10. Immune Thrombocytopenia
Immune thrombocytopenia is an autoimmune disorder, where the immune
system attacks circulating platelets. Immune thrombocytopenic purpura
(ITP) has been associated with several vaccinations, including measles,
mumps, rubella (MMR), hepatitis A, varicella, diphtheria, tetanus,
pertussis (DPT), oral polio and influenza [149]. While there is
broad awareness that the adenovirus DNA-based vaccines can cause
vaccine-induced immune thrombotic thrombocytopenia (VITT) [150], the
mRNA vaccines are not without risk to VITT, as case studies have been
published documenting such occurrences, including life threatening and
fatal cerebral venous sinus thrombosis [151-153]. The mechanism is
believed to involve VITT antibodies binding to platelet factor 4 (PF4)
and forming immune complexes that induce platelet activation. Subsequent
clotting cascades cause the formation of diffuse microclots in the
brain, lungs, liver, legs and elsewhere, associated with a dramatic drop
in platelet count (Kelton et al., 2021). The reaction to the vaccine has
been described as being very similar to heparin-induced thrombocytopenia
(HIT), except that heparin administration is notably not involved
[154].
It has been shown that the mRNA vaccines elicit primarily an
immunoglobulin G (IgG) immune response, with lesser amounts of IgA
induced [155], and even less IgM production [156]. The amount of
IgG antibodies produced is comparable to the response seen in severe
cases of COVID-19. It is IgG antibodies in complex with heparin that
induce HIT. One can hypothesize that IgG complexed with the spike
protein and PF4 is the complex that induces VITT in response to mRNA
vaccines. It has in fact been shown experimentally that the receptor
binding domain (RBD) of the spike protein binds to PF4 [157].
The underlying mechanism behind HIT has been well studied, including
through the use of humanized mouse models. Interestingly, human
platelets, but not mouse platelets, express the FcγRIIA receptor, which
responds to PF4/heparin/IgG complexes through a tyrosine phosphorylation
cascade to induce platelet activation. Upon activation, platelets
release granules and generate procoagulant microparticles. They also
take up calcium, activate protein kinase C, clump together into
microthrombi, and launch a cell death cascade via calpain activation.
These activated platelets release PF4 into the extracellular space,
supporting a vicious cycle, as this additional PF4 also binds to heparin
and IgG antibody to further promote platelet activation. Thus, FcγRIIA
is central to the disease process [158].
Studies on mice engineered to express the human FcγRIIA receptor have
shown that these transgenic mice are far more susceptible to
thrombocytopenia than their wild type counterparts [159]. It has
been proposed that platelets may serve an important role in the
clearance of antibody-antigen complexes by trapping the antigen in
thrombi and/or carrying them into the spleen for removal by immune
cells. Platelets are obviously rapidly consumed in the process, which
then results in low platelet counts (thrombocytopenia).
Platelets normally circulate with an average lifespan of only five to
nine days, so they are constantly synthesized in the bone marrow and
cleared in the spleen. Antibody-bound platelets, subsequent to platelet
activation via Fcγ receptors, migrate to the spleen where they are
trapped and removed through phagocytosis by macrophages [160]. Fully
one third of the body’s total platelets are found in the spleen. Since
the mRNA vaccines are carried into the spleen by immune cells initially
attracted to the injection site in the arm muscle, there is tremendous
opportunity for the release of spike-protein-containing exosomes by
vaccine-infected macrophages in the spleen. One can speculate that
platelet activation following the formation of a P4F/IgG/spike protein
complex in the spleen is part of the mechanism that attempts to clear
the toxic spike protein.
We mentioned earlier that one of the two microRNAs highly expressed in
exosomes released by human cells exposed to the spike protein was
miR-148a. miR-148a has been shown experimentally to suppress expression
of a protein that plays a central role in regulating FcγRIIA expression
on platelets. This protein, called T-cell ubiquitin ligand-2 (TULA-2),
specifically inhibits activity of the platelet Fcγ receptor. miR-148a
targets TULA-2 mRNA and downregulates its expression. Thus, miR-148a,
present in exosomes released by macrophages that are compelled by the
vaccine to synthesize spike protein, acts to increase the risk of
thrombocytopenia in response to immune complexes formed by spike antigen
and IgG antibodies produced against spike.