In the "Deterioration series", I have discussed four mechanisms involved in the severity of COVID-19, the disease that follows infection with coronavirus SARS-CoV-2. There are many intertwined mechanisms that contribute to COVID severity that are going to be discussed in the following features. In this message, I will summarize the previous contributions on the pathways towards deterioration in COVID and explore therapeutic options along the lines of these pathways. Each contribution mentions research spanning the last decade. Some underlying mechanisms (think: aHUS, thromboinflammation, dynamics of platelets, ADAMS17 and complement-initiated immunity syndromes) have been researched thouroughly since the 1960s, which is why COVID's thrombotic properties and tendency to cause (pulmonary) embolism is no novelty.
In this message, I will briefly discuss previously explored pathways towards deterioration in SARS-CoV-2 infection/COVID-19, in particular order. At the end of each paragraph, I will mention possible therapeutic and prophylactic options for treating diseases and symptoms associated with each pathway towards COVID-19.
1. Part I: RAS/RAAS (Renin-Angiotensin Aldosterone System) and KKS (Kallikrein-Kinin System): is enhancement of ACE2 key?
2. Part II: Coagulation disorders (haemostatic imbalance): mechanisms driving thromboinflammation and pulmonary fibrosis in COVID-19;
3. Part III: Central Nervous System: neuroinvasive potential of coronaviruses and neurological manifestations;
4. Part IV: Complement System
1. The RAS/RAAS: interaction with the Kallikrein-Kinin System (KKS) and Bradykinin contribution to vascular leakage in COVID-19
The Renin-Angiotensin-Aldosterone System (RAAS) regulates blood pressure
and fluid balance. The RAS generates angiotensin II (Ang II), which
binds to receptors in the brain, kidneys, vasculature and immune system.
Angiotensinogen (Agt) is a substrate of renin. Renin cleaves Agt to
Angiotensin I (Ang I), subsequently to be cleaved by ACE to Ang II.
Renin is primarily expressed in the kidneys. Mast cells are involved in
the release of renin. It was found in 2006 that release of renin by
cardiac mast cells can be induced by ischemia (Classical Renin-Angiotensin System in Kidney Physiology, Comprehensive Physiology, Vol. 4 Issue 3, July 2014). Bradykinin is a substrate for ACE. Bradykinin has vasodilator and
natriuretic properties. ACE inactivates bradykinin and is therefore
known as kininase II. ACE inhibitors increase the level of bradykinin (Unraveling the pivotal role of Bradykinin in ACE inhibitor activity, American Journal of Cardiovascular Drugs, 3 June 2016). The inhibition of ACE is associated with angioedema (Effect
of bradykinin receptor antagonism on ACE inhibitor-associated
angioedema, Journal of Allergy and Clinical Immunology, July 2017, Vol.
140 Issue 1).
Disruption of ACE2 upregulates Angiotensin II (Ang II). Ang II in its
turn increases blood pressure. Actions on the Ang II type I receptor
(AT1) adversely affects the
vascular wall and enhances oxidative stress, resulting in endothelial
damage and endothelial cell apoptosis. Oxidative stress increases
expression of plasminogen activator inhibitor type I, resulting in the
recruitment and binding of inflammatory cells to the endothelium, which
leads to inflammation and thrombosis. Aside from ACE2, there is ACE.
Bradykinin is a substrate for ACE. Bradykinin has vasodilator and
natriuretic properties. ACE inactivates bradykinin and is therefore
known as kininase II. ACE inhibition increases the level of bradykinin,
rendering the vasculature permeable. Thus, reduction of ACE adversely
affects degradation of bradykinin, increasing the risk of 'leaking'
vessels.
Downregulation of Ang II (to diminish oxidative stress)
Ang II is known to play a central role in endothelial dysfunction. Not
only does Ang II increase blood pressure via vasoconstriction (the
narrowing of blood vessels), actions on the Ang II type I receptor (AT1)
adversely affects the vascular wall and enhances oxidative stress,
resulting in endothelial damage and endothelial cell apoptosis.
Oxidative stress increases expression of plasminogen activator inhibitor
type I, resulting in the recruitment and binding of inflammatory cells
to the endothelium, which leads to inflammation and thrombosis (A
review of the role of bradykinin and nitric oxide in the
cardioprotective action of Angiotensin-Converting Enzyme Inhibitors:
Focus on Perindopril, Cardiology and Therapy 8, 1 October 2019).
Enhancement of ACE2 could be key (New
agents modulating the renin-angiotensin-aldosterone system- Will there
be a new therapeutic option?, Experimental Biology and Medicine, 19 July
2016). A recent follow-up of the 2008 study by Penninger proposes
human recombinant ACE2 for another mechanism that seems plausible: the
2020 study shows inhibition of the virus by hrsACE2 (Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade hrsACE2, Cell Journal Pre-Proof, April 2020).
Previously, a similar therapy was proposed involving recombinant human
ACE2, rhACE2, to decrease plasma Ang II levels and increase Ang 1-7 and
1-5 (Recombinant human ACE2: acing out Ang II in ARDS therapy, Critical Care, 13 December 2017).
Possible therapeutic options for RAAS/RAS-KKS imbalance associated with SARS-CoV-2 infection are Bradykinin 1 and 2 Receptor blockers (B1R & B2R blocker), Icatibant (Kinin B2 Receptor antagonist), Conestat Alfa (regulator of complement system and kallikrein kinin system) and human Recombinant soluble ACE2.
2. Hypercoagulation/thrombosis in COVID-19
The main feature that characterizes the severity of COVID-19 is thrombosis. The prothrombotic state of SARS-CoV-2 infection is one of the biggest, if not the one major challenge during this pandemic. During the phase of infection and inflammation, the body reacts with thrombotic activity to injury of endothelial tissue and the vasculature by aggregating platelets and generating fibrin at the site of injury. However a protective response, excessive generation of fibrin, upregulation of leukocytes and tissue factors as well as neutrophil traps will damage the vasculature. When regulatory processes such as fibrinolysis (breakdown of fibrin) and cleavage of Von Willebrand Factors by ADAMTS-13 fail, failures that are observerd in COVID-19, fibrin buildup will clog vessels. Clots from microthrombosis and Deep Vein Thrombosis can travel to the lungs and cardiovascular system, leading to pulmonary embolism and myocardial damage. The hypercoagulable state of COVID-19 can result in Multiple Organ Failure (MOF). Stroke risk is significantly elevated by SARS-CoV-2 infection and damage to the Central Nervous System is increasingly being reported.
In spite of adequate anticoagulation and thromboprophylaxis, ongoing hypercoagulant and thrombotic states occur in COVID-19 patients. Administration of anticoagulants and thromboprophylaxis at the time of hospital admission might be too late. If thromboinflammation occurs before or a few days from the onset of
symptoms, thromboprophylaxis fails to break down fibrin accumulation and
stabilized fibrin structures in the microvasculature.
Possible therapeutic and prophylactic options for treating SARS-CoV-2-related thrombosis/thromboinflammation and hypercoagulation are Low Molecular Weight Heparin (LMWH) prophylaxis, Unfractioned heparin, Tissue Plasminogen Activator (tPA), defibrotide, argatroban and Lepirudin.
3. Central Nervous System (CNS) manifestations of COVID-19
In a number of cases there is evidence of direct invasion of the
current coronavirus into the nervous system; this is confirmed by
detection of SARS-CoV-2 in the cerebral spinal fluid by RT-PCR (CSF or
cerebrospinal fluid). Direct CNS invasion by the coronavirus involves
viral encephalitis, viral meningitis and viral endothelialitis
(inflammation of endothelial tissue, resulting in, among other things,
microbleeds in the brain).
Direct neuroinvasion, e.g. viral meningitis, should be treated with antiviral therapy. In one case of SARS-CoV-2 meningoencephalitis, a patient was successfully treated with hydroxychloroquine (HCQ). If neurological manifestations are caused by immunological responses, for example Tocilizumab or Anakinra may provide improvement.
Anakinra targets IL-1-beta in systemic inflammation affecting the CNS. Tocilizumab targets the pro-inflammatory cytokine IL-6. Methylprednisolone and Dexamethasone might ameliorate inflammation of the CNS due to COVID-19.
4. The pro-inflammatory and pro-thrombotic contribution of the Complement System to COVID-19 severity
The complement system refers to a system mediating between the innate and adaptive host immune response against invasion by pathogens, such as viruses. The adaptive immune response is what is needed to ward off bespoke invader. One function is pathogen lysis by the C56-9 (C5 to 9 = C5bC6C7 to C8 to C9) Membrane Attack Complex (MAC). By doing so, the pathogen, for example a virus, is cut and subsequently stripped from its contents.
The relevance of the complement pathways with regards to SARS-CoV-2 is that complement anaphylatoxins C3a and C5a are hypothesized to contribute to cytokine storms in severe COVID cases. C5a attracts neutrophils and monocytes and is involved in the release of Reactive Oxygen Species (ROS), mast cell degranulation and vascular permeability (Inhibiting the C5-C5a receptor axis, Molecular Immunology, Volume 48, Issue 14, August 2011, p. 1631-1642; The case of complement activation in COVID-19 multiorgan impact, Kidney International (2020), 98, 314-322).
This mediator, the complement system, contributes to COVID severity through:
1. C5a and MAC (C5b-9) induction of Acute Lung Injury (ALI) and Respiratory Distress (ARDS);
2. complement anaphylatoxin C5a and IL-8 induced Reactive Oxygen Species (ROS);
3. interaction with NETs;
4. activation of coagulation factors XII, fibrin and thrombin;
5. induction of Von Willebrand Factor and endothelial dysfunction.
Extensive complement (Lectin and Alternative Pathway and specifically MAC) depositions and perivascular infiltrates accompanied by complement factors have been reported in cases of COVID-19-associated damage of the microvasculature (Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19: A report of five cases, Translational Research, June 2020, Vol. 220).
