To the best of our knowledge, this is the first pediatric case of CVST associated with a mRNA vaccine. The patient experienced CVST with elevated D-dimers, but without severe thrombocytopenia or anti-PF4 antibodies.
In most instances, CVST is triggered by single or multiple pre-disposing factors, or even by transient factors such as a systemic or local infection. At least one precipitant risk factor is identified in more than 85% of the cases, and multiple risk factors are found in approximately half.5,11,12 In our patient, a recent mRNA COVID-19 vaccination and low level of PS activity were noted by precise history and detailed laboratory work-up. CVST is a rare, although increasing, adverse event that can occur after a COVID-19 vaccination. Most COVID-19 vaccine-related cases of CVST are associated with vector-based vaccines. They are usually accompanied by TTS.2,6,13,14 The median platelet count at diagnosis is approximately 20,000 to 30,000×109/L, and in almost every patient, high levels of antibodies to PF4 are identified by enzyme-linked immunosorbent assay. However, our patient developed CVST without TTS following her third dose of a mRNA COVID-19 vaccine (BENT126b2; Pfizer-BioNTech). To date, there are a few reports of adult cases of mRNA COVID-19 vaccine-related CVST in the absence of TSS.14–16
The estimated incidence of CVST is 0.4 to 0.7 per 100,000 children per year.11,12 The reporting event rate of CVST after the Pfizer-BioNTech vaccine from December 12, 2020 to 16 March 16, 2021, was 0.4% (4/1197), less than that for viral vector vaccine-related CVST within the same period, which was 1.1% (7/639).17 Likewise, an CVST analysis after vaccination in European countries noted that it occurred far more frequently after an AstraZeneca (vector-based) vaccination than after a mRNA vaccination.6 Nevertheless, SARS-CoV-2 infection itself is associated with a markedly increased incidence of CVST when compared with the general population, patients with influenza, and people who have received the Pfizer-BioNTech or Moderna vaccines.18 These data suggest that healthcare providers, parents, and patients should be aware of the safety profiles for COVID-19 vaccines, although the benefits overweight the risks associated with a SARS-CoV-2 infection.
The main mechanism of CVST associated with viral vector vaccines is vaccine-induced immune thrombotic thrombocytopenia, which is similar to HIT.5 The mechanism underlying mRNA vaccine-related CVST is unclear, although the following have been proposed: first, the interaction between the spike glycoprotein and platelets leads to platelet aggregation19; second, binding of the spike glycoprotein to the angiotensin converting enzyme receptor activates endothelial cells and up-regulates expression of cell adhesion molecules, which promotes thrombogenesis and causes CVST20; and third, in vitro studies have shown that spike proteins can activate the alternative complement pathway, which plays a role in immune-mediated thrombogenesis.21 In our patient, in addition to these hypotheses, acquired PS deficiency secondary to the immune-mediated reaction to the mRNA vaccine may have contributed to the CVST onset.
PS deficiency is caused by inherited or acquired deficiencies, such as, liver disease, severe infection or other illness, and pregnancy and certain medications. Inherited PS deficiency is uncommon. PROS1 is found on chromosome 3 (3q11.1) and, to date, the reported detection rate of causative gene mutation in suspected PS deficiency is approximately 50%.22 Therefore, inherited PS deficiency was not excluded completely. The exact mechanism of acquired PS deficiency is not known, although it may be acquired through the induced autoantibodies and epigenetic etiology.
Since thrombotic events following administration of a mRNA COVID-19 vaccine are very rare, causality cannot be confirmed. This case may add to the evidence supporting a possible relationship between mRNA COVID-19 vaccines and thrombotic events, and raises the awareness of health care providers associated with pediatric care, as well as parents and patients, regarding this rare, critical adverse event; early recognition allows early treatment to prevent complications. In conclusion, CVST may occur following any COVID-19 vaccination, even among children. Our patient lacked the typical TTS profile, which can occur following administration of vector-based vaccine (low platelet counts and the presence of anti-PF4 antibodies). This may indicate a peculiar pathophysiology associated with thrombotic events following a mRNA vaccination. Further investigations are needed to establish whether thrombotic events are merely incidental or are a complication associated with mRNA-based vaccines.