Blood clots from the COVID vaccine... a real concern, or statistical noise?

Back in March, several European nations paused use of the AstraZeneca vaccine based on concerns about case reports of blood clots in recently vaccinated individuals. The specific blood clots formed in several of the patients were a rare and dangerous type of clot known as cerebral venous sinus thrombosis (CVST), resulting in strokes and occasionally seizures in patients. Whether in the brain or elsewhere, these blood clots were especially unusual because they were associated with low platelets (a condition known as thrombocytopenia) and sometimes bleeding. Even more concerning, the specific blood clot formed in many of the patients was. The same phenomenon was later observed with the Johnson & Johnson vaccine, resulting in a pause in the US in mid-April. Interestingly, almost all of the cases were identified in younger females aged 18-48 (although one case in a younger man has since been reported, as well as an earlier male case during clinical trials).

Platelets are blood cells that group together to form clots in response to blood vessel injury, and overactive clotting is typically associated with higher or normal, not lower platelet counts. While extremely rare (cases were estimated at an incidence of 4 per million people vaccinated with AstraZenica and 1-2 per million with Johnson & Johnson as of late April, 2021), these vaccine-associated blood clots were severe and even resulted in a few deaths.

Unlike most blood clots, these clots may be worsened by treatment with heparin, a common blood thinner. While heparin treatment is normally recommended, doctors noticed that in these cases heparin treatment caused further reduction in platelet count, a disorder known as heparin-induced thrombocytopenia (HIT). HIT can sometimes be induced as an immune-mediated adverse drug reaction where antibodies recognize a complex of heparin and platelet factor 4 (PF4). As the immune system attacks this complex platelet levels drop, remaining platelets become overactivated, and the patient becomes at risk for new clots as well as bleeding. Notably however, none of the CVST patients who died were treated with heparin.

 So how does this relate to the COVID-19 vaccine? And why has this only been observed with AstraZenica or Johnson & Johnson? It turns out, a brand new study (not yet peer-reviewed) determined that the constituents of the AstraZenica vaccine form HIT-like complexes with PF4, the same as are formed with heparin. This phenomenon was originally named Vaccine-Induced Thrombotic Thrombocytopenia (VITT), but is now known in the U.S. as “thrombosis with thrombocytopenia syndrome (TTS)” by the CDC and FDA. Interestingly, thrombocytopenia following adenovirus administration is not a new phenomenon, even observed in laboratory rodents. This side effect therefore should not really have been too much of a surprise to the vaccine developers.

It is unclear why women, and especially younger women, appear to be much more susceptible to VITT than other groups. It may be because women tend to have stronger immune systems with a higher incidence of autoimmune disease in general. As it turns out, women are also more likely to experience HIT. Alternatively, the influence of hormones has been considered. While many have conjectured that the increased risk in younger women may be related to birth control, most of the affected patients were not on birth control. Additionally, hormonal-induced blood clots are quite different than immune-induced HIT/TTS.

While the risk of blood clots from these vaccines is low, the risk is real, and it is extremely dangerous for those affected. Additionally, while the overall risk may be 4 in a million or less, the risk is much higher for susceptible populations. When considering only women under 50 the risk rises greatly to one in 80,000 (which may actually be higher than the COVID-19 death rate in younger age groups). The risk may even be significantly higher for women with a predisposition to autoimmune disease or a family history of HIT. Therefore, as recommended by the CDC, additional considerations should be made for younger women choosing what vaccine to get. While there are some individual reports of blood clots following one of the mRNA vaccines, the much more dangerous TTS has only occurred via the adenovirus vaccines.

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