Autoantibodies to Annexin A2 and cerebral thrombosis: Insights from a mouse model

Abstract

Introduction Antiphospholipid syndrome (APS) is an autoimmune disorder manifested by thromboembolic events, recurrent spontaneous abortions and elevated titers of circulating antiphospholipid antibodies. In addition, the presence of antiphospholipid antibodies seems to confer a fivefold higher risk for stroke or transient ischemic attack. Although the major antigen of APS is β2 glycoprotein I, it is now well established that antiphospholipid antibodies are heterogeneous and bind to various targets. Recently, antibodies to Annexin A2 (ANXA2) have been reported in APS. This is of special interest since data indicated ANXA2 as a key player in fibrinolysis. Therefore, in the present study we assessed whether anti-ANXA2 antibodies play a pathological role in thrombosis associated disease. Materials and Methods Mice were induced to produce anti-ANXA2 antibodies by immunization with ANXA2 (iANXA2) and control mice were immunized with adjuvant only. A middle cerebral artery occlusion stroke model was applied to the mice. The outcome of stroke severity was assessed and compared between the two groups. Results Our results indicate that antibodies to ANXA2 lead to a more severe stroke as demonstrated by a significant larger stroke infarct volume (iANXA2 133.9 ± 3.3 mm3 and control 113.7 ± 7.4 mm3; p = 0.017) and a more severe neurological outcome (iANXA2 2.2 ± 0.2, and control 1.5 ± 0.18; p = 0.03). Conclusions This study supports the hypothesis that auto-antibodies to ANXA2 are an independent risk factor for cerebral thrombosis. Consequently, we propose screening for anti-ANXA2 antibodies should be more widely used and patients that exhibit the manifestations of APS should be closely monitored by physicians.

LPS-Induced Coagulation and Neuronal Damage in a Mice Model Is Attenuated by Enoxaparin

“…Although relatively small, the presence of a motor impairment complicates drawing concrete conclusions from the behavioral tests, which measure anxiety and spatial memory based on locomotion. Previous studies supporting anxiety modifications in animal models of antiphospholipid syndrome suggest an interaction between inflammation, coagulation, and anxiety [ 46 , 47 , 48 ]. Future studies may need to focus on cognitive evaluation assessed at different points in time or should include observational studies on the effect of infection on NfL in human subjects in relevant clinical scenarios in which enoxaparin is indicated as part of routine treatment.…”

Annexin A2: The diversity of pathological effects in tumorigenesis and immune response

“…101 A study in 2021 revealed that the level of anti-ANXA2 antibodies in APLS patients was significantly higher than that in normal control subjects, and the thrombosis rate was significantly increased in mouse models with elevated anti-ANXA2 antibodies. 102 Therefore, the detection of anti-ANXA2 antibodies in serum of APLS patients might be a useful guide for prophylactic treatment of thrombosis. 101,102 Upregulation of ANXA2 on the cell membrane accelerates plasmin production, and excessive plasmin causes surrounding tissue damage and even bleeding.…”

“…102 Therefore, the detection of anti-ANXA2 antibodies in serum of APLS patients might be a useful guide for prophylactic treatment of thrombosis. 101,102 Upregulation of ANXA2 on the cell membrane accelerates plasmin production, and excessive plasmin causes surrounding tissue damage and even bleeding. 103 APL is one of the most representative cases.…”

“…According to an earlier study, serum levels of anti‐ANXA2 antibodies in patients with APLS were significantly elevated, and anti‐ANXA2 antibodies and antiphospholipid antibodies were negatively correlated 101 . A study in 2021 revealed that the level of anti‐ANXA2 antibodies in APLS patients was significantly higher than that in normal control subjects, and the thrombosis rate was significantly increased in mouse models with elevated anti‐ANXA2 antibodies 102 . Therefore, the detection of anti‐ANXA2 antibodies in serum of APLS patients might be a useful guide for prophylactic treatment of thrombosis 101,102 …”

Neurocoagulation from a Mechanistic Point of View in the Central Nervous System

“…139 140 Anti-ANXA2 antibodies are related to worse outcomes in ischemic stroke mice. 141 This may be related to the reduced fibrinolytic capacity described above, or to other direct effects on neurons or glia.…”