*2.2.2 Other agents: immunocomplexes, lupus anticoagulants, β-2 glycoprotein 1 (B2GPI) and cytokines*

The proinflammatory and prothrombotic state at the endothelial level in the microvasculature may remain in some patients due to immunocomplex formation, causing chronic reactive endotheliitis with multiple vascular involvement, especially in the lungs and central nervous system (**Figure 2**) [13].

*COVID-19 and Thrombosis: Pathophysiological Mechanisms and Therapeutic Update DOI: http://dx.doi.org/10.5772/intechopen.102834*

#### **Figure 2.**

*Neurological lesions mediated by chronic reactive endotheliitis and multiple vascular involvement.*

On the one hand, the presence of direct neurological damage by SARS-CoV-2 through the advancement into the CNS from the periphery *via* retrograde and transsynaptic neuronal transport, especially *via* vagus nerve afferent pathways, has been demonstrated. Supported by the increasing findings that SARS CoV-2 infects cells in the gastrointestinal tract, the neuroinvasive potential could even encompass the enteric nervous system [18].

On the other hand, the pivotal role of lupus anticoagulants (LA) in the thrombogenesis of SARS-CoV-2 has also been observed [19, 20] and an increased prothrombin time has been reported in COVID-19 patients. This may be indicative of a coagulation factor deficiency or the presence of an inhibitor, either specific such as the factor VIII antibody or non-specific like LA [20]. The β-2 glycoprotein 1 (B2GPI), involved in thrombogenesis, promotes LA activity, thereby stimulating platelet adhesion, tissue factor release and subsequent activation of the coagulation cascade, leading to an often irreversible prothrombotic state in advanced stages [19]. Ultimately, cytokine storm and immune abnormalities also contribute to the inflammatory process. These immune abnormalities have been associated with the severity of COVID-19 and are considered a cause of mortality in this disease [3, 11, 19]. A correlation between severe COVID-19 and abnormalities in circulating immune cells has been described [3]. In severe cases, COVID-19 can trigger an excessive immune response known as a cytokine storm, which is potentially fatal. It is characterised by over-activation of immune cells and excessive production of pro-inflammatory cytokines and chemical mediators [11]. Cytokine storm also amplifies platelet production, leading to an increased formation of disseminated microthrombi in various vascular territories, and is directly involved in the pathogenesis of thrombosis in this disease [19].

#### *2.2.3 Immune response and T lymphocytes*

In viral infections, "innocent bystander" activation of CD8+ T cells occurs, which consists of activation of CD8+ memory cells independent of T-cell receptor (TCR) stimulation. Active lymphocytes can migrate to the site of infection and kill infected cells. This form of early response, which begins before symptoms develop, may be

associated with disease resolution and avoid progression to severe disease. However, persistent bystander activation of CD8+ T cells has been associated with inflammatory pathology in both chronic infections and autoimmune processes. Therefore, it is possible that persistent T cell activation in severe COVID-19 may influence the development of lung pathology and autoimmune manifestations observed in this disease [3]. On the other hand, patients with more severe clinical manifestations have higher-circulating TNF-α and IL-6, and higher gene expression of proinflammatory pathways [3, 11].
