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.