Following up on previous reviews of the evidence, the European Medicines Agency (), , and Britain's Medicine's and Healthcare Products Regulatory Agency () 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 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, .
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 , 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 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 ().
Concurrent with the German team, the Norwegian team published a , 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 鶹ý.
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 is not new, and may play a role in 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 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 has advised that people under age 30 without underlying medical conditions should be offered a different vaccine. has halted vaccinations altogether, at least for now. Elsewhere in the world, Canada, Australia, and the Philippines have also imposed age restrictions.
Meanwhile, the 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.