Anti-protein C antibodies and acquired protein C resistance in SLE: novel markers for thromboembolic events and disease activity?

Abstract

Objectives Risk factors for thromboembolism in SLE are poorly understood. We hypothesized a possible role for protein C, based on its dual activity in inflammation and haemostasis and on the evidence of an association between acquired activated protein C (APC) resistance (APCR) and high-avidity anti-protein C antibodies (anti-PC) with a severe thrombotic phenotype in venous thrombosis APS patients. Methods In a cross-sectional study of 156 SLE patients, the presence and avidity of IgG anti-PC was established by in house-ELISA, and APCR to exogenous recombinant human APC (rhAPC) and Protac (which activates endogenous protein C) was assessed by thrombin generation-based assays. Associations with aPL profile, thrombotic history and disease activity (BILAG and SLEDAI-2K) were also established. Results Anti-PC were detected in 54.5% of patients and APCR in 59%. Anti-PC positivity was associated with APCR to both rhAPC (P <0.0001) and Protac (P =0.0001). High-avidity anti-PC, detected in 26.3% of SLE patients, were associated with APCR in patients with thrombosis only (P <0.05), and with the development of thrombosis over time (range: 0–52 years; P =0.014). High-avidity anti-PC levels correlated with SLEDAI-2K (P =0.033) and total BILAG (P =0.019); SLEDAI-2K correlated inversely with APCR to Protac (P =0.004). Conclusion Anti-PC occur in patients with SLE, independently of aPL profile, and are associated with APCR. High-avidity anti-PC are associated with thrombosis and with active disease and might prove a novel marker to monitor the risk of thrombosis and disease progression in SLE.

Systemic lupus erythematosus combined with primary hyperfibrinolysis and protein C and protein S deficiency: A case report

“…A case of SLE presenting with positive APL, acquired APCR and autoimmune hemolytic anemia was reported[ 19 ]. However, in the study by Ramirez et al [ 20 ], anti-PC was associated with APCR in patients with SLE, independently of APL. Studies showed an association between reduced PS levels and APL in patients with SLE[ 21 , 22 ]; however, another study found no association between decreased PS levels and ACL[ 23 ].…”

Comparison of Acquired Activated Protein C Resistance, Using the CAT and ST-Genesia® Analysers and Three Thrombin Generation Methods, in APS and SLE Patients

“…More recently, we also expanded on this work using both Protac ® and exogenous APC. APCr was observed in SLE independently of aPL positivity, while patients with thrombosis tended to exhibit APCr to both reagents [ 10 ].…”

“…Seventy-five healthy normal controls were also recruited and used to establish cut off values for the assays. APCr with the CAT system was previously reported for 30 thrombotic APS, 20 non-thrombotic controls [ 9 ] and for 53 SLE patients [ 10 ].…”

“…APCr using the CAT analyser: Resistance to exogenous APC was determined using 5 nM recombinant (rh) APC, and to activation of endogenous protein C using 0.1 units/mL Protac ® , an enzyme that converts protein C into APC (Pentapharm AG, Basle, Switzerland) using the CAT machine with the PPP reagent (5 pM tissue factor) as previously described [ 9 , 10 ].…”

“…Using the calibrated automated thrombogram (CAT), APCr to both exogenous APC and to activation of endogenous plasma protein C using Protac ® was shown to be greater and associated with a more severe thrombotic phenotype in antiphospholipid syndrome (APS) patients with previous venous thromboembolism [ 9 ]. Similarly, increased APCr, using the same system, and independently of criteria aPL was also demonstrated in systemic lupus erythematosus (SLE) patients [ 10 ]. In spite of the numerous attempts to standardise tests with the CAT system, the methodology is characterised by high inter- and often intra-laboratory variation, lack of standardisation, clinical validation and absence of quality controls [ 11 , 12 , 13 , 14 , 15 , 16 ].…”