Antonio Ciampa

High-density lipoprotein inversely relates to its specific autoantibody favoring oxidation in thrombotic primary antiphospholipid syndrome.

Abnormalities of the lipid profile partly explain the atherogenic tendency of systemic lupus erythematosus but the picture is unclear in thrombotic primary antiphospholipid syndrome (PAPS). Herein we compare the lipid profile, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (CHO), apolipoprotein A (ApoA-I), apolipoprotein B (ApoB), tryglicerides (TRY)), anti-lipoprotein antibodies, beta-2-glycoprotein I complexed to oxidized low-density lipoprotein (oxLDL-ß2GPI) and C-reactive protein (CRP) from thrombotic PAPS (n = 34), thrombotic patients with inherited thrombophilia (IT; n = 36), subjects persistently positive for antiphospholipid antibodies (aPL, n = 18) with no underlying autoimmune or non-autoimmune disorders and healthy controls (n = 28) and determined the reciprocal effects of anti-lipoprotein antibodies, the lipid profile, oxLDL-ß2GPI and CRP. Average concentrations of HDL (p < 0.0001), LDL (p < 0.0001), CHO (p = 0.0002), ApoA-I (p = 0.002) were lower in PAPS whereas average TRY was higher (p = 0.01) than other groups. Moreover, the aPL and PAPS group showed higher levels of IgG anti-HDL (p = 0.01) and IgG anti-ApoA-I (p < 0.0001) whereas the PAPS group showed greater average oxLDL-ß2GPI (p = 0.001) and CRP (p = 0.003). Within the PAPS group, IgG anti-HDL correlated negatively to HDL (p = 0.004) and was an independent predictor of oxLDL-ß2GPI (p = 0.009). HDL and ApoA-I correlated negatively with CRP (p = 0.001 and p = 0.007, respectively). IgG anti-HDL may hamper the antioxidant and anti-inflammatory effect of HDL favoring low-grade inflammation and enhanced oxidation in thrombotic PAPS. Lupus (2010) 19, 711—716.

Bleeding and re-thrombosis in primary antiphospholipid syndrome on oral anticoagulation An 8-year longitudinal comparison with mitral valve replacement and inherited thrombophilia

The aim of this study was to compare bleeding and re-thrombosis in primary antiphospholipid syndrome (PAPS), mitral valve replacement (MVR) and inherited thrombophilia (IT) at different oral anticoagulation intensities. It entailed a prospective 8-year follow-up on 67 patients with PAPS, 89 with IT and 24 with MVR. Anticardiolipin (aCL) antibodies detected by Elisa and lupus anticoagulant by clotting assays. At INR 2-3 minor bleeding rate was higher in MVR (33.3) than PAPS (10.9) and IT (4.2)(p<0.0001). At INR 3-4 minor bleeding rate was higher in PAPS (142) than IT (33.3) and MVR (5.8)(p<0.0001). At either INR major bleeding rate were not significantly different across the three groups, but in PAPS major and minor bleeding rates were superior at INR 3-4 than INR 2-3 (p=0.02 and p<0.0001). Re-thrombosis rate was higher in PAPS than IT at INR 2-3 (4.0 vs 0.35) (p=0.01) and at INR 3-4 (10.5 vs. nil). The hazard ratio for re-thrombosis between PAPS and IT was 13 (95% IC 1.6-102.2, p=0.015). By regression analysis, baseline IgG aCL titre (>80 GPL) p=0.001) and male sex (p=0.03) independently predicted re-thrombosis. In conclusion, in PAPS, high intensity oral anticoagulation was not superior to conventional intensity in preventing re-thrombosis but was offset by greater bleeding rates. Male sex and elevated baseline IgG aCL predicted rethrombosis in PAPS that is 13-fold more re-thrombogenic than IT.

Clinical relevance of nitric oxide metabolites and nitrative stress in thrombotic primary antiphospholipid syndrome.

Objective. To assess the role of nitrite (NO2−), nitrate (NO3−), and nitrative stress in thrombotic primary antiphospholipid syndrome (PAPS). Methods. We investigated 46 patients with PAPS: 21 asymptomatic but persistent carriers of antiphospholipid antibodies (PCaPL), 38 patients with inherited thrombophilia (IT), 33 patients with systemic lupus erythematosus (SLE), and 29 healthy controls (CTR). IgG anticardiolipin (aCL), IgG anti-beta2-glycoprotein I (anti-ß2-GPI), IgG anti-high density lipoprotein (aHDL), IgG anti-apolipoprotein A-I (aApoA-I), crude nitrotyrosine (NT) (an indicator of nitrative stress), and high sensitivity C-reactive protein (CRP) were measured by immunoassays. Plasma nitrite (NO2−), nitrate (NO3−), and total antioxidant capacity (TAC) were measured by colorimetric spectroscopic assays. Results. Average plasma NO2− was lower in PAPS, PCaPL, and IT (p < 0.0001); average NO3− was highest in SLE (p < 0.0001), whereas average NT was higher in PAPS and SLE (p = 0.01). In thrombotic PAPS, IgG aCL titer and number of vascular occlusions negatively predicted NO2− (p = 0.03 and p = 0.001, respectively), whereas arterial occlusions and smoking positively predicted NO3− (p = 0.05 and p = 0.005), and CRP positively predicted NT (p = 0.004). In the PCaPL group IgG aCL negatively predicted NO3− (p = 0.03). In the SLE group IgG aCL negatively predicted NO2− (p = 0.03) and NO3− (p = 0.02). Conclusion. PAPS is characterized by decreased NO2− in relation to type and number of vascular occlusions and to aPL titers. Nitrative stress and low grade inflammation are linked phenomena in PAPS and may have implications for thrombosis and atherosclerosis.

Increased warfarin consumption and residual fibrin turnover in thrombotic patients with primary antiphospholipid syndrome

INTRODUCTION Anedoctal reports suggest that some thrombotic primary antiphospholipid antibody syndrome (PAPS) patients on oral anticoagulation require higher than average doses to achieve given targets international normalized ratios (INR). MATERIALS AND METHODS To test the hypothesis of relative warfarin resistance in thrombotic PAPS and the effect of baseline IgG anticardiolipin antibodies, the cytochrome CYP2C9 and the vitamin K epoxide reductase (VKORC1) haplotypes we compared weekly warfarin consumption of 40 TPAPS (mean age 44 ± 16years) with that of 65 thrombotic patients with inherited thrombophilia (IT) (mean age 52 ± 18) at similar target INR 2.0-3.0 followed up between January-1994 and January 2003. To investigate an involvement of the epoxidation pathway in this difference and to assess enhanced residual fibrin turnover decarboxylated prothrombin (PIVKA-II) and D-dimers (DD) were cross-sectionally investigated in the same patients between March and May 2008. RESULTS CEX7 and VKORC1 polymorphisms explained 45.1% of the variability in warfarin consumption, whose age-adjusted mean weekly consumption was greater in PAPS than IT (27.62 vs 21.24 mg, p = 0.03). In PAPS baseline IgG aCL and VKORC1 predicted weekly warfarin consumption (p = 0.028 and p = 0.024). IgG β(2)GPI and warfarin dose independently predicted plasma PIVKA-II (p = 0.01 and p = 0.02). Age and sex adjusted DD was greater in PAPS than IT (132 ± 34 vs 83 ± 37 mg/dl, p = 0.03). CONCLUSIONS Thrombotic PAPS exhibit a degree of warfarin resistance partly accounted by antiphospholipid antibodies and are in a state of enhanced fibrin turnover despite oral anticoagulation that might have implications for re-thrombosis and atherosclerosis.

AB0604 Dilute Russel Venom Time Ration Independently Predicts Mortality in Primary Antiphospholipid Syndrome

Background Though the probability of survival at 10 years is 90.7% in the antiphospholipid syndrome (APS), eventual haemostatic of immunological predictors of mortality in primary APS (PAPS) have been poorly investigated. Objectives To identify mortality predictors in patients with PAPS. Methods Record review of all PAPS patients attending the Haemostasis Unit of the Cardarelli Hospital from 1988 to 2008. We identified 11 deceased patients (5M, 6F, age 55±9 yrs), 68 surviving thrombotic PAPS (21M, 47F, 47±14 yrs) and 29 persistent carriers of antiphospholipid antibodies (PCaPL) without thrombosis (7M, 22F,tage 50±16 yrs). The following had been tested at baseline and confirmed 6 weeks later: aPTT, DRVVT, KCT and plasma fibrinogen (FNG) by coagulation assays; IgG anticardiolipin (aCL) and von Willebrand factor (vWF) by Elisa; platelet (PLT) count on automatic analyser. Results IgG aCL (GPL) was 328±344 in deceased PAPS, 105±146 in surviving PAPS and 75±167 in PCaPL (p<0.0001); aPTT ratio was 2.17±0.46 in deceased PAPS, 1.92±0.65 in surviving PAPS and 1.79±1.01 in PCaPL (p<0.02); DRVVT ratio was 2.30±0.80 in deceased PAPS, 1.65±0.43 in surviving PAPS and 1.33±0.32 in PCaPL (p<0.0001); plasma FNG (mg/dl) was 385±70 in deceased PAPS, 335±49 in surviving PAPS and 312±63 in PCaPL (p<0.02); PLTs (109/L) were 293±105 in deceased PAPS, 202±86 in surviving PAPS and 141±77 in PCaPL (p<0.0001). KCT ratio and vWF concentration did not differ. Sex, disease duration, age at first thrombotic event, number of thrombotic events, IgG aCL titre, aPTTr, DRVVTr, FNG, vWF and platelet numbers were entered as independent variables in a stepwise Cox regression model with mortality as the dependent variable: DRVVTr was the single most powerful predictor of mortality that was 20% at 17 years. Conclusions DRVVTr is an independent predictor of mortality: efforts of future research should be aimed at measures to decrease antiphospholipid generation. References Cervera R, Serrano R, Pons-Estel GJ et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2014 Jan 24 Disclosure of Interest None declared

Reply to Rebuttal: Strong Lupus Anticoagulant can influence the prothrombin time INR falsifying the follow up of oral anticoagulation

Reply to Rebuttal: Strong Lupus Anticoagulant can influence the prothrombin time INR falsifying the follow up of oral anticoagulation -