Covid-19 – Liver – iron overload – lung cascade – coagulation
– CoVID-19 and liver damage, the hemoglobin factor.
– Why finding large numbers of mild and asymptomatic CoVID-19 cases is a bad sign, not a good sign.
– Experimental AI program identifies markers of Liver damage found at early stages of infection can predict eventual serious respiratory infection
– Iron Overload and Oxidative Stress combined with the Hemoglobin factor
– Hydroxychloroquine impact on Iron in the body and immune function.
– Implications of this disease progression on the lungs.
– Interesting New Orleans autopsies show irregular coagulation in the lungs.
Liver damage is the primary indicator of serious, critical, or fatal outcome for CoVID-19 patients. This can lead to iron overload, oxidative stress, additional respiratory stress, and hypoxia. Eventually causing a sudden cascading immune response in the lungs.
An experimental artificial intelligence program was given a dataset from a large number of CoVID-19 patients and determined that elevated levels of ALT, a marker indicative of liver damage, at an early stage of infection could predict that the patient would go on to develop serious respiratory symptoms.
The Liver may be a primary target of SARS-CoV 2 and a subsequent vector of cascading complications.
It should be noted that serious complications are almost always a result of a combination of factors putting stress on the body. A simple respiratory infection will be cleared by everyone with a healthy immune system if not combined with any other stress factors. Unfortunately there are a plethora of factors which can weaken or compromise the body and its immune response and this virus puts stress on more than just one vital process in the body.
– If we can understand the most common pathogenesis of CoVID-19 that leads to a patient requiring hospitalization, we can then identify those who are MOST at risk. While the elderly are an obvious high risk category, I believe liver dysfunction is another risk category that should be identified.
– This information will be helpful when we reboot our economy as perhaps we can continue to utilize selective, targeted isolation of those who are MOST likely to require hospitalization and let the rest of the population go back to some semblance of normal function in society.
– The human body has countermeasures for almost any possible imbalance in its homeostasis. Chronic imbalances are often the result of poor nutrition, poor or excessive diet, or some other form of internalized toxicity or deficiency. We can improve our health by identifying these problems and either eliminating toxic overload or supplementing with nutrients we find are deficient.
– This virus is a highly invasive stress test which can expose preexisting dysfunction, or induce acute dysfunction for which the body is either able to tolerate and eventually remedy, or will become overwhelmed and eventually decompensate.
There are natural remedies that can help to counteract some of the effects of CoVID and perhaps lessen the multiplication of stress factors. Natural remedies are ALWAYS the preferred pathway to health over and against toxic drug therapies. This is of course only considered alongside the following understanding.
1) Sometimes the body becomes so dysfunctional that drug therapies are necessary to regulate out of control functions.
2) Viral infections cannot be “cured” by natural remedies. It is clearly understood that the Immune System is the only thing that can clear the body of infection. However there are many things we can do to support proper and balanced immune function and prevent the complications of additional and unnecessary stress.
I will present a possible pathogenesis for CoVID-19 that may be leading to many of the serious complications.
First in a Cliff notes version, then with the data to support the theory.
– Finding large numbers of mild and asymptomatic CoVID-19 cases is a bad sign, not a good sign.
– We still do not have good data on rates and numbers of hospitalizations.
– AI program reveals Liver damage as a significant marker of impending serious complications of CoVID-19.
– The Liver is a primary target for SARS-CoV 2.
– Liver disease or decreased function is prevalent in many of the already identified high risk groups. The Elderly, Obese, and diabetic.
– A recent study claims to reveal a new cell entry pathway for SARS-CoV 2 through the CD147 Surface protein.
– Immune cells upregulate this specific surface protein in response to liver damage. This may allow the virus to attack the immune cells directly.
– Liver attack leads to higher Hemoglobin levels, another marker of future serious complications.
– Red Blood Cells also express the CD147 Surface protein, potentiating a direct attack from the virus and perhaps disrupting oxygen saturation levels in the blood.
– Hepcidin is a key component for Iron regulation that gets excessively elevated in response to infectious pathogens and corresponding cytokine expression of IL-6.
– This leads to large amounts of Iron getting Locked away into Cellular features like lysosomes and many cells throughout the body.
– This can lead to a condition of Iron Overload and potentiate cell destruction via Ferraptosis and highly destructive Reactive Oxygen Species (ROS).
– Systemic widespread cell death can lead to oxidative stress conditions in the body that can harm vital organs such as the brain, liver, kidneys, lungs, and heart.
– Artificial Extracellular iron deficiency is caused by excess Iron being locked in the cells and not accessible to be recycled back to the bone marrow and used to make new hemoglobin for oxygen transport in the blood. This may contribute to Hypoxia, which can lead to more stress on vital organs.
– Antioxidants are crucial to counteract oxidative stress throughout the body, inside and outside of the cells.
– Hydroxychloroquine paralyzes iron trafficking in the cells and may reduce ferraptosis cell death and inhibit the oxidization reactions. Despite this it also inhibits iron recycling and may contribute to further anemia.
– There are more reports of people testing positive for SARS-CoV 2 a second time after having recovered, tested negative twice, and having all symptoms resolve.
– Serum studies of the blood work of some recovered patients are showing LOW levels of antibodies and may indicated increased risk of reinfection.
– Hydroxchloroquine and other immunosuppressant drugs maybe aborting the immune response and leading to some of these low serum levels and consequently higher risk of reinfection.
– The Iron overload hypothesis provides a good explanation for why the disease can seemingly remain mild all the way into the second week post infection and then result in rapid deterioration. This Iron uptake into the cells is a silent process causing no symptoms. Only when the ferroptosis cell death begins does a rapid cascading cycle of elevated immune response occur.
– The Lungs are disproportionately the primary iron uptake site and dumping grounds for the excess hemoglobin traveling around in the blood stream. This may be in large part because Liver damage and inflammation can cause the blood flow to completely bypass the liver and proceed directly to the lungs.
– Interesting autopsy results out of new Orleans identify irregular coagulation impacting the lungs of the deceased CoVID-19 patients. Free iron in the blood can produce an insoluble fibrin like material called parafibrin that can lead to clots throughout the body.
– This may be the cause of some of the sudden collapse events seen in some CoVID-19 victims.
– New treatment regimens could be effective at preventing the cascade of serious complications caused by liver distress and iron overload conditions. These would include Iron Chelators, Poly phenols, and perhaps some anti-oxidant therapy.
Why a large percentage of asymptomatic or mild cases of Covid-19 is a BAD thing, not a good thing.
As we have ramped up testing particularly in the USA, we are starting to identify more and more positive cases of Covid-19, in particular we are starting to identify more and more “asymptomatic” and “mild” cases that have been virtually invisible up to this point. I have seen numerous articles and social media posts proclaiming that this is a GOOD thing, as the more “mild” cases we find, the less deadly the virus appears to be. While I agree that if the only thing you are concerned about is attempting to calculate the CFR (case fatality rate) at this specific moment in time and your agenda is to show that the virus is less harmful, then the increased number of mild cases is good for your narrative.
However, as I have previously shown, attempting to calculate a CFR using incomplete data and unresolved cases is a fool’s errand. It is also NOT a reliable indication of the current threat caused by this virus. As I have argued, the only two data points that matter are the rate of growth in the number of confirmed deaths and the rate of growth in the number of hospitalizations. The good news is that the mitigation measures have started to take effect and we have seen a slowdown in the growth rate. The USA was showing a 3 day doubling rate as the first wave of deaths came in, it is now reduced and we are showing a 5 day doubling rate giving us an indication of the nerfed rate of infectious spread 2-3 weeks ago. As the mitigation measures take further effect we should continue to see the impact in the following order.
1.)The growth of newly identified infections should continue to decrease.
2.)Roughly 10-11 days later, the rate of Hospitalizations will reflect that decrease
3.)Roughly another week and the death rate will reflect that decrease.
This timing is based off the WHO China report which suggested that most people will have developed symptoms by day 5 after infection, and most hospital admissions take place around day 11. The 5% of patients that require ICU care will decompensate around 14 days post infection and the deaths that will happen can occur anytime thereafter, up to 60+ days after infection.
Now we really cannot trust the number of confirmed cases still, even with the increased testing. There is no way to know how many people are being missed and we cannot assume that the scope of the testing is sufficient or consistent enough to provide reliable data. So our first clue that the mitigation measures are working is the decrease in the rate of hospitalizations.
We are now 21 days from when New York issued the stay at home order, which means we should already be seeing a decrease in the number of hospitalizations. Problem is, we currently cannot see that data. Apparently the annual budget of 11.1 billion for the CDC is insufficient to allow them to achieve basic and timely data collection and dissemination.
“Vice President Mike Pence….. asked them to complete a form each day with data on the patients they are treating with COVID-19, the disease caused by the novel coronavirus, and submit it to the Centers for Disease Control and Prevention.
Now, as COVID-19 nears an apex in some parts of the country, it’s unclear how many hospitals have submitted the requested information. For its part, the CDC has not released the data publicly, saying only that it plans to do so soon.
The U.S. health care system’s response to the coronavirus has exposed many blind spots: the inability to quickly create a test that could be deployed widely, the lack of personal protective equipment for front-line doctors and nurses, and a lack of basic data on hospitalizations to help make informed decisions.
“We’re in a fog because we have so little reliable data,” said Dr. Ashish Jha, director of the Harvard Global Health Institute, which has been studying hospital capacity.”
The data that the CDC releases is always at least a week old. So we are unfortunately left with ONLY one indicator that the virus spread is in decline. The daily death numbers. They estimate that we should see a peak in the death numbers around April 11-12th and then a gradual decrease in those numbers in the coming weeks. Even the Death numbers themselves are a bit suspect, but they will at least show us the trend. An example of how the death numbers are inaccurate on a daily basis is the following tweets from Mark Levine out of New York some days ago.
It’s not just deaths in hospitals which are up. On an average day before this crisis there were 20-25 deaths at home in NYC. Now in the midst of this pandemic the number is 200-215. *Every day*. 5/
— Mark D. Levine (@MarkLevineNYC) April 6, 2020
“NYC’s healthcare system is being pushed to the limit.
And sadly, now so is the city’s system for managing our dead. And it, too, needs more resources.
This has big implications for grieving families. And for all of us.
NYC’s “city morgue” is the Office of the Chief Medical Examiner (OCME), which luckily is the best in the world.
But they are now dealing w/ the equivalent of an ongoing 9/11. And so are hospital morgues, funeral homes & cemeteries.
Every part of this system is now backed up.
A typical hospital morgue might hold 15 bodies. Those are now all full. So OCME has sent out 80 refrigerated trailers to hospitals around the city. Each trailer can hold 100 bodies. These are now mostly full too. Some hospitals have had to add a 2nd or even a 3rd trailer.
Grieving families report calling as many as half a dozen funeral homes and finding none that can handle their deceased loved ones.
Cemeteries are not able to handle the number of burial requests and are turning most down.
It’s not just deaths in hospitals which are up. On an average day before this crisis there were 20-25 deaths at home in NYC. Now in the midst of this pandemic the number is 200-215. *Every day*.
Early on in this crisis we were able to swab people who died at home, and thus got a coronavirus reading. But those days are long gone. We simply don’t have the testing capacity for the large numbers dying at home.
Now only those few who had a test confirmation *before* dying are marked as victims of coronavirus on their death certificate. This almost certainly means we are undercounting the total number of victims of this pandemic.
And still the number of bodies continues to increase. The freezers at OCME facilities in Manhattan and Brooklyn will soon be full. And then what?”
Hundreds of people are dying at home of Covid-19 and are NOT being included in official death statistics. Good data really is priceless and apparently unobtainable.
This is similar to reports coming out of Italy showing that many, many Covid deaths are not being included in the official statistics.
Now if indeed we want to see a decrease in deaths, we should first be looking for a decrease in hospitalizations, and if we want to see a decrease in hospitalizations, we should want to see a DECREASE in new confirmed cases.
This is why it is ABSURD to suggest that finding a whole bunch of Mild and Asymptomatic cases is a good thing. The following reasons prove this point.
1.) EVERY hospitalization and death from covid-19 started out as an “asymptomatic” case, then progressed to a “mild” case, eventually became a severe case requiring hospitalization and then finally became a death.
2.) Mild and asymptomatic cases that never become serious tend to resolve to symptomless recovery in roughly 14 days.
3.) With the nature of exponential growth, if you take a snap shot of the current infections at any particular moment. The VAST majority of cases that are mild or asymptomatic are cases which have only RECENTLY been infected and have not progressed to the 11 day mark where most cases either trend toward serious complications or toward recovery. Thus you should really just throw them out of the statistics until you can determine which direction they are heading. For example based on a 5 day doubling rate, if you have 1000 infections day 1, 2000 infections by day 6 and 4000 infections by day 11. Only those First 1000 infections have now progressed to the point where you can see which way they appear to be trending. Thus at any one time, 75% of the asymptomatic or mild cases should be disregarded until they have had enough time to mature (in my example 3000 out of the 4000 are premature data points).
4.) Finally, because our testing is limited, the number of confirmed cases is an irrelevant number with regards to calculations for modelling or CFR. The one thing that the confirmed cases DO show us, is evidence of continued community spread. So when you see thousands of newly confirmed cases of asymptomatic and mild Covid infections, you are seeing clear evidence of continued community spread that has occurred in the last 14 days. This is actually very concerning, because it means there is continued spread DURING the lockdown, in SPITE of the mitigation measures. We have been in Mitigation for OVER 2 weeks, all newly confirmed cases at this point show spread in SPITE of our efforts.
What we want to see is a 100% hospitalization rate of the currently ACTIVE cases. If that could be achieved, we would have contained the virus and all known cases would be in the final stages of disease progression. For a frame of reference, the serious/critical rate for active cases worldwide right now is a mere 4%, in the USA it is 2.3%. Many people think the lower the number the better, but it is actually the opposite. The lower this number, the more community spread you have had in the last 2 weeks. If all community spread stopped RIGHT now and we went two weeks into the future. That percentage would rise to somewhere between 12-20% and continue to rise as the other 80%+ of cases resolved to recovery.
Experimental AI tool predicts which COVID-19 patients develop respiratory disease
“Instead, the new AI tool found that changes in three features — levels of the liver enzyme alanine aminotransferase (ALT), reported myalgia, and hemoglobin levels — were most accurately predictive of subsequent, severe disease. Together with other factors, the team reported being able to predict risk of ARDS with up to 80 percent accuracy.
Lastly, higher levels of hemoglobin, the iron-containing protein that enables blood cells to carry oxygen to bodily tissues, were also linked to later respiratory distress.
These are interesting results. We have explored before the scope of the infection caused by Covid-19, noting that it is far more than a simple respiratory infection. ALT is a liver enzyme that is elevated and released into the blood stream as a result of liver damage. It appears that the extent of liver damage is a primary factor associated with serious or critical outcome. The elevated hemoglobin can possibly be tied to liver damage and as I will explore later, there may be an associated Iron overload complication that is amplified by liver dysfunction and causes a host of other problems due to oxidative stress reactions.
This would fit many clinical manifestations of the disease.
– Liver disease is a common issue in those who suffer from obesity and type 2 diabetes. We have seen that these are common comorbidities in those who have died from this illness.
– The elderly often have many comorbidity issues and the liver is no exception.
“The volume and blood flow of the liver gradually decrease with aging. According to studies using ultrasound, the liver volume decreases by 20–40% as one gets older. Such changes are related to a decline in the blood flow in the liver, in that those aged 65 years or higher showed an approximately 35% decrease in the blood volume of the liver compared with those aged less than 40 years. Meanwhile, the studies that scanned the liver with radioisotopes observed a decrease not in the total liver volume but in the mass of the functional liver cells”
– If Iron overload and toxicity can be a problem, Iron levels in Men are generally higher than in Woman to begin with. So Men are more likely to manifest serious symptoms then women under this hypothesis.
Interestingly, there is some new evidence emerging that Sars-Cov 2 can mediate cell entry via CD147 surface protein and is NOT limited to the ACE2 receptor. CD147 is a highly multifunctional glycoprotein that can be expressed on numerous human cell types. Perhaps of most interest is the fact that Immune cells upregulate CD147 in response to liver injury.
CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury
“All intrahepatic leukocyte subpopulations (CD4+, CD8+, NK, B-cell and macrophages) rapidly increase CD147 surface protein and total mRNA expression during liver injury. Therefore, this data shows that following liver injury, circulating and intrahepatic leukocytes increase CD147 expression.”
This modulation of the inflammatory response may actually cause the immune cells to become accessible to viral entry. ACE2 may be its preferred pathway, yet this perhaps explains a previous discovery of a similar SARS viral infection attacking immune cells. We have seen evidence that SARS would only attack immune cells when its access of its spike protein to ACE2 was blocked, yet it was unclear how exactly the virus was gaining entry into the immune cells. We may now have our answer.
Another concern is that SARS-Cov 2 may be able to mediate cell entry through a non-endosomal route similar to original SARS.
Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites
“Analysis of both SARS-CoV infection and transduction by SARS-CoV S-pseudotyped virions has indicated that the virus is sensitive to inhibitors of endosomal acidification, and it has been shown that SARS-CoV S-pseudotyped virions use the endosomal protease cathepsin L to infect cells. These data suggested that SARS-CoV S required a novel, endocytic protease-primed cleavage event during virus entry, in contrast to the majority of class I viral fusion proteins that are primed during virus assembly or following release from the cell. However, in addition to cathepsin L, several other proteases have been shown to cleave SARS-CoV S. Early reports showed that S1–S2 cleavage was enhanced by exogenous trypsin, and it was subsequently shown that SARS-CoV infection is enhanced by the addition of exogenous proteases, such as trypsin, thermolysin, and elastase, as well as by expression of factor Xa. These data suggested that an alternative, nonendosomal route of SARS-CoV entry exists. Notably, infection mediated by exogenous proteases was considered to be 100– to 1,000-fold more efficient than by the endosomal route. Based on cleavage patterns on SDS/PAGE gels, the predominant cleavage event mediated by the exogenous protease appears to be at the S1–S2 boundary, and subsequent biochemical analysis by N-terminal sequencing identified R667 (SLLR-S) as a site of trypsin cleavage. Similarly, exogenous cathepsin L can also cleave the S1–S2 junction at residue T678 (VAYT-M).”
If SARS-CoV 2 has a similar ability to gain cell entry via a nonendosomal route, than the endocytosis blocking by Hydroxychloroquine is unlikely to completely prevent viral spread. Trypsin is produced in the pancreas and secreted into the small intestine where it may facilitate entry into the epithelial cells in the gut.
The Hemoglobin Factor
Red blood cells are another cell that presents the CD147 surface protein and may be targeted by Sars-Cov 2. There is a theory that viral entry to red blood cells is allowing disassociation of the Iron from the hemoglobin and perhaps disrupting the ability of RBC to carry oxygen. This may be a factor in the manifestation of low oxygen levels in the blood stream, though I think this has yet to be proven.
There is strong evidence that SARS-CoV 2 is directly attacking the liver. The elevated hemoglobin levels may be an indication of both hypoxia and liver distress.
Upregulation of Hemoglobin Expression by Oxidative Stress in Hepatocytes and Its Implication in Nonalcoholic Steatohepatitis
“In another population study, higher free serum hemoglobin has been associated with higher prevalence rates of NAFLD . However, the source of free hemoglobin in serum was not identified. It was assumed that free hemoglobin in serum was due to oxidative stress induced hemolysis. Our studies showed that hemoglobin was expressed in hepatocytes and it was increased in NASH. This provides a possible explanation for free hemoglobin in serum; free hemoglobin in serum could have been synthesized in hepatocytes and then released into the circulatory system. Increased serum free hemoglobin in NASH could reflect the increased hemoglobin production in the liver.
How hemoglobin expression is regulated in non-erythrocytes is not fully understood. It has been shown that hypoxia upregulates the transcription of GATA1 in alveolar epithelial cells. As a result, hemoglobin transcription is also increased by hypoxia
Together, our findings suggest that elevated oxidative stress in NASH could induce hemoglobin expression and suppression of oxidative stress by hemoglobin could be a mechanism to protect hepatocytes (liver cells) from oxidative damage.”
Iron is at the crux of many chemical interactions throughout the body. It is the key component of Hemoglobin that allows Red Blood Cells to carry oxygen.
Hepcidin is an important protein which serves to control iron levels throughout the body. Under normal circumstances, this protein is only expressed as needed to regulate iron retention. However in the face of infection, hepciden levels can become elevated. This can change the nature of iron retention in the body and If Iron becomes dysregulated, it can lead to toxic accumulations within cells.
Autocrine Formation of Hepcidin Induces Iron Retention in Human Monocytes
“In the case of an infectious challenge, monocytes/macrophages are aimed to restrict iron to invading pathogens to limit their growth.51,52 As monocytes/macrophages express ferroportin at their cell membrane to maintain iron recirculation, the rapid induction of hepcidin by cytokines and LPS would result in immediate blockage of iron export by ferroportin because of hepcidin-mediated degradation of the protein, thus resulting in iron restriction within macrophages/monocytes. This would fit to the rapid iron sequestration in macrophages seen within hours after LPS stimulation.33
Subsequently, LPS and cytokines, such as interferon-γ inhibit ferroportin mRNA expression to keep iron export low and to withhold iron from pathogens. These series of events ultimately lead to iron accumulation in monocytes/macrophages, hypoferremia, and an iron-restricted erythropoiesis contributing to the development of ACD.”
This response to infection can cause large amounts of iron to essentially become Locked up within cells and unavailable for other necessary functions, such as blood oxygen transport. This can lead to anemia and hypoxia even in those who have no prior iron deficiency. Sufficient Iron is in the body, it is just not accessible due to massive hepcidin expression.
Limitations of Serum Ferritin in Diagnosing Iron Deficiency in Inflammatory Conditions
“Patients with inflammatory conditions may have diminished iron stores, a situation described as “absolute iron deficiency.” As in patients without inflammation, this can arise due to low dietary iron intake, poor iron absorption, and/or blood loss. In some cases, however, there may be adequate iron stores, with normal levels of serum ferritin, but insufficient iron is delivered by transferrin to meet cells’ demand, a situation termed “functional iron deficiency”.
Functional iron deficiency (or iron-restricted erythropoiesis) in inflammatory conditions is caused by elevated hepcidin levels, triggered by inflammatory cytokines such as IL-6. The consequent internalization and degradation of ferroportin lowers the amount of iron available for binding to transferrin. Accordingly, TSAT is reduced.
The increase in hepcidin levels in the presence of inflammation can be profound.”
The body has no active excretion mechanism for iron and is thus vulnerable to a positive iron balance and, eventually, risk of iron overload if the homeostatic systems become disrupted or are bypassed. Excess body iron can be toxic, saturating the iron-binding capacity of transferrin and resulting in non-transferrin-bound iron , which can be taken up in an uncontrolled manner with the risk of organ damage in the endocrine system, heart, and liver.
Striking increases in serum ferritin levels can also occur in the event of acute inflammatory or infectious events.
Certain demographic and physical characteristics alter iron homeostasis and affect serum ferritin levels. Some of these (particularly obesity and old age) are frequent in patients with inflammatory conditions such as CHF. Obese patients are known to have an increased risk for iron deficiency. Patients with high body mass index have increased levels of hepcidin.
Iron deficiency often remains undiagnosed and untreated in the context of inflammatory conditions . It may not be suspected because the typical symptoms, such as fatigue, can be similar to those of the underlying disease.”
It is almost paradoxical to suffer from Intracellular Iron Overload, while simultaneously suffering from extracellular iron deficiency. This overload of Iron can lead to a specific form of Cell death called Ferroptosis.
How do we fit ferroptosis in the family of regulated cell death?
“The recent finding that plants display ferroptosis induction following heat-stress and produce compounds that block ferroptosis opens an intriguing possibility that ferroptosis may represent an adaptive response to stress and infection. As is the case for heat-stress, pathologic ischemia conditions may lead to depletion of GSH levels resulting in enhanced sensitivity to iron- and lipid peroxidation induced cell death, which could be part of a defensive response against infection.
it is cell death that occurs when anti-oxidant defences are overcome and key cellular macromolecules are chemically damaged.
Ferroptosis could also be of functional importance in conditions of oxidative stress, decreased reduction capacity in cells or upon excessive levels of free iron.”
Reclassifying Hepatic Cell Death during Liver Damage: Ferroptosis—A Novel Form of Non-Apoptotic Cell Death.
“Specifically, in cell death, autophagy can have different roles: (a) autophagy-associated cell death; (b) autophagy-mediated cell death, and (c) autophagy-dependent cell death . In the first two, autophagy has a secondary role, depending on the presence of other types of cell death (e.g., apoptosis), which are responsible for executing cell death itself. In contrast, autophagy-dependent cell death does not require other types of cell death. Interestingly, autophagy seems to act as a cell death backup mechanism, being activated when apoptosis is inhibited. In Bax/Bak double knockout mice—which are resistant to apoptosis—the pathways and morphological changes indicate the activation of autophagy when cells are exposed to death ligands”
Finally, there is evidence showing a link between the activation of autophagy and the development of ferroptosis through a process known as “ferritinophagy”, featuring the autophagic degradation of ferritin. In this process, the nuclear receptor coactivator 4 (NCOA4, a selective cargo receptor for the turnover of ferritin) helps to maintain iron homeostasis, contributing to ferritin degradation, thus increasing iron levels and promoting the development of ferroptosis. Autophagy promotes ferroptosis by the degradation of ferritin”
Dietary iron is taken up by intestinal epithelial cells (IECs) through the luminal membrane, internalized, stored, and finally released to the circulation via ferroportin.
The non-transferrin-bound iron (NTBI) is responsible for the oxidant-mediated cellular injury, and its levels increase with transferrin saturation. In physiological conditions, transferrin is saturated 30% with iron, while a value <16% indicates iron deficiency and >45% reflects iron overload; when the saturation is higher than 60%, the risk of iron accumulation in different cells increases
Interestingly, cytoplasmic-soluble free iron is an important source for oxidation reactions that produces hydroxyl and peroxyl radicals that, in turn, contribute to the peroxidation of PUFA-PLs . As a consequence, cells with an excess of iron are more sensitive to ferroptosis
key event of ferroptosis is the iron-driven production of ROS, in which the iron possibly originates both from intracellular organelles as well as cytoplasm iron stores and iron-containing enzymes.
Iron-mediated cellular injury is the basis of iron-overload disorders, resulting in organ damage including in the brain, heart, pancreas, and liver
Regardless of the cause of iron overload, uncontrolled free iron exerts significant oxidative damage in the liver, contributing to the progression of disease and the development of complications such as HCC (heptocellular carcinoma)
In patients with cirrhosis, hemoglobin levels inversely correlate with hepatic venous pressure gradient, and the presence of anemia is associated with a worsened hyperdynamic circulation in portal hypertension. Increased inflammation and the further production of IL-6 and IL-1(R) increases hepcidin transcription, leading to hypoferremia and finally to anemia.”
IL-6 is a cytokine that is prevalent CoVID-19 patients and can serve as an additional marker for predicting future respiratory failure.
Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients
“The risk of respiratory failure for patients with IL-6 levels of ≥ 80 pg/ml was 22 times higher compared to patients with lower IL-6 levels. In the current situation with overwhelmed intensive care units and overcrowded emergency rooms, correct triage of patients in need of intensive care is crucial. Our study shows that IL-6 is an effective marker that might be able to predict upcoming respiratory failure with high accuracy and help physicians correctly allocate patients at an early stage.”
The release of excess iron in the Cytoplasm of the cells where it participates in the formation of damaging ROS (Reactive Oxygen species) molecules can lead to damage in multiple critical organs including the Heart, Brain, and Liver.
Mysterious Heart Damage, Not Just Lung Troubles, Befalling COVID-19 Patients
“Doctors have found that the infection can mimic a heart attack. They have taken patients to the cardiac catheterization lab to clear a suspected blockage, only to find the patient wasn’t really experiencing a heart attack but had COVID-19.”
OXIDATIVE STRESS AND MULTI-ORGAN FAILURE IN HOSPITALIZED ELDERLY PEOPLE
“Free radicals induce oxidative stress when overproduced, leading to injury and dysfunction of vital organs. Oxidative stress has also been implicated in normal aging. The measurement of isoprostanes has been found to be a reliable marker of oxidative stress. Whether this is due to overproduction of free radicals or impaired antioxidant defenses remains to be established.
Isoprostanes are oxidation products that result from oxidative stress and are readily measured in plasma.1 They correlate highly with markers of inflammation, cytokines, and vasoconstrictive molecules. It was hypothesized that oxidative stress may be related to multi-organ failure in elderly people.
These data support the hypothesis that the development of multi-organ failure in elderly people is related to oxidant stress resulting in overproduction of free radicals in various organs.
We do have a defense against all these oxidative free radicals causing havoc in our bodies. Antioxidants can neutralize the free radicals and bring the body back into a state of balance. For example vitamin C induces a reduction of Fe3+ to Fe2+ and can be an inhibition of hepcidin expression.
Antioxidants Mediate Both Iron Homeostasis and Oxidative Stress
“Oxidative stress is a common denominator in the pathogenesis of many chronic diseases. Therefore, antioxidants are often used to protect cells and tissues and reverse oxidative damage. It is well known that iron metabolism underlies the dynamic interplay between oxidative stress and antioxidants in many pathophysiological processes. Both iron deficiency and iron overload can affect redox state, and these conditions can be restored to physiological conditions using iron supplementation and iron chelation, respectively. Similarly, the addition of antioxidants to these treatment regimens has been suggested as a viable therapeutic approach for attenuating tissue damage induced by oxidative stress. Notably, many bioactive plant-derived compounds have been shown to regulate both iron metabolism and redox state, possibly through interactive mechanisms. This review summarizes our current understanding of these mechanisms and discusses compelling preclinical evidence that bioactive plant-derived compounds can be both safe and effective for managing both iron deficiency and iron overload conditions.
Labile iron is the most important contributor of this oxidative damage to cellular components [3,4,5]. Superoxide radical (O2−) is the initial reactive species produced during these reactions, serving as the precursor for additional reactive radicals, including H2O2 and the hydroxyl radical (OH−), one of the most potent free radical species that can react with a wide range of cellular constituents
As discussed above, iron is potentially toxic due to the generation of free radicals via the Fenton reaction. Thus, the human body has developed processes to regulate the amount of iron absorbed in accordance with the body’s needs in order to prevent the adverse effects of iron overload. Despite these processes, however, iron overload can still occur.
In particular, excess iron in the blood begins to deposit in tissues when available transferrin proteins are saturated. Large amounts of labile iron in the circulation can eventually damage the liver, heart, and other metabolically active organs
an iron-dependent, oxidative form of cell death called ferroptosis has recently been identified.
The features of ferroptosis include an increased intracellular pool of liable iron, increased lipid peroxidation at the plasma membrane, and depletion of reduced nicotinamide adenine dinucleotide phosphate (NADPH)
Furthermore, ferroptosis occurs in mouse models of hemochromatosis following iron overload
The damage induced by oxidized cellular components is associated with the depletion of endogenous cellular antioxidant systems. Numerous endogenous antioxidants maintain the cell’s redox state and prevent the harmful effects of oxidative stress; these antioxidants include superoxide dismutase (SOD), catalase, glutathione (GSH), thioredoxin (Trx), and ferritin. As discussed above, superoxide (O2−) is the first reactive radical produced, and this radical can be neutralized by SOD. There are three distinct SODs, each of which performs a specific function in human cells. SOD1 (Cu/Zn-SOD) is present in the cytoplasm, whereas SOD2 (Mn-SOD) is present in the mitochondria; SOD3, on the other hand, is almost exclusively extracellular
Under certain conditions, endogenous antioxidants are unable to neutralize oxidative stress; in this case, exogenous antioxidants can be used to augment the body’s antioxidant systems. Thus, in addition to reducing the levels of oxidative stress common in many chronic diseases, antioxidants can also serve as an adjuvant to standard therapies in order to provide a synergistic clinical effect [60,61]. Vitamin A (beta-carotene), vitamin C, vitamin E (alpha-tocopherol), polyphenols, and other bioactive plant-derived compounds are effective exogenous antioxidants. Because several of these antioxidants can also regulate iron metabolism, they are ideal candidates for helping manage oxidative stress, particularly in the case of iron overload and/or iron deficiency
This may be the reason some people are benefiting from High Dose IV Vitamin C injections. It can be a powerful agent to counteract oxidative stress even though it will not have a direct impact on the Virus itself.
This iron driven, oxidative stress component of CoVID-19 might also explain why Chloroquine and Hydroxchloroquine are leading to rapid improvements in patients. These drugs are used to fight the Malaria causing parasite which gets access to the hemoglobin in the body and feeds off the iron.
They are mainly being touted as a way to block the endosomal dependent cell entry of SARS-CoV 2, however they may additionally be providing some relief to the oxidative stress conditions manifesting within cells experiencing iron overload. Consider how Chloroquine completely paralyzes the iron transfer within cells, essentially trapping it into endosomal and lysosomal compartments.
Chloroquine Interference With Hemoglobin Endocytic Trafficking Suppresses Adaptive Heme and Iron Homeostasis in Macrophages: The Paradox of an Antimalarial Agent
“We found that chloroquine exposure impairs trafficking of Hb:Hp complexes through the endosomal-lysosomal compartment after internalization by CD163. Relative quantification of intracellular Hb peptides by SRM confirmed that chloroquine blocked cellular Hb:Hp catabolism. This effect suppressed the cellular heme-oxygenase-1 (HO-1) response and shifted macrophage iron homeostasis towards inappropriately high expression of the transferrin receptor with concurrent inhibition of ferroportin expression. A functional deficiency of Hb detoxification and heme-iron recycling may therefore be an adverse consequence of chloroquine treatment during hemolysis.
Chloroquine is a lysosomotropic weak base and accumulates within acidic cellular compartments. The pharmacologic action of chloroquine includes an increase in intralysosomal pH, preventing fusion of endosomes and lysosomes, and, consequently, disruption of intracellular trafficking
We found that chloroquine treatment resulted in intracellular Hb trapping, abolished HO-1 expression, and suppression of the adaptive iron metabolism response. Our results suggest that chloroquine interferes with the hemoglobin scavenger pathway, potentially compromising efficient Hb clearance and aggravating ill effects of extracellular Hb.
Collectively, the increased SRM signal in parallel to the brown appearance of the cell pellets confirms that not only heme but also the protein component (globin) of Hb massively accumulates in the chloroquine-treated cells.
While we observed a considerable decrease of Hb peptides in control cells, Hb elimination was blocked by chloroquine treatment. Therefore, our results suggest that chloroquine impairs elimination of Hb by interfering with lysosomal Hb degradation.
By limiting Hb:Hp triggered HO-1 expression and cellular heme metabolism, chloroquine could profoundly modify macrophage iron homeostasis.
Collectively, these data support our hypothesis that chloroquine could limit the capacity of macrophages to detoxify heme and to recycle iron.
As a lysosomotropic agent, chloroquine is likely to alter the dynamics of Hb:Hp trafficking though the endosomal-lysosomal compartments.
Our data provide evidence that chloroquine or its derivatives may interfere with an established pathway for Hb clearance, thereby inhibiting heme detoxification and, potentially, heme-iron recycling. Specifically, we found that chloroquine blocks Hb:Hp degradation by paralyzing lysosomal function and limiting heme access to HO-1, the primary enzyme of Hb-heme catabolism.
In chloroquine-treated cells the Hb:Hp complexes are stacked within the early endosomal compartment, reaching the lysosome compartment only 40-minutes after completed endocytosis. Normally, trafficking of Hb:Hp complexes through the endosomal-lysosomal compartment is largely completed at this time point.
We also found that chloroquine adversely modifies Hb:Hp triggered adaptation of iron homeostasis in human macrophages preventing release of heme iron into the recycle pathway. Under normal conditions, the heme-iron load, which is imparted by endocytosis of Hb:Hp complexes, causes a rapid downregulation of the transferrin receptor and a concurrent induction of the iron exporter ferroportin . This adaptive response assures that iron homeostasis is shifted towards enhanced iron supply to the bone marrow, which is a critical process in hemolytic anemia . Chloroquine treatment appears to suppress this adaptive gene regulation and may therefore impair heme-iron recycling.”
If Chloroquine is preventing Iron recycling then it could cause more susceptibility to hypoxia and rapid decompensation in the event of a reinfection or relapse. There are more and more reports coming in of patients who had recovered, only to test positive again later.
“FEARS have been raised that the coronavirus may be able to remain in the body and “reactivate” later after 51 recovered patients tested positive again.
The center said it did not believe the patients had been reinfected, but that the virus had remained at undetectable levels in their cells and later “reactivated”.
The claim runs contrary to the bulk of current evidence about how the virus works. “
Some of these reinfections may be due to low levels of antibodies produced and persisting from the first round of CoVID-19 infection. A recent study on the serum levels of SARS-CoV 2 antibodies in the blood of recovered patients was concerning.
Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered
2 patient cohort and their implications
“It is also noteworthy that the levels of NAbs in patients were variable. About 30% of patients failed to develop high titers of NAbs after COVID-19 infection. However, the disease duration of these patients compared to others was similar. Notably, there were ten recovered patients whose NAb titers were very low, under the detectable level of this study (ID50: <40), suggesting that other immune responses, including T cells or cytokines, may contribute to the recovery of these patients. Whether these patients were at high risk of rebound or reinfection should be explored in further studies.”
I would suggest that it is very possible that the patients with low titer levels in this study may have been treated with some kind of immunosuppressant drug (like Hydroxychloroquine) which aborted a significant portion of the immune response.
There may be evidence that Chloroquine and Hydroxychloroquine are facilitating viral reemergence in patients who became asymptomatic and seemed to have recovered from SARS-CoV 2 infection.
Mechanisms of action of hydroxychloroquine and chloroquine
“Hydroxychloroquine and chloroquine are weak bases and have a characteristic ‘deep’ volume of distribution and a half-life of around 50 days. These drugs interfere with lysosomal activity and autophagy, interact with membrane stability and alter signalling pathways and transcriptional activity, which can result in inhibition of cytokine production and modulation of certain co-stimulatory molecules.
After absorption, the half-lives of the two drugs are comparably long (40–60 days) owing to a large volume of distribution in the blood
As a weak base, hydroxychloroquine accumulates within acidic vesicles, such as the lysosomal compartment
Hydroxychloroquine (HCQ) enters and accumulates in lysosomes along a pH gradient. In lysosomes, hydroxychloroquine inhibits the degradation of cargo derived externally (via endocytosis or phagocytosis) or internally (via the autophagy pathway) in autolysosomes by increasing the pH to prevent the activity of lysosomal enzymes. Inhibition of lysosomal activity can prevent MHC class II-mediated autoantigen presentation.
hydroxychloroquine can reduce the production of pro-inflammatory cytokines, including type I interferons.
Hydroxychloroquine (HCQ) can interfere with immune activation at various cellular levels by inhibiting various innate and adaptive immune processes. During autoimmunity, cellular debris can activate Toll-like receptor 7 (TLR7) and TLR7 signalling pathways in plasmacytoid dendritic cells (pDCs) and other immune antigen-presenting cells (APCs), including monocytes, macrophages and B cells, resulting in the activation of multiple cell types and secretion of various pro-inflammatory cytokines. In APCs, hydroxychloroquine potentially interferes with TLR7 and TLR9 ligand binding and TLR signalling (through lysosomal inhibition and reduced MyD88 signalling), which inhibits TLR-mediated cell activation and cytokine production. In APCs, such as pDCs and B cells, this drug also inhibits antigen processing and subsequent MHC class II presentation to T cells, preventing T cell activation, differentiation and expression of co-stimulatory molecules (such as CD154) and also reducing the production of cytokines (such as IL-1, IL-6 and TNF) by both T cells and B cells. BAFF, B-cell activating factor.
An important mode of action of chloroquine and hydroxychloroquine is the interference of lysosomal activity and autophagy. It is widely accepted that chloroquine and hydroxychloroquine accumulate in lysosomes (lysosomotropism) and inhibit their function.
Interference of lysosomal activity might inhibit the function of lymphocytes and have immunomodulatory or even anti-inflammatory effects.
One mechanism by which these drugs might have anti-inflammatory effects is by impairing antigen presentation via the lysosomal pathway. Lysosomes contain hydrolytic enzymes and cooperate with other vesicles to digest cargo (such as organelles and material from inside the cell (in a process known as autophagy) or material from outside the cell (via the endocytosis or phagocytosis pathway)). Lysosomes are involved not only in recycling cellular substrates80 but also in antigen processing and MHC class II presentation, indirectly promoting immune activation81. Autophagy is also involved in antigen presentation and immune activation82,83. For example, data from one study suggest that autophagy is important for MHC class II-mediated autoantigen presentation by antigen-presenting cells to CD4+ T cells84. As the pH in lysosomes is optimal for lysosomal enzymes involved in hydrolysis, by increasing the pH of endosomal compartments85, chloroquine and hydroxychloroquine might impair the maturation of lysosomes and autophagosomes and inhibit antigen presentation along the lysosomal pathway (Fig. 3). Overall, the available studies suggest that hydroxychloroquine and chloroquine impair or inhibit lysosomal and autophagosome functions and subsequently immune activation.
Hydroxychloroquine and chloroquine can indirectly reduce the production of anti-inflammatory cytokines by various cell types. In vitro, hydroxychloroquine and chloroquine inhibit the production of IL-1, IL-6, TNF and IFNγ by mononuclear cells98 (Fig. 4). Furthermore, treatment with hydroxychloroquine inhibits the production of TNF, IFNα, IL-6 and CCL4 (also known as MIP1β) in pDC and natural killer cell co-cultures stimulated with RNA-containing immune complexes”
This seems to be a reasonable connection to make that when a drug inhibits antigen processing and presentation to the immune system, the immune system will produce less antibodies. However, more study will likely need to be done. I would be very interested to know how many and which patients received Hydroxychloroquine treatment, both in the group of patients who have tested positive again after recovery and the group that had their antibody serum levels checked.
Either way, if there is a significant possibility of reinfection or relapse with this disease, I would rather not be taking a drug that nerfs my Immune system to this extent and will stay in my body for 5-6 months. Stick with the healthy nutrition, adequate sleep and exercise and stay away from the toxic drug therapy.
This process of Liver attack leading to iron overload in cells throughout the body may explain why this disease seems to remain mild for the initial week+ after infection, and then for some people rapidly cascades into serious complications. The iron overload is a silent symptom of the infection. You may experience some milder symptoms from the upper and lower respiratory infection, but when the cell death starts from ferroptosis the oxidative stress compounds in many vital organs and starts to drive a massive increase in immune response.
The cells are able to maintain function as the iron levels increase. At a certain point the iron levels cross a threshold and all that is necessary to trigger ferraptosis cell death is an additional stress from outside the cell (oxidative stress, immune response, and inflammation), or additional stress within the cell, namely viral intrusion. It is hypothesized that ferraptosis cell death increases in response to infection. Potentially this is one way the body may be trying to neutralize infected cells. The iron is packed into the cells and contained within the lysosomes in the cells. In ferraptosis the lysosome releases its contents into the cytoplasm of the cell and this dumps all that excess Iron into the cytoplasm. The Iron creates oxidative radicals and as the cell is destroyed, it releases its contents into the extra celluar space. Then leading to more oxidative stress, more immune signaling, more inflammation and hence triggering more cell death. It becomes a rapidly escalating and vicious cycle.
So why are the lungs disproportionately impacted? It seems the answer to this might be two fold. The alveolar macrophages are primed for iron uptake under normal circumstances and under iron overload conditions tend to accumulate even more. Interestingly as the iron levels drop in the extracellular space due to high Hepcidin expression. The macrophages in the Liver and spline tend to become iron deficient while the macrophages in the lungs continue to load up on more and more iron. This maybe because inflammation in the liver can change the pressure of the blood pathway through the liver arteries. This can actually cause the blood to bypass the liver and redirect to the lungs where the excess iron seems to be deposited.
Secondly excess hemoglobin in the blood plasma can also be taken up by the alveolar macrophages. When the Liver is damaged and cannot fully serve its function in filtering the blood, it seems the lungs become the primary dumping ground.
Iron Homeostasis in the Lungs—A Balance between Health and Disease
Exposure to high levels of systemic iron causes accumulation in different pulmonary cell types, such as alveolar macrophages, epithelial cells, and vascular smooth muscle cells. So far, the exact iron uptake mechanisms are not understood. The lung expresses the NTBI importers DMT1, ZIP14, and ZIP8, that may further contribute to the iron loading under high systemic and/or local iron levels.
NTBI can also be taken up by cells via ZRT/IRT-like protein (ZIP) 14. Genetic inactivation revealed that ZIP14 is a key player for NTBI uptake by hepatocytes under iron overload conditions. Besides hepatocytes, ZIP14 is expressed by cells in other tissues such as the pancreas and the heart. In addition, ZIP14 is detected in airway epithelial cells, and protein levels were shown to increase in the iron loaded murine lung. In 2012, another ZIP protein able to transport iron, named ZIP8, was reported. It is abundantly expressed in the human lung
Finally, in conditions of intravascular hemolysis, lung cells can also be exposed to hemoglobin and heme-iron circulating in the bloodstream. When released from RBCs, hemoglobin forms a complex with the glycoprotein haptoglobin in the plasma, which is mainly taken up by reticuloendothelial macrophages; heme released from hemoglobin in the blood forms a complex with the glycoprotein hemopexin and is taken up by liver parenchymal cells . In vivo studies have shown that the uptake of hemoglobin-haptoglobin and heme-hemopexin complexes by the lung is relatively low. Nevertheless, alveolar macrophages express the haptoglobin receptor CD163 and the hemopexin receptor CD91, and therefore are likely able to take up these complexes
Alveolar macrophages frequently accumulate iron in lung diseases and conditions of iron overload
alveolar macrophages are expected to have a protective role by scavenging the excess of iron in the lung (derived from inhaled iron particles or from plasma iron) thereby limiting its availability to induce oxidative damage
Interestingly, high lung iron content was also observed in liver-specific hepcidin deficient mice . This finding strengthens the hypothesis that lung iron loading occurs as a consequence of increased plasma iron levels and not due to the absence of a functional hepcidin/ferroportin system in the lung.
pproximately 60 to 70% of the body’s iron is localized in RBCs. The lung vasculature accommodates the entire cardiac output, allowing almost all RBCs to pass through the alveolar capillaries in order to be loaded with oxygen. Conditions that affect alveolar capillary integrity/permeability (e.g., Goodpasture’s disease) can lead to hemorrhage into the alveolar space. These patients show alterations in lung iron homeostasis with increased iron levels in alveolar macrophages, likely resulting from hemoglobin-derived iron from phagocytosed RBCs
A growing number of acute and chronic lung diseases as well as other diseases with a pathological manifestation within the lung are associated with disrupted lung iron homeostasis, leading to either iron deficiency or iron overload
It has been recently proposed that in patients with COPD, pro-inflammatory cytokines (e.g., IL-6) trigger increased hepatic hepcidin expression and secretion. This causes FPN degradation and subsequently reduces cellular iron export into the blood stream, likely resulting in the systemic iron deficiency and anemia observed in these patients. On the other hand, alveolar macrophages from COPD patients were shown to accumulate iron and the percentage of iron-loaded macrophages increased with disease severity
Importantly, numerous acute and chronic respiratory diseases are associated with disrupted iron homeostasis in the lungs. The close cellular interaction between iron regulatory pathways via IREs/IRPs or hepcidin/ferroportin and the oxygen sensing pathway via HIFs seems to be critical for healthy adaption but also for pathologic maladaptation within the lungs. Enormous progress has been made in our molecular understanding of these pathways and their suppression and/or enhancement. However, this knowledge currently needs to be applied to the lung. An improved understanding of iron trafficking and storage in the lung and its role in lung disease onset and progression will improve interventional modification of iron homeostasis within the lungs via iron-modulators.”
The Coagulation Factor
Interesting findings have emerged from some autopsies performed in New Orleans showing irregular coagulation and resulting blockage and subsequent hemorrhaging in the lungs
Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series
from New Orleans
Free iron induces irregular coagulation factors. The lungs become the primary site of Iron uptake and coagulation factors particularly in the event of severe liver disruption.
Iron-Induced Fibrin in Cardiovascular Disease
Accumulating evidence within the last two decades indicates the association between cardiovascular disease (CVD) and chronic inflammatory state.
We have shown that trivalent iron (FeIII) initiates a hydroxyl radical-catalyzed conversion of fibrinogen into a fibrin-like polymer (parafibrin) that is remarkably resistant to the proteolytic dissolution and thus promotes its intravascular deposition. Here we suggest that the persistent presence of proteolysis-resistant fibrin clots causes chronic inflammation.
We argue that the culprit is an excessive accumulation of free iron in blood, known to be associated with CVD. The only way to prevent iron overload is by supplementation with iron chelating agents.
links have been found to exist between iron body stores, cardiovascular risk factors and hypercoagulability
t is a common belief that free blood iron, via the Fenton-like reaction, is responsible for so-called oxidative stress that, in turn, leads to atherosclerosis and related cardiovascular diseases. Yet, despite this attractive, albeit simplistic, concept no effectiveness of antioxidant therapy has been demonstrated. As a result numerous natural products (specifically polyphenols) are not being clinically tried because they had been labeled as antioxidants. This highly controversial and, in fact, damaging notion was dealt with in a recent article, which emphasized the importance of polyphenolic substances as iron chelating and free radical scavenging agents that may be neither oxidants nor antioxidants
We have recently documented that trivalent iron ion (FeIII) generates in aqueous solutions powerful hydroxyl radicals that subsequently modify fibrinogen molecules converting them to insoluble fibrin-like polymer. It should be emphasized that such a polymer is not only resistant to fibrinolytic dissolution, but also to proteolytic digestion, i.e. with chymotrypsin, that normally degrades fibrin(ogen) into smaller polypeptide fragments.
The resistance of fibrin clots to enzymatic degradation can now be explained by our finding of the alternative iron-induced mechanism of blood coagulation. According to this concept free iron of blood (Fe III) generates hydroxyl radicals, which in turn convert circulating FBG into an insoluble fibrin-like material ( or parafibrin) without the action of thrombin
As a consequence such a dense fibrin polymer acquires the features of a foreign body and attracts macrophages resulting in a permanent state of inflammation known to be associated with atherosclerosis. Also it is of interest to note the reports on the relationship between inflammation and blood coagulation. Moreover there are numerous experimental and clinical studies that indicate the relationship between inflammation, iron overload and cardiovascular diseases
In conclusion, we postulate in this paper that the excess of blood free iron is responsible for the non-enzymatic generation of insoluble fibrin-like material (parafibrin) that, when deposited on the arterial wall, initiates inflammatory reactions. This pathological process, very different from the classical activation of blood coagulation, can be prevented by substances that chelate iron, scavenge hydroxyl radicals, and inhibit hydrophobic interactions in proteins.”
Finally, I would suggest that a potential therapy could be identified to specifically combat this iron dysregulation, resulting oxidative stress, and cascading lung distress. Perhaps a combination of Iron chelators and polyphenols for iron regulation and antioxidants for oxidative free radicals. I think it would be critical to halt these processes before the blood gets bogged down by the irregular coagulation factors. There is no known agent or biological process that can degrade parafibrin (the irregular modification of fibrin), so once it is saturated in the blood stream, we seem to have no effective method of treatment.
There is more work to be done, yet an effective treatment for CoVID-19 must address this disruption of the liver, iron dysregulation, and blood anomalies in addition to the overarching respiratory infection.
Would serropeptidase have any effect on the parafibrin?
Thanks for the very detailed information. For my information: is iron disregulation also occuring in persons with malaria?
It would be worthwhile to look into it. I know it can be effective at breaking down regular fibrin clots. However I think the defining characteristic of parafibrin is that it can not be broken down by the typical biological or pharmaceutical measures.
I will look back over the clinical data and see if I can find any evidence that serropeptidase could be an exception to that general finding.
Malaria is a parasitic invader that feasts off iron in the hemeglobin. So there may well be similarities in the bodies iron regulation response to counteract the infection. I am not as familiar with Malaria and would have to look into it to see if there is a similar upregulation of Hepcidin and iron loading in the cells.
I found this article about upregulation of Hepcidin, malaria and iron:
I’m a layman, so I only looked for words: but it does seem that Hepcidin is upregulated and that iron is accumulated in macrophages.
Good find, it is not surprising that the body would attempt to lock the iron away and keep it from the malaria causing parasite. Of course in that case, there is no significant liver or respiratory attack that can exert the additional stress necessary to trigger ferraptosis cell death.
It’s suggested patients with thalassemia are resistant. This follows treating w recombinant human erythropoietin.
Coronavirus resistance in infants under one year of age can be explained by the fact that fetal hemoglobin predominates in their blood, which does not contain beta chains and is probably invulnerable to viral proteins. Hemoglobin without beta chains is also synthesized in patients with thalassemia, a genetic disease common in the “malaria” regions of Africa – in these countries a low incidence of COVID-19 is noted, writes “Science first
One other interesting thing to note is that in one of the above studies it showed that SARS entry in the presence of Trypsin was 100-1000 fold more efficient then the typical Spike protien-ACE 2 endosomal route. If SARS-CoV 2 works in a similar way, this may explain why so many patients have diarrhea as one of the earlier symptom manifestations.
Good news for pregnant women. Thus far I have heard very few reports of serious or critical cases and perhaps this is due to many pregnant women suffering from iron deficiency during pregnancy. Much less likely to develop iron overload if levels are already a bit low.