Thrombotic Thrombocytopenia after AstraZeneca covid vaccination

 

Andreas Greinacher, M.D., 

Thomas Thiele, M.D., 

Theodore E. Warkentin, M.D., 

Karin Weisser, Ph.D., 

Paul A. Kyrle, M.D., 

and Sabine Eichinger, M.D.

DOI: 10.1056/NEJMoa2104840

PDF: 

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2104840?articleTools=true

Abstract

BACKGROUND

Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder.

METHODS

We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)–heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4–heparin immunoassay.

RESULTS

Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4–heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor–blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4–heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation.

CONCLUSIONS

Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.)

https://www.nejm.org/doi/full/10.1056/NEJMoa2104840?query=featured_home

Most Common Lingering Symptoms 8 Months After Mild COVID

 Loss of smell, loss of taste, dyspnea, and fatigue are the four most common symptoms that healthcare professionals in Sweden report 8 months after mild COVID-19 illness, new evidence reveals.

Approximately one in 10 healthcare workers experience one or more moderate-to-severe symptoms that negatively affect their quality of life, according to the study.

Dr Charlotte Thålin

"We see that a substantial portion of healthcare workers suffer from long-term symptoms after mild COVID-19," senior author Charlotte Thålin, MD, PhD, told Medscape Medical News. She added that loss of smell and taste "may seem trivial, but have a negative impact on work, social, and home life in the long run."

The study is noteworthy not only for tracking the COVID-19-related experiences of healthcare workers over time, but also for what it did not find. There was no increased prevalence of cognitive issues — including memory or concentration — that others have linked to what's often called long-haul COVID-19.

The Research Letter was published online April 7, 2021, in JAMA.

"Even if you are young and previously healthy, a mild COVID-19 infection may result in long-term consequences," said Thålin, from the department of clinical sciences at Danderyd Hospital, Karolinska Institute, Stockholm, Sweden.

The researchers did not observe an increased risk for long-term symptoms after asymptomatic COVID-19.

Adding to Existing Evidence

This research letter "adds to the growing body of literature showing that people recovering from COVID have reported a diverse array of symptoms lasting for months after initial infection," Lekshmi Santhosh, MD, told Medscape Medical News when asked to comment. She is physician faculty lead at the University of California, San Francisco (UCSF) Post-COVID OPTIMAL Clinic.

Dr Lekshmi Santhosh

Previous research revealed severe long-term symptoms, including heart palpitations and neurologic impairments, among people hospitalized with COVID-19. However, "there is limited data on the long-term effects after mild COVID-19, and these studies are often hampered by selection bias and without proper control groups," Thålin said.

The absence of these more severe symptoms after mild COVID-19 is "reassuring," she added.  

The current findings are part of the ongoing COMMUNITY (COVID-19 Biomarker and Immunity) study looking at long-term immunity. Healthcare professionals enrolled in the research between April 15 and May 8, 2020, and have initial blood tests repeated every 4 months.

Thålin, lead author Sebastian Havervall, MD, and their colleagues compared symptom reporting between 323 hospital employees who had mild COVID-19 at least 8 months earlier with 1072 employees who did not have COVID-19 throughout the study.

The results show that 26% of those who had COVID-19 previously had at least one moderate-to-severe symptom that lasted more than 2 months, compared with 9% in the control group.

The group with a history of mild COVID-19 was a median 43 years old and 83% were women. The controls were a median 47 years old and 86% were women.

Dr Sarah Jolley

"These data mirror what we have seen across long-term cohorts of patients with COVID-19 infection. Notably, mild illness among previously healthy individuals may be associated with long-term persistent symptoms," Sarah Jolley, MD, a pulmonologist specializing in critical care at UCHealth University of Colorado Hospital in Aurora and director of the Post-COVID Clinic, told Medscape Medical News.

"In this cohort, similar to others, this seems to be more pronounced in women," Jolley added.

Key Findings on Functioning

At 8 months, using a smartphone app, participants reported presence, duration, and severity of 23 predefined symptoms. Researchers used the Sheehan Disability Scale to gauge functional impairment.

A total of 11% participants reported at least one symptom that negatively affected work or social or home life at 8 months vs only 2% of the control group.

Seropositive participants were almost two times more likely to report that their long-term symptoms moderately to markedly disrupted their work life, 8% vs 4% of seronegative healthcare workers (relative risk [RR], 1.8; 95%; confidence interval [CI], 1.2 - 2.9).

Disruptions to a social life from long-term symptoms were 2.5 times more likely in the seropositive group. A total 15% of this cohort reported moderate-to-marked effects, compared with 6% of the seronegative group (RR, 2.5; 95% CI, 1.8 - 3.6).

The researchers also inquired about home life disruptions, which were reported by 12% of the seropositive healthcare workers and 5% of the seronegative participants (RR, 2.3; 95% CI, 1.6 - 3.4).

The study's findings "tracks with a lot of the other work we're seeing," David Putrino, PT, PhD, director of rehabilitation innovation at Mount Sinai Health System in New York City, told Medscape Medical News. He and his colleagues are responsible for managing the rehabilitation of patients with long COVID.

Dr David Putrino

Interestingly, the proportion of people with persistent symptoms might be underestimated in this research, Putrino said. "Antibodies are not an entirely reliable biomarker. So what the researchers are using here is the most conservative measure of who may have had the virus."

Potential recall bias and the subjective rating of symptoms were possible limitations of the study.

When asked to speculate why researchers did not find higher levels of cognitive dysfunction, Putrino said that self-reports are generally less reliable than measures like MoCA (Montreal Cognitive Assessment) for detecting cognitive impairment.

Furthermore, unlike many of the people with long-haul COVID-19 whom he treats clinically — ones who are "really struggling" — the healthcare workers studied in Sweden are functioning well enough to perform their duties at the hospital, so the study population may not represent the population at large.

More Research Required

"More research needs to be conducted to investigate the mechanisms underlying these persistent symptoms, and several centers, including UCSF, are conducting research into why this might be," Santhosh said.

Thålin and colleagues plan to continue following participants. "The primary aim of the COMMUNITY study is to investigate long-term immunity after COVID-19, but we will also look into possible underlying pathophysiological mechanisms behind COVID-19-related long-term symptoms," she said.

"I hope to see that taste and smell will return," Thålin added.

"We're really just starting to understand the long-term effects of COVID-19," Putrino said. "This is something we're going to see a lot of moving forward."

Thålin, Santhosh, Jolley, and Putrino disclosed no relevant financial relationships. Grants from the Knut and Alice Wallenberg Foundation, Jonas and Christina af Jochnick Foundation, Leif Lundblad Family Foundation, Region Stockholm, and Erling-Persson Family Foundation funded the research.

https://www.medscape.com/viewarticle/949072

Women, those under 40 more likely to have side effects to COVID vaccine

 Women and people under 40 years old are more likely to experience side effects from COVID-19 vaccines, an expert told The Post on Friday.

“Women and younger people have more local reactions — a sore arm, a day of not feeling so well, or aches and pains,” according to Dr. William Schaffner, an infectious diseases expert from Vanderbilt University.

“People wonder if it’s because women have more estrogen but that remains to be studied,” he said.

“The short answer is there’s got to be reasons for it but we don’t know what they are,” added Schaffner.

Side effects from COVID-19 vaccines range from nausea and flu-like symptoms to nothing at all — but your reaction says nothing about how you would have fared against the virus, experts said.

“I don’t think that there’s any relationship between your reaction to the vaccine and what would have happened to you had you gotten infected with the virus,” Schaffner said in an interview with the CBS affiliate WFMY.

But regardless of the severity of post-vaccination symptoms  — which this week included nausea and dizziness for 11 people at a shuttered Colorado Johnson & Johnson jab site — the shots are equally effective for everyone, experts said.

“People will say, ‘Well if I didn’t get a reaction, does that mean the vaccine didn’t work?’ and the answer is, no,” Dr. William Moss, a vaccines expert from Johns Hopkins University, told the outlet.

A nurse prepares a COVID-19 vaccine on a vaccination drive-thru, in Brasilia, Brazil.

EPA/Joedson Alves

He added, “[There are] no implications for protective efficacy…No implications for how your body would respond if you got infected with the actual SARS-CoV-2.”

People in Los Angeles, California wait to get the COVID-19 vaccine on Feb. 17, 2021.

Dean Musgrove/The Orange County Register/SCNG via AP

On Wednesday, around a dozen people reportedly suffered adverse reactions to the Johnson & Johnson vaccine at Dick’s Sporting Goods Park in Commerce City, prompting officials to shutter the site.

People that received a COVID-19 vaccine socially distance as they wait the required fifteen minutes to monitor for adverse reactions after getting the shot in Dallas, Texas on Jan. 20, 2021.

AP Photo/LM Otero

The  Colorado Department of Public Health and Environment later stressed that the side effects experienced were “consistent with what can be expected” with the single-dose shot.

As of Friday, more than 112 million people had received at least one dose of the COVID-19 vaccine in the US.

https://nypost.com/2021/04/09/reaction-to-covid-vax-says-nothing-about-resistance/

China Approves Third Sinopharm Covid Vaccine for Clinical Trial

 China has approved the third Covid-19 vaccine from Sinopharm Group Co. to start clinical trials, the company said.

The green light to begin testing comes after two inactivated vaccines from Sinopharm were approved and widely used both at home and in developing countries.

The latest one is a recombinant vaccine that includes parts of the coronavirus’s spike protein to stimulate immune response, according to a release posted on the company’s official WeChat account on Saturday.

https://www.bloomberg.com/news/articles/2021-04-10/china-approves-third-sinopharm-covid-vaccine-for-clinical-trial

Unwanted vaccines needed to help poor countries catch up: international health officials

 Doses of vaccines rejected as countries fine-tune their inoculation campaigns will go to poor countries where possible to counter a “shocking imbalance” in distribution, international health officials said on Friday.

Authorities in Australia and Greece became the latest to recommend alternatives to the AstraZeneca vaccine for younger people over fears of possible very rare blood clots, while Hong Kong delayed deliveries.

The city said it had enough alternatives and did not want to waste these shots while global supplies were short.

Australia’s decision effectively put paid to plans to have its population vaccinated by the end of October, highlighting the delicate public health balancing act the issue has created.

Giving alternative vaccines to younger recipients will delay inoculation campaigns by around a month in Australia, France and Britain, science information and analytics company Airfinity forecast after crunching the numbers for those countries.

Millions of doses of the AstraZeneca shot have been safely administered around the world but some governments have limited its use to older age groups as a precaution while cases of clotting are investigated.

The World Health Organization said most countries did not have anywhere near enough shots of any vaccine to cover health workers and others at high risk from exposure to the virus, which has killed almost 3 million people around the world.

WHO Director-General Tedros Adhanom Ghebreyesus said high income countries had on average vaccinated one in four people while in low income countries it was one in more than 500.

“There remains a shocking imbalance in the distribution of vaccines,” he told a press briefing on Friday.

The WHO and GAVI vaccine alliance’s COVAX mechanism aims to ensure vaccines reach poorer states. Asked whether COVAX was negotiating for doses of the AstraZeneca vaccine that had been shunned, GAVI alliance head Seth Berkley said the Anglo-Swedish company’s supply chain had “picked up”.

“As countries decide they are going to prioritise one vaccine or another, that may free up doses, and in so doing we will try to make sure those doses are made available without delay, if countries are willing to make that happen,” he said.

DIFFERING AGE LIMITS

Australia said it had doubled its order of the Pfizer shot after health authorities recommended those under 50 take it instead of AstraZeneca. Greece followed Britain in recommending people under 30 get an alternative shot.

AstraZeneca said it was working with regulators “to understand the individual cases, epidemiology and possible mechanisms that could explain these extremely rare events”.

The European Medicines Agency (EMA) received reports of 169 cases of the rare brain blood clot by early April, after 34 million doses had been administered, Sabine Straus, chair of the EMA’s safety committee, said this week.

Most of the cases reported had occurred in women under 60.

On Friday, the EMA said that if a causal relationship is confirmed or considered likely, regulatory action will be needed to minimise risk.

It also said it was looking into Johnson & Johnson’s (J&J) shot over reports of blood clots. U.S. infectious disease expert Anthony Fauci said there was nothing on reports on the J&J vaccine that is a red flag.

The AstraZeneca shot is by far the cheapest and most high-volume vaccine launched so far to curb the pandemic and avert damaging lockdowns, but supplies have been beset by delays.

However, new data in the EU, where vaccinations lag those in the United States, showed overall deliveries of vaccines were gathering momentum. Germany said it was accelerating inoculations but needed a new lockdown as well.

“Every day in which we don’t act, we lose lives,” Lothar Wieler, president of the Robert Koch Institute, said.

GLOBAL SUPPLY

Hong Kong Health Secretary Sophia Chan said the city would delay its ordered shipments of the AstraZeneca vaccine this year “so as not to cause a waste when the vaccine is still in short supply globally”.

The government was considering buying a new type of vaccine that may offer better protection, she added.

All the countries recommending age limits for the AstraZeneca shot have emphasised that its benefits far outweigh the risks of catching COVID-19 for older people.

But some people have been put off. Madrid said less than half of over 60s due to have the AstraZeneca shot on Thursday turned up, a day after Spain recommended younger people get a different shot.

The top health body in France, where vaccine hesitancy is high, recommended that those over 55 who had received a first dose of the AstraZeneca shot get a new-style messenger-RNA vaccine for the second one.

Two messenger RNA vaccines have been approved for use in France, one from Pfizer and BioNTech and another from Moderna.

https://www.reuters.com/article/us-health-coronavirus-astrazeneca/unwanted-vaccines-needed-to-help-poor-countries-catch-up-international-health-officials-say-idUSKBN2BW1MI

Possible 'missing link' to recovery detected in COVID-19 patients

 A newly published UC Davis research paper pinpoints what could be "the missing link" in why some COVID-19 patients recover and some don't.

A blood plasma biomarker discovered in hospitalized COVID-19 patients may not only predict the severity of adult respiratory distress syndrome (ARDS) but further research may lead to inhibiting the progression, a team of eight University of California researchers announced today.

The UC researchers, primarily from the laboratory of UC Davis distinguished professor Bruce Hammock, found that four compounds in the blood of COVID-19 patients are highly associated with the disease. Their paper, "Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections," is published as open access in the current edition of Frontiers in Physiology.

ARDS, characterized by fluid build-up in the lungs, is the second leading cause of death in COVID-19 patients, next to viral pneumonia, according to the National Center for Biotechnology Information.

"Different outcomes from COVID-19 infections are both terrifying from a human health perspective and fascinating from a research perspective," said UC Davis lead author and doctoral candidate Cindy McReynolds of the Hammock lab. "Our data provide an important clue to help determine what impacts the severity of COVID-19 outcomes. Initially, we focused on the immune response and cytokine profile as important drivers in severity, but considering what we now know from our study and others in the field, lipid mediators may be the missing link to answering questions such as why some people are asymptomatic while others die, or why some disease resolves quickly while others suffer from long-haul COVID."

The compounds, known as leukotoxins and leukotoxin diols, originate from linoleic acid, the body's most abundant dietary fat, said Hammock, who holds a joint appointment in the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center and directs the National Institute of Environmental Health Sciences (NEIHS) Superfund Research Program at UC Davis. "The leukotoxins (also called EpOMEs) are converted to the leukotoxin diols (also called DiHOMES) by the soluble epoxide hydrolase we work on."

"The hypothesis advanced in this paper is that because the leukotoxins have been associated with serious illness and death in humans and dogs and the symptoms are those of adult respiratory distress syndrome, these compounds are biomarkers of pulmonary involvement in COVID-19," Hammock said. "We also think that it is the conversion of leukotoxin to the toxic leukotoxin diol that causes pulmonary and perivascular edema and this could be leading to the respiratory complications."

"So the leukotoxins and leukotoxin diols," Hammock said, "are indicators of respiratory problems in COVID-19 patients as plasma biomarkers. They also present a pathway for reducing ARDS in COVID-19 if we could inhibit the soluble epoxide hydrolase, a key regulatory enzyme involved in the metabolism of immune resolving fatty acids."

Professor John Imig, director and eminent scholar of the Medical College of Wisconsin's Drug Discovery Center, who was not involved in the study, said, "The COVID-19 pandemic has demonstrated that coronaviruses can have deadly consequences. Lung distress is a major reason for death in COVID-19 patients infected with the coronavirus (SARS-CoV-2). The findings of McReynolds et al. identified lipids called leukotoxin diols in the blood of COVID-19 patients that could act as a biomarker for lung distress. In addition, leukotoxin diols could be responsible for lung distress in COVID-19 patients. Excitingly, this suggest that therapies to lower leukotoxin diols could treat lung distress and prevent death in COVID-19 patients."

"The findings presented in this paper bring important attention to a role for oxylipin metabolites in COVID-19 infections," said Professor A. Daniel Jones of Michigan State University's Department of Biochemistry and Molecular Biology and director of the university's Research Technology Facility's Mass Spectrometry and Metabolomics Core. "Most notably, metabolites known as DiHOMEs which have been previously implicated in lung inflammation show promise for their potential to predict outcomes in COVID patients and guide therapeutic, and perhaps dietary interventions beneficial to human populations." Jones, who was not involved in the study, serves as secretary of the Metabolomics Association of North America.

The UC Davis scientists used clinical data collected from six patients with laboratory-confirmed SARS-CoV-2 infection and admitted to the UC Davis Medical Center, Sacramento, and 44 healthy samples carefully chosen from the healthy control arm of a recently completed clinical study.

In the introduction, the researchers wrote: "The pandemic coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initiates an aberrant immunological response resulting in a wide range of disease severities ranging from asymptomatic cases to severe cases with rapid progression to acute respiratory distress syndrome (ARDS) and death. Patients with severe COVID-19 show evidence of hyperinflammation with increased release of inflammatory cytokines. The role of a cytokine release syndrome, or cytokine storm, in COVID-19 has drawn much attention.

However, recent reports demonstrate that although pro-inflammatory cytokine levels are elevated in severe COVID-19 patients, they are lower than levels usually observed in non-COVID ARDS, suggesting additional factors leads to severe outcomes in some patients. One of the key pathways regulating the immune response to infections is the release of regulatory lipid mediators that have dual functions of driving inflammation [e.g., prostaglandins (PGE2)] or promoting resolution of inflammation and return to homeostasis [e.g., long chain epoxy fatty acids (EpFAs)]. Recent data indicate a role of dysregulated lipid profiles in COVID-19 and identified cytochrome P450 (CYP) metabolites of polyunsaturated fatty acids (PUFA) as potential biomarkers of disease severity

The Hammock lab's 50-year research on soluble epoxide hydrolase (sEH) and its inhibitors led the professor to found and direct EicOsis Human Health, a Davis-based company that is developing a potent soluble epoxide hydrolase inhibitor for pain relief. Epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, depression, pain, inflammation and other processes.

But more recently, the Hammock lab has turned its attention to using sEH as a means to resolve inflammation associated with COVID-19 and the fibrosis that can follow.

Lipid metabolism researcher Ameer Taha of the UC Davis Department of Food Science and Technology pointed out that linoleic acid is an essential fatty acid present in only small amounts in our evolutionary diets. "In addition to nutritional and structural roles of linoleate, minor linoleate metabolites including the leukotoxin diols (also known as DiHOMEs) regulate a number functions including body temperature, cardiac health and vascular permeability. This study cautions that now with dietary linoleate levels at an all-time high, in periods of high stress as with COVID-19, these regulatory functions may become detrimental."

The paper is the work of Hammock, McReynolds and Jun Yang of the Department of Entomology and Nematology and EicOsis Human Health; Irene Cortes-Puch of the Department of Entomology and Nematology, EicOsis Human Health, and the Department of Internal Medicine's Division of Pulmonary Critical Care and Sleep Medicine; Resmi Ravindran and Imran Khan of the Department of Pathology and Laboratory Medicine; Bruce G. Hammock of UC Davis Department of Veterinary Medicine, Aquatic Health; and Pei-an Betty Shih of the UC San Diego Department of Psychiatry.

"This study resulted from an exciting collaboration with Imran Khan and Angela Haczku of the UC Davis School of Medicine to identify potential biomarkers for differentiating the severity of COVID-19 diseases," said Yang, the corresponding author.

More information: Cindy B. McReynolds et al. Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections, Frontiers in Physiology (2021). DOI: 10.3389/fphys.2021.663869

https://medicalxpress.com/news/2021-04-link-covid-patients.html

Thrombosis and COVID Vaccines

 Following up on previous reviews of the evidence, the European Medicines Agency (EMA), WHO, and Britain's Medicine's and Healthcare Products Regulatory Agency (MHRA) have issued statements saying that the overall benefits continue to outweigh the risks of very rare blood clots with low platelets reported after the AstraZeneca COVID-19 vaccine.

The WHO now states that a causal relationship is "considered plausible but is not confirmed," while the MHRA has said that the evidence is now "stronger" for a link between the vaccine and these events. The EMA calls these "unusual blood clots with low platelets" and says they should be listed as very rare side effects of the vaccine.

How Rare Are These Clots?

As of April 4, 169 cases of cerebral venous sinus thrombosis (CVST) and 53 cases of splanchnic vein (which drains blood from the digestive system) thrombosis have been reported in the European drug safety database. About 34 million doses of the AstraZeneca vaccine have been administered in Europe and the U.K., according to Sabine Straus, chair of the EMA's Pharmacovigilance Risk Assessment Committee (PRAC), as quoted by science journalist Kai Kupferschmidt in a tweet from an EMA press briefing.

The reported rate "varies very much with how good the reporting system in a member state is and how good cases are being identified.... In Germany, a lot of work has been done and I think there is a reporting rate of 1 in 100,000," Straus said at the briefing, according to Kupferschmidt.

The MHRA statement put the overall risk of these types of clots at about 4 per million recipients of the AstraZeneca vaccine. The agency said it had received 79 reports of blood clots with low platelets among 20.2 million doses of the AstraZeneca vaccine in the U.K., as of March 31. Of these, 44 were CVST and 35 were thromboses in major veins. These events occurred among 51 women and 28 men ages 18 to 79 years, among whom 19 died (13 women, 6 men). Of those who died, 11 were under age 50, and three were under 30. Fourteen had CVST with thrombocytopenia and five had thrombosis with thrombocytopenia.

In its statement, the EMA says that the PRAC reviewed 62 cases of CVST and 24 cases of thrombosis in the splanchnic vein reported in EudraVigilance (the European drug safety database), as of March 22. Most cases were in women under age 60 years, and most occurred within two weeks of the first dose of the vaccine. Eighteen people died.

On Friday, the EMA said the same problem may be occurring with the Johnson & Johnson vaccine, which, like AstraZeneca's, uses an adenovirus vector to deliver genetic code for coronavirus antigens. The agency said it had reports of three clotting episodes out of some 4.5 million people receiving the J&J product. It had not yet determined a cause-and-effect relationship, however.

Notably, the mRNA vaccines from Moderna and Pfizer/BioNTech have not been linked to excess thrombosis episodes.

What Is the Explanation?

With regard to the AstraZeneca investigation, EMA said one "plausible" explanation for the phenomenon is that the vaccine may trigger an autoimmune immune reaction leading to an "atypical heparin-induced-thrombocytopenia like disorder," for which specific risk factors have yet to be identified.

Shortly after these problems started to surface, researchers in Germany and Norway quickly identified an autoantibody called platelet factor 4 antibody that appeared to be linked to the syndrome. Platelet factor 4 antibody causes heparin-induced thrombocytopenia (HIT), a rare clotting disorder that affects 1%-2% of people after exposure to heparin. In rare cases, platelet factor 4 antibody has been associated with CVST.

On April 9 2021, the German team lead by Andreas Greinacher, MD, PhD, of the Medical University of Greifswald in Germany, published a case series about the issue in the New England Journal of Medicine. It included 11 patients in Germany and Austria who presented with unusual thromboses and moderate to severe thrombocytopenia, five to 16 days after receiving the AstraZeneca vaccine. None of these patients had received heparin in the past. Nine were women, and the median age was 36 (range 22-49). Five patients had more than one clotting event: nine had CVST, three had splanchnic vein thrombosis, three had pulmonary embolism, four had other thromboses, and five had disseminated intravascular coagulation (DIC). Six patients died.

The researchers also did platelet activation assays on 28 patients who developed thrombosis and thrombocytopenia after receiving the AstraZeneca vaccine, and who tested positive for antibodies against platelet factor 4. Results showed increased platelet activation in the presence of platelet factor 4, which was inhibited with immune globulin.

Greinacher and colleagues wrote that the disorder "resembles" severe HIT, but "unlike the usual situation" none of these patients received heparin in the past. They noted that autoimmune or spontaneous HIT can occur without exposure to heparin, and is characterized by "unusually severe thrombocytopenia, increased rates of DIC and atypical clots." They concluded that the AstraZeneca vaccine can result in a rare syndrome that "clinically mimics autoimmune heparin-induced thrombocytopenia," and propose using the term "vaccine induced immune thrombotic thrombocytopenia" (VITT) to avoid confusion.

In a past publication, Greinacher and colleagues had referred to this syndrome as vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).

Concurrent with the German team, the Norwegian team published a case series, also in the New England Journal of Medicine, involving five patients with this syndrome after the AstraZeneca vaccine; they also proposed to call it VITT. All patients in this series had high levels of platelet factor 4 autoantibodies without past exposure to heparin. Five had major cerebral thrombosis, and three died.

"These results strengthen the view that vaccination may have triggered the syndrome," wrote Nina H Schultz, MD, PhD, of Oslo University Hospital, and colleagues. "Although rare, VITT is a new phenomenon with devastating effects for otherwise healthy young adults and requires a thorough risk-benefit analysis."

Unusual Clots?

What is striking about VITT is that the brain and abdomen are atypical locations for clots to develop. COVID-19 infection itself can cause autoimmune associated thrombocytopenia and thrombosis, but the majority of those clots are deep venous thromboses (DVTs) and pulmonary embolism (PE). Thrombocytopenia has occurred with other vaccines, but in these cases, low platelets are associated with bleeding, not clots, according to Rajiv Pruthi, MBBS, a hematologist at the Mayo Clinic in Rochester, Minnesota.

"CVST is a distinctly unusual location for a blood clot that is associated with low platelets," he told MedPage Today.

Right now, explanations for these phenomena are "pure speculation," Pruthi said. However, he noted that lower extremity veins belong to different vascular beds than those in the abdomen and brain, and different vascular beds may express different proteins that play a role in clot development. The idea of vascular bed-specific hemostasis is not new, and may play a role in clot formation in different areas of the body.

"I wonder if that has something to do with this," he said. "I'm hoping we'll see more of this going forward, but it's hard to study vascular beds anywhere short of doing a biopsy. I don't think anyone would want to do a brain biopsy."

Reactions and Recommendations

Many countries in Europe have reacted by placing age restrictions on the AstraZeneca vaccine, and these vary by country. For example, Germany and the Netherlands have limited the vaccine to people over age 60; France set age 55 as the threshold. Britain's Joint Committee on Vaccination and Immunisation has advised that people under age 30 without underlying medical conditions should be offered a different vaccine. Norway has halted vaccinations altogether, at least for now. Elsewhere in the world, Canada, Australia, and the Philippines have also imposed age restrictions.

Meanwhile, the U.K.'s Expert Haematology Panel has offered guidance for diagnosis and management of these very rare events, as did Greinacher and colleagues in their NEJM publication. In probable cases, they recommend urgent use of IV immunoglobulin, use of non-heparin anticoagulants, and avoidance of platelet transfusions. They added that vitamin K antagonists (e.g., warfarin) are contraindicated in acute thrombocytopenia and DIC.

"The EMA and WHO didn't really come out and say it, but I think the conclusion is that if you're seeing these unusual thromboses with low platelets after COVID-19 vaccination, you might want to avoid heparin. That's the go-to drug for all thromboses but in this situation, think about a different treatment," Pruthi emphasized.

https://www.medpagetoday.com/special-reports/exclusives/92022