COVID-19, Pre-Eclampsia, and Complement System

Abstract

COVID-19 is characterized by virus-induced injury leading to multi-organ failure, together with inflammatory reaction, endothelial cell (EC) injury, and prothrombotic coagulopathy with thrombotic events. Complement system (C) via its cross-talk with the contact and coagulation systems contributes significantly to the severity and pathological consequences due to SARS-CoV-2 infection. These immunopathological mechanisms overlap in COVID-19 and pre-eclampsia (PE). Thus, mothers contracting SARS-CoV-2 infection during pregnancy are more vulnerable to developing PE. SARS-CoV-2 infection of ECs, via its receptor ACE2 and co-receptor TMPRSS2, can provoke endothelial dysfunction and disruption of vascular integrity, causing hyperinflammation and hypercoagulability. This is aggravated by bradykinin increase due to inhibition of ACE2 activity by the virus. C is important for the progression of normal pregnancy, and its dysregulation can impact in the form of PE-like syndrome as a consequence of SARS-CoV-2 infection. Thus, there is also an overlap between treatment regimens of COVID-19 and PE. C inhibitors, especially those targeting C3 or MASP-2, are exciting options for treating COVID-19 and consequent PE. In this review, we examine the role of C, contact and coagulation systems as well as endothelial hyperactivation with respect to SARS-CoV-2 infection during pregnancy and likely development of PE.

Evaluation of Transplacental Antibody Transfer in SARS-CoV-2-Immunized Pregnant Women

“…Previous studies have shown that antibodies produced by mothers infected with COVID-19 pass through the placenta to the fetus [8,9]. Although the risk and symptoms of pregnant women infected with COVID-19 are the same as those of non-pregnant people [10,11], several studies have found that, compared with age-matched non-pregnant women, pregnant women are more likely to have severe symptoms after being infected with COVID-19, especially when combined with risk factors such as advanced age, preeclampsia, obesity, diabetes, and high blood pressure [11][12][13]. The risk of neonatal complications such as premature delivery, meconium staining, respiratory distress, and perinatal death increases as well [12][13][14][15][16][17][18][19][20].…”

“…Although the risk and symptoms of pregnant women infected with COVID-19 are the same as those of non-pregnant people [10,11], several studies have found that, compared with age-matched non-pregnant women, pregnant women are more likely to have severe symptoms after being infected with COVID-19, especially when combined with risk factors such as advanced age, preeclampsia, obesity, diabetes, and high blood pressure [11][12][13]. The risk of neonatal complications such as premature delivery, meconium staining, respiratory distress, and perinatal death increases as well [12][13][14][15][16][17][18][19][20]. According to the characteristics of different COVID-19 vaccines, the components in the mRNA vaccine would not enter the nucleus of the host cell and remain separated from the host DNA.…”

Molecular Advances in Preeclampsia and HELLP Syndrome

“…As a result, the constant deposition of C3b generates the C5 convertase, which signals its cleavage to elements C5a and C5b (anaphylatoxins). C5b then binds to C6, C7, and multiple molecules of C9, forming the terminal complement complex C5b-9, known as the “membrane attack complex” (MAC) [ 25 ].…”

“…The complement system seems to be fundamental in the inflammatory process of PE and HELLP syndrome, with various studies demonstrating that PE is eventually a complement-mediated disease ( Figure 1 ). Elevated amounts of complement components and their activation derivatives, including C5a, and C5b-9 complex, have been detected in the circulation of PE patients compared to uncomplicated pregnancies, albeit the data in this field are highly contradictory [ 25 ]. Complement activation products were also discovered in the urine of severe PE patients and are thought to be a sign of complement-mediated kidney injury [ 27 ].…”

“…These data imply that inhibiting the terminal complement pathway (e.g., C5 blockage) may be a potential disease-mitigation approach. In this regard, a C5-activation inhibitor (Eculizumab) has been utilized in a single case report by Burwick et al, to off-label treat PE/HELLP at 27 weeks gestation, achieving 17 days of prolongation of pregnancy and minimizing neonatal morbidity [ 37 ], while it has been more extensively used as a therapeutic option in aHUS—complicated pregnancies [ 25 ]. This idea has been experimentally implemented in a currently phase 1 clinical trial (NCT Number: NCT04103489), in which investigators propose the therapeutic use of Eculizumab for women with HELLP syndrome at 23–30 weeks gestation.…”