key: cord-0742920-6ha65hhw
authors: Kadkhoda, Kamran
title: Post‐adenoviral‐based COVID‐19 vaccines thrombosis: A proposed mechanism
date: 2021-05-05
journal: J Thromb Haemost
DOI: 10.1111/jth.15348
sha: 7adc152e6ca144ca87a31b99ca794852dbea165f
doc_id: 742920
cord_uid: 6ha65hhw

There has been several reports of thrombosis and thrombocytopenia after vaccination with the ChAdOx1 nCoV-19 vaccine (Oxford-Astra-Zeneca) and Ad26.COV2.S vaccine (Johnson & Johnson/Janssen), a recombinant adenovirus serotype 26 vector encoding the SARS-CoV-2 spike glycoprotein [1, 2]. These cases clinically manifest as disseminated intravascular coagulation-like phenomena. Recently anti-platelet factor 4 (PF4) autoantibodies detected by enzyme-linked immunosorbent assays were deemed as the number one culprit, but this finding has one main issue.

ELISAs were deemed as the number one culprit, but this finding has one main issue. The main issue is: Because these cases manifest as early as 5 days post-vaccination, there is typically not enough time for immunological tolerance to break and to generate high titer and class-switched, high-affinity IgG antibodies to trigger the proposed mechanism. However, it is possible that anti-PF4 is a byproduct of an initial mechanism that in turn can eventually lead to thrombocytopenia and amplify a viscous cycle. Interestingly, a proposed mechanism was FcγRIIa (CD32a)-dependent. 1 What is the initial mechanism? Bye et al. 3 recently demonstrated the role of aberrant glycosylation of anti-SARS-CoV-2 IgG as a pro-thrombotic stimulus for platelets. They showed that in COVID-19 patients, anti-SARS-CoV-2 IgG-spike glycoprotein immune complexes can, through FcγRIIa, which is the only FcγR present on the surface of platelets, activate platelets and lead to their adhesion to endothelial cells. The latter further triggered endothelial cells to produce von Willebrand factor (VWF). Additionally, VWF has been reported to be as high as five-fold in severe cases of COVID-19 compared to other cases. [4] [5] [6] More in-depth research is needed to substantiate such a ready-to-go mechanism; that being said, here I propose the following: a single vaccine dose contains 5 × 10 10 adenoviral particles. If all is accidentally injected into the blood, for an approximate blood volume of 5000 ml, there will be an adenoviral load of 10 7 /ml. Even lower levels or leaks from the injection site (over time) would culminate in still high-level adenoviremia. Although these adenoviruses are claimed to be replication-deficient, they are still able to travel to distant sites in the body and infect a range of permissive cells. Once infected, cells such as epithelial, endothelial, and fibroblasts, etc., that are not primarily antigen-presenting cells, may also secrete copious amounts of soluble spike glycoproteins leading to a relatively high level of SARS-CoV-2 spike "antigenemia." It is important to highlight that although chimpanzee adenovirus and human adenovirus 26 use different cellular receptors, that is, sialic acid-bearing glycans and Coxsackie-adenovirus receptor, respectively, both receptors are expressed on a large range of tissues. 7 Although a vaccine that uses a modified spike that may not be shed study, in which IgG antibodies within these immune complexes are aberrantly glycosylated (for instance afucosylated), the abovementioned mechanism can be triggered. The platelet adhesion to endothelial cells may also be one of the causes for severe thrombocytopenia observed in these cases. It was also previously shown that afucosylated antibodies were much more common among severe and critical COVID-19 cases. 8 Therefore, all three conditionsthe amount of adenoviral vector leakage to the circulation, presence of specific and/or cross-reactive antibodies, and high enough titer of aberrantly glycosylated antibodies-need to be present to trigger such a mechanism. This may explain the rarity of the clinical observation. It is worth mentioning that the spike glycoprotein expressed in these vaccines is in fact the full spike antigen in its trimeric form. This means it contains highly cross-reactive domains (such as S2) that can be bound by antibodies against common CoVs.

Very shortly after vaccination, anamnestic immune responses to common CoVs are activated and antibody titers can be found in very high titers. 9 Last, the apparent clinical response to intravenous immunoglobulin (IVIg) in these cases could very well be due to the competition between high-titer non-specific IgGs in the IVIg with In 2017, the SSC of the ISTH recommended that the maximal acceptable failure rate should be 1.82% + 0.0053% × prevalence. 3 Therefore, in a low prevalence population, a new diagnostic strategy to rule out PE will be validated if the upper bound of the 95% confidence interval (CI) of the failure rate is below 1.82.

It is critical, however, to consider what we define as the "failure rate." The current definition is the number of missed PE (numerator) divided by the total number of patients in whom the strategy has been evaluated (denominator). This highlights a serious shortcoming: it is totally dependent on the tested population, which was ad- 

Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination

Thrombotic thrombocytopenia after Ad26.COV2.S vaccination

Aberrant glycosylation of anti-SARS-CoV-2 IgG is a prothrombotic stimulus for platelets

Severe COVID-19 infection associated with endothelial activation

Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, crosssectional study

Hypercoagulability of COVID-19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis

Human adenovirus type 26 uses sialic acid-bearing glycans as a primary cell entry receptor

Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity

Virological assessment of hospitalized patients with COVID-2019