A case of Long VITT associated with Adenoviral-vector COVID vaccines

A case report of VITT highlights that some cases of vaccine-related thrombosis may persist long after the initial onset of the adverse reaction.

Yesterday Joomi Kim released a rather interesting Substack piece looking at a study which examined in vitro uptake of the two mRNA vaccine platforms available.

New study shows how little we know about how mRNA vaccines "work"

The study outlines a rather interesting feature of the vaccines, in that it’s worth considering that not all cell types may uptake the LNPs from the vaccines, and so the distribution of LNP, if they circulate within the body, would not be even. This also takes into account that we still don’t know exactly what happens to cells that are forced to express the spike.

In any given case, the study made me curious about anything related to Moderna’s Spikevax vaccine which seems to have went underreported.

I didn’t come across much unfortunately, however I did come across a rather interesting paper relating to the adenoviral vaccines¹:

Vaccine-induced thrombotic thrombocytopenia is a paradoxical disease associated with the adenoviral vector platforms including J&J and AstraZeneca’s vaccines.

VITT is a paradoxical disease, in which an individual experiences thrombosis (blood clots) while simultaneously experiencing low platelet counts (thrombocytopenia).

Initial clinical markers of VITT appeared rather interesting, with many individuals with VITT appearing to have high levels of anti-platelet factor 4 antibodies. This led many researchers to compare VITT to heparin induced thrombocytopenia, or HIT.

HIT is another paradoxical disease where some people who are given the anticoagulant drug heparin sulfate may ironically experience blood clots.

Cases of HIT have provided insights into VITT, as HIT is assumed to be an autoantibody response brought on by a complex formation between heparin and PF4.

In this case, the highly anionic heparin molecule binds to PF4, leading to a conformational change in PF4 that reveals an immunogenic epitope region on the protein.

People who produce antibodies with the capabilities for binding to this complex may then produce a self-propagating response where anti-PF4 antibodies that bind to this heparin/PF4 complex may then cause an effector response that propagates the release of even more PF4, eventually resulting in clot formation throughout the body.

In the case of VITT, the clinical feature of anti-PF4 antibodies led researchers to consider a similar event, in which PF4 may complex with something and reveal the immunogenic regions of PF4.

In this case, one suggestion has come in the way of the adenoviral vector itself. It’s assumed that highly anionic pockets on the surface of the adenoviral vector may form complexes with PF4 and induce the same response seen in those with HIT.

This hypothesis of VITT was covered in a previous post which included an in silico analysis which appeared to corroborate the formation of a PF4/adenoviral vector complex.

Unfortunately, it doesn’t seem that this hypothesis has been validated by additional studies, and so far there’s no clear evidence of what exactly is causing VITT. Alas, this seems to be the only viable hypothesis as of this moment, although research doesn’t seem to be attempting to answer this conundrum.

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Many vaccine adverse reactions are assumed to be transient, however the evidence is rather apparent that some people are experiencing prolonged harms from the vaccines.

In this regard, there’s evidence that some people who experience VITT may actually suffer from this disease for many months after the initial event.

The case report from Roberge, G., & Carrier, M. serves as a follow-up to one of their previous case reports² in which an individual began experiencing acute limb ischemia (sudden blood flow cutoff to a limb) 2 weeks following the first dose of ChAdOx1 nCoV-19 vaccine.

The follow-up noted that the individual continued to experience complications related to VITT for up to nearly 18 months at the time of the article’s publication, including experiencing chronic ischemic neuropathy which has caused him to leave his job. Because of these long-term consequences, the authors remarked that this is considered to be a case of Long VITT:

We have previously published a case of VITT which can now be characterized as long VITT [6]. The patient initially had a lower limb ischemia, pulmonary embolism and cerebral vein thrombosis. He was treated with prednisone, IVIG, argatroban and had a lower limb revascularization surgery. Rivaroxaban was then initiated for the acute treatment and continued for the secondary prevention of recurrent events. The patient still demonstrates positive platelet-activation tests (performed at the McMaster Platelet Immunology Laboratory) and thrombocytopenia after more than 18 months of follow-up (Table 1 ). We also have observed one transient negative PF4-ELISA (Polyspecific anti-PF4 immunoassay, Immucor) result after 58 weeks of follow-up. However, PF4-SRA was not performed. PF4-ELISA was reported positive again ten weeks afterwards (Table 1).

It appears that the patient routinely tests positive for anti-PF4 antibodies, leaving the authors curious why this immunological activation appears to occur. It doesn’t appear that underlying conditions could explain this ongoing phenomenon, although habits and behaviors of the individual cannot be ruled out (even though possible behaviors are not outlined).

This case report suggests a serious concern where those who experience VITT may not be out of the blue as soon as the thrombocytopenia clears. Evidence in the literature suggests that cases of VITT may be long-term, and may require long-term management.

One example³ notes an individual who began experiencing headaches days after ChAdOx1 nCoV-19 vaccination, eventually leading to an intracerebral hemorrhage 100 days after symptom onset with constant treatment and complications occurring in the time between.

Because of the circumstances related to VITT long-term management is unknown, as the use of anticoagulants may be cause for concern in worsening the thrombocytopenia (Roberge, G., & Carrier, M.):

Managing long VITT is challenging considering uncertainty regarding risks and benefits of long-term anticoagulation for secondary prevention of recurrent events and potential needs of additional treatment such as IVIG if thrombocytopenia worsens. Additional data is needed to offer optimal long-term management for this patient population. We suggest that long VITT diagnosis definition might include the persistence within patient serum/plasma of anti-PF4 platelet-activating antibodies with clinical manifestations (e.g., thrombocytopenia) for more than 3 months. Clinical manifestations including recurrent thrombosis event, persistent thrombocytopenia, D-dimer or other hypercoagulability markers elevation need to be better described and included in future studies to tailor the long VITT spectrum definition.

Because the adenoviral-vector vaccines have been removed from widespread use the concerns over VITT has appeared to have dissipated. Regardless, the evidence suggests that those who experience VITT may be at continuous risk of experiencing VITT episodes. This may be related to the fact that VITT will either induce or reactivate anti-PF4 immunological responses. Such responses may, once activated, be difficult to attenuate. However, because the anti-PF4 response appears to occur by way of complex formation, this raises questions as to whether something may be working in tandem to complex with PF4, if other health circumstances may lead to complex formation, or if anti-PF4 responses may be entirely independent of complex formation.

Overall, this case report is a reminder that those who experience adverse reactions may no be out of the woods as soon as symptoms dissipate. It provides further emphasis towards elucidating these adverse reactions, and seeing what can be done for these individuals.

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1. Roberge, G., & Carrier, M. (2023). Long VITT: A case report. Thrombosis research, 223, 78–79. https://doi.org/10.1016/j.thromres.2023.01.017

2. Roberge, G., Côté, B., Calabrino, A., Gilbert, N., & Gagnon, N. (2022). Acute lower limb ischemia caused by vaccine-induced immune thrombotic thrombocytopenia: focus on perioperative considerations for 2 cases. Thrombosis journal, 20(1), 38. https://doi.org/10.1186/s12959-022-00398-8

3. Günther, A., Brämer, D., Pletz, M. W., Kamradt, T., Baumgart, S., Mayer, T. E., Baier, M., Autsch, A., Mawrin, C., Schönborn, L., Greinacher, A., & Thiele, T. (2021). Complicated Long Term Vaccine Induced Thrombotic Immune Thrombocytopenia-A Case Report. Vaccines, 9(11), 1344. https://doi.org/10.3390/vaccines9111344