Increased demand in Antiphospholipid Syndrome markers?

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by hyper-coagulability leading to recurrent thrombotic events that can affect any body vessel and organ (Ortel 2012; Gomez-Puerta and Cervera 2014; Fischer et al. 2007) and was described by Hughes in 1983. Patients may suffer from APS as a primary disease or as a secondary disorder in conjunction with connective tissue diseases, e.g. systemic lupus erythematosus. It is estimated that APS has a prevalence of 40 – 50 cases per 100,000 persons and that each year approximately 5 new cases per 100,000 persons are diagnosed (Ortel 2012; Gomez-Puerta and Cervera 2014).

Besides recurrent thrombosis, the detection of antiphospholipid antibodies has been described for patients diagnosed with APS and included in the official revised criteria for APS diagnosis (Miyakis et al. 2006; Pengo et al. 2009). Initially, the phospholipid cardiolipin was identified as the antigen of these antibodies, but three independent follow-up studies revealed that this antibody binding depends on β2-glycoprotein 1 as a cofactor (McNeil et al. 1990; Matsuura et al. 1990, Galli et al. 1990). Subsequent analyses of sera from patients diagnosed with APS using highly purified β2-glycoprotein 1 provided evidence for β2-glycoprotein 1-specific autoantibodies and suggested an association with thrombotic events (Tsutsumi et al. 1996; Guerin et al. 1997; Gomez-Pacheco et al. 1999). Besides a major epitope in domain I, autoantibody specific epitopes have also been reported for domains II – V (Giles et al. 2003; Misasi et al. 2015).

Recent studies reported an unusually high prevalence of thrombosis in COVID-19 patients and even the occurrence of anti-phospholipid antibodies was observed in affected patients. (Tung et al. 2021; Wang et al. 2021; Devreese et al. 2020; Atalar et al. 2022)

These clinical and pathological similarities raise the question whether there is a common mechanism involved that causes thrombosis in COVID-19 infections and APS. (Tung et al. 2021; Wang et al. 2021; Cavalli et al. 2020). Acquired APS is a well-known phenomenon described in literature in the context of viral infections such as HIV, HBV, HCV, EBV and Parvovirus B19 infections (Abdel-Wahab et al. 2018; Martirosyan et al. 2019; Badr et al. 2022. It is assumed that molecular mimicry, a similarity between host proteins and viral structures, could lead to the development of antiphospholipid antibodies (aPLs) and subsequently to thrombosis (Martirosyan et al. 2019).

When autoantibodies associated with APS bind to their targets on endothelial cells and platelets activation of these cell types is initiated. These events subsequently trigger T-Cell activation and proinflammatory cytokine secretion such as TNF-alpha, IFN-gamma and IL-1 and the complement system. Additionally, there is evidence that protective antioxidant pathways are downregulated at the same time (Tung et al. 2021). All these events together finally lead to blood clotting and thrombosis. (Cavalli et al. 2020).

A similar model has been proposed as the mechanism of action leading to thrombosis in Covid-19 patients. A combination of expression of adhesion molecules initiating the coagulation cascade together with the disruption of the redox pathways predispose patients to thrombosis. Further, aPLs activate platelets and trigger platelet aggregation while anti-ß2-glycoprotein I autoantibodies prevent this protein from activating anticoagulant proteins. Instead, activation of the complement cascade further promotes thrombosis. (Tung et al. 2021).

Based on these similarities the question arises whether assessment of aPLs in hospitalized Covid-19 patients could be useful to monitor and predict risk of thrombosis and therefore could enable early intervention prior to the onset of severe thrombosis.

Serrano et al. (2022) reported that the occurrence of ß2-Glycoprotein 2 can be associated with greater disposition to COVID-19 complication but also assumed this to be an independent event from Covid-19 coagulopathy that frequently arises early after disease onset.

Further, a study on the epitope specificity of aPLs from Covid-19 patients found that these were mainly directed against ß2 GPI but had a different epitope specificity than antibodies found in patients diagnosed with APL (Borghi et al. 2020).

On the other hand, Zuo et al. (2020) reported eight types of aPLs in serum from patients hospitalized with Covid-19 as well as a correlation of antibody levels with the activation of the neutrophil and coagulation pathway. Interestingly, when these antibodies were purified from patients, they were able to activate neutrophils in vitro and to increase thrombosis when injected into mice.

In summary, aPLs and anti-ß2 glycoprotein antibodies as a useful tool in diagnosis of Covid-19 patients still seems to be a matter of debate and further research will be required to fully understand whether occurrence of these antibodies in Covid-19 patients are clinically significant.

In addition, the assessment of long-term effects these antibodies might have could be a further research topic scientist will focus on in the future. However, other markers, such as an increase of D-Dimer, von Willebrand factor concentrations or proinflammatory cytokines seem to correlate with severe Covid-19 disease progression while the downregulation of other factors such as ADAMTS13 activity indicate higher mortality rate (Escher et al. 2020; Morici et al. 2020; Bazzan et al. 2020).

Related products:

Antiphospholipid Syndrome / Thromboembolic Syndrome

Thrombosis marker ELISAs

D-Dimer antibodies

D-Dimer antigens (Immunoassay control)

References:

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