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How do the lungs act as a sieve to trap blood clots?

How do the lungs act as a sieve to trap blood clots?


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Does anyone know? I'm curious to find out as my human anatomy and physiology book doesn't go into much detail on how the lungs function as such


Just as an intro…

The heart pumps deoxygenated blood from the right ventricle, through the pulmonary arteries (pic) which then eventually split into small capillary networks that surround the alveoli. The alveoli are formed by the trachea eventually branching off. So when you breathe in, the alveoli become filled with higher levels of oxygen.

The blood then becomes oxygenated and returns to the heart via the pulmonary veins to be pumped to the rest of the body.

The deoxygenated blood becomes oxygenated because there is a difference in oxygen and carbon dioxide concentration between the capillary network (O2 low / CO2 high) and the alveoli (O2 high / CO2 low) and so gas diffuses across because of the difference in concentrations (pic).

Physiology textbooks explain these mechanisms but for blood clots in particular, you'll need to check out a pathophysiology book.

Blood clots

When a blood clot travels to the lungs, it's referred to as a pulmonary embolus or PE.

Most of the time (90%), pulmonary emboli are formed in deep veins of the lower leg. These then travel to the pulmonary circulation system.

Large emboli block larger vessels - the pulmonary arteries and their branches. The smaller ones travel further into the network.

Patients can sometimes be asymptomatic and the emboli can at times resolve on its own. The extent of the severity of a PE is determined by:

  • how much blood flow is obstructed;
  • how long the embolus has been there; and
  • presence other underlying lung or heart disease.

There are a number of things that a PE can cause physiologically.

Reduced Gas Exchange - alveolar dead space occurs when an alveolus is ventilated, but not perfused with blood. This, along with other factors, cause varying levels of hypoxemia (lack of oxygen).

Pulmonary Infarction - in a small amount of cases loss of blood flow to lung tissue can cause tissue death. This is fairly uncommon.

Right Ventricular Failure - if there is a large enough blockage (> 50 - 60%), the pressure in the pulmonary arteries increase. Subsequently, the load on the right ventricle is higher. So in acute cases, the ventricle hasn't had time to adapt (hypertrophy) and so the right heart can fail.

At any rate, the haemodynamic balance can be disrupted when a PE is present.

In the elderly or people with underlying disease where their lung function is already decreased, PEs can have a significantly larger effect because they can't compensate. There are many more important points related to this but hopefully this is a useful (very) basic overview.


I'll ask the lung experts I work with later today for a better answer. To my knowledge, the lungs, as an organ, have a very extensive capillary network that facilitates gas exchange. If blood clots become mobile in the blood stream, they can travel perfectly well in large vessels, but once they get down to a capillary, they are physically blocked from passing through. The blood clots don't have to be large in size, because the capillaries are only about 6 micrometres in diameter.


Deep Vein Thrombosis (DVT, Blood Clot in the Legs)

Symptoms of deep vein thrombosis (DVT) occur when there is a blood clot in one of the deep veins (vessels that return blood to the heart after it has delivered oxygen to the tissues). Most commonly, deep vein thrombosis occurs in a vein of the leg, but it can also occur in other locations such as the pelvis. The most serious complication of deep vein thrombosis is pulmonary embolism, in which a blood clot breaks off of the DVT and travels through the bloodstream and becomes lodged in a blood vessel of the lung. Symptoms of DVT involve the overlying skin and include

What is deep vein thrombosis (DVT)?

Deep vein thrombosis or DVT describes a blood clot (thrombosis) that forms in the deep veins located in the arm or leg. It is important to know the body's anatomy and function to understand why clots form in veins and why they can be dangerous.

  • Arteries have thin muscles within their walls to be able to withstand the pressure of the heart pumping blood to the far reaches of the body. Veins don't have a significant muscle lining, and there is nothing pumping blood back to the heart except physiology. Blood returns to the heart because the body's large muscles squeeze the veins as they contract in their normal activity of moving the body. The normal activities of moving the body returns the blood back to the heart. Being mobile causes this blood return system to fail, and the resulting stagnated blood may clot.
  • There are two types of veins in the arm or leg superficial veins and deep veins. Superficial veins lie just below the skin and are easily seen on the surface. Deep veins, as their name implies, are located deep within the muscles of the extremity. Blood flows from the superficial veins into the deep venous system through small perforator veins. Superficial and perforator veins have one-way valves within them that allow blood to flow only in the direction of the heart when the veins are squeezed.
  • A blood clot (thrombus) in the deep venous system of the leg or arm, in itself, is not dangerous. It becomes potentially life threatening when a piece of the blood clot breaks off and embolizes, travels through the circulation system through the heart, and enters into one of the pulmonary arteries and becomes lodged. This can prevent blood from flowing properly through the lung and decreasing the amount of oxygen absorbed and distributed back to the body.
  • Diagnosis and treatment of a DVT is meant to prevent pulmonary embolism. in the superficial veins do not pose a danger of causing pulmonary emboli because the perforator vein valves act as a sieve to prevent clots from entering the deep venous system. They are usually not at risk of causing pulmonary embolism.

QUESTION

7 early warning signs and symptoms of DVT

The signs and symptoms of DVT are related to obstruction of blood returning to the heart and causing a backup of blood in the leg. Classic symptoms include:

You may or may not have all of these symptoms, or your may have none. The symptoms of the condition may mimic an infection or cellulitis of the arm or leg.

In the past, doctors and other healthcare professionals performed simple tests on patients to make a diagnosis of a blood clot in the leg however, they have not been effective. For example, pulling the patient's toes toward the nose (Homans' sign), and squeezing the calf to produce pain (Pratt's sign). Today, doctors and health care professionals usually do not rely upon whether these signs and symptoms are present to make the diagnosis or decide that you have DVT.

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What are the signs and symptoms of superficial blood clots?

Blood clots in the superficial vein system (closer to the surface of the skin), most often occur due to trauma to the vein, which causes a small blood clot to form. Inflammation of the vein and surrounding skin causes the symptoms similar to any other type of inflammation, for example,

You often can feel the vein as a firm, thickened cord. There may be inflammation that follows the course of part of the leg vein. Although there is inflammation, there is no infection.

Varicosities can predispose to superficial thrombophlebitis and varicose veins. This occurs when the valves of the larger veins in the superficial system fail (the greater and lesser saphenous veins), which allows blood to back up and cause the veins to swell and become distorted or tortuous. The valves fail when veins lose their elasticity and stretch. This can be due to age, prolonged standing, obesity, pregnancy, and genetic factors.

SLIDESHOW

How do you get deep vein thrombosis?

Blood is meant to flow. If it becomes stagnant, there is a potential for it to clot. The blood in veins constantly forms microscopic clots that are routinely broken down by the body. If the balance of clot formation and clot breakdown is altered, significant clotting may occur. A thrombus can form if one or a combination of the following situations.

Immobility

  • Prolonged travel and sitting, such as long airplane flights ("economy class syndrome"), car, or train travel
  • Hospitalization
  • Surgery
  • Trauma to the lower leg with or without surgery or casting
  • Pregnancy, including 6-8 weeks after delivery of the baby
  • Obesity

Coagulation of the blood faster than usual (hypercoagulation)

  • Medications such as birth control pills (oral contraceptives), for example, Ortho-Novum, Yaz, Yasmin, Microgestin, Kelnor, and other estrogens
  • Genetic or hereditary predisposition to clot formation
  • Increased number of red blood cells (Polycythemia)
  • Trauma to the vein to the leg or arm
  • Bruised leg or arm
  • Complication of an invasive procedure of the vein

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What are the risk factors for DVT?

Many people are at risk for developing blood clots, for example:

  • Immobility, including prolonged bed rest due to illness or injury and long travel in a car or airplane
  • Pregnancy or hormone therapy
  • Surgery that damages the veins in an arm or leg
  • Family history or genetic predisposition to forming blood clots
  • Obesity

What tests diagnose DVT?

The diagnosis of superficial thrombophlebitis usually is made by the doctor at the bedside of the patient, based upon history, potential risk factors present, and findings from the physical examination. Further risk stratification tools may include scoring systems that can help decide whether a DVT is likely.

If the probability of a leg thrombosis is low, a D-Dimer blood test may be ordered.

  • If the D-Dimer is negative, then it is unlikely that a DVT is the diagnosis.
  • If the D-dimer is elevated, then the possibility of a DVT exists and an imaging study, usually ultrasound, is required to look for the DVT

Ultrasound

  • Ultrasound is the standard method of diagnosing the presence of a deep vein thrombosis.
  • The ultrasound technician may be able to determine whether a clot exists, where it is located in the leg or arm, and how large it is. It also may be possible to know whether the blood clot is new or chronic. If necessary, ultrasounds may be compared over time to see whether a clot has grown or resolved.
  • Ultrasound is better at "seeing" the veins above the knee as compared to the small veins below the knee joint.
  • Clots in the chest or pelvis may not be identified on ultrasound.

D-Dimer

D-Dimer is a blood test that may be used as a screening test to determine if a blood clot exists. D-Dimer is a chemical that is produced when a blood clot in the body gradually dissolves. The test is used as a positive or negative indicator. If the result is negative, then in most cases no blood clot exists. If the D-Dimer test is positive, it does not necessarily mean that a deep vein thrombosis is present since many situations will have an expected positive result. Any bruise or blood clot will result in a positive D-Dimer result (for example, from surgery, a fall, in cancer or in pregnancy). For that reason, D-Dimer testing must be used selectively.

Other tests

  • Venography, injecting dye into the veins to look for a thrombus, is not usually performed anymore and has become more of a historical footnote.
  • Other blood testing may be considered based on the potential cause for the deep vein thrombosis.

What are the treatment and management guidelines for DVT? Does it go away?

The treatment for deep venous thrombosis is anticoagulation or "thinning the blood" with medications.

The recommended length of treatment for an uncomplicated DVT is three months. Depending upon the patient's situation, underlying medical conditions, and the reason for developing a blood clot, a longer duration of anticoagulation may be required. At three months, the doctor or otherhealth care professional should evaluate the patient in regard to the potential for future blood clot formation.

If the decision is made to continue with anticoagulation therapy for the long term, the risk/reward for preventing clots versus bleeding risks should be evaluated by your doctor.

What is the treatment of superficial blood clots?

Treatment for superficial thrombophlebitis treating the symptoms with:

  • Warm compresses
  • Leg compression
  • Anti-inflammatory medications such as ibuprofen (Motrin) or naproxen (Naproxen).

If the thrombophlebitis occurs near the groin where the superficial and deep systems join together, there is potential that the thrombus could extend into the deep venous system. These patients may require anticoagulation or blood thinning therapy.

What are the side effects and risks of anticoagulation therapy?

People who take anticoagulation medications are at risk for bleeding. The decision to use these medications must balance the risk and rewards of the treatment. Should bleeding occur, there are strategies available to reverse the anticoagulation effects.

Some people may have contraindications to anticoagulation therapy, for example a patient with bleeding in the brain, major trauma, or recent significant surgery. An alternative may be to place a filter in the inferior vena cava (the major vein that collects blood from both legs) to prevent emboli, should they arise, from reaching the heart and lungs. These filters may be effective but have the potential risk of being the source of new clot formation. An IVC filter is NOT recommended for patients who are also taking anticoagulation medications.

8 medications used for the treatment of DVT

Anticoagulation prevents further growth of the blood clot and prevents it from forming an embolus that can travel to the lung. The body has a complex mechanism to form blood clots to help repair blood vessel damage. There is a clotting cascade with numerous blood factors that have to be activated for a clot to form. There are difference types of medications that can be used for anticoagulation to treat DVT:

  1. Unfractionated heparin
  2. Low molecular weight heparin: enoxaparin (Lovenox)
  3. Novel oral anticoagulants (NOACs) also known as direct oral anticoagulants (DOACs) (Coumadin, Jantoven)

The American College of Chest Physicians has guidelines that give direction as to what medications might best be used in different situations. For example, a patient with a DVT, and no active cancer, treatment with a NOAC would be recommended. If active cancer exists, the treatment of DVT would be with enoxaparin as the drug of first choice.

NOACs work almost immediately to thin the blood and anticoagulate the patient. There is no need for blood tests to monitor dosing. The NOAC medications presently approved for deep vein thrombosis treatment include:

All four are also indicated to treat pulmonary embolism. They also may be prescribed to patients' anticoagulated with nonvalvular atrial fibrillation to prevent stroke and systemic embolus.

Warfarin (Coumadin, Jantoven)

Warfarin (Coumadin, Jantoven) is an anti-coagulation medication that acts as a Vitamin K antagonist, blocking blood-clotting factors II, VII, IX and X. Historically, it was a first-line medication for treating blood clots, but its role has been diminished because of the availability of newer drugs. While warfarin may be prescribed immediately after the diagnosis of DVT, it takes up to a week or more for it to reach therapeutic levels in the blood so that the blood is appropriately thinned. Therefore, low molecular weight heparin (enoxaparin [Lovenox)] is administered at the same time. Enoxaparin thins the blood almost immediately and is used as a bridge therapy until the warfarin has taken effect. Enoxaparin injections can be given on an outpatient basis. For those patients who have contraindications to the use of enoxaparin (for example, kidney failure does not allow the drug to be appropriately metabolized), intravenous heparin can be used as the first step in association with warfarin. This requires admission to the hospital. The dosage of warfarin is monitored by blood tests measuring the prothrombin time (PT), or INR (international normalized ratio).

Does DVT require surgery?

Surgery is a rare option in treating large deep venous thrombosis of the leg in patients who cannot take blood thinners or who have developed recurrent blood clots while on anti-coagulant medications. The surgery is usually accompanied by placing an IVC (inferior vena cava) filter to prevent future clots from embolizing to the lung.

Phlegmasia Cerulea Dolens describes a situation in which a blood clot forms in the iliac vein of the pelvis and the femoral vein of the leg, obstructing almost all blood return and compromising blood supply to the leg. In this case, surgery may be considered to remove the clot, but the patient will also require anti-coagulant medications. Stents may also be required to keep a vein open and prevent clotting. May Thurer Syndrome, also known as iliac vein compression syndrome, is a cause of phlegmasia, in which the iliac vein in the pelvis is compressed and a stent is needed.

What are the complications of DVT?

Pulmonary embolism is the major complication of deep vein thrombosis. With signs and symptoms such as chest pain and shortness of breath, it is a life-threatening condition. Most often pulmonary emboli arise from the legs.

Post-phlebitic syndrome can occur after a deep vein thrombosis. The affected leg or arm can become chronically swollen and painful with skin color changes and ulcer formation around the foot and ankle.

Is it possible to prevent DVT?

  • Minimize risk factors for DVT for example, quit smoking (especially if the person also is taking birth control pills or hormone therapy).
  • In the hospital setting, the staff works hard to provide DVT prophylaxis to minimize the potential for clot formation in immobilized patients. Surgery patients are out of bed walking (ambulatory) earlier and low dose heparin or enoxaparin is being used for deep vein thrombosis prophylaxis (measures taken to prevent DVT).
  • When traveling, it is recommended that you get up and walk every couple of hours during a long trip.

Which types of doctors treat DVT?

People with a swollen extremity or concern that a DVT exists may be cared for by a variety of health-care professionals. Both the primary care provider (including internal medicine and family medicine specialists) and a health care professional at in an urgent care (walk in) clinic or emergency department are able to recognize and diagnose the condition. Some people go to the hospital and the diagnosis is made there.

Treatment is usually started by the doctor who makes the diagnosis, but long-term treatment decisions, risk stratification, and follow-up usually is be done by the person's primary care doctor. Depending upon the situation, a hematologist (specialist in blood disorders) may be consulted. If there is need for the clot to be removed or dissolved, an interventional radiologist may also be involved.

Depending upon the medication used to anticoagulate the blood, pharmacists and anticoagulation nurses may also be involved on your treatment team.


NET basics

Neutrophils are essential for immune defense and prevention of microbial overgrowth. They are very abundant—around 100 billion are produced in a human’s bone marrow in a single day—and they circulate in the bloodstream to quickly infiltrate tissues if the neutrophils detect a microbial threat. Belonging to a class of white blood cells called granulocytes, they are characterized by a cytoplasm packed with granules containing antimicrobial proteins. Neutrophils can engulf pathogens and then fuse their granules with their phagosomes, which contain the internalized microbes. Alternatively, the cells can fuse their granules with the plasma membrane to release antimicrobials to attack extracellular parasites.

Research on neutrophils is complicated by the fact that they are short-lived cells. For instance, unlike some other human cell types, neutrophils cannot be cultured for more than a few hours, and they are not amenable to gene editing. For this reason, we still lack a detailed mechanistic picture of how exactly NETs are formed. Early reports confirmed the original hypothesis that NETs do not result from passive necrosis of neutrophils. Later studies added complexity by demonstrating that different inflammatory triggers induce various pathways that all lead to the release of NETs, and that NET release doesn’t always result in lysis of the neutrophil.

That said, most pathways of NET formation do kill the immune cell, typically as a result of the production of reactive oxygen species (ROS). Bacterial or fungal pathogens cause neutrophils to activate kinases that induce assembly of an enzyme complex called nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADPH oxidase then produces large amounts of superoxide—a highly reactive oxygen compound that carries an extra electron—during a process called the neutrophil oxidative burst. ROS resulting from the oxidative burst trigger disintegration of a multiprotein complex to release active NE, a primary component of NETs, into the cytoplasm. (See illustration on page 45.)

NE then migrates to the neutrophil’s nucleus, where it cleaves histones and other proteins to decondense the chromatin. Eventually, the chromatin fills up the entire cell until the cell lyses and extrudes the NET into the extracellular space, a process known as NETosis. We recently identified an important role for the pore-forming protein gasdermin D in both the nuclear expansion and the lysis processes, although the mechanisms aren’t yet clear. In the extracellular space, the webs are thought to trap and kill the triggering pathogens.


The lungs as a route of drug administration

Following logically from the above, the lung can be used as a means of administering therapeutic substances, whether to the alveoli locally or to achieve a systemic effect. Patton & Byron (2007) give an excellent overview. In brief, in order for a drug to be well absorbed by the lung, the drug delivery vehicle has to have certain characteristics:

  • Small size: the droplets should be smaller 5 μm in diameter if you intend for them to get out into the systemic circulation (conversely, if your target is the mucosa, feel free to inundate the upper airway with comically huge droplets)
  • High lipid solubility and small molecule size: large molecules, eg. proteins, will tend to be mopped up by alveolar macrophages.
  • It helps to be recognised as something useful: for instance, the relatively huge IgG molecules (150 kDa) are absorbed relatively rapidly by active transcytosis. This allows the noninvasive delivery of large molecules
  • Technique matters: for example, inhaling rapidly may increase or decrease the alveolar delivery of drug particles, depending on particle size
  • The excipients of the pharmaceutic preparation must be relatively benign, i.e. one would not want to go to market with an inhaler which causes some sort of pneumoconiosis with prolonged use.
  • Unless you specifically want this, it would be important to make sure the drug does not have some sort of weird preference for binding to lung tissue. Particularly, lipophilic drugs with a positive charge tend to do this. Examples of intentional retention in lung tissue are steroids like formoterol and salmeterol and antibiotics like tobramycin and pentamidine. In contrast, the binding of verapamil to lung tissue is completely pointless.

Clots, Strokes And Rashes. Is COVID -19 A Disease Of The Blood Vessels?

Clots, Strokes And Rashes. Is COVID-19 A Disease Of The Blood Vessels?

Whether it's strange rashes on the toes or blood clots in the brain, the widespread ravages of COVID-19 have increasingly led researchers to focus on how the novel coronavirus sabotages the body's blood vessels.

As scientists have come to know the disease better, they have homed in on the vascular system — the body's network of arteries, veins and capillaries, stretching more than 60,000 miles — to understand this wide-ranging disease and to find treatments that can stymie its most pernicious effects.

Some of the earliest insights into how COVID-19 can act like a vascular disease came from studying the aftermath of the most serious infections. Those reveal that the virus warps a critical piece of our vascular infrastructure: the single layer of cells lining the inside of every blood vessel, known as the endothelial cells or simply the endothelium.

Dr. William Li, a vascular biologist, compares this lining to a freshly resurfaced ice skating rink before a hockey game on which the players and pucks glide smoothly along.

"When the virus damages the inside of the blood vessel and shreds the lining, that's like the ice after a hockey game," says Li, a researcher and founder of the Angiogenesis Foundation. "You wind up with a situation that is really untenable for blood flow."

In a study published this summer, Li and an international team of researchers compared the lung tissues of people who died from COVID-19 with those who died from influenza.

They found stark differences: The lung tissues of COVID-19 patients had nine times as many tiny blood clots ("microthrombi'') compared with those of the influenza patients, and the coronavirus-infected lungs also exhibited "severe endothelial injury."

"The surprise was that this respiratory virus makes a beeline for the cells lining blood vessels, filling them up like a gumball machine and shredding the cell from the inside out," Li says. "We found blood vessels are blocked and blood clots are forming because of that lining damage."

It's already known that the coronavirus breaks into cells by way of a specific receptor, called ACE2, which is found all over the body. But scientists are still trying to understand how the virus sets off a cascade of events that cause so much destruction to blood vessels. Li says one theory is that the virus directly attacks endothelial cells. Lab experiments have shown that the coronavirus can infect engineered human endothelial cells.

It's also possible the problems begin elsewhere, and the endothelial cells sustain collateral damage along the way as the immune system reacts — and sometimes overreacts — to the invading virus.

Endothelial cells have a slew of important jobs these include preventing clotting, controlling blood pressure, regulating oxidative stress and fending off pathogens. And Li says uncovering how the virus jeopardizes the endothelium may link many of COVID-19's complications: "The effects in the brain, the blood clots in the lung and elsewhere in the legs, the COVID toe, the problem with the kidneys and even the heart."

In Spain, skin biopsies of distinctive red lesions on toes, known as chilblains, found viral particles in the endothelial cells, leading the authors to conclude that "endothelial damage induced by the virus could be the key mechanism."

Could the lining of our blood vessels be a common denominator?

With a surface area larger than a football field, the endothelium helps maintain a delicate balance in the bloodstream. These cells are essentially the "gatekeeper" to the bloodstream.

"The endothelium has developed a distant early warning system to alert the body to get ready for an invasion if there's trouble brewing," says Peter Libby, a cardiologist and research scientist at Harvard Medical School.

When that happens, endothelial cells change the way they function, he says. But that process can also go too far.

"The very functions that help us maintain health and fight off invaders, when they run out of control, then it can actually make the disease worse," Libby says.

In that case, the endothelial cells turn against their host and start to promote clotting and high blood pressure.

"In COVID-19 patients, we have both of these markers of dysfunction," says Gaetano Santulli, a cardiologist and researcher at the Albert Einstein College of Medicine in New York City.

The novel coronavirus triggers a condition seen in other cardiovascular diseases called endothelial dysfunction. Santulli, who wrote about this idea in the spring, says that may be the "cornerstone" of organ dysfunction in COVID-19 patients.

"The common denominator in all of these COVID-19 patients is endothelial dysfunction," he says. "It's like the virus knows where to go and knows how to attack these cells."

A runaway immune response adds a plot twist

A major source of damage to the vascular system likely also comes from the body's own runaway immune response to the novel coronavirus.

"What we see with the SARS-CoV-2 is really an unprecedented level of inflammation in the bloodstream," says Yogen Kanthi, a cardiologist and vascular medicine specialist at the National Institutes of Health, who's researching this phase of the illness.

"This virus is leveraging its ability to create inflammation, and that has these deleterious, nefarious effects downstream."

When inflammation spreads through the inner lining of the blood vessels — a condition called endothelialitis — blood clots can form throughout the body, starving tissues of oxygen and promoting even more inflammation.

"We start to get this relentless, self-amplifying cycle of inflammation in the body, which can then lead to more clotting and more inflammation," Kanthi says.

Another sign of endothelial damage comes from analyzing the blood of COVID-19 patients. A recent study found elevated levels of a protein produced by endothelial cells, called Von Willebrand factor, which is involved in clotting.

"They are through the roof in those who are critically ill," says Alfred Lee, a hematologist at the Yale Cancer Center, who coauthored the study with Hyung Chun, a cardiologist and vascular biologist at Yale.

Lee points out that some autoimmune diseases can lead to a similar interplay of clotting and inflammation called immunothrombosis.

Chun says the elevated levels of Von Willebrand factor show that vascular injury can be detected in patients while in the hospital — and perhaps even before, which could help predict their likelihood of developing more serious complications.

But he says it's not yet clear what's the driving force behind the blood vessel damage: "It does seem to be a progression of disease that really brings out this endothelial injury the key question is what's the root cause of this?"

After they presented their data, Lee says Yale's hospital system started putting patients who were critically ill with COVID-19 on aspirin, which can prevent clotting. While the best combinations and dosages are still being studied, research indicates that blood thinners may improve outcomes in COVID-19 patients.

Chun says treatments are also being studied that may more directly protect endothelial cells from the coronavirus.

"Is that the end-all be-all to treating COVID-19? I absolutely don't think so. There's so many aspects of the disease that we still don't understand," he says.

COVID-19 as a vascular ''stress test'' for people with preexisting vascular problems

Early in the pandemic, Roger Seheult, a critical care and pulmonary physician in Southern California, realized the patients he expected to be most vulnerable to a respiratory virus, those with underlying lung conditions such as chronic obstructive pulmonary disease and asthma, were not the ones ending up disproportionately in his intensive care unit.

Seheult, who runs the popular medical education website called MedCram, says, "Instead, what we are seeing are patients who are obese, people who have large BMIs, people who have Type 2 diabetes and with high blood pressure."

Over time, all of those conditions can cause inflammation and damage to the lining of blood vessels, he says, including a harmful chemical imbalance known as oxidative stress. Seheult says infection with the coronavirus becomes an added stress for people with those conditions that already tax the blood vessels.

"If you're right on the edge and you get the wind blown from this coronavirus, now you've gone over the edge."

He says the extensive damage to blood vessels could explain why COVID-19 patients with severe respiratory problems don't necessarily resemble patients who get sick from the flu.

"They are having shortness of breath, but we have to realize the lungs are more than just the airways," he says. "It's an issue with the blood vessels themselves."

This is why COVID-19 patients struggle to fill their blood supply with oxygen, even when air is being pumped into their lungs.

"The endothelial cells get leaky, so instead of being like Saran Wrap, it turns into a sieve and then it allows fluid from the bloodstream to accumulate in the airspaces," Harvard's Libby says.

Doctors who treat COVID-19 are now keenly aware that complications such as strokes and heart problems can appear, even after a patient gets better and their breathing improves.

"They are off oxygen, they can be discharged home, but their vasculature is not completely resolved, they still have inflammation," he says. "What can happen is they develop a blood clot, and they have a massive pulmonary embolism."

Patients can be closely monitored for these problems, but one of the big unknowns for doctors and patients are the long-term effects of COVID-19 on the circulatory system.

The Angiogenesis Foundation's Li puts it this way: "The virus enters your body and it leaves your body. You might or might not have gotten sick. But is that leaving behind a trashed vascular system?"

Copyright 2020 Kaiser Health News. To see more, visit Kaiser Health News.

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Other medical conditions

Certain medical conditions can increase your risk of developing a DVT. Some conditions are more closely linked to developing VTE than others and include the following:

  • Spinal cord injury. In addition to damaging veins deep in your body, spinal cord injury may cause paralysis, which can reduce blood flow and raise your risk of VTE. The risk is highest in the first weeks after the injury.
  • A broken hip or leg bone or other trauma.
  • Cancers such as advanced brain, breast, colon, and pancreatic cancer. Cancer chemotherapy, surgical treatment, and placement of a central venous catheter—a tube inserted into a vein to deliver chemotherapy treatment or other medicine—all increase the risk of VTE. Some cancers release substances that can make it easier for blood to clot. Some cancerous tumors may directly block blood flow by pressing on a vein. A central venous catheter increases the risk for VTE in arm veins, especially in children.
  • Heart conditions such as heart attack or congestive heart failure. . Most varicose veins do not cause problems, but large, untreated varicose veins can lead to VTE.
  • Infections, such as SARS-CoV-2, the virus responsible for COVID-19. Watch our video to learn more about how COVID-19 can lead to a blood clot in the lungs or deep veins, usually in the legs.” Additionally, we offer information and resources on how we are working hard to support necessary COVID-19 research. . This condition makes the blood clot more easily and can be a risk factor for VTE.

Clots, Strokes And Rashes. Is COVID-19 A Disease Of The Blood Vessels?

Whether it's strange rashes on the toes or blood clots in the brain, the widespread ravages of COVID-19 have increasingly led researchers to focus on how the novel coronavirus sabotages the body's blood vessels.

As scientists have come to know the disease better, they have homed in on the vascular system — the body's network of arteries, veins and capillaries, stretching more than 60,000 miles — to understand this wide-ranging disease and to find treatments that can stymie its most pernicious effects.

Some of the earliest insights into how COVID-19 can act like a vascular disease came from studying the aftermath of the most serious infections. Those reveal that the virus warps a critical piece of our vascular infrastructure: the single layer of cells lining the inside of every blood vessel, known as the endothelial cells or simply the endothelium.

Dr. William Li, a vascular biologist, compares this lining to a freshly resurfaced ice skating rink before a hockey game on which the players and pucks glide smoothly along.

"When the virus damages the inside of the blood vessel and shreds the lining, that's like the ice after a hockey game," says Li, a researcher and founder of the Angiogenesis Foundation. "You wind up with a situation that is really untenable for blood flow."

In a study published this summer, Li and an international team of researchers compared the lung tissues of people who died from COVID-19 with those who died from influenza.

They found stark differences: The lung tissues of COVID-19 patients had nine times as many tiny blood clots ("microthrombi'') compared with those of the influenza patients, and the coronavirus-infected lungs also exhibited "severe endothelial injury."

Shots - Health News

Studies Point To Big Drop In COVID-19 Death Rates

"The surprise was that this respiratory virus makes a beeline for the cells lining blood vessels, filling them up like a gumball machine and shredding the cell from the inside out," Li says. "We found blood vessels are blocked and blood clots are forming because of that lining damage."

It's already known that the coronavirus breaks into cells by way of a specific receptor, called ACE2, which is found all over the body. But scientists are still trying to understand how the virus sets off a cascade of events that cause so much destruction to blood vessels. Li says one theory is that the virus directly attacks endothelial cells. Lab experiments have shown that the coronavirus can infect engineered human endothelial cells.

It's also possible the problems begin elsewhere, and the endothelial cells sustain collateral damage along the way as the immune system reacts — and sometimes overreacts — to the invading virus.

Endothelial cells have a slew of important jobs these include preventing clotting, controlling blood pressure, regulating oxidative stress and fending off pathogens. And Li says uncovering how the virus jeopardizes the endothelium may link many of COVID-19's complications: "The effects in the brain, the blood clots in the lung and elsewhere in the legs, the COVID toe, the problem with the kidneys and even the heart."

In Spain, skin biopsies of distinctive red lesions on toes, known as chilblains, found viral particles in the endothelial cells, leading the authors to conclude that "endothelial damage induced by the virus could be the key mechanism."

Could the lining of our blood vessels be a common denominator?

With a surface area larger than a football field, the endothelium helps maintain a delicate balance in the bloodstream. These cells are essentially the "gatekeeper" to the bloodstream.

"The endothelium has developed a distant early warning system to alert the body to get ready for an invasion if there's trouble brewing," says Peter Libby, a cardiologist at Brigham and Women's Hospital and research scientist at Harvard Medical School.

When that happens, endothelial cells change the way they function, he says. But that process can also go too far.

"The very functions that help us maintain health and fight off invaders, when they run out of control, then it can actually make the disease worse," Libby says.

In that case, the endothelial cells turn against their host and start to promote clotting and high blood pressure.

"In COVID-19 patients, we have both of these markers of dysfunction," says Gaetano Santulli, a cardiologist and researcher at the Albert Einstein College of Medicine in New York City.

The novel coronavirus triggers a condition seen in other cardiovascular diseases called endothelial dysfunction. Santulli, who wrote about this idea in the spring, says that may be the "cornerstone" of organ dysfunction in COVID-19 patients.

"The common denominator in all of these COVID-19 patients is endothelial dysfunction," he says. "It's like the virus knows where to go and knows how to attack these cells."

A runaway immune response adds a plot twist

A major source of damage to the vascular system likely also comes from the body's own runaway immune response to the novel coronavirus.

"What we see with the SARS-CoV-2 is really an unprecedented level of inflammation in the bloodstream," says Yogen Kanthi, a cardiologist and vascular medicine specialist at the National Institutes of Health, who's researching this phase of the illness.

"This virus is leveraging its ability to create inflammation, and that has these deleterious, nefarious effects downstream."

When inflammation spreads through the inner lining of the blood vessels — a condition called endothelialitis — blood clots can form throughout the body, starving tissues of oxygen and promoting even more inflammation.

"We start to get this relentless, self-amplifying cycle of inflammation in the body, which can then lead to more clotting and more inflammation," Kanthi says.

Another sign of endothelial damage comes from analyzing the blood of COVID-19 patients. A recent study found elevated levels of a protein produced by endothelial cells, called Von Willebrand factor, which is involved in clotting.

"They are through the roof in those who are critically ill," says Alfred Lee, a hematologist at the Yale Cancer Center, who coauthored the study with Hyung Chun, a cardiologist and vascular biologist at Yale.

Lee points out that some autoimmune diseases can lead to a similar interplay of clotting and inflammation called immunothrombosis.

Chun says the elevated levels of Von Willebrand factor show that vascular injury can be detected in patients while in the hospital — and perhaps even before, which could help predict their likelihood of developing more serious complications.

But he says it's not yet clear what's the driving force behind the blood vessel damage: "It does seem to be a progression of disease that really brings out this endothelial injury the key question is what's the root cause of this?"

After they presented their data, Lee says Yale's hospital system started putting patients who were critically ill with COVID-19 on aspirin, which can prevent clotting. While the best combinations and dosages are still being studied, research indicates that blood thinners may improve outcomes in COVID-19 patients.

Chun says treatments are also being studied that may more directly protect endothelial cells from the coronavirus.

"Is that the end-all be-all to treating COVID-19? I absolutely don't think so. There's so many aspects of the disease that we still don't understand," he says.

COVID-19 as a vascular ''stress test'' for people with preexisting vascular problems

Early in the pandemic, Roger Seheult, a critical care and pulmonary physician in Southern California, realized the patients he expected to be most vulnerable to a respiratory virus, those with underlying lung conditions such as chronic obstructive pulmonary disease and asthma, were not the ones ending up disproportionately in his intensive care unit.

Seheult, who runs the popular medical education website called MedCram, says, "Instead, what we are seeing are patients who are obese, people who have large BMIs, people who have Type 2 diabetes and with high blood pressure."

Over time, all of those conditions can cause inflammation and damage to the lining of blood vessels, he says, including a harmful chemical imbalance known as oxidative stress. Seheult says infection with the coronavirus becomes an added stress for people with those conditions that already tax the blood vessels.

"If you're right on the edge and you get the wind blown from this coronavirus, now you've gone over the edge."

He says the extensive damage to blood vessels could explain why COVID-19 patients with severe respiratory problems don't necessarily resemble patients who get sick from the flu.

"They are having shortness of breath, but we have to realize the lungs are more than just the airways," he says. "It's an issue with the blood vessels themselves."

This is why COVID-19 patients struggle to fill their blood supply with oxygen, even when air is being pumped into their lungs.

"The endothelial cells get leaky, so instead of being like Saran Wrap, it turns into a sieve and then it allows fluid from the bloodstream to accumulate in the airspaces," Harvard's Libby says.

Doctors who treat COVID-19 are now keenly aware that complications such as strokes and heart problems can appear, even after a patient gets better and their breathing improves.

"They are off oxygen, they can be discharged home, but their vasculature is not completely resolved, they still have inflammation," he says. "What can happen is they develop a blood clot, and they have a massive pulmonary embolism."

Patients can be closely monitored for these problems, but one of the big unknowns for doctors and patients are the long-term effects of COVID-19 on the circulatory system.

The Angiogenesis Foundation's Li puts it this way: "The virus enters your body and it leaves your body. You might or might not have gotten sick. But is that leaving behind a trashed vascular system?"


Your respiratory system has built-in methods to keep harmful things in the air from entering your lungs.

Hairs in your nose help filter out large particles. Tiny hairs, called cilia, along your air passages move in a sweeping motion to keep the passages clean. But if you breathe in harmful things like cigarette smoke, the cilia can stop working. This can lead to health problems like bronchitis.

Continued

Cells in your trachea and bronchial tubes make mucus that keeps air passages moist and helps keep things like dust, bacteria and viruses, and allergy-causing things out of your lungs.

Mucus can bring up things that reach deeper into your lungs. You then cough out or swallow them.


Excessive lung release of neutrophil DNA traps may explain severe complications in COVID-19 patients

A multidisciplinary team of researchers from the University of Liège (Belgium) has detected significant amounts of DNA traps in distinct compartments of the lungs of patients who died from Covid-19. These traps, called NETs, are released massively into the airways, the lung tissue and the blood vessels. Such excessive release could be a major contributor to severe disease complications leading to in-hospital death. These results are published this week in the Journal of Experimental Medicine.

Neutrophils are innate immune cells that act as the immune system's first line of defence. However, when over-activated, they can play a toxic role, as in the case of autoimmune diseases and chronic inflammatory diseases, for example. Neutrophils have the ability to release their own DNA through DNA traps called Neutrophil Extracellular Traps or NETs. When massively released in certain compartments of the lungs, they can cause toxic effects.

"Here, we have detected substantial quantities of NETs in distinct compartments of the lungs of patients who died from Covid-19 at the University Hospital (CHU) of Liège and who exhibited histo-pathological features of diffuse alveolar damage, whereas these DNA traps were absent in the lungs of patients who died from another cause," explains Prof. Thomas Marichal, Welbio and ERC Investigator, head of the Immunophysiology Laboratory at the GIGA Institute of the University of Liège. The presence of NETs in the blood vessels, pulmonary interstitium and airways could explain the formation of fibrin-rich clots underlying highly prevalent thrombotic events and different aspects of lung damage resulting from an uncontrolled activation of the immune system leading to the "cytokine storm."

Also composed of Prof. Cécile Oury (Fund for Scientific Research -- F.R.S.-FNRS, Head of the Cardiology Laboratory, GIGA, ULiège) and Prof. Philippe Delvenne (Head of Pathological Anatomy Laboratory of the CHU of Liège, Director of the Laboratory of Experimental Pathology, ULiège) and Dr Coraline Radermecker (Postdoctoral Research for the Fund for Scientific Research -- FNRS at the Laboratory of Immunophysiology, GIGA, ULiège), the research team was able to characterize the presence and precise localization of NETs in the lungs using imaging techniques associated with histopathological analyses.

"We are the first team in the world to identify the presence of NETs in several compartments of the lungs of patients with Covid-19," explains Coraline Radermecker, first author of this study published in the Journal of Experimental Medicine.

"Clinical trials aimed at degrading these NETs in the hope of improving the condition of patients with advanced disease are being conducted by other teams around the world. Our study validates these therapeutic approaches by demonstrating that NETs are associated with the severe complications of Covid 19," added Thomas Marichal.

"NET-targeting pharmacological approaches exist, with drugs already available, such as dornase alfa used in cystic fibrosis," explains Cécile Oury. As part of the prevention and treatment of thrombotic complications, she also stresses the need to implement current heparin-based recommendations. The fight against the excessive release of NETs appears to be a complementary route that could prove efficacy.

"We will now continue our research on the effects of Covid 19 on other organs, including the heart, another organ frequently affected in this disease, and further refine our knowledge of the mechanisms that lead to severe forms of the disease," Thomas Marichal concludes.


Smoking & Homeostasis

Effects of smoking on homeostatic balance

When a cigarette is lit, heat causes the chemicals in the tobacco to be released. These chemicals are then ingested as a person inhales the smoke released from the cigarette. These released chemicals and substances travel through the trachea, bronchi and bronchioles until they reach the alveoli. They are then quickly absorbed into the blood stream across the thin alveolar walls into the surrounding capillary network. As a major part of the body’s first line of defence, the internal surface of the trachea, bronchi, and bronchioles is lined with small hairs called cilia. The cilia beat rhythmically to remove the lining of mucus, produced by goblet cells, which acts as a barrier to trap and prevent foreign and harmful particles from entering the blood (Huxley & Walter, 2005).Unfortunately, the tobacco smoke causes the cilia to stop beating (Roberts & Ingram, 2001), resulting in a build-up of mucus within the lungs. Without the natural movement of this mucus to the mouth and nasal passages, the trapped toxins are unable to be removed, thus resulting in a higher susceptibility to respiratory infections (Pietrangelo, 2014). Prolonged exposure to such infections results in cell damage which in turn may result in lung cancer or emphysema.

Nicotine, a chemical compound found in tobacco (Dr Ananya Mandal, 2014), is well known for its highly addictive nature. This mood-altering drug is a stimulant that gives the smoker a high (Pietrangelo, 2014), so when the smoke from the cigarette is inhaled, the nicotine is absorbed into the bloodstream through the alveolar walls, where it is delivered to the brain almost instantaneously. Once there, the nicotine activates the brain’s ‘pleasure centre’ (sciencemuseum.org, Unknown), and being a stimulant, this results in the smoker feeling energised and happy. However, the stimulating effects of the nicotine subside soon after it reaches the brain, leaving the smoker tired, and as a result craving more. When under stress, the brain releases a hormone called corticosterone. This stress hormone acts as a suppressant which in turn lowers the effects of nicotine. This means a larger quantity of nicotine is required to achieve the desired effect (Pietrangelo, 2014).

Among the list of harmful substances travelling through the lungs is carbon-monoxide. This poisonous gas is diffused into the capillary network much like nicotine. Once there, it binds with passing red blood cells containing a complex protein by the name of haemoglobin. Despite its affinity for oxygen, its affinity for carbon-monoxide is stronger, resulting in these molecules taking the place of oxygen. By preventing the uptake of this much needed oxygen, the body is deprived of an essential element, thus causing an accumulation of carbon-dioxide which in turn alters pH levels in tissue fluids (Huxley & Walter, 2005). With increased exposure to these chemicals the alveolar walls lose their elasticity, impacting the effective exchange of gasses. This loss of elasticity results in an increased difficulty to transfer oxygen and carbon-dioxide (Association, 2008). This means that every time a person smokes, their tissues are deprived of oxygen and the lungs begin to lose their ability to function.

Contributing also to the deprivation of oxygen is once again nicotine. The nicotine causes blood vessels to vasoconstrict, which decreases and, in some cases, blocks the flow of blood to the heart. However, this does not only impact oxygen delivery, but due to the cessation of blood flow, the heart is unable to function normally, resulting in heart failure and/or a heart attack. In extreme cases, this will often lead to death. Nicotine also causes changes within the blood itself such as the clustering of platelets and decreased

clotting time. This leads to clots within the blood which may also result in a heart attack (Metrohealth, Unknown). However, if one of these clots happens to reach the brain, a stroke is likely to occur as a result of this blockage. A stroke will result in major, and usually permanent, health issues such as paralysis in part of the body or even death (Staff, 2015).

One of the body’s core homeostatic mechanisms is the ability of the heart to alter the rate of blood flow throughout the body, so as to ensure conditions within the body remain constant. A lack of oxygen in the body causes the stimulation of receptors in the medulla, and carotid and aortic bodies which act to regulate the imbalance of carbon-dioxide. The heart rate, controlled by a centre in the brain, is increased so as to ensure a rapid delivery of oxygen to deficient areas and carbon-dioxide to the lungs. The thoracic muscles are also stimulated to increase the rate of ventilation which removes the excess carbon-dioxide from the body. Included within these reactions is the vasodilation of blood vessels to remove the unwanted carbon-dioxide. However, despite the increase in the removal CO2, there is still limited oxygen which cannot sufficiently service all areas. This means the homeostatic mechanism of negative feedback is unable to reverse these actions as the balance is not achieved. Not only does this place immense strain on the heart and lungs, but brain cells, requiring a constant level of oxygen are unable to function, thus resulting in further homeostatic imbalance (Huxley & Walter, 2005). Moreover, these brain cells, if not fed oxygen, will die resulting in a possible stroke, or brain damage (Staff, 2015).

Further affected by this imbalance is the ability of the body to maintain a constant internal temperature, allowing for the normal function of cells and systems. This mechanism, known as endothermy, relies on an effective double circulation in which oxygenated and de-oxygenated blood is completely separated. With the heart continuously pumping oxygen poor blood, tissues are deprived of oxygen, affecting constant cell metabolism, and the uptake of oxygen from respiratory surfaces becomes less effective. As the heart continues to pump at an increased rate, the release of energy in the form of heat is also increased. This results in an increased body temperature in which enzymes requiring an optimum temperature are denatured. In turn, this reduces the body’s ability to effectively metabolise. Without the proper functioning of this vital mechanism, the homeostatic balance becomes further imbalanced (Huxley & Walter, 2005).

Overall it can be seen that smoking poses an immense risk to the body and its systems. Affecting both structure and function, the body's ability to maintain homeostasis is thrown out of balance, resulting in major health issues that will affect a person both in the short term and in the long term.