Are COVID vaccines "clot shots"?
Pithy rhymes don't always reflect real life.
The gist: On occasion, people on social media who are against vaccines (especially COVID vaccines) use the term “clot shot” to describe them, implying that the vaccines are associated with some kind of markedly heightened risk of blood clots. The truth? Adenovirus-vectored vaccines are associated with a clotting condition called thrombosis with thrombocytopenia syndrome (TTS) or vaccine-induced immune thrombotic thrombocytopenia (VITT) in 3 to 15 per million initial doses depending on which specific vaccine you look at (Johnson & Johnson/Janssen vs. Oxford/Astra-Zeneca) and your age and sex. Although this condition is very rare, it can be devastating when it happens, being fatal in half of cases if not treated early. mRNA vaccines in contrast do not show a consistent increased risk in any type of clotting disorder. Early on in the vaccine rollout, there were very rare cases (~0.8 per million doses) of bleeding disorders seen in those who took mRNA vaccines, but this has not been reported since and appears to reflect the normal rate of the condition even in the absence of vaccination. Those who have the aforementioned bleeding disorders may experience a recurrence after vaccination depending on their severity.
Contents (which for some reason I can’t create links to)
A bit about clots
Vaccine-induced immune thrombotic thrombocytopenia (VITT)/ Thrombosis with Thrombocytopenia Syndrome (TTS)
Immune Thrombocytopenia after mRNA vaccines
Venous thromboembolism (VTE) risk with mRNA vaccines
Ischemic stroke
Retinal Vascular Occlusion (RVO) and mRNA vaccines
COVID-19 and risk of clotting
Conclusion
A bit about blood clots
In general, when people talk about blood clots, they are talking about venous thromboses- blood clots in the veins. In addition to these however, blood clots are possible in the arteries (arterial thromboses), in the chambers of the heart (intracardiac thromboses) and in the microcirculation. Blood clots form as a response to injury and are intended to stop bleeding (this is known as hemostasis).1 In general, blood clots tend to form in the veins over other parts of the body because the flow of blood in them is very slow compared with other vessels, which allows the blood to pool, and because of the low-oxygen environment compared with arteries and the heart. Blood that stays still for too long has a tendency to clot. Clots in the arteries can result from the rupture of fatty cholesterol plaques (this is how heart attacks happen). Clots in the heart can happen from damage after the heart attack or from a lack of movement in certain parts of the heart2. An embolism refers to an obstruction within an artery (from basically anything), but when a blood clot causes it, it is known as a thromboembolism. This is the major reason that clots become dangerous: once they reach a certain size, they can reduce or even completely block the flow of blood to the tissues they feed, which results in those tissues being starved of nutrients and unable to eliminate metabolic wastes, eventually dying3.
People often fail to appreciate how common blood clots are in general. Venous thromboembolisms (VTEs) occur in 1 to 2 people per 1000 per year with a risk that increases with age, and are the third-most common cause of cardiovascular death after heart attacks and strokes. The frequency with which blood clots occur needs to be at front of mind when we consider the findings regarding mRNA vaccines to be discussed- you can absolutely find cases of blood clots after mRNA vaccination, but if you look at isolated cases, there is no way to tell whether or not the vaccine caused them, whether they were coincidental, or whether they were idiosyncratic. The question we care about is whether or not there is an additional risk posed by mRNA vaccines beyond what we would experience by just living life, which requires large studies of many people where we compare the risk with and without the mRNA vaccines.
It is also worth spending a moment on the factors that can cause blood to clot. One is particularly noteworthy for this discussion: infections. The platelets that help to initiate blood clotting are also immune cells and can be activated by immune responses and inflammation (the interactions between the immune system and blood clotting system is often described by terms like immunothrombosis, immunocoagulation, or thromboinflammation). This phenomenon is a major contributor to the many terrible potential consequences of COVID-19. Another major factor is trauma: if it makes you bleed, it can make you clot (this is why patients are often put on blood thinners after surgery). Cancer is also another big one- clots are actually the second-most common reason that cancer patients die. Other than that conditions that put stress on the vasculature like high blood pressure, diabetes, and kidney disease are also major risk factors. Clotting disorders can also be genetic. For example, a clotting protein called Factor V (five) can have a mutation that renders it resistant to the natural clot-busting proteins in our blood called Factor V Leiden. Individuals with this mutation have a 7- to 20-fold (depending on whether they have 1 or 2 copies) heightened risk of forming clots relative to those who do not and it is found in 1 to 5% of people of European descent.
Still, it’s important to bear in mind that inflammation or immune responses alone do not cause clots. At each moment in our body, there is a dynamic balance between clot formation and clot breakdown. Clots will only form if the rate of their formation exceeds the rate of their breakdown, and clots do not start to exert health effects until they get to a certain size (depending on where they are).
Vaccine-induced immune thrombotic thrombocytopenia (VITT)/ Thrombosis with Thrombocytopenia Syndrome (TTS)
VITT (aka TTS) describe a unique and devastating clotting condition in which an immune response is directed against a protein called platelet factor 4 (PF4) which also activates platelets and induces blood clotting4. This causes the simultaneous formation of large blood clots in unusual locations (thromboses) with low platelets (thrombocytopenia). VITT should not be conflated with VTE or other types of blood clots. It is a unique condition in which blood clots occur in unusual locations such as the splanchnic veins and the cerebral venous sinuses AND causes low platelets and the mechanism by which the clots arise is distinct from that of other types of clotting issues.
In February 2021, there were some reports of clots after COVID-19 vaccination in Europe. The EMA initially investigated these and was unable to find evidence of a signal (because these events are extremely rare). However in March 2021, the European Medicines Agency reported blood clots in those who received the Oxford/AZ COVID-19 vaccine Vaxzevria at a rate above what would be expected from random chance, mainly in women younger than 55 occurring 14+ days after vaccination, and considered the events possibly related to vaccination, advising that anyone with symptoms of a blood clot seek immediate medical attention5. In May 2021, the FDA instituted a pause in administration of the Janssen/Johnson & Johnson vaccine after 6 cases (out of 7 million doses) of life-threatening blood clots in unusual sites and low platelets had been reported. Subsequent investigation showed that the clots result from antibodies against PF4, which make them very similar to a condition called autoimmune heparin-induced (thrombosis and) thrombocytopenia, wherein the blood thinner heparin induces clotting by causing the development of PF4 antibodies which can then continue to activate platelets even in the absence of heparin6. Note that heparin is normally found within the body as well. In this case, the development of PF4 antibodies appears to result from the fact that the capsids of multiple adenoviruses can bind PF4 spontaneously, and so as an immune response against the adenoviruses is induced, it can spread to PF47. Higher levels of PF4 antibodies associate with a greater drop in platelets and greater severity of illness. However, PF4 antibodies in the general population are common and do not generally cause illness, which complicates testing (i.e., it would not be appropriate to screen everyone for these antibodies before vaccination).
VITT is an extremely rare condition: an estimated 3 to 15 cases per million doses of vaccine are estimated to cause the condition. The risk is higher with Vaxzevria than with Janssen’s vaccine. However, while the condition is rare, it poses a number of major challenges. For one, it is life-threatening, especially if there is a cerebral venous sinus thrombosis (CVST); early on, death occurred in about 50% of cases- but this declines by about 90% if it is recognized early and treated. However, the early signs are subtle and nonspecific- basically a flu-like illness thought to be related to enhanced immune activation of the platelets and other immune cells involved in clotting (and possibly from the response to the vaccine itself depending on when symptoms start). Headache suggests involvement of the cerebral venous sinus or other brain vasculature, but headache after vaccination is common and is not concerning in the vast majority of instances it occurs. It is noted that the symptoms of VITT may overlap with normal symptoms seen in the course of a normal immune response to the vaccine (i.e. reactogenicity). A key factor is the timing of the condition- it occurs 4 to 30 days after the vaccination, at which point reactogenicity symptoms should normally resolve (but exceptions can occur). In some cases, platelet counts may be normal (particularly initially), and early imaging for CVST can be negative because the clots are too small and occur in the microvasculature.
It is worth noting quite clearly that to this point I have not discussed mRNA vaccines at all. This is because mRNA vaccines are not associated with VITT, which is further supported by data from the EMA’s monitoring and England, Scotland, and Wales. As Cines and Greinacher write:
The few cases of platelet activating PF4-dependent antibodies attributed to mRNA vaccines probably reflect the background rate of spontaneous or autoimmune HIT.
…
Anti-PF4 antibodies in VITT do not cross-react with spike protein,62,63 nor does COVID-19 infection increase anti-PF4 antibody titers,64 although high titer anti-PF4 antibodies have also been observed in patients with COVID-19.
In fact, those with VITT are advised to avoid adenovirus vaccines and get mRNA vaccines for subsequent doses.
There are no adenovirus-vectored COVID vaccines available in the US anymore; a preferential recommendation for mRNA vaccines was eventually made by CDC over adenovirus vaccines based on the superior safety8 and effectiveness of the mRNA vaccines:
Janssen did not pursue an update of its vaccine or full licensure (Biologics Licensure Application, BLA) after its Emergency Use Authorization (EUA) expired, noting a lack of demand.
Immune Thrombocytopenia after mRNA vaccines
Occasionally, you can develop an immune response targeting platelets called immune thrombocytopenia (ITP). This causes platelet levels to drop and can prevent appropriate clotting, which leads to a very high bleeding risk. Interestingly, in children this condition is usually benign and doesn’t require any intervention, whereas in adults it can be an issue. The condition occurs in about 1 per 20,000 people in the US each year.
Early on after the rollout of the COVID vaccines, a handful of cases of ITP were reported, particularly in those who previously had the condition. Subsequent study found that mRNA vaccines could cause a return of ITP very occasionally in those patients, with the risk being higher if they required more intense therapy to control the ITP initially (which likely reflects the fact that these individuals were extremely prone to the condition at baseline). Despite this, it is genuinely difficult to tell whether or not mRNA vaccines can cause ITP. For example, a study in Scotland found no increased risk in 2.53 million people for developing ITP after the Bnt162b2 (Pfizer/BioNTech) vaccine (aka Comirnaty/Tozinameran)- but it did find an elevated one for Vaxzevria, as well as an elevated risk of conditions consistent with VITT (this likely reflects cases of VITT/TTS, which also causes a drop in platelets). When an analysis was conducted again, this time for second doses, the risk was not observed for Comirnaty and a risk also wasn’t seen with Vaxzevria (suggesting that the risk is mainly limited to the first dose of Vaxzevria). A review of VAERS reports also found that the reported number of cases of thrombocytopenia were within what would be expected due to random chance. At the same time, in an early case series, the incidences of ITP seemed to occur after the first dose far more than the second, which would argue against the reported cases being the result of random chance. Ultimately, the incidence of ITP after mRNA vaccines seems to be estimated at 0.8 per million doses, and in the rare cases where it occurs, outcomes appear to be reassuring.
At this point, I think we can probably say: the risk of developing ITP from mRNA vaccines is so low that it is questionable that it is a true risk. The possibility that those who have had ITP can have a recurrence after vaccination does exist, but depends on the severity of the ITP.
Venous thromboembolism (VTE) risk with mRNA vaccines
In some ways this is the part that really matters because the previously described conditions represent rare, unique manifestations of clotting (or bleeding) issues, but VTEs are far more common (about 1-2 per 1000 people per year). VTEs are generally divided into deep vein thromboses (DVTs) which are blood clots that occur usually in the deep veins of the legs (but occasionally at other sites like the arms, splanchnic, or cerebral veins) and pulmonary embolisms (PE; blood clots in the lungs). VTEs begin as clots in the veins which them migrate. In particular, the concern with DVTs is that they will migrate to the lungs and cause a PE, which can readily be fatal if not promptly treated. That risk tends to be higher for clots that occur closer to the lungs (i.e., a DVT in the calf is much less likely to cause a PE than a DVT above the knee). So, what do the data say about mRNA vaccines and the risk of VTE?
A study of 6039 patients hospitalized with VTEs (and other thrombotic issues) in New Zealand found no increased risk from the Pfizer vaccine
A study of 6067 patients with an increased risk of clotting and 785 943 patients in the Mayo Clinic database with no increased risk of clotting found no increase in the risk of clots after vaccination with mRNA vaccines or Janssen (but very few people in the database received Janssen)
In a study of 6.2 million persons who received 11.8 million doses of an mRNA vaccine in the Vaccine Safety Datalink found no increased risk of venous thromboembolism or any of the other 22 targeted health outcomes
Myocarditis was given special attention here because it was flagged as a safety signal at the time of the study and an elevated risk is found when looking at males aged 12-39 specifically and it is most obvious when looking at the second dose; it is not however seen in the general population because for most other groups the risk is not appreciably higher than the background rate of the condition
A study of 29 million people in the UK found no increased risk of VTE, arterial thrombosis, heart attack, or other rare clotting events after the first dose of the Pfizer vaccine. A very slight increase in the risk of stroke was observed (more on that in the next section). The risk of all outcomes was significantly increased if there was a positive test result for SARS-CoV-2
A slightly increased risk of CVST is found in this analysis; the increase from COVID-19 is much higher, and this is also corroborated by data from Singapore and additional UK data. A US study did not find an elevated risk of CVST from mRNA vaccines, nor did a study of 2.6 million people from Wales. It is important to keep in mind that the baseline incidence of CVST is about 3 per 100,000, so even a 4-fold increase still represents a very small number of cases.
A nationwide cohort study in Israel of a number of health outcomes with an average of 884,828 people per outcome found that the Pfizer vaccine was associated with 1 fewer DVT per 100,000 people compared to the background rate. Again, COVID-19 was associated with a markedly increased risk of many health outcomes at a level far higher than the Pfizer vaccine with the exception of lymphadenopathy (swelling of the lymph nodes after vaccination from the immune response- in general this is harmless), appendicitis, and zoster reactivation9
A study of 855,686 VA patients found a 00.09927% increase in the risk of VTE after a COVID-19 vaccine (Janssen, Moderna, and Pfizer)
A systematic review comprising ~21 million doses of mRNA vaccines found no increased risk of clots
A study of 5.3 million vaccinated people in Norway, Finland, and Denmark estimated a risk of 4 additional venous thromboses for every 100,000 doses of Pfizer, 5.7 additional venous thromboses for every 100,000 doses of Moderna, and 12.6 additional venous thromboses for every 100,000 doses of Oxford/AZ
A Vaccine Safety Datalink study of 247,000 doses of mRNA vaccines given to children aged 6 months to 5 years found no increased risk of clotting as well as a number of other adverse events
A Study of 385,000 children in VSD aged 5 to 11 (and 48 ,795 V-SAFE enrollees and the VAERS reports for that group at the time) also showed no safety signals, including for clotting risk
A study of 172,032 adolescents aged 12 to 17 found no increased risk of thrombosis; there were some cases of myocarditis, most of which had resolved by the time the study was done
V-SAFE reporting from 286,380 V-SAFE registrants aged 50+ and the review of VAERS reports found no increased risk after a booster (third) dose of mRNA vaccine
A Danish nationwide cohort study of adults 18-64 receiving the Oxford/AZ vaccine followed by 2 doses of an mRNA vaccine series found no increased risk of thrombosis with the mRNA vaccine booster
A UK study looking at 1,832,841 BNT162b2 vaccinees found a very slightly increased risk of VTE after the Pfizer vaccine which was much smaller than the risks of VTE from COVID-19
A self-controlled cohort study of ~2 million people in Israel found that the first and second monovalent booster, and the first dose of bivalent booster, had no increased risk of thrombosis
I think you get the idea. In short, under the most cynical assumptions, the risk of VTE is marginally increased, but most of the time there isn’t any clear increased risk, and in one instance it looks to be lower than the natural risk of VTE. This is not at all consistent with what you might expect from the term “clot shot.” Because they’re not.
Ischemic stroke
First a bit of context- there are two types of stroke (formally called a cerebrovascular accident, CVA): ischemic and hemorrhagic (hemorrhagic is divided into subarachnoid and intracerebral hemorrhage which are classified by where they occur). Ischemia refers to a state in which a tissue does not get enough blood flow, whereas hemorrhagic refers to a stroke caused by bleeding from a vessel rupturing in the brain. In the case of an ischemic stroke, a clot forms in the brain vasculature (or a clot forms elsewhere but ends up stuck in the brain vasculature), and then cuts off blood flow to a section of the brain, resulting in the death of those cells and loss of functions corresponding to those under the control of those cells. However, if blood flow is rapidly restored (which can be done with clot-busting medications), there can be recovery of normal brain function (provided it is done quickly enough). The term ministroke is sometimes used to refer to a transient ischemic attack (TIA), which basically means a clot formed but blood flow was restored on its own before the brain tissue dies. It is a very serious indicator that a person is at extremely high risk for an ischemic stroke, especially in the 48 hours after it occurs. Everyone should know how to recognize a stroke.
In general, safety surveillance conducted throughout the vaccination campaign consistently failed to show any increased risk of stroke after mRNA vaccination. However, the CDC and FDA announced in January 2023 that adults aged 65 and older who received the bivalent Pfizer vaccine (but not Moderna) did appear to have a slightly increased risk of ischemic stroke, which they were investigating. To do that investigation, they first examined the risk of stroke from the first 21 days after the booster to the next 21 days after the booster (to be clear, you are not comparing people to their future selves- you are comparing the incidence of stroke events across the two intervals of time; this is called a self-controlled case series and it is one of the major types of studies used in studying vaccine safety). This analysis showed an unusually low rate of stroke in the comparison interval relative to what would be expected from random chance, which was driving the signal, and no increased risk with the monovalent boosters or with any Moderna vaccine. Further investigation showed that the signal was coming specifically from those who received the Pfizer bivalent and either the high-dose or adjuvanted flu vaccine at the same time and was not present in those who got just the bivalent Pfizer vaccine. We then had more studies:
A study (still preprint) of adults aged 65 or older in the TriNetX database examining about 145,000 individuals who received the bivalent or monovalent mRNA vaccines found no increased risk of ischemic stroke after the booster.
A study of 1 740 417 adults aged 50 or older in Denmark examined the risk of stroke after the bivalent BA.1 or BA.5 mRNA vaccines and found no increased risk of stroke for any of them.
A study of 470,962 vaccine recipients in France also found no increased risk of stroke, heart attack, or pulmonary embolism after a bivalent mRNA vaccine.
A study of 14.6 million doses of a BA.1 bivalent mRNA vaccine were given to persons aged 50 years and older in the UK found no increased risk of stroke from any mRNA vaccine, including when given with an influenza vaccine.
Most recently (still a preprint), the FDA performed an analysis looking at 5,397,2785 adults aged 65+ who received a bivalent mRNA vaccine finding a slightly increased risk of non-hemorrhagic stroke when taking the bivalent Pfizer vaccine with a flu vaccine and a slightly increased risk of TIA with the bivalent Moderna vaccine, mainly applicable to those aged 85 or older. However, whereas the mRNA vaccines only showed a signal when taken with the influenza vaccine, the influenza vaccine alone showed a slight increased risk of non-hemorrhagic stroke on days 22-42 after vaccination when taken alone. It is worth mentioning however that the age patterns of the risks here are a bit unusual. For example, the increased risk of non-hemorrhagic stroke with the flu vaccine appears in those 65-74 and those aged 85 and older but NOT in those 75-85. The size of the confidence interval is similar for all the age groups so this likely does not reflect that there are many more individuals in the other age groups, which makes it easier for an imbalance in risk to show statistical significance. The authors reasonably conclude:
The clinical significance of the slightly elevated NHS risk following influenza vaccination should be considered in the context of the risk of NHS following influenza infection in this population. However, our study results, in combination with the known benefits of COVID-19 and influenza vaccination, do not change the conclusion that the benefits of these vaccines outweigh their risks in persons ≥65 years.
It is important to note however that influenza vaccines have also shown a protective effect against ischemic stroke in the period shortly after vaccination in other well-designed studies (here, here, here). A possible explanation for the disparity between these findings and those of the FDA’s may lie in under-capture of COVID-19 cases because of rapid antigen tests that might not be recorded in their medical records.
Aside from the bivalent vaccines, a nationwide cohort study of all adults in Norway (about 4 million people) found no increased risk of stroke in the 28 days after mRNA vaccination with any of the first 3 doses. A French study looking at millions of adults aged 75 or older also did not find any increased risk of stroke after either the first or second dose of Pfizer vaccine. Stroke was also an outcome of interest in many of the safety studies I cited above for VTEs, and, consistently, no increased risk was found.
It is perhaps also worth noting that these risks are generally not apparent with the Moderna vaccine, which in a head-to-head comparison showed superior safety in 6 388 196 older adults, which the authors believe to reflect a stronger protective effect against COVID-19.
Also, I would be remiss not to mention that the strongest risk factor for a stroke after COVID-19 vaccination is… having COVID-19.
So- what do we conclude? The influenza vaccines for older adults might slightly increase the risk of stroke in older adults in a manner that may be amplified by the mRNA vaccine boosters (mainly Pfizer)- but this finding is not consistent across populations which typically show no increased risk from the mRNA vaccines. Cases of either COVID-19 or influenza that were underreported may explain this difference, particularly given that influenza vaccination has shown a protective effect against stroke in the past. Importantly, this risk does not come close to the risks posed by either COVID-19 (details below) or influenza in this age group, but do emphasize the importance of knowing how to recognize strokes and acting quickly if there are signs and symptoms suggestive of a stroke (there is a concept known as the golden hour when it comes to strokes and certain other medical emergencies, meaning ideally a door-to-treatment time of no more than 60 minutes to help maximize the chances of a good outcome).
Retinal Vascular Occlusion (RVO) and mRNA vaccines
RVOs in general occur in about 1-10 per 10,000 people depending on age and sex. This particular type of clot was brought to my attention through this excellent video by Dr. Susan Oliver (and rather than rehash everything she says in the video I direct you to watch it and check the description for sources):
In essence, one study suggested that COVID vaccines might be associated with retinal vascular occlusion but it has an important flaw in that it inadvertently compared vaccinated people to vaccinated people. A bunch of other studies however argue against this, showing that the risk of RVOs is similar with multiple types of vaccines, including mRNA vaccines, and that no clear increased risk of RVO is seen with mRNA vaccines.
COVID-19 and risk of clotting
A discussion about the risks of clots from the mRNA vaccines could not be complete without a discussion of the risks of clots from COVID-19. COVID-19 is a respiratory viral illness, but it also comes with a shockingly heightened risk of clot formation that far exceeds that of any vaccine. First, I think it’s important to address the cynics in the room who would say that it doesn’t matter that COVID increases the risk of clots if you still get COVID after being vaccinated. This is complete nonsense and demonstrates major ignorance of the extremely powerful capacity of the immune system to modify disease severity. We do have data on this point:
In this study, 18 818 outpatients with COVID-19 and 93 179 propensity score–matched non-infected participants were matched and followed for their risk of developing a VTE. Note that these patients are all outpatients- they are not hospitalized, they are not severely ill- they are all recovering at home. Having COVID-19 raised the risk of these individuals having a VTE by 21.42 times (95% CI, 12.63-36.31). Those who had Factor V Leiden had roughly double the risk of a VTE from COVID as those who did not. However, the vaccinated (2 dose) individuals who had COVID-19 5.95-fold (95% CI, 1.82-19.5) increased risk of VTE after COVID-19- a markedly lower risk (which frankly becomes difficult to distinguish from the background rates over time). Now, that’s not zero risk, but given the choice between the two curves, I know which one I want to be on.
This is not the only study to demonstrate a huge increase in clotting risk from COVID-19. A study of 48 million adults in the England and Wales found a 33.2-fold increase in the risk of VTEs after a COVID-19 diagnosis in the first week after diagnosis. This risk declined over time to 1.8-fold but remained elevated even at 27-48 weeks after infection. That is literally almost a year later that people still did not return to their baseline risk. This analysis considered events beyond VTE though:
The first week after COVID comes with incredibly heightened risk of heart failure, angina, TIA, ischemic stroke, and acute myocardial infarction (heart attack). These do attenuate over time but many of these risks remain elevated even at 27-49 weeks. Importantly, in this analysis, all the data is pre-vaccine. Please note however: these are just some of the cardiovascular risks with COVID-19 and COVID-19 unfortunately comes with risks beyond the cardiovascular.
Another analysis (also cited above) of 29 million people found markedly heightened risk from COVID-19 with VTE, arterial thromboembolism, ischemic stroke, heart attack, CVST, and other thrombotic complications.
A systematic review and meta-analysis from December 2020 found the pooled incidence for VTE, PE and DVT was 21.6% (14.3–29.8), 11.8% (6.4–18.5) and 18.2% (9.6–28.6) respectively (Supplementary Material 8). That’s 1 in 5 people getting a clot from having severe COVID. The NIH COVID-19 treatment guidelines have recommended antithrombotic therapy for certain patients hospitalized COVID-19 for basically as long as they have existed- is it obvious why yet?
If the mRNA vaccines are “clot shots,” then SARS-CoV-2 is a turbo clot virus.
Conclusion
mRNA vaccines appear to have minimal to no excess risk of causing blood clots with some slight variation depending on the study. Their overall safety profile remains excellent despite their significant reactogenicity.
Hemostasis -basically stopping bleeding- comprises a few basic steps. Primary hemostasis involves the formation of a platelet plug over the injury, as well as constriction of the blood vessels supplying the site of injury to reduce bleeding. Secondary hemostasis involves the activation of proteins made by the liver known as clotting factors from their inactive form, which produces a mesh made of a protein called fibrin. Eventually, cells can divide over the injury and the clot needs to be broken down, which is mediated by a protein called plasmin. This is known as tertiary hemostasis. At every moment, there is a dynamic balance between blood clotting and blood clot breakdown.
A very common heart arrhythmia is atrial fibrillation, in which the atria (the upper chambers of the heart) have chaotic rhythms that don’t allow for a normal contraction to conduct blood into the ventricles. This can lead to pooling of the blood and the formation of intracardiac thrombi, which can then be launched into other parts of the body (such as the brain or lungs, causing stroke and pulmonary embolism, respectively). For this reason, those with atrial fibrillation often need very aggressive anticoagulation (i.e., blood thinners). The left atrial appendage is a very common site for these intracardiac thrombi to form, so there is also a device which is inserted into the appendage to prevent blood from entering and pooling there.
It is worth mentioning here though that we do have collateral circulation (to varying degrees) throughout our tissues meaning that a blockage in one site does not necessarily stop blood flow to that tissue because there are other backroads that the blood can take around the blocked vessel. However, if the vessel with the clot in question is particularly large or that tissue has limited collateral circulation, then of course the clot will cause issues.
Early reports on this condition suggested that younger women were at fundamentally higher risk but this is less clear now as it may just reflect the demographics of those who were getting vaccinated at the time.
This initially led to concern that heparin could worsen VITT and a strong recommendation to use non-heparin anticoagulants. Subsequent investigation suggested that heparin was probably safe for use in VITT. Furthermore, investigation of the antibodies suggested that they bind the heparin-binding site of PF4, which is different from the binding site of the antibodies seen in heparin-induced thrombocytopenia.
This work suggests that adenoviruses can be engineered to prevent binding to PF4 and thus prevent this very rare but devastating complication.
It is at this point that some people would bring up myocarditis, which appears to be an issue with mRNA vaccines but not adenovirus-vectored vaccines. These are not parallel comparisons in terms of the risk posed. Firstly, myocarditis after the mRNA vaccines is much easier to recognize than VITT from the adenovirus vaccines because it tends to occur closer to vaccination, has a strong bias for a particular demographic (younger males), and has symptoms that are not suggestive of vaccine reactogenicity. Secondly, the outcomes for myocarditis are dramatically better than those from VITT.
The matter of zoster and appendicitis warrant some discussion. Zoster requires too much discussion to put in as a footnote and will be the subject of a future post (there is a big backlog of drafts I am working on getting out). The appendicitis finding in general has not been replicated.
The VSD cohort study found no increased risk of appendicitis
A Japanese cohort study has similar results
A Danish study of 4 million people also did not find an excess risk
A Swedish study of 9.5 million people did not find an excess risk of appendicitis for the vaccines but did find one for COVID
Under the most cynical assumptions, there is a very small increase in the risk of appendicitis but in most studies it is not apparent.