**3. COVID-19 and nervous system: indirect effects of systemic factors**

Indirect effects of systemic factors of SARS-CoV-2 can lead to acute and chronic consequences, such as respiratory failure, systemic inflammation, hypercoagulable state and, lethal systemic organ failure.

#### **3.1 Respiratory failure**

SARS-CoV-2 has been predominantly detected in pneumocytes and epithelial progenitors, which can lead to potential lung damage, causing massive alveolar damage, inflammatory cell infiltration, edema, microvascular thrombosis, and hemorrhage resulting in severe hypoxia and acute respiratory distress syndrome (ARDS) [25, 26]. The most sensitive brain regions to hypoxia, such as the neocortex, hippocampus, and cerebellum have shown neuronal impairment [27].

#### **3.2 Systemic inflammation**

The correlation between immunosuppression and disease severity has been established. Most COVID-19 patients have higher circulating levels of IL-6, IL-1b, and TNF, but also additionally IL-2, IL-8, IL-17, G-CSF, GM-CSF, IP10, MCP1, and MIP1a2, and serum levels of IL-6 and TNF leading to cytokine release syndrome [28–30]. After brain entry through the damaged BBB, certain molecules such as the nuclear protein high mobility group box 1 (HMGB1), could act as pathogenassociated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) [31]. This process activates an immune response in pericytes, brain macrophages, and microglia, which express toll-like receptors (TLR) which act as mediators for pro-inflammatory effects of SARS-CoV-2 spike protein on human macrophages through nuclear factor-kB (NF-kB) [32]. In this way, immune response boosts the level of cytokine production which results in impairment of brain function [33].

#### **3.3 Hypercoagulable state**

Another vital element of COVID-19 is significant coagulopathy. The multicenter study has been conducted, suggesting that 88% of patients displayed evidence of a hypercoagulable state. The prothrombin time (PT), activated partial thromboplastin time (aPTT), and complete blood count (CBC) are in the reference range. However, fibrinogen level, and fibrin breakdown products indicative of intravascular thrombosis (D-dimer), are both increased. Coagulopathy may start in the lungs causing endothelial damage, complement activation, activation of the procoagulant effect of IL-6, and neutrophil release of extracellular traps (NETs) that leads to the formation of a clot, resulting in intravascular thrombosis [34].
