Did the Pfizer/BioNTech COVID-19 vaccine cause a fatal case of ITP?

Three weeks ago, I wrote about how the roll out of COVID-19 vaccines under the FDA’s emergency use authorization (EUA) for the Pfizer/BioNTech and Moderna RNA-based vaccines would very likely result in a tsunami of confusion of correlation with causation to blame the vaccines on all manner of seeming “adverse events,” whether the adverse events were caused by the vaccine or not. I used the specific examples of syncope and Bell’s palsy, the former of which is a common reaction to needlesticks of many kinds (including all vaccinations) and the latter of which was almost certainly not related to vaccination against COVID-19, also explaining how the law of large numbers will mean that there will certainly be a lot of health issues manifesting themselves sometime soon after vaccination just by coincidence alone, up to and including death. (The same principle applies to claims that vaccines cause autism.) Elsewhere, I predicted:

The point is that there will be all sorts of scary stories about COVID-19 vaccines in the coming weeks and months, and a lot of people will have reactions similar to mine. Again, most symptoms other than the sort that I experienced will turn out not to be due to the vaccine. I also have another prediction. There will be people who get COVID-19 right after having the vaccine, and antivaxxers will claim that the vaccine caused it, just as they sometimes claim that the flu vaccine causes the flu. There will also be people who happen to die within a month of getting the vaccine, particularly when the vaccine rolls out to elderly general population, due to the simple law of large numbers and the fact that on any given month far more elderly people die than young people. Look for antivaxxers to spin these coincidences as “definite proof” that the COVID-19 vaccine kills, just the way they’ve done for vaccines and sudden infant death syndrome (which is not caused by vaccines) and for the HPV vaccine and deaths of teenaged girls.

Dr. Vincent Iannelli agrees.

The first such story has started circulating in the antivaccine nooks and crannies of social media, but it’s also being flogged by the usual British tabloids.

Dr. Gregory Michael, the Pfizer COVID-19 vaccine, and ITP: What happened?

Here’s the first story of a death after vaccination against COVID-19 that sounds plausible on the surface that allows me to revisit this issue because, unlike the cases of people who are, for example, hit by a car within two weeks of vaccination, we can’t just dismiss it a priori:

A Florida doctor has died several weeks after receiving a COVID-19 vaccine, although it’s not yet clear whether his death Monday was related to the shot he received on Dec. 18.

Dr. Gregory Michael, 56, an OB-GYN at Mount Sinai Medical Center in Miami Beach, died after suffering a hemorrhagic stroke apparently resulting from a lack of platelets.

Miami medical examiners are investigating his death, the Florida Department of Health said in a statement.

“The CDC and FDA are responsible for reviewing COVID-19 vaccine safety data and presenting that information for federal recommendations on vaccine administration,” communications director Jason Mahon said in an email. “The state will continue to provide all available information to the CDC as they lead this investigation.”

The USA TODAY story cited above was actually fairly cautious in its telling of the story of Dr. Michael’s tragic death due to idiopathic thrombocytopenic purpura (ITP), also known as immune thrombocytopenic purpura. ITP is a condition in which there is an immune reaction against platelets, which are responsible for clotting, leading to a decrease in their number to the point where bleeding can occur. Most often that bleeding takes the form of “petechiae”, or tiny bruise-like markings on the skin, but in rare cases ITP can lead to dangerously low numbers of platelets, levels at which the risk of spontaneous bleeding in the brain and other organs becomes very high. It’s called “idiopathic” because its causes are unknown or not well understood. (As I like to say, “idiopathic” basically means “we don’t know the cause.”)

The story further noted that ITP is rare and that in extremely rare cases, the measles, mumps and rubella (MMR) vaccine has been linked to thrombocytopenia in children, according to a 2003 study. The story also noted that ITP “can also be caused by cancer, anemia, heavy drinking, viruses, some genetic conditions, toxic chemicals and medications such as diuretics and the rarely used antibiotic chloramphenicol”. (More on the general risk of ITP after vaccination later.)

Unfortunately, pouring gasoline on the flame was, in her understandable grief, Dr. Michael’s wife Heidi Neckelmann, who wrote a Facebook post that rapidly went viral, particularly in antivaccine circles:

It’s impossible not to feel enormous sympathy and empathy Ms. Neckelmann. I can only try to imagine what she is going through now, particularly given that her husband was within a couple of years of my age. Stories like this always make me wonder how I’d react to the unexpected and rather rapid death of my wife. Be that as it may, Ms. Neckelman’s post led to sensationalistic headlines, like this one from (who else?) The Daily Mail:

And:

Heidi Neckelmann says obstetrician Gregory Michael, 56 – her ‘best friend’ and partner of 28 years – was active, healthy and had no pre-existing conditions before getting the jab on December 18.

However he died from a stroke Sunday morning after suddenly developing a rare autoimmune illness that causes the body to destroy its own platelets, the tiny fragments that help blood to clot.

Distraught Heidi, 58, thinks the groundbreaking Pfizer-BioNtech vaccine may have somehow been the trigger.

‘In my mind his death was 100 percent linked to the vaccine. There is no other explanation,’ she told DailyMail.com, fighting back tears.

‘He was in very good health. He didn’t smoke, he drank alcohol once in a while but only socially. He worked out, we had kayaks, he was a deep sea fisherman.

‘They tested him for everything you can imagine afterwards, even cancer, and there was absolutely nothing else wrong with him.’

Pfizer told DailyMail.com Wednesday that it was aware of Dr. Michael’s ‘highly unusual’ death and was investigating further.

However a spokesman cautioned: ‘We don’t believe at this time that there is any direct connection to the vaccine.’

The Daily Mail story, as sensationalistic as it is, does provide us with more information that Ms. Neckelmann’s Facebook post:

Dad-of-one Gregory suffered no immediate reaction to the injection but three days later he was taking a shower and noticed petechiae – spots of red that indicate bleeding beneath the skin – on his feet and hands.

When he checked himself into Mount Sinai Medical Center in Miami Beach, the hospital where he works and had the groundbreaking vaccine, medics discovered he was suffering from an acute lack of platelets.

‘All the blood results came back normal except for the platelets which came back as zero,’ Heidi said.

‘At first they thought it must be a mistake. So they did the test again and this time did a manual count which is supposed to be more accurate. This time it showed just one platelet.

‘He felt 100 percent, he was normal, energetic, happy. But they said you cannot go home, this is incredibly dangerous, you could suffer a brain bleed and die.’

Ultimately, Dr. Michael was diagnosed with ITP, and here’s what ultimately happened:

After two weeks of infusions and experimental treatments that failed to raise Gregory’s platelet count, doctors decided they had no choice.

However he died from a hemorrhagic stroke – when blood from an artery bleeds into the brain – before he could undergo the surgery.

‘They gave him medicine. They gave him an incredible amount of platelet infusions, I’m told all the platelets in Miami Dade County,’ Heidi said.

‘But no matter what they did, nothing helped. The blood tests came back with zero platelets every time.

What the story means by “had no choice” was the surgical treatment of ITP, namely splenectomy, or removal of the spleen. Surgeons were understandably reluctant to operate on a patient whose platelet count was so low as to be almost undetectable, given the extreme risk of bleeding. Dr. Michael apparently died before he could be operated on, as risky as surgery would be.

ITP: Causes and treatment

As I mentioned above, ITP is an autoimmune condition that results in platelet destruction in the spleen. Again, as I said before, “idiopathic” means basically “we don’t know what causes it.” There are also two forms of ITP, acute and chronic, with the acute form occurring mainly in children and the chronic form occurring in adults:

Acute ITP generally lasts less than 6 months. It mainly occurs in children—both boys and girls—and is the most common type of ITP. Acute ITP often occurs after a viral infection.

Chronic ITP lasts 6 months or longer and mostly affects adults. However, some teenagers and children do get this type of ITP. Chronic ITP affects women two to three times more often than men.

Treatment depends on the severity of bleeding and the platelet count. In mild cases, treatment may not be needed.

Another aspect of ITP is that it is usually not life-threatening. Acute ITP is often self-limited, and it’s rare for ITP in adults to be so resistant to treatment as Dr. Michael’s case:

For most children and adults, ITP isn’t a serious or life-threatening condition.

Acute ITP in children often goes away on its own within a few weeks or months and doesn’t return. In 80 percent of children who have ITP, the platelet count returns to normal within 6 to 12 months. Treatment may not be needed.

For a small number of children, ITP doesn’t go away on its own and may require further medical or surgical treatment.

Chronic ITP varies from person to person and can last for many years. Even people who have severe forms of chronic ITP can live for decades. Most people who have chronic ITP can stop treatment at some point and maintain a safe platelet count.

The most common symptoms of ITP include, of course, the petechiae and purpura mentioned before (small lesions on the skin due to bleeding under the skin), plus any or all of the following:

• bruising easily
• spontaneous nosebleeds
• bleeding from the gums (for example, during dental work)
• blood in the urine
• blood in the stool
• abnormally heavy menstruation
• prolonged bleeding from cuts
• profuse bleeding during surgery

There are a number of conditions that have been associated with the development of ITP:

• Viral infections (including chickenpox, parvovirus, hepatitis C, Epstein-Barr, and HIV)
• Systemic lupus erythematosus (SLE)
• Chronic lymphocytic leukemia (CLL)
• Drug-induced immune thrombocytopenia
• Sepsis, a severe bacterial infection in your blood
• Helicobacter pylori (H. pylori), a bacteria that can live in your digestive system

Also, medications can increase the risk of ITP:

• Certain drugs for heart problems, seizures, and infections
• Heparin, a blood thinner used to prevent blood clots

The treatments for ITP depend upon the type and severity. As mentioned above, sometimes ITP doesn’t even require treatment and can be managed expectantly by checking platelet counts regularly to make sure the patient’s platelet count is not declining or are even increasing back towards normal. Unsurprisingly, the first line of treatment, however, is corticosteroids, ranging from oral prednisone in less severe cases to intravenous dexamethasone or methylprednisolone in more severe cases in which the platelet count is so low as to risk bleeding.

In case of emergency, platelet transfusions are used, but this is usually not the first choice because the new platelets are usually chewed up by the autoimmune response just as fast as the patient’s own platelets. Thus, platelet infusions are generally not used except in emergencies when bleeding is occurring or platelet counts are as low as Dr. Michael’s were. Either way, platelet transfusions are not a long-term treatment for ITP, as they can only temporarily increase the number of functional platelets.

There are also other drugs that can be used, non-steroid immunosuppressants such as mycophenolate mofetil and azathioprine, or even the chemotherapy agent vincristine. Intravenous immunoglobulin can also sometimes be effective at decreasing the rate at which macrophages (an immune cell) destroy antibody-tagged platelets. Like platelet transfusions, though, intravenous immunoglobulin usually only transiently increases platelet counts and is usually only used in cases where steroids don’t work and bleeding is either occurring or feared to be imminent. In cases of refractory ITP, thrombopoietin receptor agonists (drugs that stimulate the receptor) can stimulate the bone marrow to make more platelets. Another treatment includes rituximab (Rituxan), a monoclonal antibody against the protein CD20, which is found on the surface of B-cells. When rituximab binds to CD20, it causes B-cell death and is used against blood cancers and autoimmune diseases.

Finally, there’s surgery. Every general surgeon knows about ITP, because it is general surgeons who are called upon to do a splenectomy in patients whose ITP is refractory to other treatments. The reason that splenectomy works is because platelets with antibodies bound to them are taken up by macrophages in the spleen. Splenectomy can result in durable remission of ITP in up to 80% of patients, but, again, it’s generally risky because of the elevated risk of bleeding in the sorts of patients for whom the operation is generally reserved, namely those with refractory severe ITP.

It’s also important to note again that severe bleeding due to ITP of the sort suffered by Dr. Michael is rare.

Does vaccination against COVID-19 cause ITP?

The study cited in the USA TODAY story estimated the attributable risk of developing ITP after MMR vaccination to be 1 in 25,000 vaccinations, which strikes me as rather high. After all, a risk of ITP that high should produce a much more noticeable incidence of ITP. Be that as it may, another later study noted that bleeding episodes were uncommon among these patients, that the ITP associated with MMR disappeared within a month in 74% patients and only persisted beyond 6 months in only 10%. And, again, this was observed in children, not adults.

Dr. Iannelli notes that ITP is rare and that there is only one vaccine for which there is a documented association, the MMR vaccine. True, ITP is listed on the Gardasil package insert as a possible adverse reaction, but, as Dr. Iannelli goes on to explain further, later studies have shown no association, and the risk of getting ITP after an actual measles infection is considerably higher than the risk of ITP after the MMR vaccine, thus leading him to point out that “worry about ITP is a not a good reason to skip or delay getting vaccinated”.

This brings us, after this long detour into the weeds of what ITP is, what can trigger it, and how it’s treated, back to the question of COVID-19 vaccination and ITP, the question at the heart of the sad story of Dr. Michael’s sudden development of ITP refractory to treatment that claimed his life within two weeks of diagnosis. Dr. Iannelli further notes that the annual incidence rate of ITP is estimated to be 3.3 per 100,000 adults/year. Given that there are over 200 million adults in the US, this would lead to an estimate of around 16 adults per day being diagnosed with ITP. That means that, in any given three day period (chosen because Dr. Michael’s wife reported that her husband’s symptoms began three days after he was vaccinated with the Pfizer/BioNTech COVID vaccine), one would expect approximately 48 adults to be diagnosed with ITP. As the COVID-19 vaccines roll out, it’s going to become more and more likely that these people will receive their diagnosis within a couple of weeks of having been vaccinated against COVID-19. It’s thus probably more likely than not that Dr. Michael’s diagnosis so soon after vaccination is a coincidence.

It must, however, be acknowledged that it is possible that COVID-19 vaccination might have caused Dr. Michael’s severe ITP. The problem then becomes determining whether his tragic outcome was a coincidence or due to the vaccine. Unfortunately, Dr. Michael’s case is, at present, a single anecdote, making it impossible to demonstrate causation. Certainly, the clinical trials for neither the Pfizer/BioNTech nor the Moderna COVID-19 vaccines detected any signal for ITP in the form of bleeding, low platelet counts, or the like within two months of vaccination. Indeed, one of the deaths in the placebo group for the Pfizer vaccine was due to a hemorrhagic stroke. Given that there were approximately 44,000 subjects in the Pfizer/BioNTech trial with not a single patient showing signs if ITP, we can reasonably conclude that, even if the Pfizer/BioNTech vaccine increases the risk of ITP or causes ITP, the risk must be very, very low.

What might lead scientists to think that there is an actual association between vaccination with the Pfizer/BioNTech COVID vaccine and ITP? Again, Dr. Iannelli suggests one possible metric for judging whether ITP really is associated with this vaccine:

But how can you know for sure?

Experts will look for safety signals and will make sure that the incidence of ITP and other conditions doesn’t rise above historical rates. For example, if all of a sudden we notice that the incidence of ITP rises to 6 or 9 per 100,000 adults/year after getting a vaccine, then that would be a signal that there could be a problem. A few media reports likely aren’t though.

Given how low the annual incidence of ITP is at baseline taken in context with the fact that there will be tens of millions of adults vaccinated with the Pfizer/BioNTech vaccine this year, we would expect to see a significant increase in the annual incidence of ITP if this vaccine did actually increase the risk of ITP. For more on how, when studying adverse events after vaccination, scientists differentiate coincidence from actual association that might be causal, here’s a good primer.

But what if there really is an association between the Pfizer/BioNTech COVID vaccine and ITP? Even in the case that there is such an association, we know that, for the phase 3 clinical trial to have missed it, the incidence of post-COVID vaccination ITP must be very, very low. That would imply that, even if there is such an association, it is far safer to get the vaccine than it is to take the risk of catching COVID-19 – and, again, this is just one story. We do not know if Dr. Michael’s case, as tragic as it is, even indicates potential causation. Again, you can’t tell that from just one case, however dramatic and tragic. It is, however, not implausible that ITP might occur after vaccination against COVID-19 given that a recent review of the literature found 45 cases of new onset ITP after COVID-19 infection. Three turned out to be exacerbations of preexisting ITP and were excluded, but the review also reported one fatality due to intracranial hemorrhage, the same complication that took Dr. Michael’s life. It was also noted that severe bleeding due to ITP after COVID-19 infection was rare and that diagnosing ITP in the setting of COVID-19 infection is challenging due to the common incidence of clotting disorders and diffuse intravascular coagulation (DIC), which can also cause platelet depletion. Clearly more study is needed, and one anecdote isn’t enough to draw any conclusions.

It’s also entirely understandable that Heidi Neckelmann would believe that it was the COVID-19 vaccine that killed her husband. Humans are, as I like to say, pattern-seeking creatures. It’s hard-wired into us to search for causes whenever something horrible happens, and we usually find one, whether it is the true cause or not. As bad as I feel for her, I just wish that Ms. Neckelmann hadn’t in her grief leapt to the conclusion that it was definitely the COVID-19 vaccine that had caused her husband’s death from ITP and trumpeted his story as a warning to the world, so that his death wouldn’t be “in vain.” Her Facebook post handed the antivaccine movement and COVID-19 cranks a powerful propaganda weapon. Again, I think I understand why she did it, but really wish she hadn’t. Her post is already doing damage to efforts to persuade people to accept COVID-19 vaccines, as antivaccine groups gleefully spread this story far and wide.