11-dehydro-thromboxane-b2 and Antiphospholipid-Syndrome

Recent studies have shown that patients with antiphospholipid antibodies (aPL) have increased lipid peroxidation. We evaluated the urinary excretion of 11-dehydro thromboxane B2 (11-DH-TXB(2) and isoprostane F(2alpha)III (IPF(2alpha)III), reflecting platelet activation and lipid peroxidation in vivo, and plasma soluble markers of endothelial cell, platelet and blood coagulation activation: soluble vascular cell adhesion molecule-1 (sVCAM-1), P- and E-selectin (sPsel and sEsel), F1 + 2 fragment of prothrombin (F1 + 2), thrombin-antithrombin complexes (TAT) and D-Dimer (DD). We studied 79 patients with aPL (47 with previous thrombosis), 45 healthy volunteers (normal controls, NC), 12 patients with systemic lupus erythematosus (SLE) without aPL and a thrombosis control group (TCG) without thrombophilia (n = 16). Urinary levels (mean, range) of eicosanoids and isoeicosanoids were significantly increased in 39 patients with aPL compared with 25 NC, 11-DH-TXB(2) 164.0 ng/mmol creatinine (9.5-1162.8) versus 43.4 ng/mmol creatinine (4.2-87.6), P < 0.001; IPF(2alpha)III 56.9 pg/mg creatinine (5.5-388.7) versus 27.0 pg/mg creatinine (4.6-87.6), P = 0.03. Both metabolites were significantly correlated (rho = 0.49, P = 0.014), but none correlated with any clinical manifestation or antibody profile. The aPL group presented increased levels of sPsel, sEsel, sVCAM-1, TAT, F1 + 2 and DD, but any soluble marker correlated with IPF2alphaIII. Urinary 11-DH-TXB(2) correlated with sPsel (rho = 0.39, P = 0.04). Compared with SLE controls, the SLE group with aPL had higher levels of F1 + 2. Plasma levels of F1 + 2 and DD were significantly increased and a trend to higher sPsel was found in aPL patients with thrombosis compared with the TCG. Platelet activation, lipid peroxidation and blood coagulation activation seem to be important in the pathophysiology of antiphospholipid syndrome.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Antithrombins; Biomarkers; Blood Coagulation; Case-Control Studies; Chi-Square Distribution; Child; Child, Preschool; E-Selectin; Endothelium, Vascular; Female; Fibrin Fibrinogen Degradation Products; Humans; Isoprostanes; Lipid Peroxidation; Lupus Erythematosus, Systemic; Male; Middle Aged; P-Selectin; Platelet Activation; Prothrombin; Statistics, Nonparametric; Thrombosis; Thromboxane B2; Vascular Cell Adhesion Molecule-1

Antiphospholipid antibodies (aPL) reactive with anionic phospholipids and beta2-glycoprotein I (beta2-GPI) are found in the sera of patients with autoimmune diseases. Clinically, aPL/beta2-GPI complexes are associated with arterial and venous thrombosis, fetal loss, and thrombocytopenia, i.e., the antiphospholipid syndrome (APS). The mechanism of thrombosis is not known. We hypothesized that aPL/beta2-GPI complexes could perturb the platelet membrane and increase production of thromboxane A2 (TXA2, a proaggregatory prostanoid).. We isolated an IgG fraction containing anticardiolipin antibody (aCL) and the plasma cofactor, beta2-GPI, from a patient with a high titer of aCL and thrombotic cerebrovascular disease. We then examined the effect of aCL, beta2-GPI, and the aCL/beta2-GPI complex on platelet TXB2 (a stable metabolite of TXA2) biosynthesis in vitro from 7 healthy controls. We also measured in vitro platelet TXB2 biosynthesis in 7 patients with APS and in 8 controls.. We found: (1) significantly increased in vitro TXB2 production by platelets from controls after incubation with aCL/beta2-GPI complexes; (2) moderately increased TXB2 production by aCL alone; (3) no increase in TXB2 production by beta2-GPI alone; and (4) significantly increased 11-dehydro-TXB2, a metabolite of TXB2 production in vivo, in the urine of patients with APS compared with controls.. These data suggest that aCL/beta2-GPI complexes play a role in activating platelets to produce TXA2, which could contribute to the prothrombotic state found in patients with APS.

Topics: Adult; Aged; Antibodies, Anticardiolipin; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Autoimmune Diseases; beta 2-Glycoprotein I; Binding Sites; Blood Platelets; Female; Glycoproteins; Humans; Immunoglobulin Fab Fragments; Male; Middle Aged; Phospholipids; Thromboxane A2; Thromboxane B2