Covid 19 Blood Clotting issues

trader32176
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Covid 19 Blood Clotting issues

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What Is Known About COVID-19 and Abnormal Blood Clotting

https://news.weill.cornell.edu/news/202 ... d-clotting

Dr. Jeffrey Laurence, a professor of medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine and a hematology and oncology specialist at NewYork-Presbyterian/Weill Cornell Medical Center, and his colleagues authored a paper in Translational Research in early April that sounded the alarm about abnormal blood clotting—which prevents blood flow—in severe COVID-19 cases. He answered questions about the phenomenon and how he and his Weill Cornell Medicine colleagues are continuing to study treatments for blood clotting in these cases.
What is the clotting problem that you and other doctors are seeing in severe COVID-19 cases?

Many COVID-19 patients in the ICU are developing blood clots, including clots in small vessels, deep vein thromboses in the legs, clots in the lungs, and stroke-causing clots in cerebral arteries. This has been happening even though these patients, in accordance with standard intensive care practice, are put on blood thinner drugs such as heparin to prevent clots as soon as they come to the ICU. This COVID-19-related clotting often does not respond well to standard prevention methods and, in some cases, to standard treatments, even with high doses of blood thinners.
In what percent of severe COVID-19 cases does clotting occur?

We don’t really know with precision—it depends on the severity of the COVID-19 case, and on how strongly you look for clotting. In many cases, an ICU patient will be hooked to a respirator and/or kidney dialysis machine, and while you can use bedside ultrasounds to look for clots in the arms and legs you can’t easily put them in a scanner to look for clots in the lungs. We first became aware of the prominence of the clotting problem when a patient was admitted to the ICU and developed an unusual rash. A skin biopsy showed that the rash was a consequence of many clots in the small blood vessels of the patient’s skin. Within days, we saw similar skin changes in other patients caused by clotting, and then demonstrated the same thing in small blood vessels of the lungs of critical COVID-19 patients.

In other examples of unusual clotting problems, a group of doctors in Paris reported recently that in a series of 29 severe COVID-19 patients who had kidney injury and were on dialysis, which is essentially a blood-filtering system, 28 of them experienced repetitive clotting that blocked access to their dialysis filter, despite the fact that they were on the usual anti-clotting medications prescribed in an ICU setting. Another recent study found that in a set of 400 hospitalized COVID-19 patients, the overall rate of clotting was 10 percent and the rate of confirmed venous thromboembolism, mainly deep vein thrombosis, was 5 percent.
Are there evident risk factors for this abnormal clotting?

The risk factors are the same as the risk factors that have already been noted for severe COVID-19, such as being older, being male, having obesity or having diabetes.

Large studies have found that being female reduces the risk of severe COVID-19 by about 20 percent, and that risk reduction would be even stronger if you considered only people in the community, not in nursing homes where females are overrepresented. Males, people who are obese, and diabetics tend to have higher baseline levels of certain pro-inflammatory molecules linked to severe COVID-19, which may explain why they are more prone to it.

There is also some preliminary evidence that certain kinds of immune suppression may be protective. Researchers are now investigating whether patients who have AIDS, for example, or are taking immunosuppressant drugs following an organ transplant, may get severe COVID-19 less often than average.
Is this clotting a significant cause of death in severe COVID-19 cases?

It’s hard to know for sure, because the clotting problem is apt to go undetected. Most often the cause of death in severe COVID-19 is respiratory failure, and that can be due to pneumonia, including a secondary bacterial or fungal pneumonia. But it may also be due to clotting. The lungs of people who die of respiratory failure due to COVID-19—especially if they have not yet been on a ventilator—often do not show the kind of damage seen in people who have died of other acute respiratory distress syndromes. Instead the lung tissue usually will have blood clots in the small vessels, which hints that clotting is at least contributing to the respiratory failure.
What do you think is causing this extreme clotting?

In our initial analyses of lung and other clot-filled tissue from COVID-19 cases, we found that the clots in small blood vessels are accompanied by the deposition of immune molecules called complement proteins. When activated in what is called the complement cascade, complement proteins can powerfully mobilize other elements of the immune system, leading to a hyper-inflamed state. They also can injure or kill infected cells and can promote the formation of blood clots while inhibiting natural clot-preventing factors in the blood. We found evidence that the spike proteins that stud the outside of the COVID-19 coronavirus bind to one of these complement proteins, known as MASP2, and this may be one mechanism by which it can directly initiate the complement cascade. In other words, the virus itself may be directly setting off an immune cascade that results in clotting.

In our paper in Translational Research describing our first five cases, we and other doctors noticed that there is an 8- to 9-day interval between the appearance of the first symptoms consistent with mild or moderate COVID-19 and then a sudden worsening that brings the patient to the ER. We suspect that in such cases, the patient’s natural immune defenses and control mechanisms that regulate the complement and coagulation responses may be working effectively during those 8 to 9 days, then are overwhelmed so that the patient requires hospital care.
Is there a better way to treat this clotting if standard blood thinners such as heparin often don’t work well, even at high doses?

We have had some anecdotal success with argatroban, which directly inhibits thrombin, a key element of the clot-forming system in the blood and have submitted a paper for review of that observation. Dr. Maria Teresa DeSancho, a professor of clinical medicine at Weill Cornell Medicine and a hematologist at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, has set up a clinical trial to determine the appropriate doses of anticoagulation that should be used before a clot is detected in such patients.

Our group, and other physicians in the U.S. and Italy, have been using anti-complement drugs, including eculizumab, a monoclonal antibody that blocks a key complement protein called C5 and was developed to treat rare complement hyperactivation disorders. We hope to formally evaluate eculizumab.

The current standard practice, based on the evidence we have to date, is to put everyone who is hospitalized with COVID-19 on a blood thinner at a minimum, and in many hospitals now, recovering COVID-19 patients are discharged on blood thinners even if normally they wouldn’t need them because we’re so concerned about clotting.
So in your view, many major complications of severe COVID-19 appear to be driven by blood clotting?

Yes—mounting evidence suggests the severe disease is largely driven by an excessive activation of complement and inflammatory pathways, leading to respiratory symptoms, kidney failure and other potentially lethal complications such as strokes.

What gave me a clue to the importance of complement was a study published about two years ago. The researchers in that study found that knocking out the complement system, either genetically or by giving anti-complement drugs, protected mice from severe disease when they were exposed to the SARS coronavirus, which is closely related to the new SARS-CoV-2 coronavirus that causes COVID-19.

Another interesting thing those researchers reported was that the virus levels were about the same in the normal mice that got sick, and in the mice that lacked complement and didn’t get sick. Similarly, in a study from China early in the COVID-19 outbreak there, doctors found that some of their mildest cases had orders of magnitude more virus in their blood and lungs, compared to severe cases. These results suggest that the coronavirus doesn’t really matter so much, once it has set off this cascade of immune-related problems in the patient.
trader32176
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Re: Covid 19 Blood Clotting issues

Post by trader32176 »

I'm adding more info here on blood clotting :

Autopsies show COVID-19 victims had blood clots in ‘almost every organ,’ doctor says


By Lia Eustachewich

July 10, 2020 | 6:23pm
https://nypost.com/2020/07/10/covid-19- ... ts-doctor/

Autopsies found blood clots in “almost every organ” of coronavirus victims, according to a top New York City pathologist, who called the results “dramatic.”

Early on, doctors found blood clots “in lines and various large vessels” of COVID-19 patients, Dr. Amy Rapkiewicz told CNN on Thursday.

But then autopsies showed the damage was far worse.

“The clotting was not only in the large vessels but also in the smaller vessels,” said Rapkiewicz, chairman of the department of pathology at NYU Langone Medical Center.

“And this was dramatic because though we might have expected it in the lungs, we found it in almost every organ that we looked at in our autopsy study.”

The autopsies also revealed that large bone marrow cells called megakaryocytes — which typically don’t travel outside the bone and lungs — circulated to other parts of the body.


“We found them in the heart and the kidneys and the liver and other organs,” said Rapkiewicz. “Notably in the heart, megakaryocytes produce something called platelets that are intimately involved in blood clotting.”

The findings are similar to those in April, when doctors at Mount Sinai spotted signs of blood thickening and clotting in different organs.

Rapkiewicz said myocarditis, or inflammation of the heart, wasn’t detected in the autopsies, though the condition was initially suspected in the early days of the coronavirus outbreak.
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TimGDixon
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Re: Covid 19 Blood Clotting issues

Post by TimGDixon »

Thank you for that Trader - we have been aware of this issue for a while and saw it first manifest in pediatric patients in the form of kawaski syndrome. The bruising around toes and fingers is indicative of this. Good work on sharing this.
trader32176
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Re: Covid 19 Blood Clotting issues

Post by trader32176 »

Thank you for your reply ,

Would this bruising on the toes ( and hands) be what people are calling covid toes ? I've read several articles and papers on covid toes . some of the info i have studied is saying this is covid related , while other info is saying it's not . I am currently studying covid toes and other dermatolic manifestations .
Do you think it is a subject that would be interesting enough for a new topic thread ?
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TimGDixon
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Re: Covid 19 Blood Clotting issues

Post by TimGDixon »

I think its safe to say that normally people are not presenting in large numbers or even small numbers, what is being termed covid toes. This is a very rare condition in the first place and it is all immunologically driven. The answer is the immune system - not pharma.
trader32176
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Re: Covid 19 Blood Clotting issues

Post by trader32176 »

Tim,
It looks like TSOI has announced a promising new patent Re: blood clotting .

What are some of your thoughts on other areas of research where blood clotting is a concern .

I have studied some and come across other things like strokes:

Doctors Link COVID-19 To Potentially Deadly Blood Clots And Strokes
https://www.npr.org/sections/health-sho ... nd-strokes
trader32176
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Re: Covid 19 Blood Clotting issues

Post by trader32176 »

I found this on another site today , and this new should also be added to blood clotting issues :

Thrombosis and COVID-19 pneumonia: the clot thickens!

https://erj.ersjournals.com/content/ear ... 01608-2020

(Excerpts)

some of the well-described mechanisms associated with infection/inflammation are likely to be relevant [22]. These include the increased production of tissue factor and amplification of the coagulation cascade


Anticoagulation is clearly not the only treatment needed in patients with COVID-19 and in many patients, on the sicker end of the spectrum, may be too late to alter outcome. The intimate association between inflammation and thrombosis would suggest an anti-inflammatory/anti-viral therapeutic approach should be considered in parallel to anticoagulation.
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TimGDixon
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Re: Covid 19 Blood Clotting issues

Post by TimGDixon »

Without a doubt a hyper-activated NLRP3 gene leads to the kinds of immune responses we see that cause clotting like in covid-19.

NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis
https://pubmed.ncbi.nlm.nih.gov/29880500/

NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis
https://pubmed.ncbi.nlm.nih.gov/29794149/

Activation of NLRP3 inflammasome complex potentiates venous thrombosis in response to hypoxia
https://pubmed.ncbi.nlm.nih.gov/28420787/

Caspase-1 Inflammasome Activation Mediates Homocysteine-Induced Pyrop-Apoptosis in Endothelial Cells
https://pubmed.ncbi.nlm.nih.gov/27006445/

Platelets at the crossroads of thrombosis, inflammation and haemolysis
https://pubmed.ncbi.nlm.nih.gov/29383704/

Atherothrombosis and the NLRP3 inflammasome - endogenous mechanisms of inhibition
https://pubmed.ncbi.nlm.nih.gov/31469975/
trader32176
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Re: Covid 19 Blood Clotting issues

Post by trader32176 »

For my reply , i'll go link by link

I found this interesting in your first link :

NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis :

NLRP3 is activated by various endogenous danger signals abundantly present in atherosclerotic lesions, such as oxidized low-density lipoprotein and cholesterol crystals. Consequently, NLRP3 inflammasome activation contributes to the vascular inflammatory response driving atherosclerosis development and progression.

and I picked this info out of your second link:

NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis

This study identifies a novel role for NLRP3 and interleukin-1β in platelet function, and provides a new potential link between thrombosis and inflammation, suggesting that therapies targeting NLRP3 or interleukin-1β might be beneficial for treating inflammation-associated thrombosis.

your 3rd link had 3 things in it that seemed important to me :

Activation of NLRP3 inflammasome complex potentiates venous thrombosis in response to hypoxia

1) Venous thromboembolism (VTE), caused by altered hemostasis, remains the third most common cause of mortality among all cardiovascular conditions.
(VTE- I learned something new today . never knew about VTE)

2) We extend the significance of these preclinical findings by studying modulation of this pathway in patients with altitude-induced venous thrombosis

3) an early proinflammatory state in the venous milieu, orchestrated by the HIF-induced NLRP3 inflammasome complex, is a key determinant of acute thrombotic events

the 4th link had me stumped there for a bit , but I did find a couple of things to be very interesting :

Caspase-1 Inflammasome Activation Mediates Homocysteine-Induced Pyrop-Apoptosis in Endothelial Cells


1) we investigated the effect of hyperhomocysteinemia on programed cell death in endothelial cells (EC).

2) homocysteine and lipopolysaccharide individually and synergistically induced inflammatory pyroptotic and noninflammatory apoptotic cell death.

3) homocysteine/lipopolysaccharide-induced nucleotide-binding oligomerization domain, and leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) protein caused NLRP3-containing inflammasome assembly

4) Hyperhomocysteinemia preferentially induces EC pyroptosis via caspase-1-dependent inflammasome activation leading to endothelial dysfunction.

On to link # 5 :

Platelets at the crossroads of thrombosis, inflammation and haemolysis

1) Platelets play a critical role at the interphase of thrombosis and inflammation

2) We have recently identified platelet TLR4, NLRP3, and Bruton tyrosine kinase (BTK) as critical regulators of platelet aggregation and thrombus formation

and from #6 - the last of your links :

Atherothrombosis and the NLRP3 inflammasome - endogenous mechanisms of inhibition


1 ) With further discussion of the existing knowledge on the proinflammatory relationship of the NLRP3 inflammasome with atherosclerosis, this review summarizes and critically evaluates the preclinical and interventional findings of endogenous NLRP3 inflammasome inhibition in attempts to elucidate anti-inflammatory mechanisms, and therapeutic targets against atherothrombosis.

2) Upstream and serving as an activator of IL-1ß lies the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome that has been well described in animal models to be activated by cholesterol crystals or hypoxia to promote cleavage and secretion of IL-1ß and IL-18 that lead to atherosclerotic deposition in arteries. Given the direct implication of an atherogenic role to the NLRP3 inflammasome in generating these cytokines, NLRP3 inhibitors are of interest

3) Further investigation focusing on the endogenous mechanisms of inhibition of the NLRP3 inflammasome would uncover diagnostic routes from defective means in inflammatory resolution

and this ends my brief study, and summary of the links you provided .
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TimGDixon
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Re: Covid 19 Blood Clotting issues

Post by TimGDixon »

You are a thinker Trader.. good job. Really good job...
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