatment of the cells significantly reduced the VCAM-1 response to these APLA. Conclusions: Our results indicate that besides its antiplatelet properties, aspirin exerts a protective effect towards APLA at the EC level by decreasing leukocyte adhesion molecule expression at the cell surface.

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Antiphospholipid Antibodies Enhance Thrombin-Induced Platelet Activation and Thromboxane Formation

Cited by 135 publications

References 37 publications

Intracellular events in platelet activation induced by antiphospholipid antibodies in the presence of low doses of thrombin

Intracellular events in platelet activation induced by antiphospholipid antibodies in the presence of low doses of thrombin

Association Between Anticardiolipin Antibodies and Recurrent Cardiac Events in Patients With Acute Coronary Syndrome

Aspirin inhibits endothelial cell activation induced by antiphospholipid antibodies

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