ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome

Authors: ALEXANDER T. BAKERHTTPS://ORCID.ORG/0000-0001-8232-0531RYAN J. BOYDHTTPS://ORCID.ORG/0000-0002-6704-8696DAIPAYAN SARKARHTTPS://ORCID.ORG/0000-0002-4167-2108ALICIA TEIJEIRA-CRESPOCHUN KIT CHANEMILY BATESHTTPS://ORCID.ORG/0000-0003-1378-6981KASIM WARAICHHTTPS://ORCID.ORG/0000-0002-2927-7383JOHN VANTHTTPS://ORCID.ORG/0000-0003-0627-4603ERIC WILSONHTTPS://ORCID.ORG/0000-0002-4104-1445[…]MITESH J. BORADHTTPS://ORCID.ORG/0000-0003-2700-2658 +16 authors Authors Info & Affiliations

Abstract

Vaccines derived from chimpanzee adenovirus Y25 (ChAdOx1), human adenovirus type 26 (HAdV-D26), and human adenovirus type 5 (HAdV-C5) are critical in combatting the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic. As part of the largest vaccination campaign in history, ultrarare side effects not seen in phase 3 trials, including thrombosis with thrombocytopenia syndrome (TTS), a rare condition resembling heparin-induced thrombocytopenia (HIT), have been observed. This study demonstrates that all three adenoviruses deployed as vaccination vectors versus SARS-CoV-2 bind to platelet factor 4 (PF4), a protein implicated in the pathogenesis of HIT. We have determined the structure of the ChAdOx1 viral vector and used it in state-of-the-art computational simulations to demonstrate an electrostatic interaction mechanism with PF4, which was confirmed experimentally by surface plasmon resonance. These data confirm that PF4 is capable of forming stable complexes with clinically relevant adenoviruses, an important step in unraveling the mechanisms underlying TTS.

For Detailed Study Information: https://www.science.org/doi/10.1126/sciadv.abl8213

Something Really Strange Is Happening At Hospitals All Over America

Authors: Authored by Michael Snyder via TheMostImportantNews.com, TURSDAY, NOV 04, 2021 – 05:11

In a year that has been filled with so many mysteries already, I have another very odd one to share with you.  Emergency rooms are filled to overflowing all over America, and nobody can seem to explain why this is happening.  Right now, the number of new COVID cases in the United States each day is less than half of what it was just a couple of months ago.  That is really good news, and many believe that this is a sign that the pandemic is fading.  Let us hope that is true.  With less people catching the virus, you would think that would mean that our emergency rooms should be emptying out, but the opposite is actually happening.  All across the country, emergency rooms are absolutely packed, and in many cases we are seeing seriously ill patients being cared for in the hallways because all of the ER rooms are already full.

Let me give you an example of what I am talking about.  The following comes from an article entitled “ERs Are Swamped With Seriously Ill Patients, Although Many Don’t Have Covid”

Inside the emergency department at Sparrow Hospital in Lansing, Michigan, staff members are struggling to care for patients showing up much sicker than they’ve ever seen.

Tiffani Dusang, the ER’s nursing director, practically vibrates with pent-up anxiety, looking at patients lying on a long line of stretchers pushed up against the beige walls of the hospital hallways. “It’s hard to watch,” she said in a warm Texas twang.

But there’s nothing she can do. The ER’s 72 rooms are already filled.

Can anyone explain why this is happening?

If the number of COVID cases was starting to spike again, it would make sense for emergency rooms to be overflowing.

But at this particular hospital in Michigan, we are being told that some of the main things that are being treated include “abdominal pain”, “respiratory problems”, “blood clots” and “heart conditions”

Months of treatment delays have exacerbated chronic conditions and worsened symptoms. Doctors and nurses say the severity of illness ranges widely and includes abdominal pain, respiratory problems, blood clots, heart conditions and suicide attempts, among other conditions.

That mention of “heart conditions” immediately got my attention, because I have been seeing this so much in the news recently.

For instance, a high school senior in Pennsylvania just dropped dead from “a sudden cardiac incident”

The high school soccer manager ‘greatly enjoyed’ his team’s championship victory Saturday. Later that evening, he was dead.

Now, late student Blake Barklage’s high school is mourning his untimely death. As 6ABC in Philly reports, the tragedy occurred at La Salle College High School in Montgomery County, Pa.

In a letter to parents, the school announced that the senior died after ‘a sudden cardiac incident’ Saturday night.

Elsewhere in the same state, an otherwise healthy 12-year-old boy just suddenly died because of an issue with his coronary artery…

As family and friends grieve, the cause of death is in for a 12-year-old taken way too soon while warming up for school basketball practice.

As TribLive in Pittsburgh reports, Jayson Kidd, 12, of Bridgeville, Pa., died of natural causes involving his coronary artery, according to the Allegheny County Medical Examiner’s Office.

Heart problems kill elderly people all the time, but it is odd that so many healthy young people have been having these problems.

Over the weekend, Barcelona striker Sergio Aguero suddenly collapsed on the pitch during a match.

He was later diagnosed with “a cardiac arrhythmia”

Sergio “Kun” Aguero, a striker for the Barcelona soccer team, has been diagnosed with a cardiac arrhythmia after collapsing during Saturday’s match against Alaves.

The 33-year-old Argentinian was examined by medical staff at the stadium before being taken to a nearby hospital where he is still waiting to undergo further examination.

Just two days later, a match in Norway was brought to a screeching halt after a player experienced “cardiac arrest” right in the middle of a match…

A football match in Norway’s second division was halted on Monday after Icelandic midfielder Emil Pálsson suffered a cardiac arrest during play.

The 28-year-old Sogndal player suffered the attack as the game against Stjordals-Blink entered the 12th minute, his club said in a statement.

I have been seeing so many stories like this.

So why are so many young people suddenly having such serious problems with their hearts?

Can anyone out there explain this to me?

Eyes can be infected by COVID-19: 4 things to know

Authors: Gabrielle Masson – Wednesday, May 19th, 2021 Print 

Cells in the eye can be directly infected by SARS-CoV-2, the virus that causes COVID-19, according to findings published May 17 by ScienceDirect. 

Below are four things to know about COVID-19 infections of the eye:

1. Researchers exposed adult human eyes to SARS-CoV-2 in an in vitro stem cell model and then studied them after 24 hours. The virus is able to infect surface cells of the eye, the researchers found. Ocular surface cells, particularly the limbus, were particularly susceptible to infection, while the central cornea was less vulnerable.

2. Researchers are currently trying to determine if the virus can be spread through the eyes, Timothy Blenkinsop, PhD, study author and assistant professor of cell, developmental and regenerative biology at New York City-based Mount Sinai Health System, told Becker’s. While aerosol transmission is thought to be the primary route of spread, viral particles detected in ocular fluid suggest the eye may be a vulnerable point of viral entry. However, scientists don’t have evidence to back the theory up yet, in part because it is difficult to develop experiments where nasal infections don’t complicate the results. 

3. To prevent the transmission of COVID-19, people in dense areas that aren’t well ventilated would benefit from eye protection. Front-line providers should definitely have eye protection, Dr. Blenkinsop said, which is already fairly standard in the U.S.  

4. Other studies have found a significant number of patients with severe COVID-19 experience abnormal nodules of the eye. Three recent reports showed retinal findings, such as hemorrhages, cotton wool spots, dilated veins or tortuous vessels, are possibly tied to COVID-19.

COVID-19 patients may develop skin rashes and discoloration, studies find

Authors: By Jacqueline Howard, CNN | Posted – Aug. 5, 2020 at 2:36 p.m.

CNN — As Covid-19 started to spread across the United States earlier this year, dermatology offices began to see suspicious signs on some patients’ skin: Red or purple toes, itchy hives, mottled bumps on fingers, a lacy red rash that spread across legs and arms.

But were those truly associated with the novel coronavirus? After all, many other factors could be at play.

“Many viral infections can trigger a skin rash, so when you catalog these case reports, you have to have other data. Was the patient on a medication a week before the rash began? Are there other possible causes?” asked Dr. Art Papier, an associate professor of dermatology at the University of Rochester Medical Center in New York.

“This is the challenge that Covid-19 brings up. With these different types of presentations and different rashes, is it hives because the patient just has hives or hives related to Covid-19?”

Case reports began to be released in medical journals. The latest, published Wednesday in the journal JAMA Dermatology, describes the experiences of four patients with severe Covid-19 who were admitted to hospitals in New York City in March and April.

The patients, ages 40 to 80, had discoloration of their skin as well as lesions called retiform purpura, according to the research report.

Biopsies were performed for each patient and they showed that the patients had a type of vasculopathy, meaning that their blood vessels were affected.

The researchers — from NewYork-Presbyterian/Weill Cornell Medical College — wrote in their report that the skin discoloration could represent partial occlusion or blockage of blood vessels, and the retiform purpura could represent full blockage.

Such rashes and discoloration of the skin can be a “clinical clue” to there being possible blood clotting in the body, the study said. Since early on in the pandemic, doctors have noticed that severe Covid-19 could cause abnormal blood clotting in patients.

The report comes with some limitations, including that the researchers were not able to confirm the precise timing of when rashes and other issues with the skin first appeared for each patient. Also, more research is needed to determine whether similar findings would emerge among a larger group of Covid-19 patients.

Yet overall, the researchers wrote in their report that physicians caring for Covid-19 patients should be aware of skin discoloration and rashes as “potential manifestations” of abnormal underlying blood clotting.

‘Many viral infections can affect the skin’

Doctors and researchers from around the world also have reported about other types of skin rashes among Covid-19 patients.

Covid-19 often triggers significant inflammation in its victims, in some cases producing the so-called cytokine storm that appears to be causing the worst damage in advanced patients.

The skin is particularly sensitive to inflammation, said board certified dermatologist Dr. Seemal Desai, a spokesperson for the American Academy of Dermatology.

“The cytokines that are cranking up the immune engine of the car is what then triggers a variety of these immune molecules to go into the skin and wreak havoc on the skin,” said Desai, a dermatologist in Plano, Texas.

In July, researchers from King’s College London in the United Kingdom called for skin rashes and “Covid fingers and toes” to be considered as a key symptom of Covid-19, even arguing that they can occur in the absence of any other symptoms.

Key coronavirus symptoms that are widely accepted include fever, cough and shortness of breath, but a range of other signs have been suggested. The loss of smell and taste, another outlier, was recently included on the list of most common symptoms by the US Centers for Disease Control and Prevention.

The Kings College researchers used data from the Covid-19 Symptom Study app, which is submitted by around 336,000 people in the UK. They found that 8.8% of people who tested positive for coronavirus reported a skin rash as a symptom, compared with 5.4% of people who tested negative.

The KLC team then set up a separate online survey, gathering information from nearly 12,000 people with skin rashes and suspected or confirmed Covid-19. The researchers found that 17% of respondents who tested positive for the coronavirus reported a rash as the first symptom of the disease. For 21% of people who reported a rash and had confirmed Covid-19, the rash was their only symptom.

The researchers reported their findings in a pre-print study posted to the online server medRXiv.org. The findings have not been published yet in a peer-reviewed journal.

“Many viral infections can affect the skin, so it’s not surprising that we are seeing these rashes in Covid-19,” Dr. Veronique Bataille, consultant dermatologist at St Thomas’ Hospital and King’s College London, who was involved in the pre-print study, said in a press release in July.

“However, it is important that people know that in some cases, a rash may be the first or only symptom of the disease,” Bataille said. “So if you notice a new rash, you should take it seriously by self-isolating and getting tested as soon as possible.”

Measles-like rashes and rashes inside the mouth

Preliminary research has suggested that skin rashes and lesions inside the mouth might be a symptom of coronavirus infection — but researchers say more study is needed.

In May, scientists around the world did a literature review and found patients were also presenting with red, itchy welts, and with a red or pinkish rash that looked a lot like measles.

“It’s a reaction that we typically call morbilliform which means measles, which presents in kind of pink spots, lots of little pink spots all over the skin,” said Papier, the dermatologist at the University of Rochester Medical Center.

Another study published in JAMA Dermatology in July, found that among 21 patients in Spain who were confirmed to have Covid-19 and skin rash, six of those patients or 29% had enanthem, or lesions or rash in the mouth.

The mean amount of time between the onset of Covid-19 symptoms and developing enanthem was about 12 days among the patients, according to researchers from the Hospital Universitario Ramon y Cajal in Madrid.

“This work describes preliminary observations and is limited by the small number of cases and the absence of a control group,” the researchers wrote, adding that their findings still suggest enanthem to be a possible Covid-19 symptom and not a reaction to medications, for instance.

“Despite the increasing reports of skin rashes in patients with COVID-19, establishing an etiological diagnosis is challenging,” the researchers wrote. “However, the presence of enanthem is a strong clue that suggests a viral etiology rather than a drug reaction.”

The-CNN-Wire™ & © 2020 Cable News Network, Inc., a Time Warner Company. All rights reserved.

How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes

Authors: By Meredith WadmanJennifer Couzin-FrankelJocelyn KaiserCatherine MatacicApr. 17, 2020 , 6:45 PM

On rounds in a 20-bed intensive care unit one recent day, physician Joshua Denson assessed two patients with seizures, many with respiratory failure and others whose kidneys were on a dangerous downhill slide. Days earlier, his rounds had been interrupted as his team tried, and failed, to resuscitate a young woman whose heart had stopped. All shared one thing, says Denson, a pulmonary and critical care physician at the Tulane University School of Medicine. “They are all COVID positive.”

As the number of confirmed cases of COVID-19 surges past 2.2 million globally and deaths surpass 150,000, clinicians and pathologists are struggling to understand the damage wrought by the coronavirus as it tears through the body. They are realizing that although the lungs are ground zero, its reach can extend to many organs including the heart and blood vessels, kidneys, gut, and brain.

“[The disease] can attack almost anything in the body with devastating consequences,” says cardiologist Harlan Krumholz of Yale University and Yale-New Haven Hospital, who is leading multiple efforts to gather clinical data on COVID-19. “Its ferocity is breathtaking and humbling.”

Understanding the rampage could help the doctors on the front lines treat the fraction of infected people who become desperately and sometimes mysteriously ill. Does a dangerous, newly observed tendency to blood clotting transform some mild cases into life-threatening emergencies? Is an overzealous immune response behind the worst cases, suggesting treatment with immune-suppressing drugs could help? What explains the startlingly low blood oxygen that some physicians are reporting in patients who nonetheless are not gasping for breath? “Taking a systems approach may be beneficial as we start thinking about therapies,” says Nilam Mangalmurti, a pulmonary intensivist at the Hospital of the University of Pennsylvania (HUP).

What follows is a snapshot of the fast-evolving understanding of how the virus attacks cells around the body, especially in the roughly 5% of patients who become critically ill. Despite the more than 1000 papers now spilling into journals and onto preprint servers every week, a clear picture is elusive, as the virus acts like no pathogen humanity has ever seen. Without larger, prospective controlled studies that are only now being launched, scientists must pull information from small studies and case reports, often published at warp speed and not yet peer reviewed. “We need to keep a very open mind as this phenomenon goes forward,” says Nancy Reau, a liver transplant physician who has been treating COVID-19 patients at Rush University Medical Center. “We are still learning.”

The infection begins

When an infected person expels virus-laden droplets and someone else inhales them, the novel coronavirus, called SARS-CoV-2, enters the nose and throat. It finds a welcome home in the lining of the nose, according to a preprint from scientists at the Wellcome Sanger Institute and elsewhere. They found that cells there are rich in a cell-surface receptor called angiotensin-converting enzyme 2 (ACE2). Throughout the body, the presence of ACE2, which normally helps regulate blood pressure, marks tissues vulnerable to infection, because the virus requires that receptor to enter a cell. Once inside, the virus hijacks the cell’s machinery, making myriad copies of itself and invading new cells.

As the virus multiplies, an infected person may shed copious amounts of it, especially during the first week or so. Symptoms may be absent at this point. Or the virus’ new victim may develop a fever, dry cough, sore throat, loss of smell and taste, or head and body aches.

If the immune system doesn’t beat back SARS-CoV-2 during this initial phase, the virus then marches down the windpipe to attack the lungs, where it can turn deadly. The thinner, distant branches of the lung’s respiratory tree end in tiny air sacs called alveoli, each lined by a single layer of cells that are also rich in ACE2 receptors.

Normally, oxygen crosses the alveoli into the capillaries, tiny blood vessels that lie beside the air sacs; the oxygen is then carried to the rest of the body. But as the immune system wars with the invader, the battle itself disrupts this healthy oxygen transfer. Front-line white blood cells release inflammatory molecules called chemokines, which in turn summon more immune cells that target and kill virus-infected cells, leaving a stew of fluid and dead cells—pus—behind. This is the underlying pathology of pneumonia, with its corresponding symptoms: coughing; fever; and rapid, shallow respiration (see graphic). Some COVID-19 patients recover, sometimes with no more support than oxygen breathed in through nasal prongs.

But others deteriorate, often quite suddenly, developing a condition called acute respiratory distress syndrome (ARDS). Oxygen levels in their blood plummet and they struggle ever harder to breathe. On x-rays and computed tomography scans, their lungs are riddled with white opacities where black space—air—should be. Commonly, these patients end up on ventilators. Many die. Autopsies show their alveoli became stuffed with fluid, white blood cells, mucus, and the detritus of destroyed lung cells.

For More Information: https://www.sciencemag.org/news/2020/04/how-does-coronavirus-kill-clinicians-trace-ferocious-rampage-through-body-brain-toes

Some COVID-19 patients have brain complications, study suggests

Authors: Mary Van Beusekom | News Writer | CIDRAP News  | Jun 26, 2020

Some COVID-19 patients, including those younger than 60 years old, appear to develop neurologic and neuropsychiatric complications such as stroke, brain inflammation, psychosis, and dementia-like symptoms, according to a study published yesterday in The Lancet Psychiatry.

The early-stage study of 153 hospitalized patients with confirmed, probable, or possible COVID-19 in the United Kingdom (UK) from Apr 2 to 26 identified 125 patients with complete data, of whom 77 (62%) had a stroke.

Of 125 patients, 114 (92%) had confirmed coronavirus infection, 5 (4%) had probable infection, and 5 (4%) were classified as possibly infected.

Stroke, encephalopathy, psychiatric diagnoses

Fifty-seven of 77 stroke patients (74%) had an ischemic stroke caused by a blood clot in the brain, 9 (12%) had a stroke caused by a brain hemorrhage, and 1 (1%) had a stroke caused by inflammation in the brain’s blood vessels. Sixty-one of the 77 stroke patients for whom age was available (82%) were older than 60 years.

Thirty-nine of 125 patients (31%) had behavioral changes indicative of an altered mental state, of whom 9 (23%) had unspecified brain dysfunction known as encephalopathy, and 7 (18%) had brain inflammation, or encephalitis.

The remaining 23 patients with altered mental states had psychiatric diagnoses, including 10 with new-onset psychosis, 7 with depression or anxiety, and 6 with a dementia-like syndrome. Only 2 patients (9%) had exacerbations of a chronic mental illness, although the authors noted that they cannot exclude the possibility that cases classified as new were simply undiagnosed before the pandemic.

Of the 37 of 39 COVID-19 patients with an altered mental state for whom age was available, 18 (49%) were younger than 60 years, which could be because they were more likely to be referred to a psychiatrist or other specialist, while physicians may be likely to attribute confusion or behavioral changes in older patients to delirium without further investigation, the authors said.

Altered mental states in younger patients

While altered mental states are not uncommon in hospitalized patients with infections, especially those requiring intensive care, they occur most often in older patients.

“In this study, we observed a disproportionate number of neuropsychiatric presentations in younger patients and a predominance of cerebrovascular complications in older patients, which might reflect the state of health of the cerebral vasculature and associated risk factors, exacerbated by critical illness in older patients,” the authors said.

For More Information: https://www.cidrap.umn.edu/news-perspective/2020/06/some-covid-19-patients-have-brain-complications-study-suggests

Coronavirus (Covid-19)

A collection of articles and other resources on the Coronavirus (Covid-19) outbreak, including clinical reports, management guidelines, and commentary.

CORONAVIRUS (COVID-19)     VACCINE RESOURCES     VACCINE FAQ https://www.nejm.org/coronavirus

All Journal content related to the Covid-19 pandemic is freely available.

For More Information: https://www.nejm.org/coronavirus

Post-acute COVID-19 syndrome

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.

Main

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for coronavirus disease 2019 (COVID-19), has caused morbidity and mortality at an unprecedented scale globally1. Scientific and clinical evidence is evolving on the subacute and long-term effects of COVID-19, which can affect multiple organ systems2. Early reports suggest residual effects of SARS-CoV-2 infection, such as fatigue, dyspnea, chest pain, cognitive disturbances, arthralgia and decline in quality of life3,4,5. Cellular damage, a robust innate immune response with inflammatory cytokine production, and a pro-coagulant state induced by SARS-CoV-2 infection may contribute to these sequelae6,7,8. Survivors of previous coronavirus infections, including the SARS epidemic of 2003 and the Middle East respiratory syndrome (MERS) outbreak of 2012, have demonstrated a similar constellation of persistent symptoms, reinforcing concern for clinically significant sequelae of COVID-19 (refs. 9,10,11,12,13,14,15).

Systematic study of sequelae after recovery from acute COVID-19 is needed to develop an evidence-based multidisciplinary team approach for caring for these patients, and to inform research priorities. A comprehensive understanding of patient care needs beyond the acute phase will help in the development of infrastructure for COVID-19 clinics that will be equipped to provide integrated multispecialty care in the outpatient setting. While the definition of the post-acute COVID-19 timeline is evolving, it has been suggested to include persistence of symptoms or development of sequelae beyond 3 or 4 weeks from the onset of acute symptoms of COVID-19 (refs. 16,17), as replication-competent SARS-CoV-2 has not been isolated after 3 weeks18. For the purpose of this review, we defined post-acute COVID-19 as persistent symptoms and/or delayed or long-term complications of SARS-CoV-2 infection beyond 4 weeks from the onset of symptoms (Fig. 1). Based on recent literature, it is further divided into two categories: (1) subacute or ongoing symptomatic COVID-19, which includes symptoms and abnormalities present from 4–12 weeks beyond acute COVID-19; and (2) chronic or post-COVID-19 syndrome, which includes symptoms and abnormalities persisting or present beyond 12 weeks of the onset of acute COVID-19 and not attributable to alternative diagnoses17,19. Herein, we summarize the epidemiology and organ-specific sequelae of post-acute COVID-19 and address management considerations for the interdisciplinary comprehensive care of these patients in COVID-19 clinics 

For More Information: https://www.nature.com/articles/s41591-021-01283-z

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19

Authors: JACC State-of-the-Art ReviewAzita H. Talasaz, PharmD,a,bParham Sadeghipour, MD,cHessam Kakavand, PharmD,a,bMaryam Aghakouchakzadeh, PharmD,aElaheh Kordzadeh-Kermani, PharmD,aBenjamin W. Van Tassell, PharmD,d,eAzin Gheymati, PharmD,aHamid Ariannejad, MD,bSeyed Hossein Hosseini, PharmD,aSepehr Jamalkhani,cMichelle Sholzberg, MDCM, MSc,f,gManuel Monreal, MD, PhD,hDavid Jimenez, MD, PhD,iGregory Piazza, MD, MS,jSahil A. Parikh, MD,k,lAjay J. Kirtane, MD, SM,k,lJohn W. Eikelboom, MBBS,mJean M. Connors, MD,nBeverley J. Hunt, MD,oStavros V. Konstantinides, MD, PhD,p,qMary Cushman, MD, MSc,r,sJeffrey I. Weitz, MD,t,uGregg W. Stone, MD,k,vHarlan M. Krumholz, MD, SM,w,x,yGregory Y.H. Lip, MD,z,aaSamuel Z. Goldhaber, MD,j and Behnood Bikdeli, MD, MSj,k,w,∗

Abstract

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.

Thromboembolism in Patients With Coronavirus Disease-2019

Microvascular and macrovascular thrombotic complications, including arterial and especially venous thromboembolism (VTE), seem to be common clinical manifestations of coronavirus disease-2019 (COVID-19), particularly among hospitalized and critically ill patients (1234). Pooled analyses have helped in providing aggregate estimates of thrombotic events (4,5). In a recent systematic review and meta-analysis, the overall incidence of VTE among inpatients with COVID-19 was estimated at 17% (95% confidence interval [CI]: 13.4 to 20.9), with variation based on study design and method of ascertainment; there was a four-fold higher incidence rate in patients in the intensive care units (ICUs) compared with non-ICU settings (28% vs. 7%) (6). In addition, postmortem studies show frequent evidence of microvascular thrombosis in patients with COVID-19 (7,8). The influence of these events on mortality rates remains unknown (9).Go to:

Pathophysiology of Thromboembolism in COVID-19: Virchow’s Triad in Action

COVID-19 can potentiate all 3 components of Virchow’s triad and increases the risk of thrombosis (Figure 1 ). First, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection may trigger endothelial dysfunction. Using the angiotensin-converting enzyme 2, which is expressed on the surface of many cells, SARS-CoV-2 enters endothelial cells and may impair their intrinsic antithrombotic properties. It is proposed that viremia, hypoxia, the inflammatory response, increased expression of tissue factor, and elevated levels of neutrophil extracellular traps (NETs) can together disrupt the hemostasis equilibrium and promote endothelial activation (101112). This induction of a procoagulant state along with the reduction in plasminogen activators further results in increased platelet reactivity (131415). Inflammatory cytokines and endothelial activation can lead to downregulation of antithrombin and protein C expression. They can also lead to an increase in the levels of plasminogen activator inhibitor; fibrinogen; factors V, VII, VIII, and X; and von Willebrand factor (16). Increased platelet reactivity, NETosis, and alterations in the aforementioned hemostatic factors result in a hypercoagulable state (171819202122).

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963001/

COVID-19 vaccines and thrombosis with thrombocytopenia syndrome

Authors: Chih-Cheng Lai 1Wen-Chien Ko 2Chih-Jung Chen 3Po-Yen Chen 4Yhu-Chering Huang 3Ping-Ing Lee 5Po-Ren Hsueh 6 7

Abstract

Introduction: To combat COVID-19, scientists all over the world have expedited the process of vaccine development. Although interim analyses of clinical trials have demonstrated the efficacy and safety of COVID-19 vaccines, a serious but rare adverse event, thrombosis with thrombocytopenia syndrome (TTS), has been reported following COVID-19 vaccination.

Areas covered: This review, using data from both peer-reviewed and non-peer-reviewed studies, aimed to provide updated information about the critical issue of COVID-19 vaccine-related TTS.

Expert opinion: : The exact epidemiological characteristics and possible pathogenesis of this adverse event remain unclear. Most cases of TTS developed in women within 2 weeks of the first dose of vaccine on the receipt of the ChAdOx1 nCoV-19 and Ad26.COV2.S vaccines. In countries with mass vaccination against COVID-19, clinicians should be aware of the relevant clinical features of this rare adverse event and perform related laboratory and imaging studies for early diagnosis. Non-heparin anticoagulants, such as fondaparinux, argatroban, or a direct oral anticoagulant (e.g. apixaban or rivaroxaban) and intravenous immunoglobulins are recommended for the treatment of TTS. However, further studies are required to explore the underlying mechanisms of this rare clinical entity.

Plain language summary: What is the context? Thrombosis with thrombocytopenia syndrome (TTS) usually develops within 2 weeks of the first doses of the ChAdOx1 nCoV-19 and Ad26.COV2.S COVID-19 vaccines. TTS mainly occurs in patients aged < 55 years and is associated with high morbidity and mortality. What is new? TTS mimics autoimmune heparin-induced thrombocytopenia and can be mediated by platelet-activating antibodies against platelet factor 4. Non-heparin anticoagulants, such as fondaparinux, argatroban, or a direct oral anticoagulant (e.g. apixaban or rivaroxaban) should be considered as the treatment of choice if the platelet count is > 50 × 109/L and there is no serious bleeding. Intravenous immunoglobulins and glucocorticoids may help increase the platelet count within days and reduce the risk of hemorrhagic transformation when anticoagulation is initiated. What is the impact? TTS should be a serious concern during the implementation of mass COVID-19 vaccination, and patients should be educated about this complication along with its symptoms such as severe headache, blurred vision, seizure, severe and persistent abdominal pain, painful swelling of the lower leg, and chest pain or dyspnea. The incidence of TTS is low; therefore, maintenance of high vaccination coverage against COVID-19 should be continued.

For More Information: https://pubmed.ncbi.nlm.nih.gov/34176415/