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Review Article | DOI: https://doi.org/10.31579/2690-4861/324
Immunology Section, Incor Health Clinic, and The Kidney Institute, Santa Cruz, Bolivia.
*Corresponding Author: Ronald Palacios Castrillo, Immunology Section, Incor Health Clinic, and The Kidney Institute, Santa Cruz, Bolivia.
Citation: Ronald P. Castrillo, (2023), Long Covid and Serious Side Reactions to mRNA-Based Vaccines (VSITV) Are Mainly Spike Protein-Induced Thrombotic Vasculitis, International Journal of Clinical Case Reports and Reviews, 14(3); DOI:10.31579/2690-4861/324
Copyright: © 2023, Ronald Palacios Castrillo. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 13 July 2023 | Accepted: 25 July 2023 | Published: 02 August 2023
Keywords: long covid; mRNA vaccines side effects; immunothrombosis; spike protein
Long COVID syndrome, known as Long COVID, refers to a series of debilitating symptoms that arise after infection with the SARS-CoV-2 virus. These symptoms are similar to those experienced by some people after vaccination with vaccines based on mRNA platforms (Pfizer, Moderna). With more than 200 million Long COVID patients worldwide and an increase in cases of moderate to severe reactions after administration of mRNA vaccines (VSITV), the effects on quality of life and economics are significant, for what is necessary to pay urgent attention to understand its pathophysiology and to provide an adequate diagnosis and treatment.
In this article, we describe our perspective that both Long COVID and common side effects of mRNA vaccines (VSITV) induce persistent and prolonged expression of the spike protein (SPIKE) in various tissues and organs of the body. This would induce coagulopathy, microscopic vasculitis, and endothelitis as the main drivers of the disease, and may also cause or worsen other common pathologies in Long COVID, such as mast cell activation syndrome, dysautonomia, and sudden deaths due to arrhythmias and heart attacks, reports of which continue to rise.
Given that the SARS-CoV-2 spike protein can independently induce fibrinoid microclot formation, platelet activation, and endothelitis, we predict that the persistence of the spike protein will be a key mechanism driving ongoing coagulopathy in Long COVID and in the VSITV. We discuss various treatment goals to address coagulopathy, endothelitis, and vasculitis and predict that treatment, especially if given early, with a combination of anticoagulants, antiplatelets, corticosteroids, and rapamycin/everolimus, will provide significant relief for many patients.
To focus attention on these treatment targets, we propose that the term Long COVID be changed to "natural Spike Protein-Induced Thrombotic Vasculitis" (NSITV) and that serious side effects of mRNA vaccines be renamed "Vaccine Spike Protein - Induced Thrombotic Vasculitis" (VSITV). Are mainly due to a persistent and disseminated cellular expression of the Spike protein". These ideas require urgent testing, especially as the world tries to live with COVID-19.
Long COVID (or the post-acute sequelae of COVID-19) is a debilitating multisystem disease that causes significant disability [1]. The World Health Organization [2] has defined Long COVID as those cases in which a probable or confirmed infection by SARS-CoV-2 occurs, with onset of symptoms within three months, a duration of at least two months and no alternative diagnosis. It is estimated that Long COVID affects more than 200 million people worldwide, with most cases considered "mild" [3,4] and even a third of them are asymptomatic [5,6]. In addition, a significant increase in the presentation of prolonged COVID-19-like symptoms (VSITV) has been observed after SARSCoV-2 vaccination, especially with mRNA- based vaccines [7–11].
Patients with Long COVID experience on average 56 symptoms affecting nine different body systems [1], the most common being fatigue, cognitive dysfunction, dyspnea, exercise intolerance, exacerbation of symptoms after exertion (PESE), sleep disorders and myalgias [1,3,12–14]. Given this broad definition, Long COVID is likely to be a multipathology disease [10–12].
Estimates of the long-term prevalence of COVID-19 vary [3,13,18,19], but studies in Scotland have shown that it affects 1.8-3.2% of the population [20,21], in compared with cancer (2.5%), chronic kidney disease (3.2%), chronic obstructive pulmonary disease (2.3%), and stroke (2.2%) [22]. Two meta-analyses have shown persistent symptoms in 43-45% of patients after the acute phase of COVID-19 [3,13]. Follow-up studies suggest that 85% of patients presenting with symptoms two months after infection remain symptomatic at one year [23]. Similarly, resolution of symptoms after 90 days appears to be rare [24], leading to disability in a previously economically active population [1]. Consequently, the economic costs are estimated to be as high as $25 billion in the UK alone [25].
In addition to its modest benefits in acute cases of COVID-19, vaccination provides a modest reduction in the odds of developing Long COVID (13% and 9% reduction after the first and second doses, respectively [26]). However, other investigations have shown that each SARS-CoV-2 reinfection increases the risk of death, hospitalization, and/or multi-organ complications, regardless of vaccination status [27]. Therefore, the protections provided by vaccination appear to be far from absolute, especially when many public health measures are being scaled back in various countries [28–30]. As a result, the prevalence of Long COVID continues to increase [31]. In addition, both the severity and type of side reactions to mRNA-based vaccines are increasing, as is the diversity of clinical manifestations and affected organs, from sudden death in healthy young people, including athletes, to myocarditis, endomyocarditis, pericarditis, venous and arterial thrombosis, meningoencephalopathies, peripheral neuropathies, systemic inflammatory syndromes such as Still's disease, gastrointestinal syndromes, and infertility due to orchitis (decreased spermatocyte production) or premature ovarian failure due to oophoritis. The list of tissues and organs affected so far is extensive (you can review the report "The Frequency and Associations of Adverse Reactions of COVID-19 Vaccines Reported to Pharmacovigilance Systems in the European Union and the United States. Supplementary file").
It is therefore evident that the majority of Long COVID and VSITV cases do not resolve over time, and their prevalence continues to rise, carrying significant economic costs for a previously productive workforce. Therefore, understanding the pathophysiology of Long COVID and VSITV is imperative, and treatments must be urgently implemented.
Vaccines based on mRNA platforms: the foundations that support VSITV
As of this writing, the following is indisputable regarding vaccines based on mRNA platforms:
Acute COVID-19: the foundations that support Long COVID-19
Endothelial cells play vital roles in vascular homeostasis and hemostasis, including regulation of vascular tone, blood flow, fibrinolysis, and platelet aggregation [32-35]. Acute COVID-19 appears to be primarily a disease of the vascular endothelium leading to microcirculatory thrombotic vasculitis [33,34,36–43]. SARS-CoV-2 spike proteins allow the virus to bind to target cells through binding to angiotensin-converting enzyme 2 (ACE2), followed by intracellular viral replication [42,44,45]. ACE2 is present in the tongue, nasal mucosa, and lungs as the initial portal of entry, and is also found in the vasculature on endothelial cells. This gives SARS-CoV-2 ample opportunity to spread easily throughout the body, including across the blood- brain barrier [33,34,37,42,46–48].
Entry of SARS-CoV-2 into endothelial cells reduces ACE2 expression, leading to a proinflammatory and prothrombotic environment [34,49–51]. Endothelial injury may be the result of direct SARS-CoV-2 infection, leading to endothelial cell apoptosis and endothelitis, as well as subsequent systemic immuno-inflammatory responses [33,34,37,39,49, 51,52].
Spike proteins change the structure of beta and gamma fibrinogen, complement 3, and prothrombin, resulting in the development of blood clots that are larger and more difficult to break down. Spike proteins can trigger clot formation in the blood even without thrombin and platelets. Spike protein alone can cause neuronal damage [53], destabilize microvascular haemostasis [54], induce thrombosis [55], (irreversibly) activate platelets [56–58] and alter endothelial function [43,59], with some effects not dependent on ACE2 [60] or possibly related to anti-spike antibodies [61]. Endothelial dysfunction results in impaired vascular tone and a prothrombotic state [32,34,35,37,43,49].
Post-mortem examination of critically ill patients with COVID-19 has revealed the presence of a generalized coagulopathy, with alveolar-capillary microthrombi nine times more frequent than in influenza A [62]. Furthermore, Pretorius et al. [40] found a significant microclot burden in acute patients with COVID-19, regardless of disease severity, compared with patients with type 2 diabetes and healthy controls. These microclots, of an amyloid nature, laid the foundation for the chronic sequelae following COVID-19.
Thrombi are known to develop from inflammation, partly due to platelet hyperactivation [63]. COVID-19 is a highly inflammatory disease, with the potential to trigger cytokine storms [64]. In fact, COVID-19 activates platelets and the complement system, causing endothelial dysfunction [43,65]. The resulting pro-inflammatory milieu can lead to a condition known as immunothrombosis, which especially affects the microvasculature [65]. In addition, the S1 subunit of the SARS-CoV-2 spike protein can directly interact with platelets and fibrin, causing microclot formation [36,56,66–68].
Specifically, the S1 subunit produces structural changes in β and γ fibrin (gene), complement 3, and prothrombin, resulting in the formation of extensive abnormal microclots [36,58,67–70]. These microclots appear to pathologically alter blood flow in systemic microcapillaries [36,71–73], including the brain [48], heart [73–75], lungs [46,73,76] and kidneys [73].
Microclots induced by spike protein are resistant to fibrinolysis, creating the potential for false-negative clot dissolving tests (such as D-dimer) [77] and making microclots persistent and central to pathogenesis of Long COVID and VSITV [36,69,78].
There are several proposed mechanisms that offer valid explanations for Long COVID. In many patients, it is possible that several of these pathologies coexist and interact with each other. Suggested ideas include mast cell activation syndrome (MCAS), neuroinflammation, viral reactivation, persistence of SARS-CoV-2 and/or spike protein, autoimmunity, and gut dysbiosis [9,79].
However, a pathology related to microclots, platelet hyperactivation, and endothelial dysfunction is being increasingly recognized [36,40,43,80–82]. In this sense, our perspective is that Long COVID and VSITV are mainly (although not exclusively) a form of thrombotic vasculitis.
Microclots in Long COVID patients were first described by Pretorius et al. [82], who found a persistent presence of fibrinolysis-resistant microclots in the blood, accompanied by platelet hyperactivation and dysregulated hemostasis disturbance. These microclots were visible macroscopically as a pellet in platelet-poor plasma samples after centrifugation (not seen in healthy controls or patients with type 2 diabetes), and levels were comparable to those found in patients with acute COVID-19 [82].
Clogging of the capillaries
Normally, human capillaries are 5–10 μm in diameter, allowing red blood cells (~8 μm in diameter) to circulate in single file due to their flexible structure [83]. However, microclots present in Long COVID patients have a diameter of 5 to 200 μm, which means that they can obstruct capillaries [82,83]. This can lead to ischemia- reperfusion injury at the microvascular level [83], explaining exacerbation of symptoms after physical exertion (PESE), which affects 75-89% of patients. PESE is a diagnostic criterion for myalgic encephalomyelitis, which can be objectively demonstrated by cardiopulmonary exercise tests performed on consecutive days [1,83–87], and subsequent recovery is prolonged [88].
Microvasculature obstruction also explains other symptoms of Long COVID, such as chest pain, which can be caused by microvasculature ischemia [89]. Evidence of capillary obstruction has been found in several studies of the microvasculature of different organs in patients with Long COVID, providing evidence of systemic vascular changes [89–95]. These microvascular changes include a reduction in sublingual vascular density comparable to that seen in severe cases of acute COVID-19 [93], as well as a reduction in retinal vascular density [94,95], presence of fibrin thrombi obstructing capillaries in the skin [92] and loss of muscle capillaries [90,91]. Biomarkers of tissue hypoxia-induced microvascular remodeling, such as vascular endothelial growth factor (VEGF), have been found in patients with Long COVID, probably as compensation for capillary occlusion [96-98]. However, any new vessels that form will also be susceptible to occlusion. Similar compensatory angiogenesis has been observed in multiple organs of severely acute patients with COVID-19 [99]. These findings are compatible with capillary occlusion by microclots.
Similar data have been observed in histopathology studies in patients suffering from VSITV, especially microscopic vasculitis and microthrombosis in different tissues and organs. In fact, a recent work reports the postmortem study of 325 patients who died after administration of the mRNA-based vaccines. They found that 53% of deaths due to VSITV affected the cardiovascular system, 17% the hematological system, 8% the respiratory system, and 7
A growing body of evidence supports that NSITV and VSITV i s primarily an endothelial and immunocoagulopathic disease initiated by SPIKE expression in cells following infection or the use of mRNA platform-based vaccines. We propose the use of the term NSITV and VSITV as it describes the pathophysiology of post-COVID-19 and post-vaccination presentations, and helps focus attention on early therapeutic intervention targeting microclots, hyperactive platelets, and endothelitis. This multifaceted coagulopathy requires synergistic polypharmacy to achieve symptomatic resolution. Thromboelastographic can be used to mitigate the risk of bleeding.
Our perspective does not deny the need to find and treat other common pathologies in Long COVID and VSITV, but highlights how thrombotic vasculitis can cause, exacerbate, and interact with other pathologies. Future research should investigate the efficacy of aggressive anticoagulation, antiplatelet therapy (particularly early), and the use of Rapamycin/Everolimus, after COVID-19 infection or post-mRNA vaccine sequelae to treat NSITV and VSITV.
Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.
