AZ COVID Vaccine: Causal Link to Severe Thrombosis Established

April 12, 2021

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Two scientific studies establishing a causal relationship between the AstraZeneca COVID-19 vaccine and severe thrombotic complications have now been published.

The articles — one from a German/Austrian/Canadian collaboration and one from a Norwegian group — were published online April 9 in the New England Journal of Medicine.  

A preliminary report of the German-led study was first published as a preprint on Research Square on March 28.

Both articles reach the same conclusion — that these unusual severe thrombotic events that are accompanied by thrombocytopenia are caused by rogue antibodies directed against platelet factor 4 (PF4), which causes massive platelet aggregation and thrombosis, and results in a reduced platelet count elsewhere, leading in turn to bleeding.  Patients can therefore have both severe thrombosis and severe bleeding.

The syndrome is very similar to the well-known condition of heparin-induced thrombocytopenia (HIT) and is diagnosed and treated in the same way, with the administration of intravenous immunoglobulins (IVIG) and anticoagulants. The syndrome associated with the vaccine has been named vaccine-induced immune thrombotic thrombocytopenia (VITT).

At a press briefing on his study, lead author of the German-led paper, Andreas Greinacher, MD, head of the Institute of Immunology and Transfusion Medicine, University Hospital Greifswald, Germany, said: "There is clear evidence that there is a very close link to this severe thrombotic complication and the AstraZeneca vaccine. There is clear causality between the pathogenic antibody and the thrombotic complications, and we have found this antibody in many people who have developed these complications after the AstraZeneca vaccine."

The German study reports a total of 28 cases of this condition, with a more detailed description of the first 11 patients, aged 22-49 years, who presented with serious thrombotic complications including cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis, disseminated intravascular coagulation (DIC), and pulmonary embolism within 5-16 days of receiving the AstraZeneca vaccine. Six patients died.  

Greinacher said they have now analyzed 40-50 cases, all of which show the presence of the PF4 antibodies. "All the cases show the same picture," he said. "Thrombotic complications develop within a couple of weeks of having the AstraZeneca vaccine and the link between the vaccine and the occurrence of this pathogenic antibody is very strong." 

In the Norwegian study, a group led by Nina Schultz, MD, Oslo University Hospital, note that older people in Norway have been given the Pfizer vaccine, with the AstraZeneca vaccine generally being used for healthcare workers under age 65 years. As of March 20, when administration of the AstraZeneca vaccine was paused, 132,686 people in Norway had received one dose of the vaccine and none had received the second dose.  

They report five cases of severe thromboembolism in unusual sites and concomitant thrombocytopenia that occurred 7-10 days after vaccination with the AstraZeneca vaccine in healthcare workers aged 32-54 years who were admitted to Oslo University Hospital. Four of the patients had severe CVST with intracranial hemorrhage and the outcome was fatal in three. A common denominator in all five cases was "strikingly high" levels of antibodies to PF4-polyanion complexes, the authors report.  

Senior author of the Norwegian study, Pål Holme, MD, professor of hematology at Oslo University Hospital, told Medscape Medical News that he was aware of another case that has not been included in this article.

The Norwegian authors conclude that: "VITT is a new phenomenon with devastating effects for otherwise healthy young adults and requires a thorough risk–benefit analysis." They add: "The findings of our study indicate that VITT may be more frequent than has been found in previous studies in which the safety of the AstraZeneca vaccine has been investigated."

Holme said: "We have not identified any particular risk factors for this condition other than receiving the AstraZeneca vaccine up to 10 days previously, and since the AstraZeneca vaccine was paused in Norway on March 20, we have not seen any more cases."

The European Medicines Agency reported last week that 169 cases of CVST and 53 cases of DIC have been reported to its drug safety database among 34 million people receiving the first dose of the AstraZeneca vaccine.

And the United Kingdom logged 79 reports of these unusual thrombotic events accompanied by a low platelet count in people aged 18-79 years, of which 19 were fatal, among 20.2 million doses of the AstraZeneca/Oxford vaccine, giving an event rate of approximately 4 in a million and a fatality rate of 1 in a million.

Different countries have made different recommendations on use of the vaccine after these reports of this severe reaction started surfacing. Norway and Denmark have completely suspended use of the vaccine, and many other European countries have limited its use to those aged over 55 or 65, as there have been fewer cases of this complication in older individuals. The UK has now recommended using an alternative vaccine in those younger than 30 years.

On how these scientific papers affected the risk benefit calculations for the vaccine, Greinacher said: "Of course the adverse reaction for the individual is tragic. But on population basis, we have to balance lives saved from vaccination vs harm caused. Epidemiologists have to answer that. This is not my expertise."

Holme told Medscape Medical News that he does not think the AstraZeneca vaccine is safe. "Historically, I cannot imagine any vaccine with such severe side effects that hasn't been withdrawn. I understand that we are in a very unusual crisis situation with COVID, but we have other vaccines that have not been shown to have this side effect.

"These decisions are very difficult and have to be made with a very careful risk-benefit analysis. But it is devastating to see a healthy 40-year old dying from a vaccine complication who would have likely been fine if they had caught COVID."

Commenting on the NEJM publications for Medscape Medical News, Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said: "These reports confirm that there is a biological mechanism and that it is now clear that these complications are caused by the AstraZeneca vaccine. What is unknown is whether all clinical cases that are currently reported with thrombosis in rare sites such as cerebral or splanchnic veins combined with thrombocytopenia are showing this phenomenon or whether other mechanisms may play a role in some cases. The case definition is therefore still unclear, which complicates the risk estimates."

Middeldorp, who was not associated with either study, agrees that it would be preferable to use a different vaccine but only if other vaccines were immediately available, without logistical delay.

"However, we don't have enough alternative vaccines available. We should also not underestimate that middle-aged people, let's say above 40 to 50 years of age, still have a considerable risk of severe COVID or death, which at this stage of the pandemic clearly outweighs the very small risk of VITT after the AstraZeneca vaccine," she said.

Sir David Spiegelhalter, PhD, chair of the Winton Centre for Risk and Evidence Communication at Cambridge University, UK, who was part of the team assessing the risk–benefit of the vaccine in various age groups in the UK, told Medscape Medical News the scientific papers would not affect their advice as "we've been essentially assuming causation in our analysis."

The analysis from the Winton Centre, which weighed potential benefits and harms of the AstraZeneca vaccine based on the UK data, found the risk of the vaccine only outweighed the benefits for the age group 20-29 years and only when the COVID exposure risk is low (an incidence of 2 in 10,000 per day as is the current situation in the UK), as shown in the table below.   

Table. Risk and harms of the AstraZeneca vaccine by age group with low COVID exposure risk (Winton Centre analysis)

Age group (years) COVID ICU admissions prevented every 16 weeks Specific blood clots as a result of the vaccine
20-29 0.8 1.1
30-39 2.7 0.8
40-49 5.7 0.5
50-59 10.5 0.4
60-69 14.1 0.2

 

If the COVID risk becomes medium (incidence of 6 in 10,000 per day), the benefits of the vaccine outweighed the risk even in the 20-29 age group in the Winton analysis.  

Also commenting for Medscape Medical News, Brian Ferguson, PhD, lecturer in innate immunity, at University of Cambridge, UK, said: "The main message from these two papers is that there is a causal link between the AstraZeneca vaccine and very rare and occasionally lethal thrombotic events. Obviously, this is concerning for those taking the AstraZeneca vaccine, but to describe the vaccine as 'not safe' is not correct. The benefit of protection against COVID-19 that this vaccine provides is much greater than the risks from catching SARS-CoV-2 or the risks of vaccine-induced clots across most of the population at an individual level and for the community as a whole.

"There is an argument for using a different vaccine, if available, for those under 30 as laid out in the beautiful analysis by the Winton Centre," he added. "But the risks from delaying or not vaccinating people because of vaccine supply issues or hesitancy are also much greater than the risks of clots, so switching vaccines should only be recommended if an alternative vaccine is readily available to be administered."  

Even with all this reassurance, there have been reports of increased vaccine hesitancy with increasing publicity on the adverse reaction, with more people not showing up for their booked appointments.

Diagnosis and Treatment of Adverse Reaction

The authors of the two scientific studies make recommendations on how to handle these thrombotic complications.

Greinacher et al point out that enzyme-linked immunosorbent assays (ELISA) to detect PF4-heparin antibodies in patients with HIT are widely available and can be used to investigate patients for potential post-vaccination thrombocytopenia or thrombosis associated with antibodies against PF4. A strongly positive ELISA result obtained in a patient who has not been recently exposed to heparin would be a "striking abnormality," they state.  

They note that the addition of PF4 greatly enhances the detection of these antibodies in a platelet activation assay. Since vaccination of millions will be complicated by a background of thrombotic events unrelated to vaccination, a PF4-dependent ELISA or PF4-enhanced platelet activation assay may also be used to confirm the diagnosis of vaccine-induced immune thrombotic thrombocytopenia, they suggest.

But they say that treatment decisions — such as administering IVIG and starting anticoagulation — do not have to await laboratory diagnosis, as  detection of these unusual platelet-activating antibodies will be highly relevant for case identification and future risk–benefit assessment of this and other vaccines.

At the press briefing, Greinacher elaborated: "Patients who develop symptoms of clot — severe headache, unusual pain or neurological symptoms — need to have a platelet count and a D-dimer test first of all. If they are within a couple of weeks of having the AstraZeneca vaccine and they have high D-dimer and low platelet count they very likely to be having this reaction," he said. "They should be given an anticoagulant and IVIG as soon as possible. The pathogenic antibody can be detected with the HIT test and later confirmed with a specialized test."

Greinacher explained that an anticoagulant was needed to stop the growth of the thrombus, whereas the immunoglobulin product blocks the rogue immune response that causes the problem. "These antibodies binding to PF4 are still in the body of patients and causing more and more activation of the clotting system. The human antibody product IVIG which is widely available can stop this process by itself binding to the PF4 receptor and [thus] blocking the pathogenic antibody. The earlier that IVIG is started the better."

If caught in time, these patients can be successfully treated," Holme said. "The platelet count quickly came back up after treatment with IVIG and steroids. But the patients who died already had severe cerebral bleeding and it was too late to save them.

"This is a very rapidly progressing reaction," he added. "It can be fatal very quickly. It is very important to catch this reaction early and there is always a delay in patients getting to the appropriate medical help. Patients need to go immediately to the emergency department if they experience a severe headache, neurological symptoms, unusual pain. The timeline is crucial."

He said it was "vitally important" for physicians to have a low threshold to test for PF4 antibodies in any patient experiencing unusual symptoms in the weeks after receiving the AstraZeneca vaccine.

But a logistical problem arises in that headache — and sometimes a bad headache — is a frequent side effect of the AstraZeneca vaccine, as well as a common unrelated occurrence, and there have been reports of emergency departments flooded with anxious patients.

Can Heparin Be Given?

There is some debate about whether heparin can be used as the anticoagulant in these patients. Given the parallels with HIT, Greinacher recommends use of non-heparin anticoagulants unless a functional test has excluded heparin-dependent enhancement of platelet activation.

But Holme countered: "We believe these patients can in some cases be treated with heparin as we have seen increasing/normalizing platelet counts and no clinical progression of thrombosis on patients who had already been given low-molecular-weight heparin. But we have a difficult therapeutic dilemma. If a patient is having a cerebral bleed, many other anticoagulants have longer half-lives and are more difficult to reverse."

Greinacher et al add that: "Clinician reluctance to start anticoagulation may be tempered by administering high-dose IVIG to raise the platelet count, especially when a patient presents with severe thrombocytopenia and thrombosis such as CVST."

Explaining more details of the mechanism behind this reaction, Greinacher said: "We are certain that massive platelet activation is associated with this condition, and it is absolutely clear that there is a causal relationship between the anti-PF4 antibody and the clinical syndrome. This antibody is only formed when something has gone wrong. This may be due to proinflammatory substances triggering a particular immune response."

He added: "We know that the AstraZeneca vaccine is inducing a relatively harsh vaccine reaction. Many people don't feel well for a few days after the vaccination. The reaction is more severe than is seen with most other vaccines. It is likely that this proinflammatory stimulus helps to induce these rogue antibodies."  

Greinacher reported that in Germany more than 1.4 million people have received the AstraZeneca vaccine and there have been 50 to 60 of these severe reactions reported. "Our lab has confirmed the antibody to be present in 40 to 50 cases. It is likely that the patients have something in their body that predisposes them to form these antibodies after the vaccination, but we don't know what this is. At present we have no way to predict who will develop these antibodies."

Other Thrombotic Risk Factors Not Relevant?

Both groups highlighted the strength of the reaction. Greinacher said: "The reaction is very strong — it is causing a major change to the clotting system."

Asked whether other thrombotic risks factors such taking the oral contraceptive pill may increase the risk of this reaction, Greinacher thought that would be unlikely. "I don't believe other thrombotic risk factors will make much difference. This anti-PF4 antibody is causing such a super strong reaction. The contraceptive pill is a very mild thrombotic risk factor in comparison. It is probably not relevant."

Holme added that there can be false positives with the HIT test, but patients experiencing this severe reaction after the AstraZeneca vaccine are showing a very unusually high positive result, "higher than we see in HIT patients." But he agreed that they should later receive a confirmatory functional platelet aggregation test.

The Norwegian authors note that 5% to 7% of blood donors have detectable PF4-heparin antibodies but rarely higher than an optical density of 1.6. And in HIT patients, optical density levels higher than 2 are unusual, whereas these patients with VITT had levels of 2.9 to 3.8.

Caused by the Virus or Vector?  

Greinacher noted that there have been discussions on the possibility that the rogue antibody is produced by the immune response to the virus spike protein in the vaccine (the wanted protective immune reaction of the vaccine), as the structure of part of the spike protein resembles part of the PF4 molecule. But evidence thus far suggests that this is not a cross-reacting antibody.

"That is fantastic news for the vaccine program as it would have meant that all vaccines would have been affected," he commented.

On whether the reaction could be caused by the adenoviral vector used in the AstraZeneca vaccine, Greinacher says it is "too early for a reasonable scientific argument to be drawn on a direct link. We know that adenovirus interacts with platelets, so in theory that could make sense. But if this was the mechanism, I would have expected many more patients to have had these problems."

In the NEJM paper, Greinacher et al add: "The amount of adenovirus in a 500 microliter vaccine injection administered 1 or 2 weeks earlier would seem unlikely to contribute to subsequent platelet activation observed in these patients."

Implications for J&J Vaccine?

There are many questions about whether other COVID-19 vaccines may be affected by this adverse reaction, particularly the Johnson & Johnson/Janssen vaccine, which is also based on an adenovirus vector. The EMA reported last week that it had started a safety review on the J&J vaccine after four cases of a similar condition linked to the vaccine had come to light. 

"While there may be a few reports of similar thrombotic complications with other vaccines, we don't know if these people have the pathogenic PF4 antibodies present," Greinacher added. "This complication can develop spontaneously on rare occasions and we have to filter out that background noise."   

"The numbers of these severe reactions with the J&J vaccine are very small — just four so far," he added. "While this vaccine has not yet been used in Europe, it has been given extensively in the US. It is likely that just as many, or even more, doses of the J&J vaccine have been used in the US as the AstraZeneca vaccine in Germany. I cannot imagine that such severe thrombotic complications would not have been detected. It doesn't appear to be as strong a signal as with the AstraZeneca vaccine."  

In regard to reports suggesting these reactions are more common in younger people, Holme said the numbers do seem to be less in older people but there have been reports in Europe in those older than 65 years. "A very simple explanation for the higher numbers in younger age groups could be that younger people usually have more active immune systems."

Greinacher noted that the UK has used more of this vaccine than anywhere else, but the rate of these serious adverse events seems to be higher in Germany. "In the UK, the elderly were vaccinated first. If they had developed CVST, it might not have been linked to the vaccine, but when this happens in a 25-year-old everyone thinks something is wrong," he said. "When you see a few of these events, then that is a signal. In Germany, the AstraZeneca vaccine was not used in the elderly, it was given mainly to younger healthcare workers — perhaps that is why the signal was detected here first."

Greinacher reports grants from Deutsche Forschungsgemeinschaft during the conduct of the study; personal fees and nonfinancial support from Aspen, grants from Ergomed, grants and non-financial support from Boehringer Ingelheim, personal fees from Bayer Vital, grants from Rovi, grants from Sagent, personal fees from Chromatec, personal fees and nonfinancial support from Instrumentation Laboratory, grants and personal fees from Macopharma, grants from Portola, grants from Biokit, personal fees from Sanofi-Aventis, grants from Fa. Blau Farmaceutics, grants from Prosensa/Biomarin, grants and other from DRK-BSD NSTOB, grants from DRK-BSD Baden-Würtemberg/Hessen, personal fees and nonfinancial support from Roche, personal fees from GTH e.V., grants from Deutsche Forschungsgemeinschaft, outside the submitted work. In addition, Greinacher reports having a patent pending for a modified SARS-CoV-2 vaccine.

Holme and Schultz have disclosed no relevant financial relationships.

N Eng J Med. Published online April 9, 2021.
Greinacher et al study. Full text
Schultz et al study. Full text

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